The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for immunocompromised adults at risk for invasive pneumococcal diseases. But booster doses reportedly can cause “hyporesponsiveness,” which make PPSV23 less suitable for some HIV-infected patients, according to researchers at University Division of Infectious Diseases, Siena,  University of Siena, San Gerardo Hospital, University of Milano-Bicocca, Monza, and Institute of Clinical Infectious Diseases, Rome, all in Italy. These researchers cite studies that have found that the humoral response to PPSV23 is weaker in HIV-infected adults and that patients with AIDS are not protected.

Related: New Developments in Adult Vaccination: Challenges and Opportunities to Protect Vulnerable Veterans From Pneumococcal Disease

Protein-conjugated pneumococcal vaccines (PCVs), both 7-valent and 13-valent, may prime the immune system for better, faster responses to booster doses, the researchers say, and could be an optimal primary prophylaxis strategy for HIV-infected patients. But to the best of their knowledge, they note, data regarding the effectiveness of PCV13 in HIV-positive adults are “scant,” and no studies have directly compared the immunogenicity of PCV13 with PPSV23 in those patients.

The researchers conducted 2 parallel studies of 100 HIV-infected adult outpatients who had never been vaccinated with any pneumococcal vaccine. In the first, 50 patients were given PCV13 in 2 doses 8 weeks apart; in the second, patients were given their first routine vaccination with PPSV23. A third group of 100 HIV-negative adults who received no vaccination was used for comparison.

Related: Intervals between Pneumococcal Vaccines

After immunization, IgG titers significantly increased in both study groups at each time point compared with baseline, although response to serotype 3 was blunted in the first group. Antibody titers for each antigen did not differ between the groups at week 48. Seroprotection and seroconversion to all serotypes were comparable.

Over time, the researchers observed a “marked decrease” in IgG levels with both vaccines.

Related: Hunting Down a C difficile Vaccine

Both vaccines were safe and well tolerated; no relevant adverse reactions were seen in either group. No HIV-infected patients developed Streptococcus pneumoniae infection during the follow-up.

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for immunocompromised adults at risk for invasive pneumococcal diseases. But booster doses reportedly can cause “hyporesponsiveness,” which make PPSV23 less suitable for some HIV-infected patients, according to researchers at University Division of Infectious Diseases, Siena,  University of Siena, San Gerardo Hospital, University of Milano-Bicocca, Monza, and Institute of Clinical Infectious Diseases, Rome, all in Italy. These researchers cite studies that have found that the humoral response to PPSV23 is weaker in HIV-infected adults and that patients with AIDS are not protected.

Related: New Developments in Adult Vaccination: Challenges and Opportunities to Protect Vulnerable Veterans From Pneumococcal Disease

Protein-conjugated pneumococcal vaccines (PCVs), both 7-valent and 13-valent, may prime the immune system for better, faster responses to booster doses, the researchers say, and could be an optimal primary prophylaxis strategy for HIV-infected patients. But to the best of their knowledge, they note, data regarding the effectiveness of PCV13 in HIV-positive adults are “scant,” and no studies have directly compared the immunogenicity of PCV13 with PPSV23 in those patients.

The researchers conducted 2 parallel studies of 100 HIV-infected adult outpatients who had never been vaccinated with any pneumococcal vaccine. In the first, 50 patients were given PCV13 in 2 doses 8 weeks apart; in the second, patients were given their first routine vaccination with PPSV23. A third group of 100 HIV-negative adults who received no vaccination was used for comparison.

Related: Intervals between Pneumococcal Vaccines

After immunization, IgG titers significantly increased in both study groups at each time point compared with baseline, although response to serotype 3 was blunted in the first group. Antibody titers for each antigen did not differ between the groups at week 48. Seroprotection and seroconversion to all serotypes were comparable.

Over time, the researchers observed a “marked decrease” in IgG levels with both vaccines.

Related: Hunting Down a C difficile Vaccine

Both vaccines were safe and well tolerated; no relevant adverse reactions were seen in either group. No HIV-infected patients developed Streptococcus pneumoniae infection during the follow-up.

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for immunocompromised adults at risk for invasive pneumococcal diseases. But booster doses reportedly can cause “hyporesponsiveness,” which make PPSV23 less suitable for some HIV-infected patients, according to researchers at University Division of Infectious Diseases, Siena,  University of Siena, San Gerardo Hospital, University of Milano-Bicocca, Monza, and Institute of Clinical Infectious Diseases, Rome, all in Italy. These researchers cite studies that have found that the humoral response to PPSV23 is weaker in HIV-infected adults and that patients with AIDS are not protected.

Related: New Developments in Adult Vaccination: Challenges and Opportunities to Protect Vulnerable Veterans From Pneumococcal Disease

Protein-conjugated pneumococcal vaccines (PCVs), both 7-valent and 13-valent, may prime the immune system for better, faster responses to booster doses, the researchers say, and could be an optimal primary prophylaxis strategy for HIV-infected patients. But to the best of their knowledge, they note, data regarding the effectiveness of PCV13 in HIV-positive adults are “scant,” and no studies have directly compared the immunogenicity of PCV13 with PPSV23 in those patients.

The researchers conducted 2 parallel studies of 100 HIV-infected adult outpatients who had never been vaccinated with any pneumococcal vaccine. In the first, 50 patients were given PCV13 in 2 doses 8 weeks apart; in the second, patients were given their first routine vaccination with PPSV23. A third group of 100 HIV-negative adults who received no vaccination was used for comparison.

Related: Intervals between Pneumococcal Vaccines

After immunization, IgG titers significantly increased in both study groups at each time point compared with baseline, although response to serotype 3 was blunted in the first group. Antibody titers for each antigen did not differ between the groups at week 48. Seroprotection and seroconversion to all serotypes were comparable.

Over time, the researchers observed a “marked decrease” in IgG levels with both vaccines.

Related: Hunting Down a C difficile Vaccine

Both vaccines were safe and well tolerated; no relevant adverse reactions were seen in either group. No HIV-infected patients developed Streptococcus pneumoniae infection during the follow-up.

One of the nation’s Centers for Innovation in Advanced Development and Manufacturing, led by the Texas A&M University System, is beginning development and manufacturing on a second-generation anthrax vaccine. The U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response is supporting this research with an 18-month, $10.49 million task order.

NasoShield, a nose spray, will require only a single dose to protect against infections caused by inhaling anthrax. The spray uses technology known as the Adenovirus 5 viral vectored delivery system that modifies a non-infectious virus to include the genetic material needed to produce an immune response against anthrax. The researchers also will focus on improving the shelf life of the anthrax vaccine.

This project is the first time the HHS’s Biomedical Advanced Research and Development Authority (BARDA) has supported development of an anthrax vaccine using this delivery system. “Anthrax remains a material threat to our national health security,” said Dr. Richard Hatchett, acting BARDA director. “To help combat the health impacts of an anthrax attack, BARDA partnered with several biotechnology firms in accelerating development of promising next-generation treatments against anthrax infection. Engaging one of our Centers for Innovation in Advanced Development and Manufacturing represents a unique approach to this development.”

One of the nation’s Centers for Innovation in Advanced Development and Manufacturing, led by the Texas A&M University System, is beginning development and manufacturing on a second-generation anthrax vaccine. The U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response is supporting this research with an 18-month, $10.49 million task order.

NasoShield, a nose spray, will require only a single dose to protect against infections caused by inhaling anthrax. The spray uses technology known as the Adenovirus 5 viral vectored delivery system that modifies a non-infectious virus to include the genetic material needed to produce an immune response against anthrax. The researchers also will focus on improving the shelf life of the anthrax vaccine.

This project is the first time the HHS’s Biomedical Advanced Research and Development Authority (BARDA) has supported development of an anthrax vaccine using this delivery system. “Anthrax remains a material threat to our national health security,” said Dr. Richard Hatchett, acting BARDA director. “To help combat the health impacts of an anthrax attack, BARDA partnered with several biotechnology firms in accelerating development of promising next-generation treatments against anthrax infection. Engaging one of our Centers for Innovation in Advanced Development and Manufacturing represents a unique approach to this development.”

One of the nation’s Centers for Innovation in Advanced Development and Manufacturing, led by the Texas A&M University System, is beginning development and manufacturing on a second-generation anthrax vaccine. The U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response is supporting this research with an 18-month, $10.49 million task order.

NasoShield, a nose spray, will require only a single dose to protect against infections caused by inhaling anthrax. The spray uses technology known as the Adenovirus 5 viral vectored delivery system that modifies a non-infectious virus to include the genetic material needed to produce an immune response against anthrax. The researchers also will focus on improving the shelf life of the anthrax vaccine.

This project is the first time the HHS’s Biomedical Advanced Research and Development Authority (BARDA) has supported development of an anthrax vaccine using this delivery system. “Anthrax remains a material threat to our national health security,” said Dr. Richard Hatchett, acting BARDA director. “To help combat the health impacts of an anthrax attack, BARDA partnered with several biotechnology firms in accelerating development of promising next-generation treatments against anthrax infection. Engaging one of our Centers for Innovation in Advanced Development and Manufacturing represents a unique approach to this development.”

Septic shock patients who received midodrine needed significantly fewer intravenous vasopressors during recovery and had shorter hospital stays, based on data from a retrospective study of 275 adults at a single tertiary care center.

In many institutions, policy dictates that patients must remain in the ICU as long as they need intravenous vasopressors, wrote Dr. Micah R. Whitson of North Shore-LIJ Health System in New Hyde Park, N.Y., and colleagues. “One solution to this problem may be replacement of IV vasopressors with an oral agent.”

“Midodrine facilitated earlier patient transfer from the ICU and more efficient allocation of ICU resources,” the researchers wrote (Chest. 2016;149[6]:1380-83).

The researchers compared data on 135 patients treated with midodrine in addition to an intravenous vasopressor and 140 patients treated with an intravenous vasopressor alone.

Overall, patients given midodrine received intravenous vasopressors for 2.9 days while the other group received intravenous vasopressors for 3.8 days, a significant 24% difference. Hospital length of stay was not significantly different, averaging 22 days in the midodrine group and 24 days in the intravenous vasopressor–only group. However, ICU length of stay averaged 7.5 days in the midodrine group and 9.4 days in the vasopressor-only group, a significant 20% reduction. Further, the midodrine group was significantly less likely to reinstitute intravenous vasopressors than the intravenous vasopressor–only group (5.2% vs. 15%, respectively). ICU and hospital mortality rates were not significantly different between the two groups, Dr. Whitson and associates reported.

Patients in the midodrine group received a starting dose of 10 mg every 8 hours, which was increased incrementally until they no longer needed intravenous vasopressors. The maximum midodrine dose in the study was 18.7 mg every 8 hours, and the average duration of use was 6 days.

The patients’ average age was 65 years in the intravenous vasopressor group and 69 years in the midodrine group. Other demographic factors did not significantly differ between the two groups.

One patient discontinued midodrine before discontinuing an intravenous vasopressor because of bradycardia, which resolved without additional treatment.

The findings were limited by the observational nature of the study and the use of data from a single center, the investigators noted. The results, however, support the safety of midodrine and the study “lays the groundwork for a prospective, randomized controlled trial that will examine efficacy, starting dose, escalation, tapering and appropriate patient selection for midodrine use during recovery from septic shock,” they said.

The researchers had no financial conflicts to disclose.

Septic shock patients who received midodrine needed significantly fewer intravenous vasopressors during recovery and had shorter hospital stays, based on data from a retrospective study of 275 adults at a single tertiary care center.

In many institutions, policy dictates that patients must remain in the ICU as long as they need intravenous vasopressors, wrote Dr. Micah R. Whitson of North Shore-LIJ Health System in New Hyde Park, N.Y., and colleagues. “One solution to this problem may be replacement of IV vasopressors with an oral agent.”

“Midodrine facilitated earlier patient transfer from the ICU and more efficient allocation of ICU resources,” the researchers wrote (Chest. 2016;149[6]:1380-83).

The researchers compared data on 135 patients treated with midodrine in addition to an intravenous vasopressor and 140 patients treated with an intravenous vasopressor alone.

Overall, patients given midodrine received intravenous vasopressors for 2.9 days while the other group received intravenous vasopressors for 3.8 days, a significant 24% difference. Hospital length of stay was not significantly different, averaging 22 days in the midodrine group and 24 days in the intravenous vasopressor–only group. However, ICU length of stay averaged 7.5 days in the midodrine group and 9.4 days in the vasopressor-only group, a significant 20% reduction. Further, the midodrine group was significantly less likely to reinstitute intravenous vasopressors than the intravenous vasopressor–only group (5.2% vs. 15%, respectively). ICU and hospital mortality rates were not significantly different between the two groups, Dr. Whitson and associates reported.

Patients in the midodrine group received a starting dose of 10 mg every 8 hours, which was increased incrementally until they no longer needed intravenous vasopressors. The maximum midodrine dose in the study was 18.7 mg every 8 hours, and the average duration of use was 6 days.

The patients’ average age was 65 years in the intravenous vasopressor group and 69 years in the midodrine group. Other demographic factors did not significantly differ between the two groups.

One patient discontinued midodrine before discontinuing an intravenous vasopressor because of bradycardia, which resolved without additional treatment.

The findings were limited by the observational nature of the study and the use of data from a single center, the investigators noted. The results, however, support the safety of midodrine and the study “lays the groundwork for a prospective, randomized controlled trial that will examine efficacy, starting dose, escalation, tapering and appropriate patient selection for midodrine use during recovery from septic shock,” they said.

The researchers had no financial conflicts to disclose.

Septic shock patients who received midodrine needed significantly fewer intravenous vasopressors during recovery and had shorter hospital stays, based on data from a retrospective study of 275 adults at a single tertiary care center.

In many institutions, policy dictates that patients must remain in the ICU as long as they need intravenous vasopressors, wrote Dr. Micah R. Whitson of North Shore-LIJ Health System in New Hyde Park, N.Y., and colleagues. “One solution to this problem may be replacement of IV vasopressors with an oral agent.”

“Midodrine facilitated earlier patient transfer from the ICU and more efficient allocation of ICU resources,” the researchers wrote (Chest. 2016;149[6]:1380-83).

The researchers compared data on 135 patients treated with midodrine in addition to an intravenous vasopressor and 140 patients treated with an intravenous vasopressor alone.

Overall, patients given midodrine received intravenous vasopressors for 2.9 days while the other group received intravenous vasopressors for 3.8 days, a significant 24% difference. Hospital length of stay was not significantly different, averaging 22 days in the midodrine group and 24 days in the intravenous vasopressor–only group. However, ICU length of stay averaged 7.5 days in the midodrine group and 9.4 days in the vasopressor-only group, a significant 20% reduction. Further, the midodrine group was significantly less likely to reinstitute intravenous vasopressors than the intravenous vasopressor–only group (5.2% vs. 15%, respectively). ICU and hospital mortality rates were not significantly different between the two groups, Dr. Whitson and associates reported.

Patients in the midodrine group received a starting dose of 10 mg every 8 hours, which was increased incrementally until they no longer needed intravenous vasopressors. The maximum midodrine dose in the study was 18.7 mg every 8 hours, and the average duration of use was 6 days.

The patients’ average age was 65 years in the intravenous vasopressor group and 69 years in the midodrine group. Other demographic factors did not significantly differ between the two groups.

One patient discontinued midodrine before discontinuing an intravenous vasopressor because of bradycardia, which resolved without additional treatment.

The findings were limited by the observational nature of the study and the use of data from a single center, the investigators noted. The results, however, support the safety of midodrine and the study “lays the groundwork for a prospective, randomized controlled trial that will examine efficacy, starting dose, escalation, tapering and appropriate patient selection for midodrine use during recovery from septic shock,” they said.

The researchers had no financial conflicts to disclose.

Rapid HIV tests in high-income countries miss about one in seven infections and should be used in combination with fourth-generation enzyme immunoassays (EIA) or nucleic acid amplification tests (NAAT) in clinical settings, according to a study in the journal AIDS.

“These infections are likely to be particularly transmissible due to the high HIV viral load in early infection ... in high-income countries, rapid tests should be used in combination with fourth-generation EIA or NAAT, except in special circumstances,” the Australian researchers said.

©jarun011/Thinkstock

They performed a systematic review and meta-analysis of 18 studies involving 110,122 HIV rapid test results. The primary outcome was the test’s sensitivity for detecting acute or established HIV infections. Sensitivity was calculated by dividing the number of confirmed positive rapid tests by the number of confirmed positive comparator tests. Specificity was calculated by dividing the number of confirmed negative rapid tests by the number of negative comparator tests.

Compared with EIA, the estimated sensitivity of rapid tests was 94.5% (95% confidence interval, 87.4-97.7). Compared with NAAT, the sensitivity of rapid tests was 93.7% (95% CI, 88.7-96.5). The sensitivity of rapid tests in high income countries was 85.7% (95% CI, 81.9-88.9), and in low income countries was 97.7% (95% CI, 95.2-98·9), compared with either EIA or NAAT (P less than .01 for difference between settings). Proportions of antibody negative acute infections were 13.6% (95% CI, 10.1-18.0) and 4.7% (95% CI, 2.8-7.7) in studies from high- and low-income countries respectively (P less than .01).

Rapid tests were less sensitive when used in clinical settings in high-income countries, regardless of whether they were compared with a NAAT or fourth-generation EIA. However, the researchers noted that the discrepancy between high- and low-income countries could be attributed to the higher proportion of acute HIV infections (antibody-negative NAAT positive) in populations tested in high-income countries, which might reflect higher background testing rates or a higher incidence of HIV in men who have sex with men.

Read the full study in AIDS (doi: 10.1097/QAD.0000000000001134).

[email protected]

On Twitter @richpizzi

Rapid HIV tests in high-income countries miss about one in seven infections and should be used in combination with fourth-generation enzyme immunoassays (EIA) or nucleic acid amplification tests (NAAT) in clinical settings, according to a study in the journal AIDS.

“These infections are likely to be particularly transmissible due to the high HIV viral load in early infection ... in high-income countries, rapid tests should be used in combination with fourth-generation EIA or NAAT, except in special circumstances,” the Australian researchers said.

©jarun011/Thinkstock

They performed a systematic review and meta-analysis of 18 studies involving 110,122 HIV rapid test results. The primary outcome was the test’s sensitivity for detecting acute or established HIV infections. Sensitivity was calculated by dividing the number of confirmed positive rapid tests by the number of confirmed positive comparator tests. Specificity was calculated by dividing the number of confirmed negative rapid tests by the number of negative comparator tests.

Compared with EIA, the estimated sensitivity of rapid tests was 94.5% (95% confidence interval, 87.4-97.7). Compared with NAAT, the sensitivity of rapid tests was 93.7% (95% CI, 88.7-96.5). The sensitivity of rapid tests in high income countries was 85.7% (95% CI, 81.9-88.9), and in low income countries was 97.7% (95% CI, 95.2-98·9), compared with either EIA or NAAT (P less than .01 for difference between settings). Proportions of antibody negative acute infections were 13.6% (95% CI, 10.1-18.0) and 4.7% (95% CI, 2.8-7.7) in studies from high- and low-income countries respectively (P less than .01).

Rapid tests were less sensitive when used in clinical settings in high-income countries, regardless of whether they were compared with a NAAT or fourth-generation EIA. However, the researchers noted that the discrepancy between high- and low-income countries could be attributed to the higher proportion of acute HIV infections (antibody-negative NAAT positive) in populations tested in high-income countries, which might reflect higher background testing rates or a higher incidence of HIV in men who have sex with men.

Read the full study in AIDS (doi: 10.1097/QAD.0000000000001134).

[email protected]

On Twitter @richpizzi

Rapid HIV tests in high-income countries miss about one in seven infections and should be used in combination with fourth-generation enzyme immunoassays (EIA) or nucleic acid amplification tests (NAAT) in clinical settings, according to a study in the journal AIDS.

“These infections are likely to be particularly transmissible due to the high HIV viral load in early infection ... in high-income countries, rapid tests should be used in combination with fourth-generation EIA or NAAT, except in special circumstances,” the Australian researchers said.

©jarun011/Thinkstock

They performed a systematic review and meta-analysis of 18 studies involving 110,122 HIV rapid test results. The primary outcome was the test’s sensitivity for detecting acute or established HIV infections. Sensitivity was calculated by dividing the number of confirmed positive rapid tests by the number of confirmed positive comparator tests. Specificity was calculated by dividing the number of confirmed negative rapid tests by the number of negative comparator tests.

Compared with EIA, the estimated sensitivity of rapid tests was 94.5% (95% confidence interval, 87.4-97.7). Compared with NAAT, the sensitivity of rapid tests was 93.7% (95% CI, 88.7-96.5). The sensitivity of rapid tests in high income countries was 85.7% (95% CI, 81.9-88.9), and in low income countries was 97.7% (95% CI, 95.2-98·9), compared with either EIA or NAAT (P less than .01 for difference between settings). Proportions of antibody negative acute infections were 13.6% (95% CI, 10.1-18.0) and 4.7% (95% CI, 2.8-7.7) in studies from high- and low-income countries respectively (P less than .01).

Rapid tests were less sensitive when used in clinical settings in high-income countries, regardless of whether they were compared with a NAAT or fourth-generation EIA. However, the researchers noted that the discrepancy between high- and low-income countries could be attributed to the higher proportion of acute HIV infections (antibody-negative NAAT positive) in populations tested in high-income countries, which might reflect higher background testing rates or a higher incidence of HIV in men who have sex with men.

Read the full study in AIDS (doi: 10.1097/QAD.0000000000001134).

[email protected]

On Twitter @richpizzi

Platelets in a blood smear

Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).

The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.

Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.

So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.

The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.

The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.

The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.

The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.

The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.

However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.

The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.

Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.

And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”

They described the development of the platform in Blood. 

Platelets in a blood smear

Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).

The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.

Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.

So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.

The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.

The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.

The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.

The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.

The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.

However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.

The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.

Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.

And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”

They described the development of the platform in Blood. 

Platelets in a blood smear

Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).

The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.

Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.

So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.

The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.

The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.

The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.

The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.

The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.

However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.

The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.

Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.

And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”

They described the development of the platform in Blood. 

Reverse total shoulder arthroplasty (RTSA) has become a reliable treatment option for many pathologic conditions of the shoulder, including rotator cuff arthropathy, proximal humerus fractures, and others.^1-4 While the treatment outcomes have generally been reported as good, some concern exists over the postoperative range of motion (ROM) in patients following RTSA, including external rotation.^5-7 The original RTSA design was introduced by Neer in the 1970s and has undergone many modifications since that time.^1,2 The original Grammont-style prosthesis involved medialization of the glenoid, inferiorizing the center of rotation (with increased deltoid tensioning), and a neck-shaft angle of 155°.^1,8 While clinical results of the 155° design were encouraging, concerns arose over the significance of the common finding of scapular notching, or contact between the scapular neck and inferior portion of the humeral polyethylene when the arm is adducted.^9,10

To address this concern, a prosthesis design with a 135° neck-shaft angle was introduced.¹¹ This new design did significantly decrease the rate of scapular notching, and although some reported a concern over implant stability with the 135° prosthesis, recent data has shown no difference in dislocation rates between the 135° and 155° prostheses.³ A different variable that has not been evaluated between these prostheses is the active ROM that is achieved postoperatively, and the change in ROM from pre- to post-RTSA.^12,13 As active ROM plays a significant role in shoulder function and patient satisfaction, the question of whether a significant difference exists in postoperative ROM between the 135° and 155° prostheses must be addressed.

The purpose of this study was to perform a systematic review investigating active ROM following RTSA to determine if active postoperative ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. The authors hypothesize that there will be no significant difference in active postoperative ROM between the 135° and 155° prostheses, and that the difference between preoperative and postoperative ROM (that is, the amount of motion gained by the surgery) will not significantly differ between the 135° and 155° prostheses.

Methods

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist.¹⁵ Systematic review registration was performed using the PROSPERO international prospective register of systematic reviews (registration date 3/9/15, registration number CRD42015017367).¹⁶ Two reviewers independently conducted the search on March 7, 2015 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (((((reverse[Title/Abstract]) AND shoulder[Title/Abstract]) AND arthroplasty[Title/Abstract]) NOT arthroscopic[Title/Abstract]) NOT cadaver[Title/Abstract]) NOT biomechanical[Title/Abstract]. English language Level I-IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine¹⁷) clinical studies that reported the type of RTSA prosthesis that was used as well as postoperative ROM with at least 12 months follow-up were eligible. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject publications were discovered, the study with the longer duration of follow-up or larger number of patients was included. Level V evidence reviews, letters to the editor, basic science, biomechanical studies, arthroscopic shoulder surgery, imaging, surgical technique, and classification studies were excluded. Studies were excluded if both a 135° and 155° prosthesis were utilized and the outcomes were not stratified by the humeral inclination. Studies that did not report ROM were excluded.

A total of 456 studies were located, and, after implementation of the exclusion criteria, 65 studies from 2005-2015 were included in the final analysis (Figure). Subjects of interest in this systematic review underwent a RTSA. Studies were not excluded based on the surgical indications (rotator cuff tear arthropathy, proximal humerus fractures, osteoarthritis) and there was no minimum follow-up or rehabilitation requirement. Study and subject demographic parameters analyzed included year of publication, journal of publication, country and continent of publication, years of subject enrollment, presence of study financial conflict of interest, number of subjects and shoulders, gender, age, the manufacturer and type of prosthesis used, and the degree of the humeral inclination (135° vs 155° humeral cup). Preoperative ROM, including forward elevation, abduction, external rotation with the arm adducted, and external rotation with the arm at 90° of abduction, were recorded. The same ROM measurements were recorded for the final follow-up visit that was reported. Internal rotation was recorded, but because of the variability with how this measurement was reported, it was not analyzed. Clinical outcome scores and complications were not assessed. Study methodological quality was evaluated using the Modified Coleman Methodology Score (MCMS).¹⁸

Statistical Analysis

Descriptive statistics were calculated, including mean ± standard deviation for quantitative continuous data and frequencies with percentages for qualitative categorical data. ROM comparisons between 135° and 155° components (pre- vs postoperative for each and postoperative between the 2) were made using 2 proportion z-test calculator (http://in-silico.net/tools/statistics/ztest) using alpha .05 because of the difference in sample sizes between compared groups.

Results

Sixty-five studies with 3302 patients (3434 shoulders) were included in this study. There was a total of 1211 shoulders in the 135° lateralized glenosphere group and 2223 shoulders in the 155° group. The studies had an average MCMS of 40.4 ± 8.2 (poor), 48% of studies reported a conflict of interest, 32% had no conflict of interest, and 20% did not report whether a conflict of interest existed or not. The majority of studies included were level IV evidence (85%). Mean patient age was 71.1 ± 7.6 years; 29% of patients were male and 71% were female. No significant difference existed between patient age at the time of surgery; the average age of patients in the 135° lateralized glenosphere group was 71.67 ± 3.8 years, while the average patient age of patients in the 155° group was 70.97 ± 8.8 years. Mean follow-up for all patients included in this study was 37.2 ± 16.5 months. Of the 65 studies included, 3 were published from Asia, 4 were published from Australia, 24 were from North America, and 34 were from Europe. Of the individual countries whose studies were included, the United States had 23 included studies, France had 13 included studies, and Italy had 4 included studies. All other countries had <4 studies included.

Patients who received either a 135° or a 155° prosthesis showed significant improvements in external rotation with the arm at the side (P < .05), forward elevation (P < .05), and abduction (P < .05) following surgery (Table). When comparing the 135° and 155° groups, patients who received a 135° prosthesis showed significantly greater improvements in external rotation with the arm at the side (P < .001) and had significantly more overall external rotation postoperatively (P < .001) than patients who received a 155° prosthesis. The only preoperative ROM difference between groups was the 155° group started with significantly more forward elevation than the 135°group prior to surgery (P = .002).

Discussion

RTSA is indicated in patients with rotator cuff tear arthropathy, pseudoparalysis, and a functional deltoid.^1,2,4 The purpose of this systematic review was to determine if active ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. Forward elevation, abduction, and external rotation all significantly improved following surgery in both groups, with no significant difference between groups in motion or amount of motion improvement, mostly confirming the study hypotheses. However, patients in the 135° group had significantly greater postoperative external rotation and greater amount of external rotation improvement compared to the 155° group.

Two of the frequently debated issues regarding implant geometry is stability and scapular notching between the 135° and 155° humeral inclination designs. Erickson and colleagues3 recently evaluated the rate of scapular notching and dislocations between the 135° and 155° RTSA prostheses. The authors found that the 135° prosthesis had a significantly lower incidence of scapular notching vs the 155° group and that the rate of dislocations was not significantly different between groups.³ In the latter systematic review, the authors attempted to evaluate ROM between the 135° and 155° prostheses, but as the inclusion criteria of the study was reporting on scapular notching and dislocation rates, many studies reporting solely on ROM were excluded, and the influence of humeral inclination on ROM was inconclusive.³ Furthermore, there have been no studies that have directly compared ROM following RTSA between the 135° and 155° prostheses. While studies evaluating each prosthesis on an individual level have shown an improvement in ROM from pre- to postsurgery, there have been no large studies that have compared the postoperative ROM and change in pre- to postoperative ROM between the 135° and 155° prostheses.^11,13,19,20

One study by Valenti and colleagues²¹ evaluated a group of 30 patients with an average age of 69.5 years who underwent RTSA using either a 135° or a 155° prosthesis. Although the study did not directly compare the 2 types of prostheses, it did report the separate outcomes for each prosthesis. At an average follow-up of 36.4 months, the authors found that patients who had the 135° prosthesis implanted had a mean increase in forward elevation and external rotation of 53° and 9°, while patients who had the 155° showed an increase of 56° in forward elevation and a loss of 1° of external rotation. Both prostheses showed a significant increase in forward elevation, but neither had a significant increase in external rotation. Furthermore, scapular notching was seen in 4 patients in the 155° group, while no patients in the 135° group had evidence of notching.

The results of the current study were similar in that both the 135° and 155° prosthesis showed improvements in forward elevation following surgery, and the 135° group showed a significantly greater gain in external rotation than the 155° group. A significant component of shoulder function and patient satisfaction following RTSA is active ROM. However, this variable has not explicitly been evaluated in the literature until now. The clinical significance of this finding is unclear. Patients with adequate external rotation prior to surgery likely would not see a functional difference between prostheses, while those patients who were borderline on a functional amount of external rotation would see a clinically significant benefit with the 135° prosthesis. Studies have shown that the 135° prosthesis is more anatomic than the 155°, and this could explain the difference seen in ROM outcomes between the 2 prostheses.¹⁹ Ladermann and colleagues²² recently created and evaluated a 3-dimensional computer model to evaluate possible differences between the 135° and 155° prosthesis. The authors found a significant increase in external rotation of the 135° compared to the 155°, likely related to a difference in acromiohumeral distance as well as inlay vs onlay humeral trays between the 2 prostheses. The results of this study parallel the computer model, thereby validating these experimental results.

It is important to understand what the minimum functional ROM of the shoulder is (in other words, the ROM necessary to complete activities of daily living (ADLs).²³ Namdari and colleagues²⁴ used motion analysis software to evaluate the shoulder ROM necessary to complete 10 different ADLs, including combing hair, washing the back of the opposite shoulder, and reaching a shelf above their head without bending their elbow in 20 patients with a mean age of 29.2 years. They found that patients required 121° ± 6.7° of flexion, 46° ± 5.3° of extension, 128° ± 7.9° of abduction, 116° ± 9.1° of cross-body adduction, 59° ± 10° of external rotation with the arm 90° abducted, and 102° ± 7.7° of internal rotation with the arm at the side (external rotation with the arm at the side was not well defined).²⁴ Hence, while abduction and forward elevation seem comparable, the results from the current study do raise concerns about the amount of external rotation obtained following RTSA as it relates to a patients’ ability to perform ADLs, specifically in the 155° prosthesis, as the average postoperative external rotation in this group was 20.5°. Therefore, based on the results of this study, it appears that, while both the 135° and 155° RTSA prostheses provide similar gain in forward elevation and abduction ROM as well as overall forward elevation and abduction, the 135° prosthesis provides significantly more external rotation with the arm at the side than the 155° prosthesis.

Limitations

Although this study attempted to look at all studies that reported active ROM in patients following a RTSA, and 2 authors performed the search, there is a possibility that some studies were missed, introducing study selection bias. Furthermore, the mean follow-up was over 3 years following surgery, but the minimum follow-up requirement for studies to be included was only 12 months. Hence, this transfer bias introduces the possibility that the patient’s ROM would have changed had they been followed for a standard period of time. There are many variables that come into play in evaluating ROM, and although the study attempted to control for these, there are some that could not be controlled for due to lack of reporting by some studies. Glenosphere size and humeral retroversion were not recorded, as they were not reliably reported in all studies, so motion outcomes based on these variables was not evaluated. Complications and clinical outcomes were not assessed in this review and as such, conclusions regarding these variables cannot be drawn from this study. Finally, indications for surgery were not reliably reported in the studies included in this paper, so differences may have existed between surgical indications of the 135° and 155° groups that could have affected outcomes.

Conclusion

Patients who receive a 135° RTSA gain significantly more external rotation from pre- to postsurgery and have an overall greater amount of external rotation than patients who receive a 155° prosthesis. Both groups show improvements in forward elevation, external rotation, and abduction following surgery.

Reverse total shoulder arthroplasty (RTSA) has become a reliable treatment option for many pathologic conditions of the shoulder, including rotator cuff arthropathy, proximal humerus fractures, and others.^1-4 While the treatment outcomes have generally been reported as good, some concern exists over the postoperative range of motion (ROM) in patients following RTSA, including external rotation.^5-7 The original RTSA design was introduced by Neer in the 1970s and has undergone many modifications since that time.^1,2 The original Grammont-style prosthesis involved medialization of the glenoid, inferiorizing the center of rotation (with increased deltoid tensioning), and a neck-shaft angle of 155°.^1,8 While clinical results of the 155° design were encouraging, concerns arose over the significance of the common finding of scapular notching, or contact between the scapular neck and inferior portion of the humeral polyethylene when the arm is adducted.^9,10

To address this concern, a prosthesis design with a 135° neck-shaft angle was introduced.¹¹ This new design did significantly decrease the rate of scapular notching, and although some reported a concern over implant stability with the 135° prosthesis, recent data has shown no difference in dislocation rates between the 135° and 155° prostheses.³ A different variable that has not been evaluated between these prostheses is the active ROM that is achieved postoperatively, and the change in ROM from pre- to post-RTSA.^12,13 As active ROM plays a significant role in shoulder function and patient satisfaction, the question of whether a significant difference exists in postoperative ROM between the 135° and 155° prostheses must be addressed.

The purpose of this study was to perform a systematic review investigating active ROM following RTSA to determine if active postoperative ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. The authors hypothesize that there will be no significant difference in active postoperative ROM between the 135° and 155° prostheses, and that the difference between preoperative and postoperative ROM (that is, the amount of motion gained by the surgery) will not significantly differ between the 135° and 155° prostheses.

Methods

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist.¹⁵ Systematic review registration was performed using the PROSPERO international prospective register of systematic reviews (registration date 3/9/15, registration number CRD42015017367).¹⁶ Two reviewers independently conducted the search on March 7, 2015 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (((((reverse[Title/Abstract]) AND shoulder[Title/Abstract]) AND arthroplasty[Title/Abstract]) NOT arthroscopic[Title/Abstract]) NOT cadaver[Title/Abstract]) NOT biomechanical[Title/Abstract]. English language Level I-IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine¹⁷) clinical studies that reported the type of RTSA prosthesis that was used as well as postoperative ROM with at least 12 months follow-up were eligible. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject publications were discovered, the study with the longer duration of follow-up or larger number of patients was included. Level V evidence reviews, letters to the editor, basic science, biomechanical studies, arthroscopic shoulder surgery, imaging, surgical technique, and classification studies were excluded. Studies were excluded if both a 135° and 155° prosthesis were utilized and the outcomes were not stratified by the humeral inclination. Studies that did not report ROM were excluded.

A total of 456 studies were located, and, after implementation of the exclusion criteria, 65 studies from 2005-2015 were included in the final analysis (Figure). Subjects of interest in this systematic review underwent a RTSA. Studies were not excluded based on the surgical indications (rotator cuff tear arthropathy, proximal humerus fractures, osteoarthritis) and there was no minimum follow-up or rehabilitation requirement. Study and subject demographic parameters analyzed included year of publication, journal of publication, country and continent of publication, years of subject enrollment, presence of study financial conflict of interest, number of subjects and shoulders, gender, age, the manufacturer and type of prosthesis used, and the degree of the humeral inclination (135° vs 155° humeral cup). Preoperative ROM, including forward elevation, abduction, external rotation with the arm adducted, and external rotation with the arm at 90° of abduction, were recorded. The same ROM measurements were recorded for the final follow-up visit that was reported. Internal rotation was recorded, but because of the variability with how this measurement was reported, it was not analyzed. Clinical outcome scores and complications were not assessed. Study methodological quality was evaluated using the Modified Coleman Methodology Score (MCMS).¹⁸

Statistical Analysis

Descriptive statistics were calculated, including mean ± standard deviation for quantitative continuous data and frequencies with percentages for qualitative categorical data. ROM comparisons between 135° and 155° components (pre- vs postoperative for each and postoperative between the 2) were made using 2 proportion z-test calculator (http://in-silico.net/tools/statistics/ztest) using alpha .05 because of the difference in sample sizes between compared groups.

Results

Sixty-five studies with 3302 patients (3434 shoulders) were included in this study. There was a total of 1211 shoulders in the 135° lateralized glenosphere group and 2223 shoulders in the 155° group. The studies had an average MCMS of 40.4 ± 8.2 (poor), 48% of studies reported a conflict of interest, 32% had no conflict of interest, and 20% did not report whether a conflict of interest existed or not. The majority of studies included were level IV evidence (85%). Mean patient age was 71.1 ± 7.6 years; 29% of patients were male and 71% were female. No significant difference existed between patient age at the time of surgery; the average age of patients in the 135° lateralized glenosphere group was 71.67 ± 3.8 years, while the average patient age of patients in the 155° group was 70.97 ± 8.8 years. Mean follow-up for all patients included in this study was 37.2 ± 16.5 months. Of the 65 studies included, 3 were published from Asia, 4 were published from Australia, 24 were from North America, and 34 were from Europe. Of the individual countries whose studies were included, the United States had 23 included studies, France had 13 included studies, and Italy had 4 included studies. All other countries had <4 studies included.

Patients who received either a 135° or a 155° prosthesis showed significant improvements in external rotation with the arm at the side (P < .05), forward elevation (P < .05), and abduction (P < .05) following surgery (Table). When comparing the 135° and 155° groups, patients who received a 135° prosthesis showed significantly greater improvements in external rotation with the arm at the side (P < .001) and had significantly more overall external rotation postoperatively (P < .001) than patients who received a 155° prosthesis. The only preoperative ROM difference between groups was the 155° group started with significantly more forward elevation than the 135°group prior to surgery (P = .002).

Discussion

RTSA is indicated in patients with rotator cuff tear arthropathy, pseudoparalysis, and a functional deltoid.^1,2,4 The purpose of this systematic review was to determine if active ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. Forward elevation, abduction, and external rotation all significantly improved following surgery in both groups, with no significant difference between groups in motion or amount of motion improvement, mostly confirming the study hypotheses. However, patients in the 135° group had significantly greater postoperative external rotation and greater amount of external rotation improvement compared to the 155° group.

Two of the frequently debated issues regarding implant geometry is stability and scapular notching between the 135° and 155° humeral inclination designs. Erickson and colleagues3 recently evaluated the rate of scapular notching and dislocations between the 135° and 155° RTSA prostheses. The authors found that the 135° prosthesis had a significantly lower incidence of scapular notching vs the 155° group and that the rate of dislocations was not significantly different between groups.³ In the latter systematic review, the authors attempted to evaluate ROM between the 135° and 155° prostheses, but as the inclusion criteria of the study was reporting on scapular notching and dislocation rates, many studies reporting solely on ROM were excluded, and the influence of humeral inclination on ROM was inconclusive.³ Furthermore, there have been no studies that have directly compared ROM following RTSA between the 135° and 155° prostheses. While studies evaluating each prosthesis on an individual level have shown an improvement in ROM from pre- to postsurgery, there have been no large studies that have compared the postoperative ROM and change in pre- to postoperative ROM between the 135° and 155° prostheses.^11,13,19,20

One study by Valenti and colleagues²¹ evaluated a group of 30 patients with an average age of 69.5 years who underwent RTSA using either a 135° or a 155° prosthesis. Although the study did not directly compare the 2 types of prostheses, it did report the separate outcomes for each prosthesis. At an average follow-up of 36.4 months, the authors found that patients who had the 135° prosthesis implanted had a mean increase in forward elevation and external rotation of 53° and 9°, while patients who had the 155° showed an increase of 56° in forward elevation and a loss of 1° of external rotation. Both prostheses showed a significant increase in forward elevation, but neither had a significant increase in external rotation. Furthermore, scapular notching was seen in 4 patients in the 155° group, while no patients in the 135° group had evidence of notching.

The results of the current study were similar in that both the 135° and 155° prosthesis showed improvements in forward elevation following surgery, and the 135° group showed a significantly greater gain in external rotation than the 155° group. A significant component of shoulder function and patient satisfaction following RTSA is active ROM. However, this variable has not explicitly been evaluated in the literature until now. The clinical significance of this finding is unclear. Patients with adequate external rotation prior to surgery likely would not see a functional difference between prostheses, while those patients who were borderline on a functional amount of external rotation would see a clinically significant benefit with the 135° prosthesis. Studies have shown that the 135° prosthesis is more anatomic than the 155°, and this could explain the difference seen in ROM outcomes between the 2 prostheses.¹⁹ Ladermann and colleagues²² recently created and evaluated a 3-dimensional computer model to evaluate possible differences between the 135° and 155° prosthesis. The authors found a significant increase in external rotation of the 135° compared to the 155°, likely related to a difference in acromiohumeral distance as well as inlay vs onlay humeral trays between the 2 prostheses. The results of this study parallel the computer model, thereby validating these experimental results.

It is important to understand what the minimum functional ROM of the shoulder is (in other words, the ROM necessary to complete activities of daily living (ADLs).²³ Namdari and colleagues²⁴ used motion analysis software to evaluate the shoulder ROM necessary to complete 10 different ADLs, including combing hair, washing the back of the opposite shoulder, and reaching a shelf above their head without bending their elbow in 20 patients with a mean age of 29.2 years. They found that patients required 121° ± 6.7° of flexion, 46° ± 5.3° of extension, 128° ± 7.9° of abduction, 116° ± 9.1° of cross-body adduction, 59° ± 10° of external rotation with the arm 90° abducted, and 102° ± 7.7° of internal rotation with the arm at the side (external rotation with the arm at the side was not well defined).²⁴ Hence, while abduction and forward elevation seem comparable, the results from the current study do raise concerns about the amount of external rotation obtained following RTSA as it relates to a patients’ ability to perform ADLs, specifically in the 155° prosthesis, as the average postoperative external rotation in this group was 20.5°. Therefore, based on the results of this study, it appears that, while both the 135° and 155° RTSA prostheses provide similar gain in forward elevation and abduction ROM as well as overall forward elevation and abduction, the 135° prosthesis provides significantly more external rotation with the arm at the side than the 155° prosthesis.

Limitations

Although this study attempted to look at all studies that reported active ROM in patients following a RTSA, and 2 authors performed the search, there is a possibility that some studies were missed, introducing study selection bias. Furthermore, the mean follow-up was over 3 years following surgery, but the minimum follow-up requirement for studies to be included was only 12 months. Hence, this transfer bias introduces the possibility that the patient’s ROM would have changed had they been followed for a standard period of time. There are many variables that come into play in evaluating ROM, and although the study attempted to control for these, there are some that could not be controlled for due to lack of reporting by some studies. Glenosphere size and humeral retroversion were not recorded, as they were not reliably reported in all studies, so motion outcomes based on these variables was not evaluated. Complications and clinical outcomes were not assessed in this review and as such, conclusions regarding these variables cannot be drawn from this study. Finally, indications for surgery were not reliably reported in the studies included in this paper, so differences may have existed between surgical indications of the 135° and 155° groups that could have affected outcomes.

Conclusion

Patients who receive a 135° RTSA gain significantly more external rotation from pre- to postsurgery and have an overall greater amount of external rotation than patients who receive a 155° prosthesis. Both groups show improvements in forward elevation, external rotation, and abduction following surgery.

Reverse total shoulder arthroplasty (RTSA) has become a reliable treatment option for many pathologic conditions of the shoulder, including rotator cuff arthropathy, proximal humerus fractures, and others.^1-4 While the treatment outcomes have generally been reported as good, some concern exists over the postoperative range of motion (ROM) in patients following RTSA, including external rotation.^5-7 The original RTSA design was introduced by Neer in the 1970s and has undergone many modifications since that time.^1,2 The original Grammont-style prosthesis involved medialization of the glenoid, inferiorizing the center of rotation (with increased deltoid tensioning), and a neck-shaft angle of 155°.^1,8 While clinical results of the 155° design were encouraging, concerns arose over the significance of the common finding of scapular notching, or contact between the scapular neck and inferior portion of the humeral polyethylene when the arm is adducted.^9,10

To address this concern, a prosthesis design with a 135° neck-shaft angle was introduced.¹¹ This new design did significantly decrease the rate of scapular notching, and although some reported a concern over implant stability with the 135° prosthesis, recent data has shown no difference in dislocation rates between the 135° and 155° prostheses.³ A different variable that has not been evaluated between these prostheses is the active ROM that is achieved postoperatively, and the change in ROM from pre- to post-RTSA.^12,13 As active ROM plays a significant role in shoulder function and patient satisfaction, the question of whether a significant difference exists in postoperative ROM between the 135° and 155° prostheses must be addressed.

The purpose of this study was to perform a systematic review investigating active ROM following RTSA to determine if active postoperative ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. The authors hypothesize that there will be no significant difference in active postoperative ROM between the 135° and 155° prostheses, and that the difference between preoperative and postoperative ROM (that is, the amount of motion gained by the surgery) will not significantly differ between the 135° and 155° prostheses.

Methods

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist.¹⁵ Systematic review registration was performed using the PROSPERO international prospective register of systematic reviews (registration date 3/9/15, registration number CRD42015017367).¹⁶ Two reviewers independently conducted the search on March 7, 2015 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (((((reverse[Title/Abstract]) AND shoulder[Title/Abstract]) AND arthroplasty[Title/Abstract]) NOT arthroscopic[Title/Abstract]) NOT cadaver[Title/Abstract]) NOT biomechanical[Title/Abstract]. English language Level I-IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine¹⁷) clinical studies that reported the type of RTSA prosthesis that was used as well as postoperative ROM with at least 12 months follow-up were eligible. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject publications were discovered, the study with the longer duration of follow-up or larger number of patients was included. Level V evidence reviews, letters to the editor, basic science, biomechanical studies, arthroscopic shoulder surgery, imaging, surgical technique, and classification studies were excluded. Studies were excluded if both a 135° and 155° prosthesis were utilized and the outcomes were not stratified by the humeral inclination. Studies that did not report ROM were excluded.

A total of 456 studies were located, and, after implementation of the exclusion criteria, 65 studies from 2005-2015 were included in the final analysis (Figure). Subjects of interest in this systematic review underwent a RTSA. Studies were not excluded based on the surgical indications (rotator cuff tear arthropathy, proximal humerus fractures, osteoarthritis) and there was no minimum follow-up or rehabilitation requirement. Study and subject demographic parameters analyzed included year of publication, journal of publication, country and continent of publication, years of subject enrollment, presence of study financial conflict of interest, number of subjects and shoulders, gender, age, the manufacturer and type of prosthesis used, and the degree of the humeral inclination (135° vs 155° humeral cup). Preoperative ROM, including forward elevation, abduction, external rotation with the arm adducted, and external rotation with the arm at 90° of abduction, were recorded. The same ROM measurements were recorded for the final follow-up visit that was reported. Internal rotation was recorded, but because of the variability with how this measurement was reported, it was not analyzed. Clinical outcome scores and complications were not assessed. Study methodological quality was evaluated using the Modified Coleman Methodology Score (MCMS).¹⁸

Statistical Analysis

Descriptive statistics were calculated, including mean ± standard deviation for quantitative continuous data and frequencies with percentages for qualitative categorical data. ROM comparisons between 135° and 155° components (pre- vs postoperative for each and postoperative between the 2) were made using 2 proportion z-test calculator (http://in-silico.net/tools/statistics/ztest) using alpha .05 because of the difference in sample sizes between compared groups.

Results

Sixty-five studies with 3302 patients (3434 shoulders) were included in this study. There was a total of 1211 shoulders in the 135° lateralized glenosphere group and 2223 shoulders in the 155° group. The studies had an average MCMS of 40.4 ± 8.2 (poor), 48% of studies reported a conflict of interest, 32% had no conflict of interest, and 20% did not report whether a conflict of interest existed or not. The majority of studies included were level IV evidence (85%). Mean patient age was 71.1 ± 7.6 years; 29% of patients were male and 71% were female. No significant difference existed between patient age at the time of surgery; the average age of patients in the 135° lateralized glenosphere group was 71.67 ± 3.8 years, while the average patient age of patients in the 155° group was 70.97 ± 8.8 years. Mean follow-up for all patients included in this study was 37.2 ± 16.5 months. Of the 65 studies included, 3 were published from Asia, 4 were published from Australia, 24 were from North America, and 34 were from Europe. Of the individual countries whose studies were included, the United States had 23 included studies, France had 13 included studies, and Italy had 4 included studies. All other countries had <4 studies included.

Patients who received either a 135° or a 155° prosthesis showed significant improvements in external rotation with the arm at the side (P < .05), forward elevation (P < .05), and abduction (P < .05) following surgery (Table). When comparing the 135° and 155° groups, patients who received a 135° prosthesis showed significantly greater improvements in external rotation with the arm at the side (P < .001) and had significantly more overall external rotation postoperatively (P < .001) than patients who received a 155° prosthesis. The only preoperative ROM difference between groups was the 155° group started with significantly more forward elevation than the 135°group prior to surgery (P = .002).

Discussion

RTSA is indicated in patients with rotator cuff tear arthropathy, pseudoparalysis, and a functional deltoid.^1,2,4 The purpose of this systematic review was to determine if active ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. Forward elevation, abduction, and external rotation all significantly improved following surgery in both groups, with no significant difference between groups in motion or amount of motion improvement, mostly confirming the study hypotheses. However, patients in the 135° group had significantly greater postoperative external rotation and greater amount of external rotation improvement compared to the 155° group.

Two of the frequently debated issues regarding implant geometry is stability and scapular notching between the 135° and 155° humeral inclination designs. Erickson and colleagues3 recently evaluated the rate of scapular notching and dislocations between the 135° and 155° RTSA prostheses. The authors found that the 135° prosthesis had a significantly lower incidence of scapular notching vs the 155° group and that the rate of dislocations was not significantly different between groups.³ In the latter systematic review, the authors attempted to evaluate ROM between the 135° and 155° prostheses, but as the inclusion criteria of the study was reporting on scapular notching and dislocation rates, many studies reporting solely on ROM were excluded, and the influence of humeral inclination on ROM was inconclusive.³ Furthermore, there have been no studies that have directly compared ROM following RTSA between the 135° and 155° prostheses. While studies evaluating each prosthesis on an individual level have shown an improvement in ROM from pre- to postsurgery, there have been no large studies that have compared the postoperative ROM and change in pre- to postoperative ROM between the 135° and 155° prostheses.^11,13,19,20

One study by Valenti and colleagues²¹ evaluated a group of 30 patients with an average age of 69.5 years who underwent RTSA using either a 135° or a 155° prosthesis. Although the study did not directly compare the 2 types of prostheses, it did report the separate outcomes for each prosthesis. At an average follow-up of 36.4 months, the authors found that patients who had the 135° prosthesis implanted had a mean increase in forward elevation and external rotation of 53° and 9°, while patients who had the 155° showed an increase of 56° in forward elevation and a loss of 1° of external rotation. Both prostheses showed a significant increase in forward elevation, but neither had a significant increase in external rotation. Furthermore, scapular notching was seen in 4 patients in the 155° group, while no patients in the 135° group had evidence of notching.

The results of the current study were similar in that both the 135° and 155° prosthesis showed improvements in forward elevation following surgery, and the 135° group showed a significantly greater gain in external rotation than the 155° group. A significant component of shoulder function and patient satisfaction following RTSA is active ROM. However, this variable has not explicitly been evaluated in the literature until now. The clinical significance of this finding is unclear. Patients with adequate external rotation prior to surgery likely would not see a functional difference between prostheses, while those patients who were borderline on a functional amount of external rotation would see a clinically significant benefit with the 135° prosthesis. Studies have shown that the 135° prosthesis is more anatomic than the 155°, and this could explain the difference seen in ROM outcomes between the 2 prostheses.¹⁹ Ladermann and colleagues²² recently created and evaluated a 3-dimensional computer model to evaluate possible differences between the 135° and 155° prosthesis. The authors found a significant increase in external rotation of the 135° compared to the 155°, likely related to a difference in acromiohumeral distance as well as inlay vs onlay humeral trays between the 2 prostheses. The results of this study parallel the computer model, thereby validating these experimental results.

It is important to understand what the minimum functional ROM of the shoulder is (in other words, the ROM necessary to complete activities of daily living (ADLs).²³ Namdari and colleagues²⁴ used motion analysis software to evaluate the shoulder ROM necessary to complete 10 different ADLs, including combing hair, washing the back of the opposite shoulder, and reaching a shelf above their head without bending their elbow in 20 patients with a mean age of 29.2 years. They found that patients required 121° ± 6.7° of flexion, 46° ± 5.3° of extension, 128° ± 7.9° of abduction, 116° ± 9.1° of cross-body adduction, 59° ± 10° of external rotation with the arm 90° abducted, and 102° ± 7.7° of internal rotation with the arm at the side (external rotation with the arm at the side was not well defined).²⁴ Hence, while abduction and forward elevation seem comparable, the results from the current study do raise concerns about the amount of external rotation obtained following RTSA as it relates to a patients’ ability to perform ADLs, specifically in the 155° prosthesis, as the average postoperative external rotation in this group was 20.5°. Therefore, based on the results of this study, it appears that, while both the 135° and 155° RTSA prostheses provide similar gain in forward elevation and abduction ROM as well as overall forward elevation and abduction, the 135° prosthesis provides significantly more external rotation with the arm at the side than the 155° prosthesis.

Limitations

Although this study attempted to look at all studies that reported active ROM in patients following a RTSA, and 2 authors performed the search, there is a possibility that some studies were missed, introducing study selection bias. Furthermore, the mean follow-up was over 3 years following surgery, but the minimum follow-up requirement for studies to be included was only 12 months. Hence, this transfer bias introduces the possibility that the patient’s ROM would have changed had they been followed for a standard period of time. There are many variables that come into play in evaluating ROM, and although the study attempted to control for these, there are some that could not be controlled for due to lack of reporting by some studies. Glenosphere size and humeral retroversion were not recorded, as they were not reliably reported in all studies, so motion outcomes based on these variables was not evaluated. Complications and clinical outcomes were not assessed in this review and as such, conclusions regarding these variables cannot be drawn from this study. Finally, indications for surgery were not reliably reported in the studies included in this paper, so differences may have existed between surgical indications of the 135° and 155° groups that could have affected outcomes.

Conclusion

Patients who receive a 135° RTSA gain significantly more external rotation from pre- to postsurgery and have an overall greater amount of external rotation than patients who receive a 155° prosthesis. Both groups show improvements in forward elevation, external rotation, and abduction following surgery.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Developing a high-efficiency operating room (OR) is both a challenging and rewarding goal for any healthcare system. The OR is traditionally a high-cost/high-revenue environment¹ and operative efficacy has been correlated with low complication rates and surgical success.² An efficient OR is one that maximizes utilization while providing safe, reproducible, cost-effective, high-quality care. Total joint arthroplasty (TJA) has occupied the center stage for OR efficiency research, in part due to increasing demands from our aging population³ and economic pressures related to high implant costs, decreased reimbursement, and competition for market shares when OR time and space are limited.

A PubMed search on OR efficiency in TJA shows a disproportionately high focus on surgical technique, such as use of patient-specific instrumentation (PSI), computer-assisted surgery (CAS), minimally invasive surgery, and closure with barbed suture. In a retrospective review of 352 TKA patients who had PSI vs conventional instrumentation, DeHaan and colleagues⁴ found that PSI was associated with significantly decreased operative and room turnover times (20.4 minutes and 6.4 minutes, respectively). In another prospective multicenter study, Mont and colleagues⁵ showed a reduction in surgical time by 8.90 min for navigated total knee arthroplasty (TKA) performed with single-use instruments, cutting blocks, and trials. Other investigators compared PSI to CAS in TKA and found PSI to be 1.45 times more profitable than CAS, with 3 PSI cases performed in an 8-hour OR day compared to 2 CAS cases.⁶

There is no question that improved surgical technique can enhance OR efficiency. However, this model, while promising, is difficult to implement on a wide scale due to surgeon preferences, vendor limitations, and added costs related to the advanced preoperative imaging studies, manufacturing of the custom guides, and maintenance of navigation equipment. In addition, while interventions such as the use of barbed suture have the potential for speeding closure time, the time saved (4.7 minutes in one randomized trial)⁷ may not be enough to affect major utilization differences per OR per day. These technologies are also frequently employed by high-volume surgeons with high-volume teams and institutions.

Ideally, we need investment in the human capital and a collective change in work cultures to produce high-quality, well-choreographed, easily reproducible routines. An efficient OR requires the synchronous involvement of a large team of individuals, including hospital administrators, surgery schedulers, surgeons, anesthesiologists, preoperative holding area staff, OR nurses, surgical attendants, sterile processing personnel, and recovery room nurses. Case schedulers should match allocated block time with time required for surgery based on the historical performance of the individual surgeon, preferably scheduling similar cases on the same day. Preoperative work-up and medical clearance should be completed prior to scheduling to avoid last-minute cancellations. Patient reminders and accommodations for those traveling from long distances can further minimize late arrivals. Prompt initiation of the perioperative clinical pathway upon a patient’s check-in is important. The surgical site should be marked and the anesthesia plan confirmed upon arrival in the preoperative holding area. Necessary products need to be ready and/or administrated in time for transfer to the OR. These include prophylactic antibiotics, coagulation factors (eg, tranexamic acid), and blood products as indicated. Spinal anesthesia, regional nerve blocks, and intravenous (IV) lines should be completed before transfer to the OR. A “block room” close to the OR can allow concurrent induction of anesthesia and has been shown to increase the number of surgical cases performed during a regular workday.⁸ Hair clipping within the surgical site and pre-scrubbing of the operative extremity should also be performed prior to transfer to the OR in order to minimize micro-organisms and dispersal of loose hair onto the sterile field.

Upon arrival of the patient to the OR, instrument tables based on the surgeon preference cards should be opened, instrument count and implant templating completed, necessary imaging displayed, and OR staff ready with specific responsibilities assigned to each member. Small and colleagues⁹ showed that using dedicated orthopedic staff familiar with the surgical routine decreased operative time by 19 minutes per procedure, or 1.25 hours for a surgeon performing 4 primary TJAs per day. Practices such as routine placement of a urinary catheter should be seriously scrutinized. In a randomized prospective study of patients undergoing total hip arthroplasty under spinal anesthesia, Miller and colleagues¹⁰ found no benefit for indwelling catheters in preventing urinary retention. In another randomized prospective study, Huang and colleagues¹¹ found the prevalence of urinary tract infections was significantly higher in TJA patients who received indwelling urinary catheters.

A scrub nurse familiar with the instruments, their assembly, and the sequence of events can ensure efficient surgical flow. The scrub nurse needs to anticipate missing or defective tools and call for them, ideally before the incision is made. Direct comparison studies are needed to assess the efficacy of routine intraoperative imaging vs commercially available universal cup alignment guides or clinical examinations in determining acceptable component positioning and limb length. Following component implantation and before wound closure, the circulating nurse should initiate the process of acquisition of a recovery room bed, make sure dressing supplies and necessary equipment are available, and call for surgical attendants. Lack of surgical attendants, delayed transfer from the OR table to hospital bed, and prolonged acquisition of a recovery room bed have been identified as major OR inefficiencies in a retrospective study by Attarian and colleagues.¹²

In summary, time is the OR’s most valuable resource.¹³ We believe that a consistent, almost automated attitude to the above procedures decreases variability and improves efficiency. By providing clear communication of the surgical needs with the team, having consistent anesthesia and nursing staff, implementing consistent perioperative protocols, and insuring that all necessary instruments and modalities are available prior to starting the procedure, we were able to sustainably increase OR throughput in a large teaching hospital.^9,14 This process, however, requires constant review to identify and eliminate new gaps, with each member of the team sharing a frank desire to improve. In this regard, hospital administrators share the duty to facilitate the implementation of any necessary changes, allocation of needed resources, and rewarding good effort, which could ultimately increase staff satisfaction and retention. Because efficiency is the ratio of benefits (eg, revenue, safety, etc.) to investment (eg, implant costs, wages, etc.), raises the question: what would be the effect of transitioning from hourly-wage to a salary-based system for key support staff? Unlike hourly-wage personnel, who have no incentive for productivity, a salaried employee assigned to a high-efficiency OR will inherently strive for improvement, employing higher organizational skills to accomplish a common goal. To our knowledge, there is no published data on this topic.

Developing a high-efficiency operating room (OR) is both a challenging and rewarding goal for any healthcare system. The OR is traditionally a high-cost/high-revenue environment¹ and operative efficacy has been correlated with low complication rates and surgical success.² An efficient OR is one that maximizes utilization while providing safe, reproducible, cost-effective, high-quality care. Total joint arthroplasty (TJA) has occupied the center stage for OR efficiency research, in part due to increasing demands from our aging population³ and economic pressures related to high implant costs, decreased reimbursement, and competition for market shares when OR time and space are limited.

A PubMed search on OR efficiency in TJA shows a disproportionately high focus on surgical technique, such as use of patient-specific instrumentation (PSI), computer-assisted surgery (CAS), minimally invasive surgery, and closure with barbed suture. In a retrospective review of 352 TKA patients who had PSI vs conventional instrumentation, DeHaan and colleagues⁴ found that PSI was associated with significantly decreased operative and room turnover times (20.4 minutes and 6.4 minutes, respectively). In another prospective multicenter study, Mont and colleagues⁵ showed a reduction in surgical time by 8.90 min for navigated total knee arthroplasty (TKA) performed with single-use instruments, cutting blocks, and trials. Other investigators compared PSI to CAS in TKA and found PSI to be 1.45 times more profitable than CAS, with 3 PSI cases performed in an 8-hour OR day compared to 2 CAS cases.⁶

There is no question that improved surgical technique can enhance OR efficiency. However, this model, while promising, is difficult to implement on a wide scale due to surgeon preferences, vendor limitations, and added costs related to the advanced preoperative imaging studies, manufacturing of the custom guides, and maintenance of navigation equipment. In addition, while interventions such as the use of barbed suture have the potential for speeding closure time, the time saved (4.7 minutes in one randomized trial)⁷ may not be enough to affect major utilization differences per OR per day. These technologies are also frequently employed by high-volume surgeons with high-volume teams and institutions.

Ideally, we need investment in the human capital and a collective change in work cultures to produce high-quality, well-choreographed, easily reproducible routines. An efficient OR requires the synchronous involvement of a large team of individuals, including hospital administrators, surgery schedulers, surgeons, anesthesiologists, preoperative holding area staff, OR nurses, surgical attendants, sterile processing personnel, and recovery room nurses. Case schedulers should match allocated block time with time required for surgery based on the historical performance of the individual surgeon, preferably scheduling similar cases on the same day. Preoperative work-up and medical clearance should be completed prior to scheduling to avoid last-minute cancellations. Patient reminders and accommodations for those traveling from long distances can further minimize late arrivals. Prompt initiation of the perioperative clinical pathway upon a patient’s check-in is important. The surgical site should be marked and the anesthesia plan confirmed upon arrival in the preoperative holding area. Necessary products need to be ready and/or administrated in time for transfer to the OR. These include prophylactic antibiotics, coagulation factors (eg, tranexamic acid), and blood products as indicated. Spinal anesthesia, regional nerve blocks, and intravenous (IV) lines should be completed before transfer to the OR. A “block room” close to the OR can allow concurrent induction of anesthesia and has been shown to increase the number of surgical cases performed during a regular workday.⁸ Hair clipping within the surgical site and pre-scrubbing of the operative extremity should also be performed prior to transfer to the OR in order to minimize micro-organisms and dispersal of loose hair onto the sterile field.

Upon arrival of the patient to the OR, instrument tables based on the surgeon preference cards should be opened, instrument count and implant templating completed, necessary imaging displayed, and OR staff ready with specific responsibilities assigned to each member. Small and colleagues⁹ showed that using dedicated orthopedic staff familiar with the surgical routine decreased operative time by 19 minutes per procedure, or 1.25 hours for a surgeon performing 4 primary TJAs per day. Practices such as routine placement of a urinary catheter should be seriously scrutinized. In a randomized prospective study of patients undergoing total hip arthroplasty under spinal anesthesia, Miller and colleagues¹⁰ found no benefit for indwelling catheters in preventing urinary retention. In another randomized prospective study, Huang and colleagues¹¹ found the prevalence of urinary tract infections was significantly higher in TJA patients who received indwelling urinary catheters.

A scrub nurse familiar with the instruments, their assembly, and the sequence of events can ensure efficient surgical flow. The scrub nurse needs to anticipate missing or defective tools and call for them, ideally before the incision is made. Direct comparison studies are needed to assess the efficacy of routine intraoperative imaging vs commercially available universal cup alignment guides or clinical examinations in determining acceptable component positioning and limb length. Following component implantation and before wound closure, the circulating nurse should initiate the process of acquisition of a recovery room bed, make sure dressing supplies and necessary equipment are available, and call for surgical attendants. Lack of surgical attendants, delayed transfer from the OR table to hospital bed, and prolonged acquisition of a recovery room bed have been identified as major OR inefficiencies in a retrospective study by Attarian and colleagues.¹²

In summary, time is the OR’s most valuable resource.¹³ We believe that a consistent, almost automated attitude to the above procedures decreases variability and improves efficiency. By providing clear communication of the surgical needs with the team, having consistent anesthesia and nursing staff, implementing consistent perioperative protocols, and insuring that all necessary instruments and modalities are available prior to starting the procedure, we were able to sustainably increase OR throughput in a large teaching hospital.^9,14 This process, however, requires constant review to identify and eliminate new gaps, with each member of the team sharing a frank desire to improve. In this regard, hospital administrators share the duty to facilitate the implementation of any necessary changes, allocation of needed resources, and rewarding good effort, which could ultimately increase staff satisfaction and retention. Because efficiency is the ratio of benefits (eg, revenue, safety, etc.) to investment (eg, implant costs, wages, etc.), raises the question: what would be the effect of transitioning from hourly-wage to a salary-based system for key support staff? Unlike hourly-wage personnel, who have no incentive for productivity, a salaried employee assigned to a high-efficiency OR will inherently strive for improvement, employing higher organizational skills to accomplish a common goal. To our knowledge, there is no published data on this topic.

Developing a high-efficiency operating room (OR) is both a challenging and rewarding goal for any healthcare system. The OR is traditionally a high-cost/high-revenue environment¹ and operative efficacy has been correlated with low complication rates and surgical success.² An efficient OR is one that maximizes utilization while providing safe, reproducible, cost-effective, high-quality care. Total joint arthroplasty (TJA) has occupied the center stage for OR efficiency research, in part due to increasing demands from our aging population³ and economic pressures related to high implant costs, decreased reimbursement, and competition for market shares when OR time and space are limited.

A PubMed search on OR efficiency in TJA shows a disproportionately high focus on surgical technique, such as use of patient-specific instrumentation (PSI), computer-assisted surgery (CAS), minimally invasive surgery, and closure with barbed suture. In a retrospective review of 352 TKA patients who had PSI vs conventional instrumentation, DeHaan and colleagues⁴ found that PSI was associated with significantly decreased operative and room turnover times (20.4 minutes and 6.4 minutes, respectively). In another prospective multicenter study, Mont and colleagues⁵ showed a reduction in surgical time by 8.90 min for navigated total knee arthroplasty (TKA) performed with single-use instruments, cutting blocks, and trials. Other investigators compared PSI to CAS in TKA and found PSI to be 1.45 times more profitable than CAS, with 3 PSI cases performed in an 8-hour OR day compared to 2 CAS cases.⁶

There is no question that improved surgical technique can enhance OR efficiency. However, this model, while promising, is difficult to implement on a wide scale due to surgeon preferences, vendor limitations, and added costs related to the advanced preoperative imaging studies, manufacturing of the custom guides, and maintenance of navigation equipment. In addition, while interventions such as the use of barbed suture have the potential for speeding closure time, the time saved (4.7 minutes in one randomized trial)⁷ may not be enough to affect major utilization differences per OR per day. These technologies are also frequently employed by high-volume surgeons with high-volume teams and institutions.

Ideally, we need investment in the human capital and a collective change in work cultures to produce high-quality, well-choreographed, easily reproducible routines. An efficient OR requires the synchronous involvement of a large team of individuals, including hospital administrators, surgery schedulers, surgeons, anesthesiologists, preoperative holding area staff, OR nurses, surgical attendants, sterile processing personnel, and recovery room nurses. Case schedulers should match allocated block time with time required for surgery based on the historical performance of the individual surgeon, preferably scheduling similar cases on the same day. Preoperative work-up and medical clearance should be completed prior to scheduling to avoid last-minute cancellations. Patient reminders and accommodations for those traveling from long distances can further minimize late arrivals. Prompt initiation of the perioperative clinical pathway upon a patient’s check-in is important. The surgical site should be marked and the anesthesia plan confirmed upon arrival in the preoperative holding area. Necessary products need to be ready and/or administrated in time for transfer to the OR. These include prophylactic antibiotics, coagulation factors (eg, tranexamic acid), and blood products as indicated. Spinal anesthesia, regional nerve blocks, and intravenous (IV) lines should be completed before transfer to the OR. A “block room” close to the OR can allow concurrent induction of anesthesia and has been shown to increase the number of surgical cases performed during a regular workday.⁸ Hair clipping within the surgical site and pre-scrubbing of the operative extremity should also be performed prior to transfer to the OR in order to minimize micro-organisms and dispersal of loose hair onto the sterile field.

Upon arrival of the patient to the OR, instrument tables based on the surgeon preference cards should be opened, instrument count and implant templating completed, necessary imaging displayed, and OR staff ready with specific responsibilities assigned to each member. Small and colleagues⁹ showed that using dedicated orthopedic staff familiar with the surgical routine decreased operative time by 19 minutes per procedure, or 1.25 hours for a surgeon performing 4 primary TJAs per day. Practices such as routine placement of a urinary catheter should be seriously scrutinized. In a randomized prospective study of patients undergoing total hip arthroplasty under spinal anesthesia, Miller and colleagues¹⁰ found no benefit for indwelling catheters in preventing urinary retention. In another randomized prospective study, Huang and colleagues¹¹ found the prevalence of urinary tract infections was significantly higher in TJA patients who received indwelling urinary catheters.

A scrub nurse familiar with the instruments, their assembly, and the sequence of events can ensure efficient surgical flow. The scrub nurse needs to anticipate missing or defective tools and call for them, ideally before the incision is made. Direct comparison studies are needed to assess the efficacy of routine intraoperative imaging vs commercially available universal cup alignment guides or clinical examinations in determining acceptable component positioning and limb length. Following component implantation and before wound closure, the circulating nurse should initiate the process of acquisition of a recovery room bed, make sure dressing supplies and necessary equipment are available, and call for surgical attendants. Lack of surgical attendants, delayed transfer from the OR table to hospital bed, and prolonged acquisition of a recovery room bed have been identified as major OR inefficiencies in a retrospective study by Attarian and colleagues.¹²

In summary, time is the OR’s most valuable resource.¹³ We believe that a consistent, almost automated attitude to the above procedures decreases variability and improves efficiency. By providing clear communication of the surgical needs with the team, having consistent anesthesia and nursing staff, implementing consistent perioperative protocols, and insuring that all necessary instruments and modalities are available prior to starting the procedure, we were able to sustainably increase OR throughput in a large teaching hospital.^9,14 This process, however, requires constant review to identify and eliminate new gaps, with each member of the team sharing a frank desire to improve. In this regard, hospital administrators share the duty to facilitate the implementation of any necessary changes, allocation of needed resources, and rewarding good effort, which could ultimately increase staff satisfaction and retention. Because efficiency is the ratio of benefits (eg, revenue, safety, etc.) to investment (eg, implant costs, wages, etc.), raises the question: what would be the effect of transitioning from hourly-wage to a salary-based system for key support staff? Unlike hourly-wage personnel, who have no incentive for productivity, a salaried employee assigned to a high-efficiency OR will inherently strive for improvement, employing higher organizational skills to accomplish a common goal. To our knowledge, there is no published data on this topic.

Since Neer and colleagues¹ first reported in 1982, glenoid loosening persists as a common cause of anatomic total shoulder arthroplasty (TSA) failure.^1-4 Currently, cemented, all-polyethylene glenoid components are the gold standard, and minimum clinical survival of 10 to 15 years is expected.^3,5 Several clinical studies^5-9 and in vitro biomechanical studies¹⁰ have suggested an advantage of pegged over keeled glenoid components, but glenoid component loosening remains a frequent complication,¹¹ with the cement–implant interface suggested as the weak link of fixation.^10,12 In addition to mechanical loosening, poor cement penetration and heat-induced necrosis have been postulated as contributing to glenoid component loosening.^13,14

Because of these potential complications, there is a growing consideration to minimize or abandon cement fixation and rely on biological fixation to polyethylene for long-term component stability.¹⁵ A newer pegged glenoid component design consists of traditional, peripherally located pegs designed for cement fixation as well as a central, uncemented, fluted, interference-fit peg that allows for bony ingrowth. Short-term clinical studies have shown that bony ingrowth into the space between the flutes can be achieved with a hybrid cementation technique and that, when that occurs, excellent outcomes are likely.^13,16-19 The immediate in vivo stability of this implant design upon initial implantation, before the cement has cured, has prompted some surgeons to consider implanting the device without cement. In a recent series in which this implant design was used without cement, clinical and radiographic results were promising.¹⁵

Despite the widespread clinical use, little biomechanical work has been done to characterize initial fixation of all-polyethylene pegged glenoid implants. We conducted a study to compare glenoid micromotion in an all-polyethylene, centrally fluted pegged glenoid component as a function of 3 fixation techniques: cementless interference-fit fixation, hybrid partial cementation based on manufacturer recommendations, and full cementation to simulate a gold-standard, traditional, cemented, pegged design.

Materials and MethodsBiomechanical Testing

The biomechanical testing methodology used in this study was based on previous studies20-23 and on ASTM standard F2028-1224 using polyurethane bone substitute 0.24 g/cm³ (Pacific Research Laboratories) with ultimate strength of 4.9 MPa and compressive modulus of 123 MPa for component implantation. This material was selected because its mechanical properties are similar to those of cancellous glenoid bone in primary shoulder arthroplasty,25 and it minimizes variability with use of cadaveric specimens. Components were mounted on an MTS 858 Mini-Bionix II materials testing frame (Figure 1). A static compressive load of 756 N (170 lb) was applied via a mass-pulley system simulating the joint compressive force the shoulder is likely to experience during higher load activities.^24,26 The glenoid component was positioned on a linear bearing to allow for joint compression.

Test Groups and Cement Fixation Techniques

All-polyethylene pegged glenoid components (Anchor Peg Glenoid, size 44; DePuy Orthopaedics) were used for biomechanical testing (Figure 1). Polyurethane blocks were reamed with a size 44 reamer until the superior-inferior distance reached 33 mm, ensuring complete seating of implant. Three fixation-technique groups were formed: interference-fit, hybrid cement, and fully cemented. Interference-fit fixation was done without polymethylmethacrylate (PMMA) cement. In hybrid fixation, 2 cm³ of PMMA (SpeedSet Cement, Stryker Orthopaedics) was injected (using a catheter tip syringe) into the peripheral peg holes and manually pressurized; the central peg was press-fit into polyurethane bone substitute. In the fully cemented group, both peripheral and central peg holes received PMMA; the peripheral peg holes were cemented as in hybrid fixation, and the central peg hole was injected with 3 cm³ of PMMA, which was then manually pressurized. The humeral head component (Global Advantage, 44×18 mm; DePuy Synthes) was mounted on the test frame actuator and centrally located within the glenoid at the start of the test.

Determination of Humeral Head Translation via Subluxation Testing

Humeral head subluxation distance, simulating a humeral head rim loading event, was calculated on the basis of preliminary tests outlined in the ASTM standard.²⁴ Three glenoids (1 per fixation technique) were mounted on the test frame with a humeral head positioned centrally within the glenoid. After the joint compressive force was applied, the humeral head was translated along the true superior axis of the glenoid at a rate of 50 mm/min. Testing software was used to record humeral head displacement and load data at a frequency of 100 Hz. Humeral head subluxation displacement was determined at the end of the linear region of the force versus displacement response. This distance, averaged from the 3 subluxation tests, was used as the subluxation distance during cyclic testing.

Determination of Glenoid Component Motion via Cyclic Testing

After subluxation displacement was determined, glenoid components were mounted on the test frame (5 per fixation technique) and subjected to 50,000 cycles of humeral head translation at a frequency of 2 Hz. Amplitude of the humeral head displacement against the glenoid component followed a sinusoidal pattern with maxima and minima represented by the subluxation displacement (positive and negative, respectively). Glenoid edge compression/distraction of the superior edge and glenoid inferior/superior translation were monitored with 2 variable resistance reluctance transducers (Microminiature DVRT; 4.5-µm resolution; MicroStrain) secured to the glenoid component and testing fixture.

Microminiature DVRT measurements of glenoid motion were taken for 5 consecutive cycles at cycles 1, 20, 100, 500, 1000, 5000, 10,000, 15,000, 20,000, 30,000, 40,000, and 50,000. Distraction-compression displacement and superior-inferior translation measurements were recorded relative to the glenoid position with the humeral head at the neutral position at a given cycle. Final glenoid micromotion data were calculated from the mean of consecutive cycles at each cycle time point.

Statistical Analysis

Glenoid motion results are reported as means and standard deviations. Comparisons with 2 factors of fixation technique and number of cycles for glenoid distraction, glenoid compression, and absolute glenoid translation were characterized with 2-way analysis of variance (SigmaPlot Version 11.0; Systat Software), with the Holm-Šídák test used for post hoc determination of significant relationships.

Results

Under subluxation testing, the humeral head translation distance at the end of the linear region was determined to be 0.50 mm. Subsequently for cyclic testing, the humeral head was then translated 0.50 mm from the neutral position of the humeral head along both the superior and inferior axes of the glenoid. All glenoids successfully completed the entire 50,000 cycles of testing. For the glenoid component, Figure 2 depicts distraction and compression, and Figure 3 depicts superior-inferior translation.

Glenoid Component Distraction

Overall, mean (SD) glenoid distraction was significantly higher for interference-fit fixation, 0.21 (0.10) mm, than for hybrid cement fixation, 0.16 (0.05) mm (P < .001), and fully cemented fixation, 0.09 (0.07) mm (P < .001). It was also significantly higher for hybrid fixation than fully cemented fixation (P < .001). From cycle 1000 to cycle 50,000, distraction was significantly higher for interference-fit fixation than for fully cemented fixation at each time point (P < .05).

Glenoid Component Compression

Mean (SD) compression was significantly higher for hybrid cement fixation, 0.31 (0.13) mm, than for interference-fit fixation, 0.17 (0.07) mm (P < .001), and fully cemented fixation, 0.17 (0.08) mm (P < .001). No significant difference was found between interference-fit and fully cemented fixation (P = .793) (Figure 2). At cycles 1, 20, 100, and 500, compression was significantly higher for hybrid fixation than for fully cemented fixation (P < .05). In addition, at cycle 500, it was significantly higher for hybrid fixation than for interference-fit fixation (P < .05).

Glenoid Component Translation

Mean (SD) glenoid translation was significantly lower for fully cemented fixation, 0.10 (0.04) mm, than for interference-fit fixation, 0.13 (0.04) mm (P < .001), and hybrid cement fixation, 0.13 (0.03) mm (P < .001), with all time points considered. There was no significant difference between interference-fit and hybrid fixation (P = .343). Initial translation at cycle 1 was significantly higher for interference-fit and hybid fixation than for fully cemented fixation.

Discussion

Despite advances in glenoid component design, glenoid loosening remains the most common cause of anatomical TSA failure. Recent implants have been designed to take advantage of an all-polyethylene component while providing long-lasting fixation through bony ingrowth into a central peg. In a study of the hybrid cementation technique drescribed here, Groh¹⁷ found no glenoid loosening or radiolucent lines but discovered fingerlike projections of bone between the flanges of the implant in 24 (29%) of 83 cases. Churchill and colleagues¹⁶ also reported bony ingrowth into the central peg in 15 (75%) of 20 patients. Furthermore, Arnold and colleagues13 reported complete bony ingrowth (6/6 inter-fin compartments) in 23 (71%) of 35 shoulders at a mean of 43 months. Wirth and colleagues¹⁹ reported increased radiodensity between the flanges of the central peg in 30 of 44 cases (68%) and osteolysis around the central peg in 3 of 44 cases (7%) at 3 years.

There are also reports of successful bony ingrowth associated with all-polyethylene components implanted without cement. In a canine study using an early ingrowth implant design, Wirth and colleagues²⁷ showed that, though initial fixation was superior with a cemented, keeled implant, pullout strength of the uncemented, pegged implant improved over time and eventually far surpassed that of the cemented, keeled implant owing to both the loosening of the cemented component and the bony ingrowth into the central peg component. Furthermore, Anglin and colleagues¹⁰ confirmed that component micromotion was lower with pegged glenoid components than with keeled components in a biomechanical model. De Wilde and colleagues¹⁵ recently reported on a series of uncemented, central fluted peg glenoids implanted in 34 patients followed clinically and with computed tomography for a minimum of 24 months. The investigators found bony ingrowth into the central peg in 27 (79%) of 34 patients and no signs of loosening in 30 (88%) of 34 patients. Incomplete lucencies around 1 or 2 peripheral pegs were found in 2 (6%) of 34 patients, and complete lucencies around 2 or more peripheral pegs were found in 2 (6%) of 34 patients. However, there was no statistical difference in clinical outcome between patients with and without loosening.

With this type of implant, initial fixation that provides stability while minimizing micromotion under biomechanical loading likely is crucial for attaining bony growth within the central peg flanges. To our knowledge, this is the first biomechanical study to compare micromotion using 3 different fixation methods with a central fluted peg glenoid component design. Of all these fixation methods, fully cemented fixation yielded the most stable glenoid throughout testing with respect to the evaluated parameters. However, this method is not necessarily clinically applicable, as a fully cemented glenoid would inhibit any bony growth within the central flange, which is necessary for long-term biological fixation. Our data showed that, though glenoid distraction was significantly lower with hybrid cement fixation, this fixation method exhibited significantly higher glenoid compression. In addition, there were no significant differences between glenoid components with hybrid fixation and glenoid components with interference-fit fixation with respect to component translation in the superior-inferior direction. These findings may indicate that initial fixation is not significantly improved by the addition of cement to the peripheral pegs in a glenoid component with a central fluted peg design.

The interference fit of the central peg is primarily responsible for conferring long-term implant stability,^13,27 which is ultimately achieved by bony formation between the flutes of the peg. Other authors have reported that, for bony ingrowth to occur, micromotion between the bone–implant interface must not exceed 20 to 150 µm.^28-30 Other than for interference-fit distraction at more than 1000 cycles and hybrid cement fixation compression at each time point throughout testing, our data fall within the reported upper limits of micromotion to support bony ingrowth. Increased micromotion in the interference-fit fixation group is seen at later time points and may be caused by the inability to simulate the potential fixation gained from bony ingrowth allowed with this surgical technique. Research is needed to further explain this increase in distraction.

Results from this study must be interpreted with caution because of limitations of the in vitro testing methodology. This biomechanical model using bone substitute characterizes glenoid fixation at time zero, directly after implantation, followed by repetitive cyclic loading simulating 5 years of implant service. This differs from the clinical scenario in which the shoulder undergoes postoperative immobilization or protected motion during which the early phases of bony remodeling are likely occurring. Furthermore, simulation of 5 years of implant service may not be necessary for an implant that is expected to achieve ultimate fixation by bony ingrowth within the first several months after implantation. Use of this implant without cement is classified off-label, and surgeons should take this into consideration during implantation. Last, this study could not simulate the effect of bony ingrowth on fixation, though our experimental technique of cementing the central peg may be a gross approximation of a fully ingrown central peg and its expected rigid fixation.

Fully cemented fixation of a polyethylene glenoid is superior to hybrid cement fixation and interference-fit fixation with respect to early glenoid micromotion. However, the long-term stability of a fully cemented polyethylene glenoid component remains a clinical concern, as fixation is achieved by bony ingrowth around the central fluted peg of the implant. In this study, interference-fit and hybrid fixation had equivocal component micromotion in biomechanical testing. Our findings suggest that cementation of the peripheral pegs confers no additional initial stability over an uncemented interference-fit technique in a biomechanical model. More research is needed to further evaluate interference-fit fixation as a viable option for implantation of a central fluted, all-polyethylene glenoid component.

Since Neer and colleagues¹ first reported in 1982, glenoid loosening persists as a common cause of anatomic total shoulder arthroplasty (TSA) failure.^1-4 Currently, cemented, all-polyethylene glenoid components are the gold standard, and minimum clinical survival of 10 to 15 years is expected.^3,5 Several clinical studies^5-9 and in vitro biomechanical studies¹⁰ have suggested an advantage of pegged over keeled glenoid components, but glenoid component loosening remains a frequent complication,¹¹ with the cement–implant interface suggested as the weak link of fixation.^10,12 In addition to mechanical loosening, poor cement penetration and heat-induced necrosis have been postulated as contributing to glenoid component loosening.^13,14

Because of these potential complications, there is a growing consideration to minimize or abandon cement fixation and rely on biological fixation to polyethylene for long-term component stability.¹⁵ A newer pegged glenoid component design consists of traditional, peripherally located pegs designed for cement fixation as well as a central, uncemented, fluted, interference-fit peg that allows for bony ingrowth. Short-term clinical studies have shown that bony ingrowth into the space between the flutes can be achieved with a hybrid cementation technique and that, when that occurs, excellent outcomes are likely.^13,16-19 The immediate in vivo stability of this implant design upon initial implantation, before the cement has cured, has prompted some surgeons to consider implanting the device without cement. In a recent series in which this implant design was used without cement, clinical and radiographic results were promising.¹⁵

Despite the widespread clinical use, little biomechanical work has been done to characterize initial fixation of all-polyethylene pegged glenoid implants. We conducted a study to compare glenoid micromotion in an all-polyethylene, centrally fluted pegged glenoid component as a function of 3 fixation techniques: cementless interference-fit fixation, hybrid partial cementation based on manufacturer recommendations, and full cementation to simulate a gold-standard, traditional, cemented, pegged design.

Materials and MethodsBiomechanical Testing

The biomechanical testing methodology used in this study was based on previous studies20-23 and on ASTM standard F2028-1224 using polyurethane bone substitute 0.24 g/cm³ (Pacific Research Laboratories) with ultimate strength of 4.9 MPa and compressive modulus of 123 MPa for component implantation. This material was selected because its mechanical properties are similar to those of cancellous glenoid bone in primary shoulder arthroplasty,25 and it minimizes variability with use of cadaveric specimens. Components were mounted on an MTS 858 Mini-Bionix II materials testing frame (Figure 1). A static compressive load of 756 N (170 lb) was applied via a mass-pulley system simulating the joint compressive force the shoulder is likely to experience during higher load activities.^24,26 The glenoid component was positioned on a linear bearing to allow for joint compression.

Test Groups and Cement Fixation Techniques

All-polyethylene pegged glenoid components (Anchor Peg Glenoid, size 44; DePuy Orthopaedics) were used for biomechanical testing (Figure 1). Polyurethane blocks were reamed with a size 44 reamer until the superior-inferior distance reached 33 mm, ensuring complete seating of implant. Three fixation-technique groups were formed: interference-fit, hybrid cement, and fully cemented. Interference-fit fixation was done without polymethylmethacrylate (PMMA) cement. In hybrid fixation, 2 cm³ of PMMA (SpeedSet Cement, Stryker Orthopaedics) was injected (using a catheter tip syringe) into the peripheral peg holes and manually pressurized; the central peg was press-fit into polyurethane bone substitute. In the fully cemented group, both peripheral and central peg holes received PMMA; the peripheral peg holes were cemented as in hybrid fixation, and the central peg hole was injected with 3 cm³ of PMMA, which was then manually pressurized. The humeral head component (Global Advantage, 44×18 mm; DePuy Synthes) was mounted on the test frame actuator and centrally located within the glenoid at the start of the test.

Determination of Humeral Head Translation via Subluxation Testing

Humeral head subluxation distance, simulating a humeral head rim loading event, was calculated on the basis of preliminary tests outlined in the ASTM standard.²⁴ Three glenoids (1 per fixation technique) were mounted on the test frame with a humeral head positioned centrally within the glenoid. After the joint compressive force was applied, the humeral head was translated along the true superior axis of the glenoid at a rate of 50 mm/min. Testing software was used to record humeral head displacement and load data at a frequency of 100 Hz. Humeral head subluxation displacement was determined at the end of the linear region of the force versus displacement response. This distance, averaged from the 3 subluxation tests, was used as the subluxation distance during cyclic testing.

Determination of Glenoid Component Motion via Cyclic Testing

After subluxation displacement was determined, glenoid components were mounted on the test frame (5 per fixation technique) and subjected to 50,000 cycles of humeral head translation at a frequency of 2 Hz. Amplitude of the humeral head displacement against the glenoid component followed a sinusoidal pattern with maxima and minima represented by the subluxation displacement (positive and negative, respectively). Glenoid edge compression/distraction of the superior edge and glenoid inferior/superior translation were monitored with 2 variable resistance reluctance transducers (Microminiature DVRT; 4.5-µm resolution; MicroStrain) secured to the glenoid component and testing fixture.

Microminiature DVRT measurements of glenoid motion were taken for 5 consecutive cycles at cycles 1, 20, 100, 500, 1000, 5000, 10,000, 15,000, 20,000, 30,000, 40,000, and 50,000. Distraction-compression displacement and superior-inferior translation measurements were recorded relative to the glenoid position with the humeral head at the neutral position at a given cycle. Final glenoid micromotion data were calculated from the mean of consecutive cycles at each cycle time point.

Statistical Analysis

Glenoid motion results are reported as means and standard deviations. Comparisons with 2 factors of fixation technique and number of cycles for glenoid distraction, glenoid compression, and absolute glenoid translation were characterized with 2-way analysis of variance (SigmaPlot Version 11.0; Systat Software), with the Holm-Šídák test used for post hoc determination of significant relationships.

Results

Under subluxation testing, the humeral head translation distance at the end of the linear region was determined to be 0.50 mm. Subsequently for cyclic testing, the humeral head was then translated 0.50 mm from the neutral position of the humeral head along both the superior and inferior axes of the glenoid. All glenoids successfully completed the entire 50,000 cycles of testing. For the glenoid component, Figure 2 depicts distraction and compression, and Figure 3 depicts superior-inferior translation.

Glenoid Component Distraction

Overall, mean (SD) glenoid distraction was significantly higher for interference-fit fixation, 0.21 (0.10) mm, than for hybrid cement fixation, 0.16 (0.05) mm (P < .001), and fully cemented fixation, 0.09 (0.07) mm (P < .001). It was also significantly higher for hybrid fixation than fully cemented fixation (P < .001). From cycle 1000 to cycle 50,000, distraction was significantly higher for interference-fit fixation than for fully cemented fixation at each time point (P < .05).

Glenoid Component Compression

Mean (SD) compression was significantly higher for hybrid cement fixation, 0.31 (0.13) mm, than for interference-fit fixation, 0.17 (0.07) mm (P < .001), and fully cemented fixation, 0.17 (0.08) mm (P < .001). No significant difference was found between interference-fit and fully cemented fixation (P = .793) (Figure 2). At cycles 1, 20, 100, and 500, compression was significantly higher for hybrid fixation than for fully cemented fixation (P < .05). In addition, at cycle 500, it was significantly higher for hybrid fixation than for interference-fit fixation (P < .05).

Glenoid Component Translation

Mean (SD) glenoid translation was significantly lower for fully cemented fixation, 0.10 (0.04) mm, than for interference-fit fixation, 0.13 (0.04) mm (P < .001), and hybrid cement fixation, 0.13 (0.03) mm (P < .001), with all time points considered. There was no significant difference between interference-fit and hybrid fixation (P = .343). Initial translation at cycle 1 was significantly higher for interference-fit and hybid fixation than for fully cemented fixation.

Discussion

Despite advances in glenoid component design, glenoid loosening remains the most common cause of anatomical TSA failure. Recent implants have been designed to take advantage of an all-polyethylene component while providing long-lasting fixation through bony ingrowth into a central peg. In a study of the hybrid cementation technique drescribed here, Groh¹⁷ found no glenoid loosening or radiolucent lines but discovered fingerlike projections of bone between the flanges of the implant in 24 (29%) of 83 cases. Churchill and colleagues¹⁶ also reported bony ingrowth into the central peg in 15 (75%) of 20 patients. Furthermore, Arnold and colleagues13 reported complete bony ingrowth (6/6 inter-fin compartments) in 23 (71%) of 35 shoulders at a mean of 43 months. Wirth and colleagues¹⁹ reported increased radiodensity between the flanges of the central peg in 30 of 44 cases (68%) and osteolysis around the central peg in 3 of 44 cases (7%) at 3 years.

There are also reports of successful bony ingrowth associated with all-polyethylene components implanted without cement. In a canine study using an early ingrowth implant design, Wirth and colleagues²⁷ showed that, though initial fixation was superior with a cemented, keeled implant, pullout strength of the uncemented, pegged implant improved over time and eventually far surpassed that of the cemented, keeled implant owing to both the loosening of the cemented component and the bony ingrowth into the central peg component. Furthermore, Anglin and colleagues¹⁰ confirmed that component micromotion was lower with pegged glenoid components than with keeled components in a biomechanical model. De Wilde and colleagues¹⁵ recently reported on a series of uncemented, central fluted peg glenoids implanted in 34 patients followed clinically and with computed tomography for a minimum of 24 months. The investigators found bony ingrowth into the central peg in 27 (79%) of 34 patients and no signs of loosening in 30 (88%) of 34 patients. Incomplete lucencies around 1 or 2 peripheral pegs were found in 2 (6%) of 34 patients, and complete lucencies around 2 or more peripheral pegs were found in 2 (6%) of 34 patients. However, there was no statistical difference in clinical outcome between patients with and without loosening.

With this type of implant, initial fixation that provides stability while minimizing micromotion under biomechanical loading likely is crucial for attaining bony growth within the central peg flanges. To our knowledge, this is the first biomechanical study to compare micromotion using 3 different fixation methods with a central fluted peg glenoid component design. Of all these fixation methods, fully cemented fixation yielded the most stable glenoid throughout testing with respect to the evaluated parameters. However, this method is not necessarily clinically applicable, as a fully cemented glenoid would inhibit any bony growth within the central flange, which is necessary for long-term biological fixation. Our data showed that, though glenoid distraction was significantly lower with hybrid cement fixation, this fixation method exhibited significantly higher glenoid compression. In addition, there were no significant differences between glenoid components with hybrid fixation and glenoid components with interference-fit fixation with respect to component translation in the superior-inferior direction. These findings may indicate that initial fixation is not significantly improved by the addition of cement to the peripheral pegs in a glenoid component with a central fluted peg design.

The interference fit of the central peg is primarily responsible for conferring long-term implant stability,^13,27 which is ultimately achieved by bony formation between the flutes of the peg. Other authors have reported that, for bony ingrowth to occur, micromotion between the bone–implant interface must not exceed 20 to 150 µm.^28-30 Other than for interference-fit distraction at more than 1000 cycles and hybrid cement fixation compression at each time point throughout testing, our data fall within the reported upper limits of micromotion to support bony ingrowth. Increased micromotion in the interference-fit fixation group is seen at later time points and may be caused by the inability to simulate the potential fixation gained from bony ingrowth allowed with this surgical technique. Research is needed to further explain this increase in distraction.

Results from this study must be interpreted with caution because of limitations of the in vitro testing methodology. This biomechanical model using bone substitute characterizes glenoid fixation at time zero, directly after implantation, followed by repetitive cyclic loading simulating 5 years of implant service. This differs from the clinical scenario in which the shoulder undergoes postoperative immobilization or protected motion during which the early phases of bony remodeling are likely occurring. Furthermore, simulation of 5 years of implant service may not be necessary for an implant that is expected to achieve ultimate fixation by bony ingrowth within the first several months after implantation. Use of this implant without cement is classified off-label, and surgeons should take this into consideration during implantation. Last, this study could not simulate the effect of bony ingrowth on fixation, though our experimental technique of cementing the central peg may be a gross approximation of a fully ingrown central peg and its expected rigid fixation.

Fully cemented fixation of a polyethylene glenoid is superior to hybrid cement fixation and interference-fit fixation with respect to early glenoid micromotion. However, the long-term stability of a fully cemented polyethylene glenoid component remains a clinical concern, as fixation is achieved by bony ingrowth around the central fluted peg of the implant. In this study, interference-fit and hybrid fixation had equivocal component micromotion in biomechanical testing. Our findings suggest that cementation of the peripheral pegs confers no additional initial stability over an uncemented interference-fit technique in a biomechanical model. More research is needed to further evaluate interference-fit fixation as a viable option for implantation of a central fluted, all-polyethylene glenoid component.

Since Neer and colleagues¹ first reported in 1982, glenoid loosening persists as a common cause of anatomic total shoulder arthroplasty (TSA) failure.^1-4 Currently, cemented, all-polyethylene glenoid components are the gold standard, and minimum clinical survival of 10 to 15 years is expected.^3,5 Several clinical studies^5-9 and in vitro biomechanical studies¹⁰ have suggested an advantage of pegged over keeled glenoid components, but glenoid component loosening remains a frequent complication,¹¹ with the cement–implant interface suggested as the weak link of fixation.^10,12 In addition to mechanical loosening, poor cement penetration and heat-induced necrosis have been postulated as contributing to glenoid component loosening.^13,14

Because of these potential complications, there is a growing consideration to minimize or abandon cement fixation and rely on biological fixation to polyethylene for long-term component stability.¹⁵ A newer pegged glenoid component design consists of traditional, peripherally located pegs designed for cement fixation as well as a central, uncemented, fluted, interference-fit peg that allows for bony ingrowth. Short-term clinical studies have shown that bony ingrowth into the space between the flutes can be achieved with a hybrid cementation technique and that, when that occurs, excellent outcomes are likely.^13,16-19 The immediate in vivo stability of this implant design upon initial implantation, before the cement has cured, has prompted some surgeons to consider implanting the device without cement. In a recent series in which this implant design was used without cement, clinical and radiographic results were promising.¹⁵

Despite the widespread clinical use, little biomechanical work has been done to characterize initial fixation of all-polyethylene pegged glenoid implants. We conducted a study to compare glenoid micromotion in an all-polyethylene, centrally fluted pegged glenoid component as a function of 3 fixation techniques: cementless interference-fit fixation, hybrid partial cementation based on manufacturer recommendations, and full cementation to simulate a gold-standard, traditional, cemented, pegged design.

Materials and MethodsBiomechanical Testing

The biomechanical testing methodology used in this study was based on previous studies20-23 and on ASTM standard F2028-1224 using polyurethane bone substitute 0.24 g/cm³ (Pacific Research Laboratories) with ultimate strength of 4.9 MPa and compressive modulus of 123 MPa for component implantation. This material was selected because its mechanical properties are similar to those of cancellous glenoid bone in primary shoulder arthroplasty,25 and it minimizes variability with use of cadaveric specimens. Components were mounted on an MTS 858 Mini-Bionix II materials testing frame (Figure 1). A static compressive load of 756 N (170 lb) was applied via a mass-pulley system simulating the joint compressive force the shoulder is likely to experience during higher load activities.^24,26 The glenoid component was positioned on a linear bearing to allow for joint compression.

Test Groups and Cement Fixation Techniques

All-polyethylene pegged glenoid components (Anchor Peg Glenoid, size 44; DePuy Orthopaedics) were used for biomechanical testing (Figure 1). Polyurethane blocks were reamed with a size 44 reamer until the superior-inferior distance reached 33 mm, ensuring complete seating of implant. Three fixation-technique groups were formed: interference-fit, hybrid cement, and fully cemented. Interference-fit fixation was done without polymethylmethacrylate (PMMA) cement. In hybrid fixation, 2 cm³ of PMMA (SpeedSet Cement, Stryker Orthopaedics) was injected (using a catheter tip syringe) into the peripheral peg holes and manually pressurized; the central peg was press-fit into polyurethane bone substitute. In the fully cemented group, both peripheral and central peg holes received PMMA; the peripheral peg holes were cemented as in hybrid fixation, and the central peg hole was injected with 3 cm³ of PMMA, which was then manually pressurized. The humeral head component (Global Advantage, 44×18 mm; DePuy Synthes) was mounted on the test frame actuator and centrally located within the glenoid at the start of the test.

Determination of Humeral Head Translation via Subluxation Testing

Humeral head subluxation distance, simulating a humeral head rim loading event, was calculated on the basis of preliminary tests outlined in the ASTM standard.²⁴ Three glenoids (1 per fixation technique) were mounted on the test frame with a humeral head positioned centrally within the glenoid. After the joint compressive force was applied, the humeral head was translated along the true superior axis of the glenoid at a rate of 50 mm/min. Testing software was used to record humeral head displacement and load data at a frequency of 100 Hz. Humeral head subluxation displacement was determined at the end of the linear region of the force versus displacement response. This distance, averaged from the 3 subluxation tests, was used as the subluxation distance during cyclic testing.

Determination of Glenoid Component Motion via Cyclic Testing

After subluxation displacement was determined, glenoid components were mounted on the test frame (5 per fixation technique) and subjected to 50,000 cycles of humeral head translation at a frequency of 2 Hz. Amplitude of the humeral head displacement against the glenoid component followed a sinusoidal pattern with maxima and minima represented by the subluxation displacement (positive and negative, respectively). Glenoid edge compression/distraction of the superior edge and glenoid inferior/superior translation were monitored with 2 variable resistance reluctance transducers (Microminiature DVRT; 4.5-µm resolution; MicroStrain) secured to the glenoid component and testing fixture.

Microminiature DVRT measurements of glenoid motion were taken for 5 consecutive cycles at cycles 1, 20, 100, 500, 1000, 5000, 10,000, 15,000, 20,000, 30,000, 40,000, and 50,000. Distraction-compression displacement and superior-inferior translation measurements were recorded relative to the glenoid position with the humeral head at the neutral position at a given cycle. Final glenoid micromotion data were calculated from the mean of consecutive cycles at each cycle time point.

Statistical Analysis

Glenoid motion results are reported as means and standard deviations. Comparisons with 2 factors of fixation technique and number of cycles for glenoid distraction, glenoid compression, and absolute glenoid translation were characterized with 2-way analysis of variance (SigmaPlot Version 11.0; Systat Software), with the Holm-Šídák test used for post hoc determination of significant relationships.

Results

Under subluxation testing, the humeral head translation distance at the end of the linear region was determined to be 0.50 mm. Subsequently for cyclic testing, the humeral head was then translated 0.50 mm from the neutral position of the humeral head along both the superior and inferior axes of the glenoid. All glenoids successfully completed the entire 50,000 cycles of testing. For the glenoid component, Figure 2 depicts distraction and compression, and Figure 3 depicts superior-inferior translation.

Glenoid Component Distraction

Overall, mean (SD) glenoid distraction was significantly higher for interference-fit fixation, 0.21 (0.10) mm, than for hybrid cement fixation, 0.16 (0.05) mm (P < .001), and fully cemented fixation, 0.09 (0.07) mm (P < .001). It was also significantly higher for hybrid fixation than fully cemented fixation (P < .001). From cycle 1000 to cycle 50,000, distraction was significantly higher for interference-fit fixation than for fully cemented fixation at each time point (P < .05).

Glenoid Component Compression

Mean (SD) compression was significantly higher for hybrid cement fixation, 0.31 (0.13) mm, than for interference-fit fixation, 0.17 (0.07) mm (P < .001), and fully cemented fixation, 0.17 (0.08) mm (P < .001). No significant difference was found between interference-fit and fully cemented fixation (P = .793) (Figure 2). At cycles 1, 20, 100, and 500, compression was significantly higher for hybrid fixation than for fully cemented fixation (P < .05). In addition, at cycle 500, it was significantly higher for hybrid fixation than for interference-fit fixation (P < .05).

Glenoid Component Translation

Mean (SD) glenoid translation was significantly lower for fully cemented fixation, 0.10 (0.04) mm, than for interference-fit fixation, 0.13 (0.04) mm (P < .001), and hybrid cement fixation, 0.13 (0.03) mm (P < .001), with all time points considered. There was no significant difference between interference-fit and hybrid fixation (P = .343). Initial translation at cycle 1 was significantly higher for interference-fit and hybid fixation than for fully cemented fixation.

Discussion

Despite advances in glenoid component design, glenoid loosening remains the most common cause of anatomical TSA failure. Recent implants have been designed to take advantage of an all-polyethylene component while providing long-lasting fixation through bony ingrowth into a central peg. In a study of the hybrid cementation technique drescribed here, Groh¹⁷ found no glenoid loosening or radiolucent lines but discovered fingerlike projections of bone between the flanges of the implant in 24 (29%) of 83 cases. Churchill and colleagues¹⁶ also reported bony ingrowth into the central peg in 15 (75%) of 20 patients. Furthermore, Arnold and colleagues13 reported complete bony ingrowth (6/6 inter-fin compartments) in 23 (71%) of 35 shoulders at a mean of 43 months. Wirth and colleagues¹⁹ reported increased radiodensity between the flanges of the central peg in 30 of 44 cases (68%) and osteolysis around the central peg in 3 of 44 cases (7%) at 3 years.

There are also reports of successful bony ingrowth associated with all-polyethylene components implanted without cement. In a canine study using an early ingrowth implant design, Wirth and colleagues²⁷ showed that, though initial fixation was superior with a cemented, keeled implant, pullout strength of the uncemented, pegged implant improved over time and eventually far surpassed that of the cemented, keeled implant owing to both the loosening of the cemented component and the bony ingrowth into the central peg component. Furthermore, Anglin and colleagues¹⁰ confirmed that component micromotion was lower with pegged glenoid components than with keeled components in a biomechanical model. De Wilde and colleagues¹⁵ recently reported on a series of uncemented, central fluted peg glenoids implanted in 34 patients followed clinically and with computed tomography for a minimum of 24 months. The investigators found bony ingrowth into the central peg in 27 (79%) of 34 patients and no signs of loosening in 30 (88%) of 34 patients. Incomplete lucencies around 1 or 2 peripheral pegs were found in 2 (6%) of 34 patients, and complete lucencies around 2 or more peripheral pegs were found in 2 (6%) of 34 patients. However, there was no statistical difference in clinical outcome between patients with and without loosening.

With this type of implant, initial fixation that provides stability while minimizing micromotion under biomechanical loading likely is crucial for attaining bony growth within the central peg flanges. To our knowledge, this is the first biomechanical study to compare micromotion using 3 different fixation methods with a central fluted peg glenoid component design. Of all these fixation methods, fully cemented fixation yielded the most stable glenoid throughout testing with respect to the evaluated parameters. However, this method is not necessarily clinically applicable, as a fully cemented glenoid would inhibit any bony growth within the central flange, which is necessary for long-term biological fixation. Our data showed that, though glenoid distraction was significantly lower with hybrid cement fixation, this fixation method exhibited significantly higher glenoid compression. In addition, there were no significant differences between glenoid components with hybrid fixation and glenoid components with interference-fit fixation with respect to component translation in the superior-inferior direction. These findings may indicate that initial fixation is not significantly improved by the addition of cement to the peripheral pegs in a glenoid component with a central fluted peg design.

The interference fit of the central peg is primarily responsible for conferring long-term implant stability,^13,27 which is ultimately achieved by bony formation between the flutes of the peg. Other authors have reported that, for bony ingrowth to occur, micromotion between the bone–implant interface must not exceed 20 to 150 µm.^28-30 Other than for interference-fit distraction at more than 1000 cycles and hybrid cement fixation compression at each time point throughout testing, our data fall within the reported upper limits of micromotion to support bony ingrowth. Increased micromotion in the interference-fit fixation group is seen at later time points and may be caused by the inability to simulate the potential fixation gained from bony ingrowth allowed with this surgical technique. Research is needed to further explain this increase in distraction.

Results from this study must be interpreted with caution because of limitations of the in vitro testing methodology. This biomechanical model using bone substitute characterizes glenoid fixation at time zero, directly after implantation, followed by repetitive cyclic loading simulating 5 years of implant service. This differs from the clinical scenario in which the shoulder undergoes postoperative immobilization or protected motion during which the early phases of bony remodeling are likely occurring. Furthermore, simulation of 5 years of implant service may not be necessary for an implant that is expected to achieve ultimate fixation by bony ingrowth within the first several months after implantation. Use of this implant without cement is classified off-label, and surgeons should take this into consideration during implantation. Last, this study could not simulate the effect of bony ingrowth on fixation, though our experimental technique of cementing the central peg may be a gross approximation of a fully ingrown central peg and its expected rigid fixation.

Fully cemented fixation of a polyethylene glenoid is superior to hybrid cement fixation and interference-fit fixation with respect to early glenoid micromotion. However, the long-term stability of a fully cemented polyethylene glenoid component remains a clinical concern, as fixation is achieved by bony ingrowth around the central fluted peg of the implant. In this study, interference-fit and hybrid fixation had equivocal component micromotion in biomechanical testing. Our findings suggest that cementation of the peripheral pegs confers no additional initial stability over an uncemented interference-fit technique in a biomechanical model. More research is needed to further evaluate interference-fit fixation as a viable option for implantation of a central fluted, all-polyethylene glenoid component.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.