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Incredible edibles … Guilty as charged
“We should not consider marijuana ‘innocent until proven guilty,’ given what we already know about the harms to adolescents,”1 Sharon Levy, MD, chair of the American Academy of Pediatrics Committee on Substance Abuse, said in an AAP press release, speaking of the legalization of marijuana in Washington and Colorado. The press release was issued in 2015 when the AAP updated its policy on the impact of marijuana policies on youth (Pediatrics. 2015. doi: 10.1542/peds.2014-4146), reaffirming its opposition to legalization of marijuana because it contended that limited studies had been done on “medical marijuana” in adults, and that there were no published studies either on the form of marijuana or other preparations that involved children.
Marijuana is a schedule I controlled substance, so the Food and Drug Administration does not regulate marijuana edibles, resulting in poor labeling and unregulated formulations.2
Edibles are marijuana-infused foods. Extraction of the cannabinoid THC, the major psychoactive ingredient, from the cannabis plant involves heating the flowers from the female plant in an oil base liquid. As it is heated, the inactive tetrahydrocannabinoid acid (THCA) is converted to THC and dissolves into the oil base liquids, and it is this additive that is used in food products to create the edible. A safe “serving size,” was determined to be 10 mg of THC,3 but an edible may contain 100 mg of THC if consumed in its entirety.
Many prefer ingesting edibles, compared with smoking, because there are no toxic effects from the inhalation of smoke, no odors, it’s more potent, and its duration of action is longer.3 The downside is the onset of action is slower, compared with smoking, so many will consume more before the “high” begins, and therefore there is a greater risk for intoxication. For example, a chocolate bar may contain 100 mg of THC, and despite the “serving size” stated as one square, a person might consume the entire bar before the onset of the high begins. Improved labeling and warning of intoxication now are required on packaging, but this does little to reduce the risk.3
Edibles also are made in way that is attractive to children. Commonly, they come in packaging and forms that resemble candy, such as gummies and chocolate bars. Although laws have been put in place to require them to be sold in childproof containers, 3,4 As feared, once cannabis oil is obtained legally, there is little control over what it is put in.
As for medicinal purposes, edibles have a great advantage for children when used for that purpose. Ease of administration, long duration of action, and a great taste are all positive attributes. As with all good things, there is a downside when used inappropriately.
Marijuana overdoses can result in cognitive and motor impairment, extreme sedation, agitation, anxiety, cardiac stress, and vomiting. High quantities of THC have been reported to cause transient psychotic symptoms such as hallucinations, delusions, and anxiety.3
As pediatricians, it is essential to educate teens and their families on the harmful effects of marijuana and dispel the myth that is benign. They need to be informed of the negative impact of marijuana, which leads to impairment of memory and executive function, on the developing brain. Parents also need to be aware of the current trends of use and formulations, so they can be aware of potential exposures.5
Dr. Pearce is a pediatrician in Frankfort, Ill. She said she had no relevant financial disclosures. Email her at [email protected].
References
1. “American Academy of Pediatrics Reaffirms Opposition to Legalizing Marijuana for Recreational or Medical Use,” AAP press release on Jan. 26, 2015.
2. N Engl J Med. 2015;372:989-91.
3. Methods Rep RTI Press. 2016 Nov. doi: 10.3768/rtipress.2016.op.0035.1611.
4. JAMA. 2015;313(3):241-2.
5. Pediatrics. 2017 Mar;139(3):e20164069.
“We should not consider marijuana ‘innocent until proven guilty,’ given what we already know about the harms to adolescents,”1 Sharon Levy, MD, chair of the American Academy of Pediatrics Committee on Substance Abuse, said in an AAP press release, speaking of the legalization of marijuana in Washington and Colorado. The press release was issued in 2015 when the AAP updated its policy on the impact of marijuana policies on youth (Pediatrics. 2015. doi: 10.1542/peds.2014-4146), reaffirming its opposition to legalization of marijuana because it contended that limited studies had been done on “medical marijuana” in adults, and that there were no published studies either on the form of marijuana or other preparations that involved children.
Marijuana is a schedule I controlled substance, so the Food and Drug Administration does not regulate marijuana edibles, resulting in poor labeling and unregulated formulations.2
Edibles are marijuana-infused foods. Extraction of the cannabinoid THC, the major psychoactive ingredient, from the cannabis plant involves heating the flowers from the female plant in an oil base liquid. As it is heated, the inactive tetrahydrocannabinoid acid (THCA) is converted to THC and dissolves into the oil base liquids, and it is this additive that is used in food products to create the edible. A safe “serving size,” was determined to be 10 mg of THC,3 but an edible may contain 100 mg of THC if consumed in its entirety.
Many prefer ingesting edibles, compared with smoking, because there are no toxic effects from the inhalation of smoke, no odors, it’s more potent, and its duration of action is longer.3 The downside is the onset of action is slower, compared with smoking, so many will consume more before the “high” begins, and therefore there is a greater risk for intoxication. For example, a chocolate bar may contain 100 mg of THC, and despite the “serving size” stated as one square, a person might consume the entire bar before the onset of the high begins. Improved labeling and warning of intoxication now are required on packaging, but this does little to reduce the risk.3
Edibles also are made in way that is attractive to children. Commonly, they come in packaging and forms that resemble candy, such as gummies and chocolate bars. Although laws have been put in place to require them to be sold in childproof containers, 3,4 As feared, once cannabis oil is obtained legally, there is little control over what it is put in.
As for medicinal purposes, edibles have a great advantage for children when used for that purpose. Ease of administration, long duration of action, and a great taste are all positive attributes. As with all good things, there is a downside when used inappropriately.
Marijuana overdoses can result in cognitive and motor impairment, extreme sedation, agitation, anxiety, cardiac stress, and vomiting. High quantities of THC have been reported to cause transient psychotic symptoms such as hallucinations, delusions, and anxiety.3
As pediatricians, it is essential to educate teens and their families on the harmful effects of marijuana and dispel the myth that is benign. They need to be informed of the negative impact of marijuana, which leads to impairment of memory and executive function, on the developing brain. Parents also need to be aware of the current trends of use and formulations, so they can be aware of potential exposures.5
Dr. Pearce is a pediatrician in Frankfort, Ill. She said she had no relevant financial disclosures. Email her at [email protected].
References
1. “American Academy of Pediatrics Reaffirms Opposition to Legalizing Marijuana for Recreational or Medical Use,” AAP press release on Jan. 26, 2015.
2. N Engl J Med. 2015;372:989-91.
3. Methods Rep RTI Press. 2016 Nov. doi: 10.3768/rtipress.2016.op.0035.1611.
4. JAMA. 2015;313(3):241-2.
5. Pediatrics. 2017 Mar;139(3):e20164069.
“We should not consider marijuana ‘innocent until proven guilty,’ given what we already know about the harms to adolescents,”1 Sharon Levy, MD, chair of the American Academy of Pediatrics Committee on Substance Abuse, said in an AAP press release, speaking of the legalization of marijuana in Washington and Colorado. The press release was issued in 2015 when the AAP updated its policy on the impact of marijuana policies on youth (Pediatrics. 2015. doi: 10.1542/peds.2014-4146), reaffirming its opposition to legalization of marijuana because it contended that limited studies had been done on “medical marijuana” in adults, and that there were no published studies either on the form of marijuana or other preparations that involved children.
Marijuana is a schedule I controlled substance, so the Food and Drug Administration does not regulate marijuana edibles, resulting in poor labeling and unregulated formulations.2
Edibles are marijuana-infused foods. Extraction of the cannabinoid THC, the major psychoactive ingredient, from the cannabis plant involves heating the flowers from the female plant in an oil base liquid. As it is heated, the inactive tetrahydrocannabinoid acid (THCA) is converted to THC and dissolves into the oil base liquids, and it is this additive that is used in food products to create the edible. A safe “serving size,” was determined to be 10 mg of THC,3 but an edible may contain 100 mg of THC if consumed in its entirety.
Many prefer ingesting edibles, compared with smoking, because there are no toxic effects from the inhalation of smoke, no odors, it’s more potent, and its duration of action is longer.3 The downside is the onset of action is slower, compared with smoking, so many will consume more before the “high” begins, and therefore there is a greater risk for intoxication. For example, a chocolate bar may contain 100 mg of THC, and despite the “serving size” stated as one square, a person might consume the entire bar before the onset of the high begins. Improved labeling and warning of intoxication now are required on packaging, but this does little to reduce the risk.3
Edibles also are made in way that is attractive to children. Commonly, they come in packaging and forms that resemble candy, such as gummies and chocolate bars. Although laws have been put in place to require them to be sold in childproof containers, 3,4 As feared, once cannabis oil is obtained legally, there is little control over what it is put in.
As for medicinal purposes, edibles have a great advantage for children when used for that purpose. Ease of administration, long duration of action, and a great taste are all positive attributes. As with all good things, there is a downside when used inappropriately.
Marijuana overdoses can result in cognitive and motor impairment, extreme sedation, agitation, anxiety, cardiac stress, and vomiting. High quantities of THC have been reported to cause transient psychotic symptoms such as hallucinations, delusions, and anxiety.3
As pediatricians, it is essential to educate teens and their families on the harmful effects of marijuana and dispel the myth that is benign. They need to be informed of the negative impact of marijuana, which leads to impairment of memory and executive function, on the developing brain. Parents also need to be aware of the current trends of use and formulations, so they can be aware of potential exposures.5
Dr. Pearce is a pediatrician in Frankfort, Ill. She said she had no relevant financial disclosures. Email her at [email protected].
References
1. “American Academy of Pediatrics Reaffirms Opposition to Legalizing Marijuana for Recreational or Medical Use,” AAP press release on Jan. 26, 2015.
2. N Engl J Med. 2015;372:989-91.
3. Methods Rep RTI Press. 2016 Nov. doi: 10.3768/rtipress.2016.op.0035.1611.
4. JAMA. 2015;313(3):241-2.
5. Pediatrics. 2017 Mar;139(3):e20164069.
Time to HIV rebound in infants off ART linked to birth health
BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.
Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.
The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).
In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.
They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.
Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.
The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.
In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)
In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.
Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.
The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
SOURCE: Violari A et al. CROI 2018, Abstract 137
BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.
Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.
The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).
In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.
They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.
Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.
The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.
In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)
In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.
Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.
The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
SOURCE: Violari A et al. CROI 2018, Abstract 137
BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.
Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.
The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).
In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.
They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.
Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.
The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.
In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)
In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.
Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.
The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
SOURCE: Violari A et al. CROI 2018, Abstract 137
FROM CROI 2018
Key clinical point: Early initiation of antiretroviral therapy in infants is associated with better outcomes.
Major finding: Longer time to viral rebound was associated with higher baseline CD4, higher birth weight, and viral suppression within 40 weeks of starting ART.
Study details: Analysis of outcomes in 183 infants with HIV infection in the CHER trial.
Disclosures: The study was funded by the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
Source: Violari A et al. CROI 2018, Abstract 137.
Implant Survivorship and Complication Rates After Total Knee Arthroplasty With a Third-Generation Cemented System: 15-Year Follow-Up
ABSTRACT
This work is a retrospective cohort study evaluating patients who had undergone third-generation cemented total knee arthroplasty (TKA) with prostheses (NexGen, Zimmer Biomet) utilizing posterior-stabilized (PS) and cruciate-retaining (CR) designs at a single center at their 15-year follow-up.
The purpose of this study is to determine the functional knee scores, reoperations, and long-term survivorship for patients with the NexGen Zimmer Biomet Knee system at the 15-year follow-up. In total, 99 patients who had undergone primary TKA were followed for 15 years.
At the 15-year follow-up, survivorship in both study groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups also showed similar functionality: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Reoperation rates were 2% for the PS group and 0% for the CR group (P = .38). No differences in any of the outcomes analyzed were observed between patients who had CR TKA and those who had undergone PS TKA.
Our study found no significant differences in functional outcomes between PS and CR NexGen knee implants. Patients treated by both methods showed excellent longevity and survivorship at the 15-year follow-up.
Continue to: Total knee arthroplasty...
Total knee arthroplasty (TKA) is an orthopedic procedure with increasing demand.1 Over the past 2 decades, a surge in TKA implants has been observed. Of the available prosthetic designs, only a few implants with long-term follow-up have been reported.2-9 The NexGen TKA system (Zimmer Biomet) has been shown to have excellent clinical and radiographic results at an intermediate follow-up term of 8 years.10 This system is a third-generation prosthetic design that was developed to improve problems seen with its predecessors, such as the Miller-Galante II system (Zimmer Biomet), the Insall-Burstein II system (Zimmer Biomet), and the Constrained Condylar Knee (Zimmer Biomet), which were mainly for patellar maltracking.11-17 The NexGen TKA system is a fixed-bearing system designed to include an anatomic femoral trochlea with the option of cruciate-retaining (CR), posterior-stabilized (PS), or more constrained implants. This study evaluates the long-term success of the CR and PS NexGen TKA systems. Outcomes measured include functional knee scores and reoperation rates at the 15-year follow-up. Based on the measured outcomes, potential differences between the PS and CR implants from this system are cited.
MATERIAL AND METHODS
Between July 1995 and July 1997, 334 consecutive primary TKAs were performed on 287 patients at our institution. In total, 167 patients (186 knees) underwent posterior CR TKAs with the NexGen CR prosthesis (Zimmer Biomet), and 120 patients (148 knees) underwent PS TKAs using the NexGen Legacy PS prosthesis (Zimmer Biomet). This retrospective double cohort study was reviewed and approved by our Institutional Review Board. At the 15-year postoperative follow-up, 99 patients were available (Figure 1).
The CR and PS implants were used with similar frequencies by the surgeons who performed the procedures. Patients were not randomized into either the PS- or CR-implant teams; the final decision on implant selection was left to the operating surgeon’s discretion. However, in addition to standard indications for TKA (pain and disability associated with severe arthritic change seen on radiographs and refractory to conservative measures), absolute contraindications to the CR implant included severe combined deformity (flexion contraction >30° combined with a varus or valgus deformity >20°) or posterior cruciate ligament insufficiency (often associated with inflammatory arthritis).
The surgical technique for the CR and PS designs was identical, and included a median parapatellar approach, femoral rotational alignment perpendicular to the transepicondylar axis, measured resection of the flexion and extension gaps, intramedullary femoral alignment, and extramedullary tibial alignment. All components were cemented, and the patella of each patient was resurfaced. All patients received preoperative antibiotics that were continued for 48 hours postoperatively, and 4 weeks of anticoagulation with dose-adjusted warfarin to maintain an international normalized ratio of 1.5 to 2.0.
Patients were observed postoperatively at the 5- to 8-year and 15-year time points. The 5-year data were previously published in 2005 by Bozic and colleagues.10 Patients available for follow-up at the 15-year time-point were evaluated using the 100-point Hospital for Special Surgery (HSS) knee scoring system, which assigns up to 30 points for pain, 22 points for function, 18 points for range of motion, and 10 points each for quadricep strength, deformity, and instability. In addition, common medical conditions limiting patient activity were assessed; these included joint replacement; arthritis in another joint, the back, or spine; weakness or fatigue; breathing or heart ailments; and others.
Continue to: At the 15-year follow-up...
At the 15-year follow-up, patients were contacted via telephone to obtain their HSS knee scores. If patients were unavailable/unable to answer the questions asked, knee score information was collected from a first-degree relative or caretaker. Patients that could not be contacted by phone were sent a HSS knee score survey to their last known address. The online Social Security Death Index was queried for confirmation of death. If deceased, a first-degree relative was contacted for confirmation.
Survivorship was evaluated using revision for any reason and revision for aseptic loosening as separate endpoints via the Kaplan-Meier product-limit method, and the CR and PS TKA groups were compared using the log-rank test. The power of the study for detecting differences between the TKA groups was determined to be 80%, based on a moderate hazard ratio of 1.5, using the log-rank test. Differences between PS and CR TKAs were assessed using the Pearson chi-square test for knee pain and functional outcomes, Fisher’s exact test for patient limitations, such as joint replacement, and the non-parametric Mann Whitney U-test for median pain scores (Table 1). Spearman correlations between the patients’ self-reported knee scores (as a percentage of normal) and physician-based knee scores were performed to assess whether self-reported knee scores were significantly correlated with physician-based knee scores. Kaplan-Meier analysis was performed to evaluate time-related freedom from reoperation at 95% confidence intervals. Statistical analysis was conducted using IBM SPSS Statistics (version 21.0, IBM). Two-tailed P < .05 was considered statistically significant.
RESULTS
Of the 287 patients (334 knees) who had primary TKAs, 99 patients (121 knees; 75 CR and 46 PS) were available at the 15-year follow-up. A total of 155 patients (171 knees) died before the 15-year follow-up, and 33 (42 knees) were lost to follow-up (Figure 1). The functional status of the knees of patients who were lost to follow-up or who had died since the previous follow-up data were published is unknown.
Demographic and outcome data for the cohort of 121 TKAs (99 patients) are summarized in Table 2. The median age at surgery was 64 years, and 71% of the cohort was female.
At the 15-year follow-up, survivorship in both groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups were also similar functionally: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Approximately half of the patients in both groups (52% PS; 50% CR; P = .88) required walking support (canes or walkers) and nearly half of both groups (46% PS; 48% CR; P = .62) could walk <5 blocks or only short distances in their homes. In addition, 46% of the patients in both groups reported needing arm assistance to functionally rise from a chair (P = .43); 91% of the patients in both groups could also walk up and down stairs (P = .77). No statistical difference in the medical conditions limiting the patients in the 2 groups was found: joint replacement (2% PS; 6% CR; P = .71), arthritis in another joint (43% PS; 45% CR; P = .84), back or spine arthritis (31% PS; 33% CR; P = 1.00), weakness or fatigue (24% PS; 25% CR; P = 1.00), breathing or heart ailments (11% PS; 20% CR; P = .40), and other reasons (27% PS; 25% CR; P = 1.00). In addition, median self-reported knee scores were 95 and 93 points for the PS and CR groups, respectively (P = .55).
Continue to: Patients reported 2 complications...
Patients reported 2 complications since the previous 5- to 8-year follow-up, 1 in each group. The first case underwent a PS TKA that required open reduction internal fixation for a bilateral supracondylar peri-prosthesis femur fracture following a fall, which was subsequently complicated with infection and ultimately led to above-the-knee amputation. In the second case, a CR TKA patient experienced persistent swelling and knee instability. The patient followed up with a local orthopaedist, but to date, no reoperations on the knee have been reported.
Spearman correlations between the patients’ self-reported knee scores (as a percentage of normal) and physician-based knee scores were moderately correlated with physician-based knee scores (rs = 0.42; P < .001).
Reoperation rates were 2% for PS and 0% for CR (P = .38). Kaplan-Meier analysis was performed to evaluate time-related freedom from reoperation and no significance difference between the PS and CR groups was revealed (log-rank test = 1.40, P = .24, Figure 2).
DISCUSSION
The success of TKA in pain relief and restoration of function has led to increased demands for this surgery.1 Such demand has enabled the introduction of a new joint replacement prosthesis to the market.18 Considering the increased incidence of osteoarthritis in the younger population (<55 years of age), critically reviewing the longevity and durability of TKA implant designs is of great importance. Compared with other TKA implant designs, the NexGen Zimmer Biomet Knee system has shown excellent longevity at the 15-year follow-up.5,6,9,11-15 Our study began with 136 patients, and, after eliminating the deceased, those lost to follow-up, and non-responders, a total of 99 patients were available for the 15-year follow-up. At this time-point, 80% of the PS implants and 89% of the CR implants were associated with no or mild pain. Survivorship at the 15-year follow-up was similar in both groups: 98% for PS TKAs and 100% for CR TKAs. The reoperation rate was low in both groups, and no evidence of aseptic loosening was found. Based on our results, the NexGen Zimmer Biomet Knee system can be concluded to show excellent longevity and functional outcomes at the 15-year follow-up.
Our study includes several limiting factors that were taken into consideration during the analysis of the results. One of the main limitations of this work is that it required a 15-year follow-up of predominantly elderly patients; many of the participants may be expected to be deceased at this time-point. In our study, a total of 7 patients were confirmed to be deceased by a first-degree relative or the Social Security Death Index. In addition, unlike Bozic and colleagues’10 previous 5-year follow-up study, radiographic imaging data were not collected at the 15-year follow-up. However, given that this study aimed to assess the functional knee scores and reoperation rates of the PS and CR NexGen Zimmer Biomet Knee system, radiographic information did not appear to be necessary.
CONCLUSION
This study found no significant differences in functional outcomes between the PS and CR NexGen knee implants. Patients who received these implants showed excellent longevity and survivorship at their 15-year follow-up.
1. Lützner J, Hübel U, Kirschner S, Günther KP, Krummenauer F. Langzeitergebnisse in der Knieendoprothetik. Chirurg. 2011;82(7):618-624. doi:10.1007/s00104-010-2001-8.
2. Font-Rodriguez DE, Scuderi GR, Insall J. Survivorship of cemented total knee arthroplasty. Clin Orthop Relat Res. 1997;345:79-86.
3. Rodriguez JA, Bhende H, Ranawat CS. Total condylar knee replacement: a 20-year followup study. Clin Orthop Relat Res. 2001;388:10-17.
4. Van Loon CJM, Wisse MA, de Waal Malefijt MC, Jansen RH, Veth RPH. The kinematic total knee arthroplasty. Arch Orth Traum Surg. 2000;120(1-2):48-52. doi:10.1007/PL00021215.
5. Buechel FFS. Long-term followup after mobile-bearing total knee replacement. Clin Orthop Relat Res. 2002;404:40-50.
6. Ito J, Koshino T, Okamoto R, Saito T. 15-year follow-up study of total knee arthroplasty in patients with rheumatoid arthritis. J Arthroplasty. 2003;18(8):984-992. doi:10.1016/S0883-5403(03)00262-6.
7. Dixon MC, Brown RR, Parsch D, Scott RD. Modular fixed-bearing total knee arthroplasty with retention of the posterior cruciate ligament. J Bone Joint Surg. 2005;87(3):598-603. doi:10.2106/JBJS.C.00591.
8. Duffy GP, Crowder AR, Trousdale RR, Berry DJ. Cemented total knee arthroplasty using a modern prosthesis in young patients with osteoarthritis. J Arthroplasty. 2007;22(6 Suppl 2):67-70. doi:10.1016/j.arth.2007.05.001.
9. Baker PN, Khaw FM, Kirk LMG, Esler CNA, Gregg PJ. A randomised controlled trial of cemented versus cementless press-fit condylar total knee replacement: 15-year survival analysis. J Bone Joint Surg. 2007;89-B(12):1608-1614. doi:10.1302/0301-620x.89b12.19363.
10. Bozic KJ, Kinder J, Menegini M, Zurakowski D, Rosenberg AG, Galante JO. Implant survivorship and complication rates after total knee arthroplasty with a third-generation cemented system: 5 to 8 years followup. Clin Orthop Relat Res. 2005;430:117-124. doi:10.1097/01.blo.0000146539.23869.14.
11. Effenberger H, Berka J, Hilzensauer G, Ramsauer T, Dorn U, Kißlinger E. Miller-Galante total knee arthroplasty: the importance of material and design on the revision rate. Int Orthop. 2001;25(6):378-381. doi:10.1007/s002640100294.
12. Kirk PG, Rorabeck CH, Bourne RB. Clinical comparison of the Miller Galante I and AMK total knee systems. J Arthroplasty. 1994;9(2):131-136. doi:10.1016/0883-5403(94)90061-2.
13. Kobori M, Kamisato S, Yoshida M, Kobori K. Revision of failed metal-backed patellar component of Miller/Galante-I total knee prosthesis. J Orthop Sci. 2000;5(5):436-438. doi:10.1007/s007760070020.
14. Larson CM, Lachiewicz PF. Patellofemoral complications with the insall-burstein II posterior-stabilized total knee arthroplasty. J Arthroplasty. 1999;14(3):288-292. doi:http://dx.doi.org/10.1016/S0883-5403(99)90053-0.
15. Matsuda S, Miura H, Nagamine R, Urabe K, Hirata G, Iwamoto Y. Effect of femoral and tibial component position on patellar tracking following total knee arthroplasty: 10-year follow-up of Miller-Galante I knees. Am J Knee Surg. 2001;14(3):152-156.
16. Miyagi T, Matsuda S, Miura H, Nagamine R, Urabe K. Changes in patellar tracking after total knee arthroplasty: 10-year follow-up of Miller-Balante I knees. Orthopedics. 2002;25(8):811-813. doi:10.3928/0147-7447-20020801-10.
17. Rao AR, Engh GA, Collier MB, Lounici S. Tibial interface wear in retrieved total knee components and correlations with modular insert motion. J Bone Joint Surg. 2002;84(10):1849-1855.
18. Anand R, Graves SE, de Steiger RN, et al. What is the benefit of introducing new hip and knee prostheses? J Bone Joint Surg. 2011;93(3):51-54. doi:10.2106/JBJS.K.00867.
ABSTRACT
This work is a retrospective cohort study evaluating patients who had undergone third-generation cemented total knee arthroplasty (TKA) with prostheses (NexGen, Zimmer Biomet) utilizing posterior-stabilized (PS) and cruciate-retaining (CR) designs at a single center at their 15-year follow-up.
The purpose of this study is to determine the functional knee scores, reoperations, and long-term survivorship for patients with the NexGen Zimmer Biomet Knee system at the 15-year follow-up. In total, 99 patients who had undergone primary TKA were followed for 15 years.
At the 15-year follow-up, survivorship in both study groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups also showed similar functionality: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Reoperation rates were 2% for the PS group and 0% for the CR group (P = .38). No differences in any of the outcomes analyzed were observed between patients who had CR TKA and those who had undergone PS TKA.
Our study found no significant differences in functional outcomes between PS and CR NexGen knee implants. Patients treated by both methods showed excellent longevity and survivorship at the 15-year follow-up.
Continue to: Total knee arthroplasty...
Total knee arthroplasty (TKA) is an orthopedic procedure with increasing demand.1 Over the past 2 decades, a surge in TKA implants has been observed. Of the available prosthetic designs, only a few implants with long-term follow-up have been reported.2-9 The NexGen TKA system (Zimmer Biomet) has been shown to have excellent clinical and radiographic results at an intermediate follow-up term of 8 years.10 This system is a third-generation prosthetic design that was developed to improve problems seen with its predecessors, such as the Miller-Galante II system (Zimmer Biomet), the Insall-Burstein II system (Zimmer Biomet), and the Constrained Condylar Knee (Zimmer Biomet), which were mainly for patellar maltracking.11-17 The NexGen TKA system is a fixed-bearing system designed to include an anatomic femoral trochlea with the option of cruciate-retaining (CR), posterior-stabilized (PS), or more constrained implants. This study evaluates the long-term success of the CR and PS NexGen TKA systems. Outcomes measured include functional knee scores and reoperation rates at the 15-year follow-up. Based on the measured outcomes, potential differences between the PS and CR implants from this system are cited.
MATERIAL AND METHODS
Between July 1995 and July 1997, 334 consecutive primary TKAs were performed on 287 patients at our institution. In total, 167 patients (186 knees) underwent posterior CR TKAs with the NexGen CR prosthesis (Zimmer Biomet), and 120 patients (148 knees) underwent PS TKAs using the NexGen Legacy PS prosthesis (Zimmer Biomet). This retrospective double cohort study was reviewed and approved by our Institutional Review Board. At the 15-year postoperative follow-up, 99 patients were available (Figure 1).
The CR and PS implants were used with similar frequencies by the surgeons who performed the procedures. Patients were not randomized into either the PS- or CR-implant teams; the final decision on implant selection was left to the operating surgeon’s discretion. However, in addition to standard indications for TKA (pain and disability associated with severe arthritic change seen on radiographs and refractory to conservative measures), absolute contraindications to the CR implant included severe combined deformity (flexion contraction >30° combined with a varus or valgus deformity >20°) or posterior cruciate ligament insufficiency (often associated with inflammatory arthritis).
The surgical technique for the CR and PS designs was identical, and included a median parapatellar approach, femoral rotational alignment perpendicular to the transepicondylar axis, measured resection of the flexion and extension gaps, intramedullary femoral alignment, and extramedullary tibial alignment. All components were cemented, and the patella of each patient was resurfaced. All patients received preoperative antibiotics that were continued for 48 hours postoperatively, and 4 weeks of anticoagulation with dose-adjusted warfarin to maintain an international normalized ratio of 1.5 to 2.0.
Patients were observed postoperatively at the 5- to 8-year and 15-year time points. The 5-year data were previously published in 2005 by Bozic and colleagues.10 Patients available for follow-up at the 15-year time-point were evaluated using the 100-point Hospital for Special Surgery (HSS) knee scoring system, which assigns up to 30 points for pain, 22 points for function, 18 points for range of motion, and 10 points each for quadricep strength, deformity, and instability. In addition, common medical conditions limiting patient activity were assessed; these included joint replacement; arthritis in another joint, the back, or spine; weakness or fatigue; breathing or heart ailments; and others.
Continue to: At the 15-year follow-up...
At the 15-year follow-up, patients were contacted via telephone to obtain their HSS knee scores. If patients were unavailable/unable to answer the questions asked, knee score information was collected from a first-degree relative or caretaker. Patients that could not be contacted by phone were sent a HSS knee score survey to their last known address. The online Social Security Death Index was queried for confirmation of death. If deceased, a first-degree relative was contacted for confirmation.
Survivorship was evaluated using revision for any reason and revision for aseptic loosening as separate endpoints via the Kaplan-Meier product-limit method, and the CR and PS TKA groups were compared using the log-rank test. The power of the study for detecting differences between the TKA groups was determined to be 80%, based on a moderate hazard ratio of 1.5, using the log-rank test. Differences between PS and CR TKAs were assessed using the Pearson chi-square test for knee pain and functional outcomes, Fisher’s exact test for patient limitations, such as joint replacement, and the non-parametric Mann Whitney U-test for median pain scores (Table 1). Spearman correlations between the patients’ self-reported knee scores (as a percentage of normal) and physician-based knee scores were performed to assess whether self-reported knee scores were significantly correlated with physician-based knee scores. Kaplan-Meier analysis was performed to evaluate time-related freedom from reoperation at 95% confidence intervals. Statistical analysis was conducted using IBM SPSS Statistics (version 21.0, IBM). Two-tailed P < .05 was considered statistically significant.
RESULTS
Of the 287 patients (334 knees) who had primary TKAs, 99 patients (121 knees; 75 CR and 46 PS) were available at the 15-year follow-up. A total of 155 patients (171 knees) died before the 15-year follow-up, and 33 (42 knees) were lost to follow-up (Figure 1). The functional status of the knees of patients who were lost to follow-up or who had died since the previous follow-up data were published is unknown.
Demographic and outcome data for the cohort of 121 TKAs (99 patients) are summarized in Table 2. The median age at surgery was 64 years, and 71% of the cohort was female.
At the 15-year follow-up, survivorship in both groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups were also similar functionally: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Approximately half of the patients in both groups (52% PS; 50% CR; P = .88) required walking support (canes or walkers) and nearly half of both groups (46% PS; 48% CR; P = .62) could walk <5 blocks or only short distances in their homes. In addition, 46% of the patients in both groups reported needing arm assistance to functionally rise from a chair (P = .43); 91% of the patients in both groups could also walk up and down stairs (P = .77). No statistical difference in the medical conditions limiting the patients in the 2 groups was found: joint replacement (2% PS; 6% CR; P = .71), arthritis in another joint (43% PS; 45% CR; P = .84), back or spine arthritis (31% PS; 33% CR; P = 1.00), weakness or fatigue (24% PS; 25% CR; P = 1.00), breathing or heart ailments (11% PS; 20% CR; P = .40), and other reasons (27% PS; 25% CR; P = 1.00). In addition, median self-reported knee scores were 95 and 93 points for the PS and CR groups, respectively (P = .55).
Continue to: Patients reported 2 complications...
Patients reported 2 complications since the previous 5- to 8-year follow-up, 1 in each group. The first case underwent a PS TKA that required open reduction internal fixation for a bilateral supracondylar peri-prosthesis femur fracture following a fall, which was subsequently complicated with infection and ultimately led to above-the-knee amputation. In the second case, a CR TKA patient experienced persistent swelling and knee instability. The patient followed up with a local orthopaedist, but to date, no reoperations on the knee have been reported.
Spearman correlations between the patients’ self-reported knee scores (as a percentage of normal) and physician-based knee scores were moderately correlated with physician-based knee scores (rs = 0.42; P < .001).
Reoperation rates were 2% for PS and 0% for CR (P = .38). Kaplan-Meier analysis was performed to evaluate time-related freedom from reoperation and no significance difference between the PS and CR groups was revealed (log-rank test = 1.40, P = .24, Figure 2).
DISCUSSION
The success of TKA in pain relief and restoration of function has led to increased demands for this surgery.1 Such demand has enabled the introduction of a new joint replacement prosthesis to the market.18 Considering the increased incidence of osteoarthritis in the younger population (<55 years of age), critically reviewing the longevity and durability of TKA implant designs is of great importance. Compared with other TKA implant designs, the NexGen Zimmer Biomet Knee system has shown excellent longevity at the 15-year follow-up.5,6,9,11-15 Our study began with 136 patients, and, after eliminating the deceased, those lost to follow-up, and non-responders, a total of 99 patients were available for the 15-year follow-up. At this time-point, 80% of the PS implants and 89% of the CR implants were associated with no or mild pain. Survivorship at the 15-year follow-up was similar in both groups: 98% for PS TKAs and 100% for CR TKAs. The reoperation rate was low in both groups, and no evidence of aseptic loosening was found. Based on our results, the NexGen Zimmer Biomet Knee system can be concluded to show excellent longevity and functional outcomes at the 15-year follow-up.
Our study includes several limiting factors that were taken into consideration during the analysis of the results. One of the main limitations of this work is that it required a 15-year follow-up of predominantly elderly patients; many of the participants may be expected to be deceased at this time-point. In our study, a total of 7 patients were confirmed to be deceased by a first-degree relative or the Social Security Death Index. In addition, unlike Bozic and colleagues’10 previous 5-year follow-up study, radiographic imaging data were not collected at the 15-year follow-up. However, given that this study aimed to assess the functional knee scores and reoperation rates of the PS and CR NexGen Zimmer Biomet Knee system, radiographic information did not appear to be necessary.
CONCLUSION
This study found no significant differences in functional outcomes between the PS and CR NexGen knee implants. Patients who received these implants showed excellent longevity and survivorship at their 15-year follow-up.
ABSTRACT
This work is a retrospective cohort study evaluating patients who had undergone third-generation cemented total knee arthroplasty (TKA) with prostheses (NexGen, Zimmer Biomet) utilizing posterior-stabilized (PS) and cruciate-retaining (CR) designs at a single center at their 15-year follow-up.
The purpose of this study is to determine the functional knee scores, reoperations, and long-term survivorship for patients with the NexGen Zimmer Biomet Knee system at the 15-year follow-up. In total, 99 patients who had undergone primary TKA were followed for 15 years.
At the 15-year follow-up, survivorship in both study groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups also showed similar functionality: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Reoperation rates were 2% for the PS group and 0% for the CR group (P = .38). No differences in any of the outcomes analyzed were observed between patients who had CR TKA and those who had undergone PS TKA.
Our study found no significant differences in functional outcomes between PS and CR NexGen knee implants. Patients treated by both methods showed excellent longevity and survivorship at the 15-year follow-up.
Continue to: Total knee arthroplasty...
Total knee arthroplasty (TKA) is an orthopedic procedure with increasing demand.1 Over the past 2 decades, a surge in TKA implants has been observed. Of the available prosthetic designs, only a few implants with long-term follow-up have been reported.2-9 The NexGen TKA system (Zimmer Biomet) has been shown to have excellent clinical and radiographic results at an intermediate follow-up term of 8 years.10 This system is a third-generation prosthetic design that was developed to improve problems seen with its predecessors, such as the Miller-Galante II system (Zimmer Biomet), the Insall-Burstein II system (Zimmer Biomet), and the Constrained Condylar Knee (Zimmer Biomet), which were mainly for patellar maltracking.11-17 The NexGen TKA system is a fixed-bearing system designed to include an anatomic femoral trochlea with the option of cruciate-retaining (CR), posterior-stabilized (PS), or more constrained implants. This study evaluates the long-term success of the CR and PS NexGen TKA systems. Outcomes measured include functional knee scores and reoperation rates at the 15-year follow-up. Based on the measured outcomes, potential differences between the PS and CR implants from this system are cited.
MATERIAL AND METHODS
Between July 1995 and July 1997, 334 consecutive primary TKAs were performed on 287 patients at our institution. In total, 167 patients (186 knees) underwent posterior CR TKAs with the NexGen CR prosthesis (Zimmer Biomet), and 120 patients (148 knees) underwent PS TKAs using the NexGen Legacy PS prosthesis (Zimmer Biomet). This retrospective double cohort study was reviewed and approved by our Institutional Review Board. At the 15-year postoperative follow-up, 99 patients were available (Figure 1).
The CR and PS implants were used with similar frequencies by the surgeons who performed the procedures. Patients were not randomized into either the PS- or CR-implant teams; the final decision on implant selection was left to the operating surgeon’s discretion. However, in addition to standard indications for TKA (pain and disability associated with severe arthritic change seen on radiographs and refractory to conservative measures), absolute contraindications to the CR implant included severe combined deformity (flexion contraction >30° combined with a varus or valgus deformity >20°) or posterior cruciate ligament insufficiency (often associated with inflammatory arthritis).
The surgical technique for the CR and PS designs was identical, and included a median parapatellar approach, femoral rotational alignment perpendicular to the transepicondylar axis, measured resection of the flexion and extension gaps, intramedullary femoral alignment, and extramedullary tibial alignment. All components were cemented, and the patella of each patient was resurfaced. All patients received preoperative antibiotics that were continued for 48 hours postoperatively, and 4 weeks of anticoagulation with dose-adjusted warfarin to maintain an international normalized ratio of 1.5 to 2.0.
Patients were observed postoperatively at the 5- to 8-year and 15-year time points. The 5-year data were previously published in 2005 by Bozic and colleagues.10 Patients available for follow-up at the 15-year time-point were evaluated using the 100-point Hospital for Special Surgery (HSS) knee scoring system, which assigns up to 30 points for pain, 22 points for function, 18 points for range of motion, and 10 points each for quadricep strength, deformity, and instability. In addition, common medical conditions limiting patient activity were assessed; these included joint replacement; arthritis in another joint, the back, or spine; weakness or fatigue; breathing or heart ailments; and others.
Continue to: At the 15-year follow-up...
At the 15-year follow-up, patients were contacted via telephone to obtain their HSS knee scores. If patients were unavailable/unable to answer the questions asked, knee score information was collected from a first-degree relative or caretaker. Patients that could not be contacted by phone were sent a HSS knee score survey to their last known address. The online Social Security Death Index was queried for confirmation of death. If deceased, a first-degree relative was contacted for confirmation.
Survivorship was evaluated using revision for any reason and revision for aseptic loosening as separate endpoints via the Kaplan-Meier product-limit method, and the CR and PS TKA groups were compared using the log-rank test. The power of the study for detecting differences between the TKA groups was determined to be 80%, based on a moderate hazard ratio of 1.5, using the log-rank test. Differences between PS and CR TKAs were assessed using the Pearson chi-square test for knee pain and functional outcomes, Fisher’s exact test for patient limitations, such as joint replacement, and the non-parametric Mann Whitney U-test for median pain scores (Table 1). Spearman correlations between the patients’ self-reported knee scores (as a percentage of normal) and physician-based knee scores were performed to assess whether self-reported knee scores were significantly correlated with physician-based knee scores. Kaplan-Meier analysis was performed to evaluate time-related freedom from reoperation at 95% confidence intervals. Statistical analysis was conducted using IBM SPSS Statistics (version 21.0, IBM). Two-tailed P < .05 was considered statistically significant.
RESULTS
Of the 287 patients (334 knees) who had primary TKAs, 99 patients (121 knees; 75 CR and 46 PS) were available at the 15-year follow-up. A total of 155 patients (171 knees) died before the 15-year follow-up, and 33 (42 knees) were lost to follow-up (Figure 1). The functional status of the knees of patients who were lost to follow-up or who had died since the previous follow-up data were published is unknown.
Demographic and outcome data for the cohort of 121 TKAs (99 patients) are summarized in Table 2. The median age at surgery was 64 years, and 71% of the cohort was female.
At the 15-year follow-up, survivorship in both groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups were also similar functionally: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Approximately half of the patients in both groups (52% PS; 50% CR; P = .88) required walking support (canes or walkers) and nearly half of both groups (46% PS; 48% CR; P = .62) could walk <5 blocks or only short distances in their homes. In addition, 46% of the patients in both groups reported needing arm assistance to functionally rise from a chair (P = .43); 91% of the patients in both groups could also walk up and down stairs (P = .77). No statistical difference in the medical conditions limiting the patients in the 2 groups was found: joint replacement (2% PS; 6% CR; P = .71), arthritis in another joint (43% PS; 45% CR; P = .84), back or spine arthritis (31% PS; 33% CR; P = 1.00), weakness or fatigue (24% PS; 25% CR; P = 1.00), breathing or heart ailments (11% PS; 20% CR; P = .40), and other reasons (27% PS; 25% CR; P = 1.00). In addition, median self-reported knee scores were 95 and 93 points for the PS and CR groups, respectively (P = .55).
Continue to: Patients reported 2 complications...
Patients reported 2 complications since the previous 5- to 8-year follow-up, 1 in each group. The first case underwent a PS TKA that required open reduction internal fixation for a bilateral supracondylar peri-prosthesis femur fracture following a fall, which was subsequently complicated with infection and ultimately led to above-the-knee amputation. In the second case, a CR TKA patient experienced persistent swelling and knee instability. The patient followed up with a local orthopaedist, but to date, no reoperations on the knee have been reported.
Spearman correlations between the patients’ self-reported knee scores (as a percentage of normal) and physician-based knee scores were moderately correlated with physician-based knee scores (rs = 0.42; P < .001).
Reoperation rates were 2% for PS and 0% for CR (P = .38). Kaplan-Meier analysis was performed to evaluate time-related freedom from reoperation and no significance difference between the PS and CR groups was revealed (log-rank test = 1.40, P = .24, Figure 2).
DISCUSSION
The success of TKA in pain relief and restoration of function has led to increased demands for this surgery.1 Such demand has enabled the introduction of a new joint replacement prosthesis to the market.18 Considering the increased incidence of osteoarthritis in the younger population (<55 years of age), critically reviewing the longevity and durability of TKA implant designs is of great importance. Compared with other TKA implant designs, the NexGen Zimmer Biomet Knee system has shown excellent longevity at the 15-year follow-up.5,6,9,11-15 Our study began with 136 patients, and, after eliminating the deceased, those lost to follow-up, and non-responders, a total of 99 patients were available for the 15-year follow-up. At this time-point, 80% of the PS implants and 89% of the CR implants were associated with no or mild pain. Survivorship at the 15-year follow-up was similar in both groups: 98% for PS TKAs and 100% for CR TKAs. The reoperation rate was low in both groups, and no evidence of aseptic loosening was found. Based on our results, the NexGen Zimmer Biomet Knee system can be concluded to show excellent longevity and functional outcomes at the 15-year follow-up.
Our study includes several limiting factors that were taken into consideration during the analysis of the results. One of the main limitations of this work is that it required a 15-year follow-up of predominantly elderly patients; many of the participants may be expected to be deceased at this time-point. In our study, a total of 7 patients were confirmed to be deceased by a first-degree relative or the Social Security Death Index. In addition, unlike Bozic and colleagues’10 previous 5-year follow-up study, radiographic imaging data were not collected at the 15-year follow-up. However, given that this study aimed to assess the functional knee scores and reoperation rates of the PS and CR NexGen Zimmer Biomet Knee system, radiographic information did not appear to be necessary.
CONCLUSION
This study found no significant differences in functional outcomes between the PS and CR NexGen knee implants. Patients who received these implants showed excellent longevity and survivorship at their 15-year follow-up.
1. Lützner J, Hübel U, Kirschner S, Günther KP, Krummenauer F. Langzeitergebnisse in der Knieendoprothetik. Chirurg. 2011;82(7):618-624. doi:10.1007/s00104-010-2001-8.
2. Font-Rodriguez DE, Scuderi GR, Insall J. Survivorship of cemented total knee arthroplasty. Clin Orthop Relat Res. 1997;345:79-86.
3. Rodriguez JA, Bhende H, Ranawat CS. Total condylar knee replacement: a 20-year followup study. Clin Orthop Relat Res. 2001;388:10-17.
4. Van Loon CJM, Wisse MA, de Waal Malefijt MC, Jansen RH, Veth RPH. The kinematic total knee arthroplasty. Arch Orth Traum Surg. 2000;120(1-2):48-52. doi:10.1007/PL00021215.
5. Buechel FFS. Long-term followup after mobile-bearing total knee replacement. Clin Orthop Relat Res. 2002;404:40-50.
6. Ito J, Koshino T, Okamoto R, Saito T. 15-year follow-up study of total knee arthroplasty in patients with rheumatoid arthritis. J Arthroplasty. 2003;18(8):984-992. doi:10.1016/S0883-5403(03)00262-6.
7. Dixon MC, Brown RR, Parsch D, Scott RD. Modular fixed-bearing total knee arthroplasty with retention of the posterior cruciate ligament. J Bone Joint Surg. 2005;87(3):598-603. doi:10.2106/JBJS.C.00591.
8. Duffy GP, Crowder AR, Trousdale RR, Berry DJ. Cemented total knee arthroplasty using a modern prosthesis in young patients with osteoarthritis. J Arthroplasty. 2007;22(6 Suppl 2):67-70. doi:10.1016/j.arth.2007.05.001.
9. Baker PN, Khaw FM, Kirk LMG, Esler CNA, Gregg PJ. A randomised controlled trial of cemented versus cementless press-fit condylar total knee replacement: 15-year survival analysis. J Bone Joint Surg. 2007;89-B(12):1608-1614. doi:10.1302/0301-620x.89b12.19363.
10. Bozic KJ, Kinder J, Menegini M, Zurakowski D, Rosenberg AG, Galante JO. Implant survivorship and complication rates after total knee arthroplasty with a third-generation cemented system: 5 to 8 years followup. Clin Orthop Relat Res. 2005;430:117-124. doi:10.1097/01.blo.0000146539.23869.14.
11. Effenberger H, Berka J, Hilzensauer G, Ramsauer T, Dorn U, Kißlinger E. Miller-Galante total knee arthroplasty: the importance of material and design on the revision rate. Int Orthop. 2001;25(6):378-381. doi:10.1007/s002640100294.
12. Kirk PG, Rorabeck CH, Bourne RB. Clinical comparison of the Miller Galante I and AMK total knee systems. J Arthroplasty. 1994;9(2):131-136. doi:10.1016/0883-5403(94)90061-2.
13. Kobori M, Kamisato S, Yoshida M, Kobori K. Revision of failed metal-backed patellar component of Miller/Galante-I total knee prosthesis. J Orthop Sci. 2000;5(5):436-438. doi:10.1007/s007760070020.
14. Larson CM, Lachiewicz PF. Patellofemoral complications with the insall-burstein II posterior-stabilized total knee arthroplasty. J Arthroplasty. 1999;14(3):288-292. doi:http://dx.doi.org/10.1016/S0883-5403(99)90053-0.
15. Matsuda S, Miura H, Nagamine R, Urabe K, Hirata G, Iwamoto Y. Effect of femoral and tibial component position on patellar tracking following total knee arthroplasty: 10-year follow-up of Miller-Galante I knees. Am J Knee Surg. 2001;14(3):152-156.
16. Miyagi T, Matsuda S, Miura H, Nagamine R, Urabe K. Changes in patellar tracking after total knee arthroplasty: 10-year follow-up of Miller-Balante I knees. Orthopedics. 2002;25(8):811-813. doi:10.3928/0147-7447-20020801-10.
17. Rao AR, Engh GA, Collier MB, Lounici S. Tibial interface wear in retrieved total knee components and correlations with modular insert motion. J Bone Joint Surg. 2002;84(10):1849-1855.
18. Anand R, Graves SE, de Steiger RN, et al. What is the benefit of introducing new hip and knee prostheses? J Bone Joint Surg. 2011;93(3):51-54. doi:10.2106/JBJS.K.00867.
1. Lützner J, Hübel U, Kirschner S, Günther KP, Krummenauer F. Langzeitergebnisse in der Knieendoprothetik. Chirurg. 2011;82(7):618-624. doi:10.1007/s00104-010-2001-8.
2. Font-Rodriguez DE, Scuderi GR, Insall J. Survivorship of cemented total knee arthroplasty. Clin Orthop Relat Res. 1997;345:79-86.
3. Rodriguez JA, Bhende H, Ranawat CS. Total condylar knee replacement: a 20-year followup study. Clin Orthop Relat Res. 2001;388:10-17.
4. Van Loon CJM, Wisse MA, de Waal Malefijt MC, Jansen RH, Veth RPH. The kinematic total knee arthroplasty. Arch Orth Traum Surg. 2000;120(1-2):48-52. doi:10.1007/PL00021215.
5. Buechel FFS. Long-term followup after mobile-bearing total knee replacement. Clin Orthop Relat Res. 2002;404:40-50.
6. Ito J, Koshino T, Okamoto R, Saito T. 15-year follow-up study of total knee arthroplasty in patients with rheumatoid arthritis. J Arthroplasty. 2003;18(8):984-992. doi:10.1016/S0883-5403(03)00262-6.
7. Dixon MC, Brown RR, Parsch D, Scott RD. Modular fixed-bearing total knee arthroplasty with retention of the posterior cruciate ligament. J Bone Joint Surg. 2005;87(3):598-603. doi:10.2106/JBJS.C.00591.
8. Duffy GP, Crowder AR, Trousdale RR, Berry DJ. Cemented total knee arthroplasty using a modern prosthesis in young patients with osteoarthritis. J Arthroplasty. 2007;22(6 Suppl 2):67-70. doi:10.1016/j.arth.2007.05.001.
9. Baker PN, Khaw FM, Kirk LMG, Esler CNA, Gregg PJ. A randomised controlled trial of cemented versus cementless press-fit condylar total knee replacement: 15-year survival analysis. J Bone Joint Surg. 2007;89-B(12):1608-1614. doi:10.1302/0301-620x.89b12.19363.
10. Bozic KJ, Kinder J, Menegini M, Zurakowski D, Rosenberg AG, Galante JO. Implant survivorship and complication rates after total knee arthroplasty with a third-generation cemented system: 5 to 8 years followup. Clin Orthop Relat Res. 2005;430:117-124. doi:10.1097/01.blo.0000146539.23869.14.
11. Effenberger H, Berka J, Hilzensauer G, Ramsauer T, Dorn U, Kißlinger E. Miller-Galante total knee arthroplasty: the importance of material and design on the revision rate. Int Orthop. 2001;25(6):378-381. doi:10.1007/s002640100294.
12. Kirk PG, Rorabeck CH, Bourne RB. Clinical comparison of the Miller Galante I and AMK total knee systems. J Arthroplasty. 1994;9(2):131-136. doi:10.1016/0883-5403(94)90061-2.
13. Kobori M, Kamisato S, Yoshida M, Kobori K. Revision of failed metal-backed patellar component of Miller/Galante-I total knee prosthesis. J Orthop Sci. 2000;5(5):436-438. doi:10.1007/s007760070020.
14. Larson CM, Lachiewicz PF. Patellofemoral complications with the insall-burstein II posterior-stabilized total knee arthroplasty. J Arthroplasty. 1999;14(3):288-292. doi:http://dx.doi.org/10.1016/S0883-5403(99)90053-0.
15. Matsuda S, Miura H, Nagamine R, Urabe K, Hirata G, Iwamoto Y. Effect of femoral and tibial component position on patellar tracking following total knee arthroplasty: 10-year follow-up of Miller-Galante I knees. Am J Knee Surg. 2001;14(3):152-156.
16. Miyagi T, Matsuda S, Miura H, Nagamine R, Urabe K. Changes in patellar tracking after total knee arthroplasty: 10-year follow-up of Miller-Balante I knees. Orthopedics. 2002;25(8):811-813. doi:10.3928/0147-7447-20020801-10.
17. Rao AR, Engh GA, Collier MB, Lounici S. Tibial interface wear in retrieved total knee components and correlations with modular insert motion. J Bone Joint Surg. 2002;84(10):1849-1855.
18. Anand R, Graves SE, de Steiger RN, et al. What is the benefit of introducing new hip and knee prostheses? J Bone Joint Surg. 2011;93(3):51-54. doi:10.2106/JBJS.K.00867.
TAKE-HOME POINTS
- TKA has a high success rate in pain relief and restoration of function in patients with severe osteoarthritis.
- NexGen (Zimmer Biomet) knee implants showed excellent functional outcomes at 15 years.
- There are no significant differences in functional outcomes between the PS and CR knee systems.
- NexGen knee implants showed excellent longevity and survivorship at 15-year follow-up with no evidence of aseptic loosening.
- There is an increased incidence of knee osteoarthritis in the younger population (<55 years of age).
FDA approves highest capacity insulin pen
This will be the highest capacity long-acting insulin pen to be available commercially, according to a company press release.
The Max SoloStar pen holds more than 900 units of insulin glargine and can provide up to 160 units/mL in a single injection, which may reduce the number of injections needed to deliver the necessary dosage to adults. Another benefit of the higher capacity is that the device will require fewer refills and the associated copays, which could potentially lower costs for patients, depending on their insurance coverage.
The dosing instructions for insulin glargine vary depending on whether patients use the older SoloStar or the high capacity Max SoloStar. The SoloStar holds 450 units (1.5mL) of insulin glargine and delivers doses in 1 unit increments, delivering a maximum dose of 80 units per injection. The MaxSoloStar has twice the capacity of the original – 900 units (3 mL) of insulin glargine – and delivers doses in 2 unit increments up to a maximum 160 unit injection. This is recommended for patients who require at least 20 units per day. All insulin glargine injections should be administered subcutaneously in the abdomen, thigh, or deltoid at the same time each day.
The most common side effect of insulin products, such as insulin glargine, is hypoglycemia.
The Max SoloStar will be available in retail pharmacies throughout the United States in the third quarter of 2018.
This will be the highest capacity long-acting insulin pen to be available commercially, according to a company press release.
The Max SoloStar pen holds more than 900 units of insulin glargine and can provide up to 160 units/mL in a single injection, which may reduce the number of injections needed to deliver the necessary dosage to adults. Another benefit of the higher capacity is that the device will require fewer refills and the associated copays, which could potentially lower costs for patients, depending on their insurance coverage.
The dosing instructions for insulin glargine vary depending on whether patients use the older SoloStar or the high capacity Max SoloStar. The SoloStar holds 450 units (1.5mL) of insulin glargine and delivers doses in 1 unit increments, delivering a maximum dose of 80 units per injection. The MaxSoloStar has twice the capacity of the original – 900 units (3 mL) of insulin glargine – and delivers doses in 2 unit increments up to a maximum 160 unit injection. This is recommended for patients who require at least 20 units per day. All insulin glargine injections should be administered subcutaneously in the abdomen, thigh, or deltoid at the same time each day.
The most common side effect of insulin products, such as insulin glargine, is hypoglycemia.
The Max SoloStar will be available in retail pharmacies throughout the United States in the third quarter of 2018.
This will be the highest capacity long-acting insulin pen to be available commercially, according to a company press release.
The Max SoloStar pen holds more than 900 units of insulin glargine and can provide up to 160 units/mL in a single injection, which may reduce the number of injections needed to deliver the necessary dosage to adults. Another benefit of the higher capacity is that the device will require fewer refills and the associated copays, which could potentially lower costs for patients, depending on their insurance coverage.
The dosing instructions for insulin glargine vary depending on whether patients use the older SoloStar or the high capacity Max SoloStar. The SoloStar holds 450 units (1.5mL) of insulin glargine and delivers doses in 1 unit increments, delivering a maximum dose of 80 units per injection. The MaxSoloStar has twice the capacity of the original – 900 units (3 mL) of insulin glargine – and delivers doses in 2 unit increments up to a maximum 160 unit injection. This is recommended for patients who require at least 20 units per day. All insulin glargine injections should be administered subcutaneously in the abdomen, thigh, or deltoid at the same time each day.
The most common side effect of insulin products, such as insulin glargine, is hypoglycemia.
The Max SoloStar will be available in retail pharmacies throughout the United States in the third quarter of 2018.
Sessile serrated colon polyps may be detectable noninvasively
Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.
Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.
They also found a distinct DNA methylation pattern unique to SSPs.
“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.
Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.
Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.
“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.
To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.
They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.
The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.
They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.
Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.
“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.
The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.
Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.
Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.
They also found a distinct DNA methylation pattern unique to SSPs.
“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.
Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.
Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.
“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.
To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.
They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.
The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.
They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.
Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.
“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.
The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.
Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.
Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.
They also found a distinct DNA methylation pattern unique to SSPs.
“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.
Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.
Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.
“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.
To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.
They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.
The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.
They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.
Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.
“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.
The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.
PLOS ONE
Key clinical point: Sessile serrated polyps appear to arise from a single oncogenic mutation that can be detected noninvasively.
Major finding: A distinct DNA methylation signature can distinguish SSPs from adenomatous polyps.
Study details: Genomic and DNA methylation studies of biopsy samples from patients with SSPs and others with familial adenomatous polyps.
Disclosures: The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
Source: Dehghanizadeh S et al. PLOS One 13(3):e0192499.
Waning vaccine immunity linked to pertussis resurgence
researchers said.
In the March 28, 2018, edition of Science Translational Medicine, researchers reported on a study that used different models of transmission to explore what might be the cause of the steady increase in pertussis infections since the mid-1970s.
Using 16 years’ worth of detailed, age-stratified incidence data from Massachusetts, researchers found that the model which assumed a gradual waning in protection was the best fit for the observed patterns of pertussis incidence across the population.
This model suggested significant variability in how the level of protection changes over time, with a 10% risk of vaccine protection waning to zero within 10 years of completing routine vaccination and a 55% chance that the vaccine would confer lifelong protection.
“Crucially, we find that the vaccine is effective at reducing pathogen circulation but not so effective that eradication of this highly contagious bacterium should be possible without targeted booster campaigns,” wrote Dr. Matthieu Domenech de Cellès, PhD, of the Institut Pasteur at the University of Versailles (France) and his coauthors.
The model also considered the possibility that the whole-cell and acellular pertussis vaccines might show differences in immunity, which had been suggested as one explanation for the resurgence of the disease. However, the authors found little evidence of a marked epidemiological switch from the whole-cell to acellular vaccines, although their results did suggest the acellular vaccine has a moderately reduced efficacy.
“Our results suggest that the train of events leading to the resurgence of pertussis was set in motion well before the shift to the DTaP vaccine,” Dr. Domenech de Cellès and his associates said.
The model also pointed to big shifts in the age-specific immunological profile caused by introduction of vaccination, which led to a reduction in transmission and also a reduction in natural infections both in vaccinated and unvaccinated individuals.
This meant individuals who either did not get vaccinated as children or who did not gain immunity from vaccination were growing to adulthood without ever being exposed to natural infection.
“Concurrently, older cohorts, with their long-lived immunity derived from natural infections experienced during the prevaccine period, were gradually dying out,” the authors said. “The resulting rise in the number of susceptible adults sets the stage for the pertussis resurgence, especially among adults.”
Two authors were supported by the National Institutes of Health and by Models of Infectious Disease Agent Study–National Institute of General Medical Sciences. No conflicts of interest were declared.
SOURCE: Domenech de Cellès M et al. Sci Transl Med. 2018 Mar 28;10:eaaj1748.
researchers said.
In the March 28, 2018, edition of Science Translational Medicine, researchers reported on a study that used different models of transmission to explore what might be the cause of the steady increase in pertussis infections since the mid-1970s.
Using 16 years’ worth of detailed, age-stratified incidence data from Massachusetts, researchers found that the model which assumed a gradual waning in protection was the best fit for the observed patterns of pertussis incidence across the population.
This model suggested significant variability in how the level of protection changes over time, with a 10% risk of vaccine protection waning to zero within 10 years of completing routine vaccination and a 55% chance that the vaccine would confer lifelong protection.
“Crucially, we find that the vaccine is effective at reducing pathogen circulation but not so effective that eradication of this highly contagious bacterium should be possible without targeted booster campaigns,” wrote Dr. Matthieu Domenech de Cellès, PhD, of the Institut Pasteur at the University of Versailles (France) and his coauthors.
The model also considered the possibility that the whole-cell and acellular pertussis vaccines might show differences in immunity, which had been suggested as one explanation for the resurgence of the disease. However, the authors found little evidence of a marked epidemiological switch from the whole-cell to acellular vaccines, although their results did suggest the acellular vaccine has a moderately reduced efficacy.
“Our results suggest that the train of events leading to the resurgence of pertussis was set in motion well before the shift to the DTaP vaccine,” Dr. Domenech de Cellès and his associates said.
The model also pointed to big shifts in the age-specific immunological profile caused by introduction of vaccination, which led to a reduction in transmission and also a reduction in natural infections both in vaccinated and unvaccinated individuals.
This meant individuals who either did not get vaccinated as children or who did not gain immunity from vaccination were growing to adulthood without ever being exposed to natural infection.
“Concurrently, older cohorts, with their long-lived immunity derived from natural infections experienced during the prevaccine period, were gradually dying out,” the authors said. “The resulting rise in the number of susceptible adults sets the stage for the pertussis resurgence, especially among adults.”
Two authors were supported by the National Institutes of Health and by Models of Infectious Disease Agent Study–National Institute of General Medical Sciences. No conflicts of interest were declared.
SOURCE: Domenech de Cellès M et al. Sci Transl Med. 2018 Mar 28;10:eaaj1748.
researchers said.
In the March 28, 2018, edition of Science Translational Medicine, researchers reported on a study that used different models of transmission to explore what might be the cause of the steady increase in pertussis infections since the mid-1970s.
Using 16 years’ worth of detailed, age-stratified incidence data from Massachusetts, researchers found that the model which assumed a gradual waning in protection was the best fit for the observed patterns of pertussis incidence across the population.
This model suggested significant variability in how the level of protection changes over time, with a 10% risk of vaccine protection waning to zero within 10 years of completing routine vaccination and a 55% chance that the vaccine would confer lifelong protection.
“Crucially, we find that the vaccine is effective at reducing pathogen circulation but not so effective that eradication of this highly contagious bacterium should be possible without targeted booster campaigns,” wrote Dr. Matthieu Domenech de Cellès, PhD, of the Institut Pasteur at the University of Versailles (France) and his coauthors.
The model also considered the possibility that the whole-cell and acellular pertussis vaccines might show differences in immunity, which had been suggested as one explanation for the resurgence of the disease. However, the authors found little evidence of a marked epidemiological switch from the whole-cell to acellular vaccines, although their results did suggest the acellular vaccine has a moderately reduced efficacy.
“Our results suggest that the train of events leading to the resurgence of pertussis was set in motion well before the shift to the DTaP vaccine,” Dr. Domenech de Cellès and his associates said.
The model also pointed to big shifts in the age-specific immunological profile caused by introduction of vaccination, which led to a reduction in transmission and also a reduction in natural infections both in vaccinated and unvaccinated individuals.
This meant individuals who either did not get vaccinated as children or who did not gain immunity from vaccination were growing to adulthood without ever being exposed to natural infection.
“Concurrently, older cohorts, with their long-lived immunity derived from natural infections experienced during the prevaccine period, were gradually dying out,” the authors said. “The resulting rise in the number of susceptible adults sets the stage for the pertussis resurgence, especially among adults.”
Two authors were supported by the National Institutes of Health and by Models of Infectious Disease Agent Study–National Institute of General Medical Sciences. No conflicts of interest were declared.
SOURCE: Domenech de Cellès M et al. Sci Transl Med. 2018 Mar 28;10:eaaj1748.
FROM SCIENCE TRANSLATIONAL MEDICINE
VIDEO: Nanotechnology is making a mark in gastroenterology
BOSTON – Nanotechnology, though small in scale, is making a big difference in gastroenterology. Nanoparticles can deliver therapeutic compounds or enable other diagnostic tools, said Vadim Backman, PhD, the Walter Dill Scott Professor of Biomedical Engineering at Northwestern University, Chicago, in a video interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. Nanotechnology can treat disease by reprogramming gene expression or gene regulation. Nanoparticle formulations are FDA approved now for treatment of esophageal, colon, and pancreatic cancers, said Dr. Backman in a video interview, but the ability of nanotechnology to reprogram biological processes at the genetic level has researchers looking at treating inflammatory diseases and regenerating tissues.
BOSTON – Nanotechnology, though small in scale, is making a big difference in gastroenterology. Nanoparticles can deliver therapeutic compounds or enable other diagnostic tools, said Vadim Backman, PhD, the Walter Dill Scott Professor of Biomedical Engineering at Northwestern University, Chicago, in a video interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. Nanotechnology can treat disease by reprogramming gene expression or gene regulation. Nanoparticle formulations are FDA approved now for treatment of esophageal, colon, and pancreatic cancers, said Dr. Backman in a video interview, but the ability of nanotechnology to reprogram biological processes at the genetic level has researchers looking at treating inflammatory diseases and regenerating tissues.
BOSTON – Nanotechnology, though small in scale, is making a big difference in gastroenterology. Nanoparticles can deliver therapeutic compounds or enable other diagnostic tools, said Vadim Backman, PhD, the Walter Dill Scott Professor of Biomedical Engineering at Northwestern University, Chicago, in a video interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. Nanotechnology can treat disease by reprogramming gene expression or gene regulation. Nanoparticle formulations are FDA approved now for treatment of esophageal, colon, and pancreatic cancers, said Dr. Backman in a video interview, but the ability of nanotechnology to reprogram biological processes at the genetic level has researchers looking at treating inflammatory diseases and regenerating tissues.
FROM THE 2018 AGA TECH SUMMIT
VIDEO: Adipogenic genes upregulated in high-BMI sucralose users
CHICAGO – , there was significant upregulation of genes that promote intracellular glucose transport. Genes known to be adipogenic and those governing sweet taste receptors also were significantly upregulated with sucralose exposure.
“Effects of sucralose are particularly more detrimental in obese individuals who are prediabetic or diabetic, rather than nonobese consumers of low-calorie sweetener,” said Sabyasachi Sen, MD, during a press conference at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
These new findings, together with in vitro examination of human adipose-derived mesenchymal stromal cells (MSCs) exposed to sucralose, are helping solve the puzzle of how a sweetener that delivers no energy may contribute to metabolic derangement, said Dr. Sen, professor of endocrinology at George Washington University in Washington.
Dr. Sen and his collaborators first exposed the MSCs to concentrations of sucralose ranging from 0 mM to 0.2 mM – a physiologic level for high sucralose consumers – to the supraphysiologic concentration of 1 mM.
The adipogenic genes CEBPa and FABP4 were upregulated in the sucralose-exposed MSCs, which also showed more intracellular fat droplet accumulation. Reactive oxygen species increased in the MSCs in a dose-dependent fashion as well, said Dr. Sen in a video interview.
All of this upregulation, said Dr. Sen, was pushing the MSCs toward becoming fat cells. “At the same time, we saw that there are certain genes that were upregulating that were allowing more glucose to enter the cell.” The increase in reactive oxygen species paralleled what was seen in a similar model that used glucose rather than sucralose, he said.
The investigators then took subcutaneous fat biopsies from four normal-weight individuals (body mass index, 23.4-24.8 kg/m2), and from 14 obese individuals (BMI, 32-64 kg/m2). Each group had sucralose users and nonusers. Using mRNA gene expression profiles, they saw that glucose transporter genes, adipogenic genes, and antioxidant genes were upregulated among sucralose consumers with obesity, significantly more than for the normal-weight participants.
The pattern, said Dr. Sen, was strikingly similar to what had been seen with the MSC-sucralose exposure findings. “The upregulation that we saw in the petri dish could now be seen in the human fat samples,” he said.
“We think that the sucralose is … allowing more glucose to enter the cell,” said Dr. Sen. “We think that we actually have figured out a mechanism.” He and his colleagues next plan to tag glucose molecules to follow what actually happens as they enter cells in the presence of sucralose.
When Dr. Sen’s patients ask whether they should switch to low-calorie sweetened beverages, he answers with an emphatic “no.” “I say, ‘It’s not going to do you any good, because it still may allow glucose to enter the cells … you’re going to come back to the same status quo’ ” in the context of obesity and insulin resistance, he said.
Dr. Sen reported that he has no relevant disclosures.
SOURCE: Sen S et al. ENDO 2018, Abstract SUN-071.
CHICAGO – , there was significant upregulation of genes that promote intracellular glucose transport. Genes known to be adipogenic and those governing sweet taste receptors also were significantly upregulated with sucralose exposure.
“Effects of sucralose are particularly more detrimental in obese individuals who are prediabetic or diabetic, rather than nonobese consumers of low-calorie sweetener,” said Sabyasachi Sen, MD, during a press conference at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
These new findings, together with in vitro examination of human adipose-derived mesenchymal stromal cells (MSCs) exposed to sucralose, are helping solve the puzzle of how a sweetener that delivers no energy may contribute to metabolic derangement, said Dr. Sen, professor of endocrinology at George Washington University in Washington.
Dr. Sen and his collaborators first exposed the MSCs to concentrations of sucralose ranging from 0 mM to 0.2 mM – a physiologic level for high sucralose consumers – to the supraphysiologic concentration of 1 mM.
The adipogenic genes CEBPa and FABP4 were upregulated in the sucralose-exposed MSCs, which also showed more intracellular fat droplet accumulation. Reactive oxygen species increased in the MSCs in a dose-dependent fashion as well, said Dr. Sen in a video interview.
All of this upregulation, said Dr. Sen, was pushing the MSCs toward becoming fat cells. “At the same time, we saw that there are certain genes that were upregulating that were allowing more glucose to enter the cell.” The increase in reactive oxygen species paralleled what was seen in a similar model that used glucose rather than sucralose, he said.
The investigators then took subcutaneous fat biopsies from four normal-weight individuals (body mass index, 23.4-24.8 kg/m2), and from 14 obese individuals (BMI, 32-64 kg/m2). Each group had sucralose users and nonusers. Using mRNA gene expression profiles, they saw that glucose transporter genes, adipogenic genes, and antioxidant genes were upregulated among sucralose consumers with obesity, significantly more than for the normal-weight participants.
The pattern, said Dr. Sen, was strikingly similar to what had been seen with the MSC-sucralose exposure findings. “The upregulation that we saw in the petri dish could now be seen in the human fat samples,” he said.
“We think that the sucralose is … allowing more glucose to enter the cell,” said Dr. Sen. “We think that we actually have figured out a mechanism.” He and his colleagues next plan to tag glucose molecules to follow what actually happens as they enter cells in the presence of sucralose.
When Dr. Sen’s patients ask whether they should switch to low-calorie sweetened beverages, he answers with an emphatic “no.” “I say, ‘It’s not going to do you any good, because it still may allow glucose to enter the cells … you’re going to come back to the same status quo’ ” in the context of obesity and insulin resistance, he said.
Dr. Sen reported that he has no relevant disclosures.
SOURCE: Sen S et al. ENDO 2018, Abstract SUN-071.
CHICAGO – , there was significant upregulation of genes that promote intracellular glucose transport. Genes known to be adipogenic and those governing sweet taste receptors also were significantly upregulated with sucralose exposure.
“Effects of sucralose are particularly more detrimental in obese individuals who are prediabetic or diabetic, rather than nonobese consumers of low-calorie sweetener,” said Sabyasachi Sen, MD, during a press conference at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
These new findings, together with in vitro examination of human adipose-derived mesenchymal stromal cells (MSCs) exposed to sucralose, are helping solve the puzzle of how a sweetener that delivers no energy may contribute to metabolic derangement, said Dr. Sen, professor of endocrinology at George Washington University in Washington.
Dr. Sen and his collaborators first exposed the MSCs to concentrations of sucralose ranging from 0 mM to 0.2 mM – a physiologic level for high sucralose consumers – to the supraphysiologic concentration of 1 mM.
The adipogenic genes CEBPa and FABP4 were upregulated in the sucralose-exposed MSCs, which also showed more intracellular fat droplet accumulation. Reactive oxygen species increased in the MSCs in a dose-dependent fashion as well, said Dr. Sen in a video interview.
All of this upregulation, said Dr. Sen, was pushing the MSCs toward becoming fat cells. “At the same time, we saw that there are certain genes that were upregulating that were allowing more glucose to enter the cell.” The increase in reactive oxygen species paralleled what was seen in a similar model that used glucose rather than sucralose, he said.
The investigators then took subcutaneous fat biopsies from four normal-weight individuals (body mass index, 23.4-24.8 kg/m2), and from 14 obese individuals (BMI, 32-64 kg/m2). Each group had sucralose users and nonusers. Using mRNA gene expression profiles, they saw that glucose transporter genes, adipogenic genes, and antioxidant genes were upregulated among sucralose consumers with obesity, significantly more than for the normal-weight participants.
The pattern, said Dr. Sen, was strikingly similar to what had been seen with the MSC-sucralose exposure findings. “The upregulation that we saw in the petri dish could now be seen in the human fat samples,” he said.
“We think that the sucralose is … allowing more glucose to enter the cell,” said Dr. Sen. “We think that we actually have figured out a mechanism.” He and his colleagues next plan to tag glucose molecules to follow what actually happens as they enter cells in the presence of sucralose.
When Dr. Sen’s patients ask whether they should switch to low-calorie sweetened beverages, he answers with an emphatic “no.” “I say, ‘It’s not going to do you any good, because it still may allow glucose to enter the cells … you’re going to come back to the same status quo’ ” in the context of obesity and insulin resistance, he said.
Dr. Sen reported that he has no relevant disclosures.
SOURCE: Sen S et al. ENDO 2018, Abstract SUN-071.
REPORTING FROM ENDO 2018
Insomnia – going beyond sleep hygiene
Difficulties with sleep are prevalent and significant across the developmental spectrum. Not only does poor sleep affect daytime functioning in relation to mood, focus, appetite, and emotional regulation, but ineffective bedtime routines can cause significant distress for youth and caregivers, as well. The American Academy of Sleep Medicine describes insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.’’1
Pediatric providers likely are familiar already with initial steps in the evaluation and treatment of insomnia. The emphasis here is assessment and intervention approaches beyond the foundational use of sleep hygiene recommendations.
In working with a patient such as Katie who comes laden with diagnoses and medications, stepping back to reconsider the assessment is an important starting point. Problems related to sleep are rife in psychiatric conditions, from depression, anxiety, and PTSD to bipolar disorder, ADHD, and autism.2
Next is see if there are external factors engendering insomnia. Sleep hygiene focuses on these, but sometimes recent stressors or familial conflict are overlooked, which may be linchpins to improving sleep patterns. Commonly prescribed medications (steroids, bupropion, and stimulants) and intoxication or withdrawal symptoms from substance use can contribute to wakefulness and deserve consideration. It can be useful to track sleep for a while to identify contributing factors, impediments to sleep, and ineffective patterns (see tools at sleepfoundation.org or the free app CBT-I Coach).
After assessment, the bulk of the evidence for pediatric insomnia is for behavioral treatments, mostly for infants and young children. This may be familiar territory, and it offers a good time to assess the level of motivation. Are the patient and family aware of how insomnia affects their lives on a day-to-day basis and is this problem a priority?
For adolescents who are convinced of the life-changing properties of a good night’s sleep, cognitive-behavioral therapy for insomnia (CBT-i) is developing a strong evidence base for insomnia in adolescents.3 CBT-i adds to the usual interventions for addressing insomnia in infants and young children by additionally training adolescents relaxation techniques, by addressing cognitive distortions about sleep, and by actually restricting sleep. This last technique involves initially reducing the amount of sleep in order to build a tight association between sleep and the bedroom, improve sleep efficiency, and increase sleep drive.
In general, medications are considered when other appropriate interventions have proven inadequate. There is very little evidence for using pharmacologic interventions for pediatric insomnia, so even if a medication is selected, behavioral approaches should remain a mainstay.4 Patients and caregivers should agree to specific short-term goals ahead of time when using sleep medicine, given the limited effectiveness and recommended short duration of use. Many medications change sleep architecture, and none have been clearly shown to sustainably improve sleep quality or quantity or reduce daytime symptoms of insomnia.
Prescribing guidelines for insomnia suggest selecting an agent matched to the symptoms and relevant to any comorbidities. Melatonin may be most helpful in shifting the sleep phase rather than for direct hypnotic effects; thus adolescents or patients with ADHD whose sleep schedule has naturally shifted later may benefit from a small dose of melatonin (1-3 mg) several hours before bedtime to prime their system. Beware that melatonin is not regulated by the Food and Drug Administration and animal studies have shown significant alterations of the gonadal hormone axis, although this has not been examined in human trials. Alpha-2 agonists – such as clonidine and guanfacine – may be helpful for sleep initiation, especially in populations with comorbid ADHD, aggression, or tics, where these medications might be otherwise indicated. Prazosin, an alpha-1 antagonist, has some limited evidence as a treatment for nightmares and PTSD symptoms, so it may be a good choice for children with trauma-related hypervigilance.
In patients with depression, low doses of trazodone (12.5-50 mg) or mirtazapine (7.5-15 mg) may be effective. Although short-acting benzodiazepines may be useful in the short-term, particularly for sleep-onset difficulties, they generally are not recommended because of the risks of abuse, diversion, withdrawal, cognitive side effects, disinhibition, development of tolerance, and contraindication with such comorbidities as sleep apnea. However, the benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone, while lacking evidence in the pediatric population, may be worthwhile considerations as their varying half-lives allow for specificity in treating sleep-onset vs. sleep-maintenance problems. Caregivers should be warned about the potential for sleepwalking or other complex sleep-related behaviors with this class of medicines.
Avoid tricyclic antidepressants because of the potential for anticholinergic effects and cardiotoxicity. Atypical antipsychotics generally are not worth the risk of serious and rapid side effects associated with this class of medications, which include metabolic syndrome.
The assessment and treatment of pediatric insomnia may require several visits to complete. But, given growing knowledge of how much sleep contributes to learning, longevity, and well-being, and the consequences of sleep deprivation with regard to safety, irritability, poor concentration, disordered metabolism and appetite, etc., the potential benefits seem well worth the time.
Dr. Rosenfeld is assistant professor of psychiatry at Vermont Center for Children, Youth & Families, at the University of Vermont Medical Center, and the University of Vermont, Burlington. He has received honorarium from Oakstone Publishing for contributing board review course content on human development.
References
1. International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd edition. (Westchester: American Academy of Sleep Medicine, 2005).
2. Child Adolesc Psychiatr Clin N Am. 2009 Oct;18(4):979-1000
3. J Child Psychol Psychiatry. 2017, Oct 20. doi: 10.1111/jcpp.12834.
4. Child Adolesc Psychiatric Clin N Am. 2009, Oct;18(4):1001-16.
Difficulties with sleep are prevalent and significant across the developmental spectrum. Not only does poor sleep affect daytime functioning in relation to mood, focus, appetite, and emotional regulation, but ineffective bedtime routines can cause significant distress for youth and caregivers, as well. The American Academy of Sleep Medicine describes insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.’’1
Pediatric providers likely are familiar already with initial steps in the evaluation and treatment of insomnia. The emphasis here is assessment and intervention approaches beyond the foundational use of sleep hygiene recommendations.
In working with a patient such as Katie who comes laden with diagnoses and medications, stepping back to reconsider the assessment is an important starting point. Problems related to sleep are rife in psychiatric conditions, from depression, anxiety, and PTSD to bipolar disorder, ADHD, and autism.2
Next is see if there are external factors engendering insomnia. Sleep hygiene focuses on these, but sometimes recent stressors or familial conflict are overlooked, which may be linchpins to improving sleep patterns. Commonly prescribed medications (steroids, bupropion, and stimulants) and intoxication or withdrawal symptoms from substance use can contribute to wakefulness and deserve consideration. It can be useful to track sleep for a while to identify contributing factors, impediments to sleep, and ineffective patterns (see tools at sleepfoundation.org or the free app CBT-I Coach).
After assessment, the bulk of the evidence for pediatric insomnia is for behavioral treatments, mostly for infants and young children. This may be familiar territory, and it offers a good time to assess the level of motivation. Are the patient and family aware of how insomnia affects their lives on a day-to-day basis and is this problem a priority?
For adolescents who are convinced of the life-changing properties of a good night’s sleep, cognitive-behavioral therapy for insomnia (CBT-i) is developing a strong evidence base for insomnia in adolescents.3 CBT-i adds to the usual interventions for addressing insomnia in infants and young children by additionally training adolescents relaxation techniques, by addressing cognitive distortions about sleep, and by actually restricting sleep. This last technique involves initially reducing the amount of sleep in order to build a tight association between sleep and the bedroom, improve sleep efficiency, and increase sleep drive.
In general, medications are considered when other appropriate interventions have proven inadequate. There is very little evidence for using pharmacologic interventions for pediatric insomnia, so even if a medication is selected, behavioral approaches should remain a mainstay.4 Patients and caregivers should agree to specific short-term goals ahead of time when using sleep medicine, given the limited effectiveness and recommended short duration of use. Many medications change sleep architecture, and none have been clearly shown to sustainably improve sleep quality or quantity or reduce daytime symptoms of insomnia.
Prescribing guidelines for insomnia suggest selecting an agent matched to the symptoms and relevant to any comorbidities. Melatonin may be most helpful in shifting the sleep phase rather than for direct hypnotic effects; thus adolescents or patients with ADHD whose sleep schedule has naturally shifted later may benefit from a small dose of melatonin (1-3 mg) several hours before bedtime to prime their system. Beware that melatonin is not regulated by the Food and Drug Administration and animal studies have shown significant alterations of the gonadal hormone axis, although this has not been examined in human trials. Alpha-2 agonists – such as clonidine and guanfacine – may be helpful for sleep initiation, especially in populations with comorbid ADHD, aggression, or tics, where these medications might be otherwise indicated. Prazosin, an alpha-1 antagonist, has some limited evidence as a treatment for nightmares and PTSD symptoms, so it may be a good choice for children with trauma-related hypervigilance.
In patients with depression, low doses of trazodone (12.5-50 mg) or mirtazapine (7.5-15 mg) may be effective. Although short-acting benzodiazepines may be useful in the short-term, particularly for sleep-onset difficulties, they generally are not recommended because of the risks of abuse, diversion, withdrawal, cognitive side effects, disinhibition, development of tolerance, and contraindication with such comorbidities as sleep apnea. However, the benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone, while lacking evidence in the pediatric population, may be worthwhile considerations as their varying half-lives allow for specificity in treating sleep-onset vs. sleep-maintenance problems. Caregivers should be warned about the potential for sleepwalking or other complex sleep-related behaviors with this class of medicines.
Avoid tricyclic antidepressants because of the potential for anticholinergic effects and cardiotoxicity. Atypical antipsychotics generally are not worth the risk of serious and rapid side effects associated with this class of medications, which include metabolic syndrome.
The assessment and treatment of pediatric insomnia may require several visits to complete. But, given growing knowledge of how much sleep contributes to learning, longevity, and well-being, and the consequences of sleep deprivation with regard to safety, irritability, poor concentration, disordered metabolism and appetite, etc., the potential benefits seem well worth the time.
Dr. Rosenfeld is assistant professor of psychiatry at Vermont Center for Children, Youth & Families, at the University of Vermont Medical Center, and the University of Vermont, Burlington. He has received honorarium from Oakstone Publishing for contributing board review course content on human development.
References
1. International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd edition. (Westchester: American Academy of Sleep Medicine, 2005).
2. Child Adolesc Psychiatr Clin N Am. 2009 Oct;18(4):979-1000
3. J Child Psychol Psychiatry. 2017, Oct 20. doi: 10.1111/jcpp.12834.
4. Child Adolesc Psychiatric Clin N Am. 2009, Oct;18(4):1001-16.
Difficulties with sleep are prevalent and significant across the developmental spectrum. Not only does poor sleep affect daytime functioning in relation to mood, focus, appetite, and emotional regulation, but ineffective bedtime routines can cause significant distress for youth and caregivers, as well. The American Academy of Sleep Medicine describes insomnia as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family.’’1
Pediatric providers likely are familiar already with initial steps in the evaluation and treatment of insomnia. The emphasis here is assessment and intervention approaches beyond the foundational use of sleep hygiene recommendations.
In working with a patient such as Katie who comes laden with diagnoses and medications, stepping back to reconsider the assessment is an important starting point. Problems related to sleep are rife in psychiatric conditions, from depression, anxiety, and PTSD to bipolar disorder, ADHD, and autism.2
Next is see if there are external factors engendering insomnia. Sleep hygiene focuses on these, but sometimes recent stressors or familial conflict are overlooked, which may be linchpins to improving sleep patterns. Commonly prescribed medications (steroids, bupropion, and stimulants) and intoxication or withdrawal symptoms from substance use can contribute to wakefulness and deserve consideration. It can be useful to track sleep for a while to identify contributing factors, impediments to sleep, and ineffective patterns (see tools at sleepfoundation.org or the free app CBT-I Coach).
After assessment, the bulk of the evidence for pediatric insomnia is for behavioral treatments, mostly for infants and young children. This may be familiar territory, and it offers a good time to assess the level of motivation. Are the patient and family aware of how insomnia affects their lives on a day-to-day basis and is this problem a priority?
For adolescents who are convinced of the life-changing properties of a good night’s sleep, cognitive-behavioral therapy for insomnia (CBT-i) is developing a strong evidence base for insomnia in adolescents.3 CBT-i adds to the usual interventions for addressing insomnia in infants and young children by additionally training adolescents relaxation techniques, by addressing cognitive distortions about sleep, and by actually restricting sleep. This last technique involves initially reducing the amount of sleep in order to build a tight association between sleep and the bedroom, improve sleep efficiency, and increase sleep drive.
In general, medications are considered when other appropriate interventions have proven inadequate. There is very little evidence for using pharmacologic interventions for pediatric insomnia, so even if a medication is selected, behavioral approaches should remain a mainstay.4 Patients and caregivers should agree to specific short-term goals ahead of time when using sleep medicine, given the limited effectiveness and recommended short duration of use. Many medications change sleep architecture, and none have been clearly shown to sustainably improve sleep quality or quantity or reduce daytime symptoms of insomnia.
Prescribing guidelines for insomnia suggest selecting an agent matched to the symptoms and relevant to any comorbidities. Melatonin may be most helpful in shifting the sleep phase rather than for direct hypnotic effects; thus adolescents or patients with ADHD whose sleep schedule has naturally shifted later may benefit from a small dose of melatonin (1-3 mg) several hours before bedtime to prime their system. Beware that melatonin is not regulated by the Food and Drug Administration and animal studies have shown significant alterations of the gonadal hormone axis, although this has not been examined in human trials. Alpha-2 agonists – such as clonidine and guanfacine – may be helpful for sleep initiation, especially in populations with comorbid ADHD, aggression, or tics, where these medications might be otherwise indicated. Prazosin, an alpha-1 antagonist, has some limited evidence as a treatment for nightmares and PTSD symptoms, so it may be a good choice for children with trauma-related hypervigilance.
In patients with depression, low doses of trazodone (12.5-50 mg) or mirtazapine (7.5-15 mg) may be effective. Although short-acting benzodiazepines may be useful in the short-term, particularly for sleep-onset difficulties, they generally are not recommended because of the risks of abuse, diversion, withdrawal, cognitive side effects, disinhibition, development of tolerance, and contraindication with such comorbidities as sleep apnea. However, the benzodiazepine receptor agonists such as zaleplon, zolpidem, and eszopiclone, while lacking evidence in the pediatric population, may be worthwhile considerations as their varying half-lives allow for specificity in treating sleep-onset vs. sleep-maintenance problems. Caregivers should be warned about the potential for sleepwalking or other complex sleep-related behaviors with this class of medicines.
Avoid tricyclic antidepressants because of the potential for anticholinergic effects and cardiotoxicity. Atypical antipsychotics generally are not worth the risk of serious and rapid side effects associated with this class of medications, which include metabolic syndrome.
The assessment and treatment of pediatric insomnia may require several visits to complete. But, given growing knowledge of how much sleep contributes to learning, longevity, and well-being, and the consequences of sleep deprivation with regard to safety, irritability, poor concentration, disordered metabolism and appetite, etc., the potential benefits seem well worth the time.
Dr. Rosenfeld is assistant professor of psychiatry at Vermont Center for Children, Youth & Families, at the University of Vermont Medical Center, and the University of Vermont, Burlington. He has received honorarium from Oakstone Publishing for contributing board review course content on human development.
References
1. International Classification of Sleep Disorders: Diagnostic & Coding Manual. 2nd edition. (Westchester: American Academy of Sleep Medicine, 2005).
2. Child Adolesc Psychiatr Clin N Am. 2009 Oct;18(4):979-1000
3. J Child Psychol Psychiatry. 2017, Oct 20. doi: 10.1111/jcpp.12834.
4. Child Adolesc Psychiatric Clin N Am. 2009, Oct;18(4):1001-16.
Dexcom G6 gets FDA nod
from the Food and Drug Administration.
The Dexcom G6 is about 28% smaller than its predecessor, the G5, can be worn for up to 10 days – 43% longer than the G5 – and doesn’t require any finger-stick calibrations or treatment decisions. It’s the first FDA-approved integrated continuous glucose monitoring (iCGM) system that can link electronically to other compatible devices, including automated insulin dosing systems, insulin pumps, blood glucose meters, and other electronic devices used for diabetes management, the FDA said in a press statement. Its revamped sensor doesn’t interact with acetaminophen – another distinct advantage over the G5.
The device will be commercially available sometime this year, the Dexcom website noted.
The device also set a new premarketing review standard for CGM’s, which can now utilize the less-burdensome 510(k) clearance pathway. Until now, they have been treated as the highest-risk Class III medical devices.
According to the FDA statement, the agency “…recognized this as an opportunity to reduce the regulatory burden for this type of device by establishing criteria that would classify these as ‘moderate risk,’ class II medical devices with special controls.”
G6 was approved through this new pathway, dedicated to novel, low-to-moderate-risk devices that are not “substantially equivalent” to an already legally marketed device, the press statement said.
The FDA evaluated data from two clinical studies of the Dexcom G6, which included 324 adults and children aged 2 years and older with diabetes. Both studies included multiple clinical visits within a 10-day period where system readings were compared to a laboratory test method that measures blood glucose values. No serious adverse events were reported during the studies.
from the Food and Drug Administration.
The Dexcom G6 is about 28% smaller than its predecessor, the G5, can be worn for up to 10 days – 43% longer than the G5 – and doesn’t require any finger-stick calibrations or treatment decisions. It’s the first FDA-approved integrated continuous glucose monitoring (iCGM) system that can link electronically to other compatible devices, including automated insulin dosing systems, insulin pumps, blood glucose meters, and other electronic devices used for diabetes management, the FDA said in a press statement. Its revamped sensor doesn’t interact with acetaminophen – another distinct advantage over the G5.
The device will be commercially available sometime this year, the Dexcom website noted.
The device also set a new premarketing review standard for CGM’s, which can now utilize the less-burdensome 510(k) clearance pathway. Until now, they have been treated as the highest-risk Class III medical devices.
According to the FDA statement, the agency “…recognized this as an opportunity to reduce the regulatory burden for this type of device by establishing criteria that would classify these as ‘moderate risk,’ class II medical devices with special controls.”
G6 was approved through this new pathway, dedicated to novel, low-to-moderate-risk devices that are not “substantially equivalent” to an already legally marketed device, the press statement said.
The FDA evaluated data from two clinical studies of the Dexcom G6, which included 324 adults and children aged 2 years and older with diabetes. Both studies included multiple clinical visits within a 10-day period where system readings were compared to a laboratory test method that measures blood glucose values. No serious adverse events were reported during the studies.
from the Food and Drug Administration.
The Dexcom G6 is about 28% smaller than its predecessor, the G5, can be worn for up to 10 days – 43% longer than the G5 – and doesn’t require any finger-stick calibrations or treatment decisions. It’s the first FDA-approved integrated continuous glucose monitoring (iCGM) system that can link electronically to other compatible devices, including automated insulin dosing systems, insulin pumps, blood glucose meters, and other electronic devices used for diabetes management, the FDA said in a press statement. Its revamped sensor doesn’t interact with acetaminophen – another distinct advantage over the G5.
The device will be commercially available sometime this year, the Dexcom website noted.
The device also set a new premarketing review standard for CGM’s, which can now utilize the less-burdensome 510(k) clearance pathway. Until now, they have been treated as the highest-risk Class III medical devices.
According to the FDA statement, the agency “…recognized this as an opportunity to reduce the regulatory burden for this type of device by establishing criteria that would classify these as ‘moderate risk,’ class II medical devices with special controls.”
G6 was approved through this new pathway, dedicated to novel, low-to-moderate-risk devices that are not “substantially equivalent” to an already legally marketed device, the press statement said.
The FDA evaluated data from two clinical studies of the Dexcom G6, which included 324 adults and children aged 2 years and older with diabetes. Both studies included multiple clinical visits within a 10-day period where system readings were compared to a laboratory test method that measures blood glucose values. No serious adverse events were reported during the studies.