A 50-year-old African-American man is referred to dermatology by his primary care provider for evaluation of colored stripes in most of his fingernails. These have been present, without change, for most of his adult life.

The patient has been told these changes probably represent fungal infection, but being dubious of that diagnosis, he declined recommended treatment. Nonetheless, he is interested in knowing exactly what is happening to his nails.

He denies personal or family history of skin cancer and of excessive sun exposure. He reports that several maternal family members have similar nail changes.

EXAMINATION
Seven of the patient’s 10 fingernails demonstrate linear brown streaks that uniformly average 1.5 to 2 mm in width. The streaks run the length of the nail, with no involvement of the adjacent cuticle. Some are darker than others.

The patient has type V skin with no evidence of excessive sun damage.

What’s the diagnosis?

DISCUSSION
Fortunately, this patient’s problem is benign and likely to remain so. Termed longitudinal (or linear) melanonychia (LM), these changes are seen in nearly all African-Americans older than 50 (although it is not uncommon for the condition to develop in the third decade of life). Other populations with dark skin are also at risk for LM, albeit at far lower rates. In white populations, the incidence is around 0.5% to 1%.

LM is caused by activation and proliferation of melanocytes in the nail matrix; they are focally incorporated into the nail plate as onychocytes that grow out with the nail. Typically 1 to 3 mm in uniform width, the streaks of LM range from tan to dark brown and can be solitary or multiple in a given nail.

As mentioned, LM is entirely benign, with almost no potential for malignant transformation. However, two notes of caution are in order: First, although African-American persons generally have very low risk for melanoma, the malignancy tends to manifest in this population in areas with the least pigment (eg, palms, soles, oral cavities, nail beds—unusual locations for most other racial groups). Second, the prognosis for these types of melanomas is poor; most patients and providers are unaware of them until an advanced stage that typically includes metastasis.

Therefore, in patients with skin of color, new or changing lesions in the nail bed must be evaluated by a knowledgeable dermatology provider, who may choose to biopsy the proximal aspect of the lesion to rule out cancer. Of course, any such lesion in a white person needs to be monitored carefully as well, since linear melanonychia is relatively uncommon in this group. Changes in the width, color, or border should cause concern, as should extension of the darker color onto the adjacent cuticle.

The differential for linear discoloration in nails or nail beds includes foreign body, warts, benign tumors (eg, nevi), glomus tumors (which are usually painful), and of course, fungal, mold, or yeast infections.

TAKE-HOME LEARNING POINTS

• Longitudinal (or linear) melanonychia (LM) is quite common in African-Americans, approaching a prevalence of 100% in those older than 50.
• Having multiple LMs in more than one finger is common in this population.
• However, a new or changing subungual lesion bears close monitoring, or even biopsy, by an experienced dermatology provider.
• Although African-Americans rarely develop melanoma, when they do, it’s often in the least pigmented areas (eg, palms, soles, mouth, and nails).
• The prognosis for proven melanoma in African-American patients is poor, making close monitoring a necessity.

A 50-year-old African-American man is referred to dermatology by his primary care provider for evaluation of colored stripes in most of his fingernails. These have been present, without change, for most of his adult life.

The patient has been told these changes probably represent fungal infection, but being dubious of that diagnosis, he declined recommended treatment. Nonetheless, he is interested in knowing exactly what is happening to his nails.

He denies personal or family history of skin cancer and of excessive sun exposure. He reports that several maternal family members have similar nail changes.

EXAMINATION
Seven of the patient’s 10 fingernails demonstrate linear brown streaks that uniformly average 1.5 to 2 mm in width. The streaks run the length of the nail, with no involvement of the adjacent cuticle. Some are darker than others.

The patient has type V skin with no evidence of excessive sun damage.

What’s the diagnosis?

DISCUSSION
Fortunately, this patient’s problem is benign and likely to remain so. Termed longitudinal (or linear) melanonychia (LM), these changes are seen in nearly all African-Americans older than 50 (although it is not uncommon for the condition to develop in the third decade of life). Other populations with dark skin are also at risk for LM, albeit at far lower rates. In white populations, the incidence is around 0.5% to 1%.

LM is caused by activation and proliferation of melanocytes in the nail matrix; they are focally incorporated into the nail plate as onychocytes that grow out with the nail. Typically 1 to 3 mm in uniform width, the streaks of LM range from tan to dark brown and can be solitary or multiple in a given nail.

As mentioned, LM is entirely benign, with almost no potential for malignant transformation. However, two notes of caution are in order: First, although African-American persons generally have very low risk for melanoma, the malignancy tends to manifest in this population in areas with the least pigment (eg, palms, soles, oral cavities, nail beds—unusual locations for most other racial groups). Second, the prognosis for these types of melanomas is poor; most patients and providers are unaware of them until an advanced stage that typically includes metastasis.

Therefore, in patients with skin of color, new or changing lesions in the nail bed must be evaluated by a knowledgeable dermatology provider, who may choose to biopsy the proximal aspect of the lesion to rule out cancer. Of course, any such lesion in a white person needs to be monitored carefully as well, since linear melanonychia is relatively uncommon in this group. Changes in the width, color, or border should cause concern, as should extension of the darker color onto the adjacent cuticle.

The differential for linear discoloration in nails or nail beds includes foreign body, warts, benign tumors (eg, nevi), glomus tumors (which are usually painful), and of course, fungal, mold, or yeast infections.

TAKE-HOME LEARNING POINTS

• Longitudinal (or linear) melanonychia (LM) is quite common in African-Americans, approaching a prevalence of 100% in those older than 50.
• Having multiple LMs in more than one finger is common in this population.
• However, a new or changing subungual lesion bears close monitoring, or even biopsy, by an experienced dermatology provider.
• Although African-Americans rarely develop melanoma, when they do, it’s often in the least pigmented areas (eg, palms, soles, mouth, and nails).
• The prognosis for proven melanoma in African-American patients is poor, making close monitoring a necessity.

A 50-year-old African-American man is referred to dermatology by his primary care provider for evaluation of colored stripes in most of his fingernails. These have been present, without change, for most of his adult life.

The patient has been told these changes probably represent fungal infection, but being dubious of that diagnosis, he declined recommended treatment. Nonetheless, he is interested in knowing exactly what is happening to his nails.

He denies personal or family history of skin cancer and of excessive sun exposure. He reports that several maternal family members have similar nail changes.

EXAMINATION
Seven of the patient’s 10 fingernails demonstrate linear brown streaks that uniformly average 1.5 to 2 mm in width. The streaks run the length of the nail, with no involvement of the adjacent cuticle. Some are darker than others.

The patient has type V skin with no evidence of excessive sun damage.

What’s the diagnosis?

DISCUSSION
Fortunately, this patient’s problem is benign and likely to remain so. Termed longitudinal (or linear) melanonychia (LM), these changes are seen in nearly all African-Americans older than 50 (although it is not uncommon for the condition to develop in the third decade of life). Other populations with dark skin are also at risk for LM, albeit at far lower rates. In white populations, the incidence is around 0.5% to 1%.

LM is caused by activation and proliferation of melanocytes in the nail matrix; they are focally incorporated into the nail plate as onychocytes that grow out with the nail. Typically 1 to 3 mm in uniform width, the streaks of LM range from tan to dark brown and can be solitary or multiple in a given nail.

As mentioned, LM is entirely benign, with almost no potential for malignant transformation. However, two notes of caution are in order: First, although African-American persons generally have very low risk for melanoma, the malignancy tends to manifest in this population in areas with the least pigment (eg, palms, soles, oral cavities, nail beds—unusual locations for most other racial groups). Second, the prognosis for these types of melanomas is poor; most patients and providers are unaware of them until an advanced stage that typically includes metastasis.

Therefore, in patients with skin of color, new or changing lesions in the nail bed must be evaluated by a knowledgeable dermatology provider, who may choose to biopsy the proximal aspect of the lesion to rule out cancer. Of course, any such lesion in a white person needs to be monitored carefully as well, since linear melanonychia is relatively uncommon in this group. Changes in the width, color, or border should cause concern, as should extension of the darker color onto the adjacent cuticle.

The differential for linear discoloration in nails or nail beds includes foreign body, warts, benign tumors (eg, nevi), glomus tumors (which are usually painful), and of course, fungal, mold, or yeast infections.

TAKE-HOME LEARNING POINTS

• Longitudinal (or linear) melanonychia (LM) is quite common in African-Americans, approaching a prevalence of 100% in those older than 50.
• Having multiple LMs in more than one finger is common in this population.
• However, a new or changing subungual lesion bears close monitoring, or even biopsy, by an experienced dermatology provider.
• Although African-Americans rarely develop melanoma, when they do, it’s often in the least pigmented areas (eg, palms, soles, mouth, and nails).
• The prognosis for proven melanoma in African-American patients is poor, making close monitoring a necessity.

More bad news for Alzheimer’s research. Two more BACE inhibitors fall far short of the finish line.

Not only did both verubecestat and atabecestat fail to improve cognition and function patients with prodromal Alzheimer’s disease, they also made things worse. Declining cognitive scores, falls, suicidal ideation, and liver enzyme abnormalities were all seen in clinical trials.

The news doesn’t bode well for the therapeutic target of BACE (beta-site APP cleaving enzyme) inhibition. BACE is one of the enzymes that trims the amyloid precursor protein (APP). Inhibiting it does reduce the amount of toxic amyloid-beta in cerebrospinal fluid, and amyloid plaque in the brain. But none of these molecules has shown clinical benefit in dementia patients, whether their disease is mild, or moderate or – now – prodromal. And it is now apparent that inhibiting BACE also produces serious off-target problems.

“BACE-1 inhibition certainly seemed to have a sound rationale assuming the basis for amyloid’s role in Alzheimer’s disease pathogenesis is a gain of toxicity,” Richard J. Caselli, MD, of the Mayo Clinic, Rochester, Minn., said in an interview. “That APP is important for Alzheimer’s pathogenesis still seems clear but whether amyloid-beta toxicity is the driving force is no longer clear. Further, interruption of the APP system disrupts more than amyloid-beta peptide, possibly explaining the adverse cognitive effects of BACE-1 inhibition shown exhibited now by three different BACE-1 inhibitors.”
 

Verubecestat

Researchers got their first dose of bad news regarding verubecestat at the 2017 Clinical Trials in Alzheimer’s Disease meeting. There, Michael F. Egan, MD, Merck’s associate vice president of clinical neuroscience, discussed the molecule’s failure to slow cognitive decline in patients with mild to moderate Alzheimer’s disease. There was plenty of biomarker evidence that the drug did block amyloid-beta production, but there also was a plethora of concerning adverse events, Dr. Egan said in an interview.

However, verubecestat still was being pursued in patients with prodromal Alzheimer’s disease. In February, Merck stopped the trial after a futility analysis and announced that the company was terminating studies of verubecestat in that population as well. In the April 11 issue of the New England Journal of Medicine, Dr. Egan and his colleagues report the full extent of verubecestat’s failure in prodromal patients, and the accompanying adverse events.

At the time of termination, 1,454 patients had been enrolled. Of these, 485 received 12 mg/day, 484 received 40 mg/day, and 485 received placebo. About half of each group completed 104 weeks of treatment in the study, which was designed to extend up to 5 years.

The primary outcome was change in the Clinical Dementia Rating Scale–Sum of Boxes score (CDR-SB). Seven secondary outcomes examined other cognitive and functional end points, along with changes in hippocampal volume on MRI and amyloid burden as determined in PET imaging.

Not only did verubecestat fail to slow cognitive decline, it appeared to exacerbate it. The mean change on the CDR-SB was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group, favoring placebo.

“In an exploratory analysis according to time point, scores on the CDR-SB were also higher [signifying more impairment of cognition and daily functioning] in the 40-mg group than in the placebo group at 13, 26, and 52 weeks ... suggesting but not confirming the possibility of worse performance at these earlier time points in the high-dose verubecestat group,” the investigators said.

Verubecestat also was associated with more conversions to Alzheimer’s disease. Per 100 patient-years, the Alzheimer’s disease event rates were 24.5 in the 12-mg group, 25.5 in the 40-mg group, and 19.3 in the placebo group. Compared with placebo, those taking 12-mg doses were 30% more likely to develop Alzheimer’s disease and those taking 40-mg doses were 38% more likely. The findings suggest that “verubecestat may have accelerated the progression to diagnosis of dementia due to Alzheimer’s disease,” the investigators said.

The negative impact of verubecestat was apparent quite early in the study. “In exploratory analyses, both dose levels of verubecestat were associated with poorer outcomes on the [Composite Cognition Score-3 Domain] and the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] measures of cognition that, relative to placebo, appeared worse at week 13 and did not appear to progress thereafter.”

Results of the secondary end points, including the ADAS-Cog and the Mini-Mental State Exam, also indicated that verubecestat may have worsened cognitive performance.

Imaging outcomes were positive, however. Hippocampal volume was 6,448 mL in the 12-mg group, 6,469 mL in the 40-mg group, and 6,435 mL in the placebo group. Brain amyloid increased in the placebo group, as expected, and decreased in the active groups. The small group of patients who underwent cerebrospinal fluid sampling showed reductions of more than 60% in amyloid-beta and soluble APP-beta associated with verubecestat. These results show that the molecule was indeed hitting its intended target, but that doing so was not clinically beneficial.

Adverse events were more common in the verubecestat groups. These included rash, dermatitis, urticaria, sleep disturbance, weight loss, and cough. Hair coloring changed in 2.5% of patients in the 12-mg group and 5% of the 40-mg group, but in none of the subjects taking placebo.

Patients taking verubecestat were more likely to sustain falls and injuries and to express suicidal ideation.

The results of this trial differ from the study of verubecestat in mild to moderate Alzheimer’s disease, the investigators noted. Those patients did not decline cognitively as did those with prodromal disease.

“Patients at an earlier stage of the disease may be more sensitive to the effects of substantial BACE-1 inhibition, perhaps because of a role of BACE-1 in normal synaptic function. It is also possible that the effects of verubecestat are due to inhibition of BACE-2,” they said.

Atabecestat

In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.

The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.

This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.

“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”

Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.

“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.

This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.

Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.

“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.

[email protected]

SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.

More bad news for Alzheimer’s research. Two more BACE inhibitors fall far short of the finish line.

Not only did both verubecestat and atabecestat fail to improve cognition and function patients with prodromal Alzheimer’s disease, they also made things worse. Declining cognitive scores, falls, suicidal ideation, and liver enzyme abnormalities were all seen in clinical trials.

The news doesn’t bode well for the therapeutic target of BACE (beta-site APP cleaving enzyme) inhibition. BACE is one of the enzymes that trims the amyloid precursor protein (APP). Inhibiting it does reduce the amount of toxic amyloid-beta in cerebrospinal fluid, and amyloid plaque in the brain. But none of these molecules has shown clinical benefit in dementia patients, whether their disease is mild, or moderate or – now – prodromal. And it is now apparent that inhibiting BACE also produces serious off-target problems.

“BACE-1 inhibition certainly seemed to have a sound rationale assuming the basis for amyloid’s role in Alzheimer’s disease pathogenesis is a gain of toxicity,” Richard J. Caselli, MD, of the Mayo Clinic, Rochester, Minn., said in an interview. “That APP is important for Alzheimer’s pathogenesis still seems clear but whether amyloid-beta toxicity is the driving force is no longer clear. Further, interruption of the APP system disrupts more than amyloid-beta peptide, possibly explaining the adverse cognitive effects of BACE-1 inhibition shown exhibited now by three different BACE-1 inhibitors.”
 

Verubecestat

Researchers got their first dose of bad news regarding verubecestat at the 2017 Clinical Trials in Alzheimer’s Disease meeting. There, Michael F. Egan, MD, Merck’s associate vice president of clinical neuroscience, discussed the molecule’s failure to slow cognitive decline in patients with mild to moderate Alzheimer’s disease. There was plenty of biomarker evidence that the drug did block amyloid-beta production, but there also was a plethora of concerning adverse events, Dr. Egan said in an interview.

However, verubecestat still was being pursued in patients with prodromal Alzheimer’s disease. In February, Merck stopped the trial after a futility analysis and announced that the company was terminating studies of verubecestat in that population as well. In the April 11 issue of the New England Journal of Medicine, Dr. Egan and his colleagues report the full extent of verubecestat’s failure in prodromal patients, and the accompanying adverse events.

At the time of termination, 1,454 patients had been enrolled. Of these, 485 received 12 mg/day, 484 received 40 mg/day, and 485 received placebo. About half of each group completed 104 weeks of treatment in the study, which was designed to extend up to 5 years.

The primary outcome was change in the Clinical Dementia Rating Scale–Sum of Boxes score (CDR-SB). Seven secondary outcomes examined other cognitive and functional end points, along with changes in hippocampal volume on MRI and amyloid burden as determined in PET imaging.

Not only did verubecestat fail to slow cognitive decline, it appeared to exacerbate it. The mean change on the CDR-SB was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group, favoring placebo.

“In an exploratory analysis according to time point, scores on the CDR-SB were also higher [signifying more impairment of cognition and daily functioning] in the 40-mg group than in the placebo group at 13, 26, and 52 weeks ... suggesting but not confirming the possibility of worse performance at these earlier time points in the high-dose verubecestat group,” the investigators said.

Verubecestat also was associated with more conversions to Alzheimer’s disease. Per 100 patient-years, the Alzheimer’s disease event rates were 24.5 in the 12-mg group, 25.5 in the 40-mg group, and 19.3 in the placebo group. Compared with placebo, those taking 12-mg doses were 30% more likely to develop Alzheimer’s disease and those taking 40-mg doses were 38% more likely. The findings suggest that “verubecestat may have accelerated the progression to diagnosis of dementia due to Alzheimer’s disease,” the investigators said.

The negative impact of verubecestat was apparent quite early in the study. “In exploratory analyses, both dose levels of verubecestat were associated with poorer outcomes on the [Composite Cognition Score-3 Domain] and the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] measures of cognition that, relative to placebo, appeared worse at week 13 and did not appear to progress thereafter.”

Results of the secondary end points, including the ADAS-Cog and the Mini-Mental State Exam, also indicated that verubecestat may have worsened cognitive performance.

Imaging outcomes were positive, however. Hippocampal volume was 6,448 mL in the 12-mg group, 6,469 mL in the 40-mg group, and 6,435 mL in the placebo group. Brain amyloid increased in the placebo group, as expected, and decreased in the active groups. The small group of patients who underwent cerebrospinal fluid sampling showed reductions of more than 60% in amyloid-beta and soluble APP-beta associated with verubecestat. These results show that the molecule was indeed hitting its intended target, but that doing so was not clinically beneficial.

Adverse events were more common in the verubecestat groups. These included rash, dermatitis, urticaria, sleep disturbance, weight loss, and cough. Hair coloring changed in 2.5% of patients in the 12-mg group and 5% of the 40-mg group, but in none of the subjects taking placebo.

Patients taking verubecestat were more likely to sustain falls and injuries and to express suicidal ideation.

The results of this trial differ from the study of verubecestat in mild to moderate Alzheimer’s disease, the investigators noted. Those patients did not decline cognitively as did those with prodromal disease.

“Patients at an earlier stage of the disease may be more sensitive to the effects of substantial BACE-1 inhibition, perhaps because of a role of BACE-1 in normal synaptic function. It is also possible that the effects of verubecestat are due to inhibition of BACE-2,” they said.

Atabecestat

In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.

The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.

This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.

“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”

Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.

“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.

This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.

Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.

“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.

[email protected]

SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.

More bad news for Alzheimer’s research. Two more BACE inhibitors fall far short of the finish line.

Not only did both verubecestat and atabecestat fail to improve cognition and function patients with prodromal Alzheimer’s disease, they also made things worse. Declining cognitive scores, falls, suicidal ideation, and liver enzyme abnormalities were all seen in clinical trials.

The news doesn’t bode well for the therapeutic target of BACE (beta-site APP cleaving enzyme) inhibition. BACE is one of the enzymes that trims the amyloid precursor protein (APP). Inhibiting it does reduce the amount of toxic amyloid-beta in cerebrospinal fluid, and amyloid plaque in the brain. But none of these molecules has shown clinical benefit in dementia patients, whether their disease is mild, or moderate or – now – prodromal. And it is now apparent that inhibiting BACE also produces serious off-target problems.

“BACE-1 inhibition certainly seemed to have a sound rationale assuming the basis for amyloid’s role in Alzheimer’s disease pathogenesis is a gain of toxicity,” Richard J. Caselli, MD, of the Mayo Clinic, Rochester, Minn., said in an interview. “That APP is important for Alzheimer’s pathogenesis still seems clear but whether amyloid-beta toxicity is the driving force is no longer clear. Further, interruption of the APP system disrupts more than amyloid-beta peptide, possibly explaining the adverse cognitive effects of BACE-1 inhibition shown exhibited now by three different BACE-1 inhibitors.”
 

Verubecestat

Researchers got their first dose of bad news regarding verubecestat at the 2017 Clinical Trials in Alzheimer’s Disease meeting. There, Michael F. Egan, MD, Merck’s associate vice president of clinical neuroscience, discussed the molecule’s failure to slow cognitive decline in patients with mild to moderate Alzheimer’s disease. There was plenty of biomarker evidence that the drug did block amyloid-beta production, but there also was a plethora of concerning adverse events, Dr. Egan said in an interview.

However, verubecestat still was being pursued in patients with prodromal Alzheimer’s disease. In February, Merck stopped the trial after a futility analysis and announced that the company was terminating studies of verubecestat in that population as well. In the April 11 issue of the New England Journal of Medicine, Dr. Egan and his colleagues report the full extent of verubecestat’s failure in prodromal patients, and the accompanying adverse events.

At the time of termination, 1,454 patients had been enrolled. Of these, 485 received 12 mg/day, 484 received 40 mg/day, and 485 received placebo. About half of each group completed 104 weeks of treatment in the study, which was designed to extend up to 5 years.

The primary outcome was change in the Clinical Dementia Rating Scale–Sum of Boxes score (CDR-SB). Seven secondary outcomes examined other cognitive and functional end points, along with changes in hippocampal volume on MRI and amyloid burden as determined in PET imaging.

Not only did verubecestat fail to slow cognitive decline, it appeared to exacerbate it. The mean change on the CDR-SB was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group, favoring placebo.

“In an exploratory analysis according to time point, scores on the CDR-SB were also higher [signifying more impairment of cognition and daily functioning] in the 40-mg group than in the placebo group at 13, 26, and 52 weeks ... suggesting but not confirming the possibility of worse performance at these earlier time points in the high-dose verubecestat group,” the investigators said.

Verubecestat also was associated with more conversions to Alzheimer’s disease. Per 100 patient-years, the Alzheimer’s disease event rates were 24.5 in the 12-mg group, 25.5 in the 40-mg group, and 19.3 in the placebo group. Compared with placebo, those taking 12-mg doses were 30% more likely to develop Alzheimer’s disease and those taking 40-mg doses were 38% more likely. The findings suggest that “verubecestat may have accelerated the progression to diagnosis of dementia due to Alzheimer’s disease,” the investigators said.

The negative impact of verubecestat was apparent quite early in the study. “In exploratory analyses, both dose levels of verubecestat were associated with poorer outcomes on the [Composite Cognition Score-3 Domain] and the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognitive Subscale] measures of cognition that, relative to placebo, appeared worse at week 13 and did not appear to progress thereafter.”

Results of the secondary end points, including the ADAS-Cog and the Mini-Mental State Exam, also indicated that verubecestat may have worsened cognitive performance.

Imaging outcomes were positive, however. Hippocampal volume was 6,448 mL in the 12-mg group, 6,469 mL in the 40-mg group, and 6,435 mL in the placebo group. Brain amyloid increased in the placebo group, as expected, and decreased in the active groups. The small group of patients who underwent cerebrospinal fluid sampling showed reductions of more than 60% in amyloid-beta and soluble APP-beta associated with verubecestat. These results show that the molecule was indeed hitting its intended target, but that doing so was not clinically beneficial.

Adverse events were more common in the verubecestat groups. These included rash, dermatitis, urticaria, sleep disturbance, weight loss, and cough. Hair coloring changed in 2.5% of patients in the 12-mg group and 5% of the 40-mg group, but in none of the subjects taking placebo.

Patients taking verubecestat were more likely to sustain falls and injuries and to express suicidal ideation.

The results of this trial differ from the study of verubecestat in mild to moderate Alzheimer’s disease, the investigators noted. Those patients did not decline cognitively as did those with prodromal disease.

“Patients at an earlier stage of the disease may be more sensitive to the effects of substantial BACE-1 inhibition, perhaps because of a role of BACE-1 in normal synaptic function. It is also possible that the effects of verubecestat are due to inhibition of BACE-2,” they said.

Atabecestat

In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.

The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.

This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.

“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”

Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.

“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.

This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.

Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.

“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.

[email protected]

SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A lack of consistency exists surrounding the management of intracranial hemorrhage (ICH) in patients with von Willebrand disease (VWD), according to a clinical case report and literature review.

“Intracranial hemorrhage (ICH) in von Willebrand patients is a very rare event,” Ezio Zanon, MD, of the University Hospital of Padua (Italy), and his colleagues wrote in a letter to the editor published in Haemophilia.

The researchers reported findings from a case of a woman with type 2B VWD who experienced two spontaneous ICH events 12 years apart. Shortly after her admission for the second episode, the patient died as a result of severe bleeding.

Additionally, the team reviewed the body of literature for other cases of ICH and summarized the management strategies used in these patients.

“To date, only a few cases of intracranial hemorrhages in VWD are reported in literature,” the researchers wrote.

After analysis, the researchers found that a lack of consistency exists in the management of ICH in patients with VWD.

With respect to management strategies, Dr. Zanon and his colleagues suggested that ongoing prophylactic therapy with replacement concentrate could lower the risk of ICH recurrence. In the case presented, the patient was started on prophylaxis after the first ICH episode but it was interrupted 1 year later.

The team also recommended that hypertension should be closely monitored as it is a key risk factor for developing ICH. In the case presented, the patient had poorly controlled arterial hypertension.

“Studies and registries would be very important to define the burden of ICH in VWD patients clearly and establish its proper management,” they wrote.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Zanon E et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13742.
 

A lack of consistency exists surrounding the management of intracranial hemorrhage (ICH) in patients with von Willebrand disease (VWD), according to a clinical case report and literature review.

“Intracranial hemorrhage (ICH) in von Willebrand patients is a very rare event,” Ezio Zanon, MD, of the University Hospital of Padua (Italy), and his colleagues wrote in a letter to the editor published in Haemophilia.

The researchers reported findings from a case of a woman with type 2B VWD who experienced two spontaneous ICH events 12 years apart. Shortly after her admission for the second episode, the patient died as a result of severe bleeding.

Additionally, the team reviewed the body of literature for other cases of ICH and summarized the management strategies used in these patients.

“To date, only a few cases of intracranial hemorrhages in VWD are reported in literature,” the researchers wrote.

After analysis, the researchers found that a lack of consistency exists in the management of ICH in patients with VWD.

With respect to management strategies, Dr. Zanon and his colleagues suggested that ongoing prophylactic therapy with replacement concentrate could lower the risk of ICH recurrence. In the case presented, the patient was started on prophylaxis after the first ICH episode but it was interrupted 1 year later.

The team also recommended that hypertension should be closely monitored as it is a key risk factor for developing ICH. In the case presented, the patient had poorly controlled arterial hypertension.

“Studies and registries would be very important to define the burden of ICH in VWD patients clearly and establish its proper management,” they wrote.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Zanon E et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13742.
 

A lack of consistency exists surrounding the management of intracranial hemorrhage (ICH) in patients with von Willebrand disease (VWD), according to a clinical case report and literature review.

“Intracranial hemorrhage (ICH) in von Willebrand patients is a very rare event,” Ezio Zanon, MD, of the University Hospital of Padua (Italy), and his colleagues wrote in a letter to the editor published in Haemophilia.

The researchers reported findings from a case of a woman with type 2B VWD who experienced two spontaneous ICH events 12 years apart. Shortly after her admission for the second episode, the patient died as a result of severe bleeding.

Additionally, the team reviewed the body of literature for other cases of ICH and summarized the management strategies used in these patients.

“To date, only a few cases of intracranial hemorrhages in VWD are reported in literature,” the researchers wrote.

After analysis, the researchers found that a lack of consistency exists in the management of ICH in patients with VWD.

With respect to management strategies, Dr. Zanon and his colleagues suggested that ongoing prophylactic therapy with replacement concentrate could lower the risk of ICH recurrence. In the case presented, the patient was started on prophylaxis after the first ICH episode but it was interrupted 1 year later.

The team also recommended that hypertension should be closely monitored as it is a key risk factor for developing ICH. In the case presented, the patient had poorly controlled arterial hypertension.

“Studies and registries would be very important to define the burden of ICH in VWD patients clearly and establish its proper management,” they wrote.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Zanon E et al. Haemophilia. 2019 Mar 29. doi: 10.1111/hae.13742.
 

A wide variety of genetic mutations, including two novel variants, were found in a cohort of Vietnamese patients with hemophilia A, according to a recent report.

Dung Vu Luu, MD, of the Hanoi (Vietnam) Medical University and his colleagues conducted a genetic analysis of 103 patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.

“In this letter, we report the spectrum of F8 mutations in Vietnamese patients with a well‐established clinical diagnosis of hemophilia A,” the researchers wrote.

Clinical assessment and validation of hemophilia was completed by hematologists from Vietnam’s National Institute of Hematology and Blood Transfusion. The team analyzed DNA that was extracted and isolated from blood samples collected from the patients.

After analysis, the researchers found that disease-causing genetic variants were present in 89% of patients. The intron 22 inversion mutation was detected in 34% of patients in the cohort.

Dr. Luu and his colleagues reported that two novel F8 mutations were also detected that resulted in a severe clinical phenotype: c.4550‐4551insA; p.His1518Serfs*13 and c.1268‐1269insG; p.Asp366GluFs*5.

“To our knowledge, and after an extensive search in many databases, these two variants have not been reported in any F8 mutation database or reported in any published articles,” they explained.

The researchers acknowledged that future studies need to be larger in size.

“The results of this study are adding to the global knowledge base for [hemophilia A] and thus will promote better awareness for molecular diagnosis and care for [hemophilia A] patients in Vietnam,” they wrote.

The study was supported by grant funding from the Ministry of Health of Vietnam. The authors reported having no conflicts of interest.

SOURCE: Luu DV et al. Haemophilia. 2019 Mar 26. doi: 10.1111/hae.13738.

A wide variety of genetic mutations, including two novel variants, were found in a cohort of Vietnamese patients with hemophilia A, according to a recent report.

Dung Vu Luu, MD, of the Hanoi (Vietnam) Medical University and his colleagues conducted a genetic analysis of 103 patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.

“In this letter, we report the spectrum of F8 mutations in Vietnamese patients with a well‐established clinical diagnosis of hemophilia A,” the researchers wrote.

Clinical assessment and validation of hemophilia was completed by hematologists from Vietnam’s National Institute of Hematology and Blood Transfusion. The team analyzed DNA that was extracted and isolated from blood samples collected from the patients.

After analysis, the researchers found that disease-causing genetic variants were present in 89% of patients. The intron 22 inversion mutation was detected in 34% of patients in the cohort.

Dr. Luu and his colleagues reported that two novel F8 mutations were also detected that resulted in a severe clinical phenotype: c.4550‐4551insA; p.His1518Serfs*13 and c.1268‐1269insG; p.Asp366GluFs*5.

“To our knowledge, and after an extensive search in many databases, these two variants have not been reported in any F8 mutation database or reported in any published articles,” they explained.

The researchers acknowledged that future studies need to be larger in size.

“The results of this study are adding to the global knowledge base for [hemophilia A] and thus will promote better awareness for molecular diagnosis and care for [hemophilia A] patients in Vietnam,” they wrote.

The study was supported by grant funding from the Ministry of Health of Vietnam. The authors reported having no conflicts of interest.

SOURCE: Luu DV et al. Haemophilia. 2019 Mar 26. doi: 10.1111/hae.13738.

A wide variety of genetic mutations, including two novel variants, were found in a cohort of Vietnamese patients with hemophilia A, according to a recent report.

Dung Vu Luu, MD, of the Hanoi (Vietnam) Medical University and his colleagues conducted a genetic analysis of 103 patients with hemophilia A. The results of the analysis were reported in a letter to the editor published in Haemophilia.

“In this letter, we report the spectrum of F8 mutations in Vietnamese patients with a well‐established clinical diagnosis of hemophilia A,” the researchers wrote.

Clinical assessment and validation of hemophilia was completed by hematologists from Vietnam’s National Institute of Hematology and Blood Transfusion. The team analyzed DNA that was extracted and isolated from blood samples collected from the patients.

After analysis, the researchers found that disease-causing genetic variants were present in 89% of patients. The intron 22 inversion mutation was detected in 34% of patients in the cohort.

Dr. Luu and his colleagues reported that two novel F8 mutations were also detected that resulted in a severe clinical phenotype: c.4550‐4551insA; p.His1518Serfs*13 and c.1268‐1269insG; p.Asp366GluFs*5.

“To our knowledge, and after an extensive search in many databases, these two variants have not been reported in any F8 mutation database or reported in any published articles,” they explained.

The researchers acknowledged that future studies need to be larger in size.

“The results of this study are adding to the global knowledge base for [hemophilia A] and thus will promote better awareness for molecular diagnosis and care for [hemophilia A] patients in Vietnam,” they wrote.

The study was supported by grant funding from the Ministry of Health of Vietnam. The authors reported having no conflicts of interest.

SOURCE: Luu DV et al. Haemophilia. 2019 Mar 26. doi: 10.1111/hae.13738.

NEW ORLEANS – Mounting evidence shows that heart failure patient mortality increased as an unintended consequence of a Medicare program that penalizes hospitals with too many 30-day readmissions of heart failure patients. This has prompted discussions among cardiologists, Medicare officials, and other stakeholders in an attempt to modify the penalty program so it no longer considers just readmissions but instead bases penalties on broader and more nuanced measures of patient outcomes.

Mitchel L. Zoler/MDedge News

Staffers at the Centers for Medicare & Medicaid Services, the federal agency that manages Medicare, “said that they take this seriously and will look into it, and they are interested in next-generation measures that are more patient centered” than simply the 30-day readmission rate, Gregg C. Fonarow, MD, said in an interview at the annual meeting of the American College of Cardiology. “This is a case where there is credible evidence of increased mortality that is consistent, reproducible, and strongly associated with the penalty and cannot be otherwise explained,” said Dr. Fonarow, professor of medicine and cochief of cardiology at the University of California, Los Angeles.

He is among the most active researchers to document that, while CMS’s Hospital Readmissions Reduction Program (HRRP) led to significantly reduced readmission rates in patients with heart failure, this came at a cost of a significant increase in mortality among the same patients. For example, an article he published in 2018 that analyzed more than 115,000 Medicare beneficiaries during 2006-2014 showed that during the penalty phase, which began in 2012, readmissions fell after adjustment by a relative 8%, but adjusted mortality rose by a relative 10%, compared with how patients had fared prior to launching the HRRP (JAMA Cardiol. 2018 Jan;3[1]:44-53). Recent reports from other research groups have had similar findings, such as a study of more than 3 million Medicare beneficiaries with heart failure during 2005-2015 that also showed significantly increased mortality after the penalty phase for readmissions began (JAMA. 2018 Dec 25;320[24]:2542-52). In a commentary that accompanied this report, Dr. Fonarow cited the multiple analyses that show consistent findings and the need for CMS to “initiate an expeditious reconsideration and revision” of their current approach to penalizing hospitals for heart failure readmissions (JAMA. 2018 Dec 25;320[24]:2539-41).

The groups recently in discussion with CMS about this issue include the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, the American College of Physicians, the American Hospital Association, and several other medical professional groups, said Biykem Bozkurt, MD, who has worked with Dr. Fonarow and representatives from these organizations in talks with CMS.

“We are trying to find a harmonized approach with patient-centric outcomes that reflect true improvements in quality of care,” she said in an interview. One possibility up for consideration is a combined measure of heart failure readmissions, mortality, and a patient-reported outcome. The measure would go to CMS directly from each patient’s electronic medical record, making data collection less burdensome to clinicians, said Dr. Bozkurt, professor of medicine at Baylor College of Medicine and cardiology section chief at the VA Medical Center in Houston. She expressed hope that a change in the CMS metric might happen later this year.

“CMS can’t simply stop the HRRP, so the discussion is on how to get a meaningful change. I’m increasingly optimistic, because the findings of harm [from current policies] are impossible to ignore,” Dr. Fonarow said. “There will be increasing pressure on CMS to develop a pathway to make modifications. It’s egregious to continue a policy that’s been associated with harm” to heart failure patients.

Dr. Fonarow and Dr. Bozkurt had no relevant commercial disclosures.

[email protected]

NEW ORLEANS – Mounting evidence shows that heart failure patient mortality increased as an unintended consequence of a Medicare program that penalizes hospitals with too many 30-day readmissions of heart failure patients. This has prompted discussions among cardiologists, Medicare officials, and other stakeholders in an attempt to modify the penalty program so it no longer considers just readmissions but instead bases penalties on broader and more nuanced measures of patient outcomes.

Mitchel L. Zoler/MDedge News

Staffers at the Centers for Medicare & Medicaid Services, the federal agency that manages Medicare, “said that they take this seriously and will look into it, and they are interested in next-generation measures that are more patient centered” than simply the 30-day readmission rate, Gregg C. Fonarow, MD, said in an interview at the annual meeting of the American College of Cardiology. “This is a case where there is credible evidence of increased mortality that is consistent, reproducible, and strongly associated with the penalty and cannot be otherwise explained,” said Dr. Fonarow, professor of medicine and cochief of cardiology at the University of California, Los Angeles.

He is among the most active researchers to document that, while CMS’s Hospital Readmissions Reduction Program (HRRP) led to significantly reduced readmission rates in patients with heart failure, this came at a cost of a significant increase in mortality among the same patients. For example, an article he published in 2018 that analyzed more than 115,000 Medicare beneficiaries during 2006-2014 showed that during the penalty phase, which began in 2012, readmissions fell after adjustment by a relative 8%, but adjusted mortality rose by a relative 10%, compared with how patients had fared prior to launching the HRRP (JAMA Cardiol. 2018 Jan;3[1]:44-53). Recent reports from other research groups have had similar findings, such as a study of more than 3 million Medicare beneficiaries with heart failure during 2005-2015 that also showed significantly increased mortality after the penalty phase for readmissions began (JAMA. 2018 Dec 25;320[24]:2542-52). In a commentary that accompanied this report, Dr. Fonarow cited the multiple analyses that show consistent findings and the need for CMS to “initiate an expeditious reconsideration and revision” of their current approach to penalizing hospitals for heart failure readmissions (JAMA. 2018 Dec 25;320[24]:2539-41).

The groups recently in discussion with CMS about this issue include the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, the American College of Physicians, the American Hospital Association, and several other medical professional groups, said Biykem Bozkurt, MD, who has worked with Dr. Fonarow and representatives from these organizations in talks with CMS.

“We are trying to find a harmonized approach with patient-centric outcomes that reflect true improvements in quality of care,” she said in an interview. One possibility up for consideration is a combined measure of heart failure readmissions, mortality, and a patient-reported outcome. The measure would go to CMS directly from each patient’s electronic medical record, making data collection less burdensome to clinicians, said Dr. Bozkurt, professor of medicine at Baylor College of Medicine and cardiology section chief at the VA Medical Center in Houston. She expressed hope that a change in the CMS metric might happen later this year.

“CMS can’t simply stop the HRRP, so the discussion is on how to get a meaningful change. I’m increasingly optimistic, because the findings of harm [from current policies] are impossible to ignore,” Dr. Fonarow said. “There will be increasing pressure on CMS to develop a pathway to make modifications. It’s egregious to continue a policy that’s been associated with harm” to heart failure patients.

Dr. Fonarow and Dr. Bozkurt had no relevant commercial disclosures.

[email protected]

NEW ORLEANS – Mounting evidence shows that heart failure patient mortality increased as an unintended consequence of a Medicare program that penalizes hospitals with too many 30-day readmissions of heart failure patients. This has prompted discussions among cardiologists, Medicare officials, and other stakeholders in an attempt to modify the penalty program so it no longer considers just readmissions but instead bases penalties on broader and more nuanced measures of patient outcomes.

Mitchel L. Zoler/MDedge News

Staffers at the Centers for Medicare & Medicaid Services, the federal agency that manages Medicare, “said that they take this seriously and will look into it, and they are interested in next-generation measures that are more patient centered” than simply the 30-day readmission rate, Gregg C. Fonarow, MD, said in an interview at the annual meeting of the American College of Cardiology. “This is a case where there is credible evidence of increased mortality that is consistent, reproducible, and strongly associated with the penalty and cannot be otherwise explained,” said Dr. Fonarow, professor of medicine and cochief of cardiology at the University of California, Los Angeles.

He is among the most active researchers to document that, while CMS’s Hospital Readmissions Reduction Program (HRRP) led to significantly reduced readmission rates in patients with heart failure, this came at a cost of a significant increase in mortality among the same patients. For example, an article he published in 2018 that analyzed more than 115,000 Medicare beneficiaries during 2006-2014 showed that during the penalty phase, which began in 2012, readmissions fell after adjustment by a relative 8%, but adjusted mortality rose by a relative 10%, compared with how patients had fared prior to launching the HRRP (JAMA Cardiol. 2018 Jan;3[1]:44-53). Recent reports from other research groups have had similar findings, such as a study of more than 3 million Medicare beneficiaries with heart failure during 2005-2015 that also showed significantly increased mortality after the penalty phase for readmissions began (JAMA. 2018 Dec 25;320[24]:2542-52). In a commentary that accompanied this report, Dr. Fonarow cited the multiple analyses that show consistent findings and the need for CMS to “initiate an expeditious reconsideration and revision” of their current approach to penalizing hospitals for heart failure readmissions (JAMA. 2018 Dec 25;320[24]:2539-41).

The groups recently in discussion with CMS about this issue include the American College of Cardiology, the American Heart Association, the Heart Failure Society of America, the American College of Physicians, the American Hospital Association, and several other medical professional groups, said Biykem Bozkurt, MD, who has worked with Dr. Fonarow and representatives from these organizations in talks with CMS.

“We are trying to find a harmonized approach with patient-centric outcomes that reflect true improvements in quality of care,” she said in an interview. One possibility up for consideration is a combined measure of heart failure readmissions, mortality, and a patient-reported outcome. The measure would go to CMS directly from each patient’s electronic medical record, making data collection less burdensome to clinicians, said Dr. Bozkurt, professor of medicine at Baylor College of Medicine and cardiology section chief at the VA Medical Center in Houston. She expressed hope that a change in the CMS metric might happen later this year.

“CMS can’t simply stop the HRRP, so the discussion is on how to get a meaningful change. I’m increasingly optimistic, because the findings of harm [from current policies] are impossible to ignore,” Dr. Fonarow said. “There will be increasing pressure on CMS to develop a pathway to make modifications. It’s egregious to continue a policy that’s been associated with harm” to heart failure patients.

Dr. Fonarow and Dr. Bozkurt had no relevant commercial disclosures.

[email protected]

A single intra-articular injection of platelet-rich plasma showed better pain and function scores at 6 months than did weekly injections of hyaluronic acid in patients with hemophilic arthropathy of the knee.

“In patients with chronic knee joint pain, our study shows that treatment with intra-articular [platelet-rich plasma] injection could reduce pain, improve hyperaemia and enhance knee joint function,” wrote Tsung-Ying Li, MD, of Tri-Service General Hospital in Taipei, Taiwan, and his colleagues. The results of the comparison study were published in Haemophilia.

Researchers conducted a nonrandomized, single-center, open-label comparison study of 22 patients with hemophilia A who had chronic hemophilic arthropathy of the knee. Patients were stratified into two treatment groups using a matched sampling method.

“Patients who could commit to hyaluronic acid treatment were allocated to the hyaluronic acid group, otherwise patients were allocated to the platelet‐rich plasma group,” the researchers wrote.

Participants in the hyaluronic acid arm were given five sequential weekly injections and those in the platelet-rich plasma arm received only a single injection. Outcomes were measured via the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version, and ultrasonography to determine synovial change.

Pain and function scores were significantly lower in patients administered intra-articular platelet-rich plasma versus hyaluronic acid at 6 months (P less than .05), the researchers reported. However, comparative analysis found no significant differences at earlier follow-up time points.

“Both treatments were found to be effective in reducing pain and improving functional status of the knee,” the researchers wrote.

They acknowledged a key limitation of the study was the short duration of follow-up, which was due to budget restrictions at the treatment facility.

“Further investigation using rigorous research methodology is warranted to establish the benefit of [platelet-rich plasma] on hemophilic arthropathy and standardized [platelet-rich plasma] preparation and dosing regimens,” they wrote.

The study was supported by grant funding from Tri-Service General Hospital in Taiwan. Three of the authors reported receiving research grants from Shire.

SOURCE: Li TY et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13711.

A single intra-articular injection of platelet-rich plasma showed better pain and function scores at 6 months than did weekly injections of hyaluronic acid in patients with hemophilic arthropathy of the knee.

“In patients with chronic knee joint pain, our study shows that treatment with intra-articular [platelet-rich plasma] injection could reduce pain, improve hyperaemia and enhance knee joint function,” wrote Tsung-Ying Li, MD, of Tri-Service General Hospital in Taipei, Taiwan, and his colleagues. The results of the comparison study were published in Haemophilia.

Researchers conducted a nonrandomized, single-center, open-label comparison study of 22 patients with hemophilia A who had chronic hemophilic arthropathy of the knee. Patients were stratified into two treatment groups using a matched sampling method.

“Patients who could commit to hyaluronic acid treatment were allocated to the hyaluronic acid group, otherwise patients were allocated to the platelet‐rich plasma group,” the researchers wrote.

Participants in the hyaluronic acid arm were given five sequential weekly injections and those in the platelet-rich plasma arm received only a single injection. Outcomes were measured via the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version, and ultrasonography to determine synovial change.

Pain and function scores were significantly lower in patients administered intra-articular platelet-rich plasma versus hyaluronic acid at 6 months (P less than .05), the researchers reported. However, comparative analysis found no significant differences at earlier follow-up time points.

“Both treatments were found to be effective in reducing pain and improving functional status of the knee,” the researchers wrote.

They acknowledged a key limitation of the study was the short duration of follow-up, which was due to budget restrictions at the treatment facility.

“Further investigation using rigorous research methodology is warranted to establish the benefit of [platelet-rich plasma] on hemophilic arthropathy and standardized [platelet-rich plasma] preparation and dosing regimens,” they wrote.

The study was supported by grant funding from Tri-Service General Hospital in Taiwan. Three of the authors reported receiving research grants from Shire.

SOURCE: Li TY et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13711.

A single intra-articular injection of platelet-rich plasma showed better pain and function scores at 6 months than did weekly injections of hyaluronic acid in patients with hemophilic arthropathy of the knee.

“In patients with chronic knee joint pain, our study shows that treatment with intra-articular [platelet-rich plasma] injection could reduce pain, improve hyperaemia and enhance knee joint function,” wrote Tsung-Ying Li, MD, of Tri-Service General Hospital in Taipei, Taiwan, and his colleagues. The results of the comparison study were published in Haemophilia.

Researchers conducted a nonrandomized, single-center, open-label comparison study of 22 patients with hemophilia A who had chronic hemophilic arthropathy of the knee. Patients were stratified into two treatment groups using a matched sampling method.

“Patients who could commit to hyaluronic acid treatment were allocated to the hyaluronic acid group, otherwise patients were allocated to the platelet‐rich plasma group,” the researchers wrote.

Participants in the hyaluronic acid arm were given five sequential weekly injections and those in the platelet-rich plasma arm received only a single injection. Outcomes were measured via the visual analogue scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Chinese Version, and ultrasonography to determine synovial change.

Pain and function scores were significantly lower in patients administered intra-articular platelet-rich plasma versus hyaluronic acid at 6 months (P less than .05), the researchers reported. However, comparative analysis found no significant differences at earlier follow-up time points.

“Both treatments were found to be effective in reducing pain and improving functional status of the knee,” the researchers wrote.

They acknowledged a key limitation of the study was the short duration of follow-up, which was due to budget restrictions at the treatment facility.

“Further investigation using rigorous research methodology is warranted to establish the benefit of [platelet-rich plasma] on hemophilic arthropathy and standardized [platelet-rich plasma] preparation and dosing regimens,” they wrote.

The study was supported by grant funding from Tri-Service General Hospital in Taiwan. Three of the authors reported receiving research grants from Shire.

SOURCE: Li TY et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13711.

SNOWMASS, COLO. – Percutaneous mitral valve plication shows early promise as a primary therapy for severely symptomatic, drug-refractory hypertrophic obstructive cardiomyopathy (HOCM), Paul Sorajja, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

He and his coworkers at the Minneapolis Heart Institute developed the novel procedure and published the first experience in the world with it. But further study in a much larger patient population is needed before percutaneous mitral plication is ready for prime time as a treatment for symptomatic HOCM, according to Dr. Sorajja, director of the Center of Valve and Structural Heart Disease at the institute.

Surgical myectomy is the guideline-recommended standard for treatment of patients with disabling symptoms caused by left ventricular outflow tract obstruction in the setting of hypertrophic cardiomyopathy. Alcohol septal ablation is a widely utilized alternative in patients who are frail and elderly or otherwise high-risk surgical candidates, or who lack ready access to an experienced surgical myectomy center, where the best outcomes are achieved. But roughly 20% of patients evaluated for alcohol septal ablation don’t have a septal artery anatomy amenable to the procedure. Other patients are put off by the 10%-50% risk that they will require a permanent pacemaker after alcohol septal ablation, depending upon their baseline ECG. And a small percentage of well-chosen patients – less than 10% – will experience inadequate gradient relief following alcohol septal ablation. So there is room for a novel therapeutic approach.

A percutaneous mitral clip–based solution, while technically challenging, offers several advantages over surgical myectomy and alcohol septal ablation. It’s less invasive, doesn’t create a potentially arrhythmogenic ablation scar requiring a permanent pacemaker, and it targets the mitral valve directly, addressing the mitral regurgitation that causes the left ventricular outflow tract obstruction. In contrast, both surgical myectomy and alcohol septal ablation target the ventricular septum.

Dr. Sorajja summarized his experience to date with percutaneous mitral valve plication for symptomatic HOCM, which encompasses the six patients in the published study (J Am Coll Cardiol. 2016 Jun 21;67[24]:2811-8) and the four others treated since then. The procedure was completed with placement of a single MitraClip in 9 of 10 patients. One patient experienced cardiac tamponade, resulting in a halt of the procedure; in the other nine, the intervention eliminated systolic anterior motion and markedly decreased the intraoperative left ventricular outflow tract gradient and mitral regurgitation.

At 2-5 years of follow-up, all patients have improved from New York Heart Association functional class III preprocedurally to class I or II. One patient required alcohol septal ablation. High systolic left ventricular outflow tract velocities in excess of 4 cm/s have been documented via follow-up echocardiography in some patients, the significance of which is under study.

Dr. Sorajja reported receiving research funding from Abbott Structural, Boston Scientific, Edwards Lifesciences, and Medtronic, and serving as a consultant to those companies and several others.

[email protected]

SNOWMASS, COLO. – Percutaneous mitral valve plication shows early promise as a primary therapy for severely symptomatic, drug-refractory hypertrophic obstructive cardiomyopathy (HOCM), Paul Sorajja, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

He and his coworkers at the Minneapolis Heart Institute developed the novel procedure and published the first experience in the world with it. But further study in a much larger patient population is needed before percutaneous mitral plication is ready for prime time as a treatment for symptomatic HOCM, according to Dr. Sorajja, director of the Center of Valve and Structural Heart Disease at the institute.

Surgical myectomy is the guideline-recommended standard for treatment of patients with disabling symptoms caused by left ventricular outflow tract obstruction in the setting of hypertrophic cardiomyopathy. Alcohol septal ablation is a widely utilized alternative in patients who are frail and elderly or otherwise high-risk surgical candidates, or who lack ready access to an experienced surgical myectomy center, where the best outcomes are achieved. But roughly 20% of patients evaluated for alcohol septal ablation don’t have a septal artery anatomy amenable to the procedure. Other patients are put off by the 10%-50% risk that they will require a permanent pacemaker after alcohol septal ablation, depending upon their baseline ECG. And a small percentage of well-chosen patients – less than 10% – will experience inadequate gradient relief following alcohol septal ablation. So there is room for a novel therapeutic approach.

A percutaneous mitral clip–based solution, while technically challenging, offers several advantages over surgical myectomy and alcohol septal ablation. It’s less invasive, doesn’t create a potentially arrhythmogenic ablation scar requiring a permanent pacemaker, and it targets the mitral valve directly, addressing the mitral regurgitation that causes the left ventricular outflow tract obstruction. In contrast, both surgical myectomy and alcohol septal ablation target the ventricular septum.

Dr. Sorajja summarized his experience to date with percutaneous mitral valve plication for symptomatic HOCM, which encompasses the six patients in the published study (J Am Coll Cardiol. 2016 Jun 21;67[24]:2811-8) and the four others treated since then. The procedure was completed with placement of a single MitraClip in 9 of 10 patients. One patient experienced cardiac tamponade, resulting in a halt of the procedure; in the other nine, the intervention eliminated systolic anterior motion and markedly decreased the intraoperative left ventricular outflow tract gradient and mitral regurgitation.

At 2-5 years of follow-up, all patients have improved from New York Heart Association functional class III preprocedurally to class I or II. One patient required alcohol septal ablation. High systolic left ventricular outflow tract velocities in excess of 4 cm/s have been documented via follow-up echocardiography in some patients, the significance of which is under study.

Dr. Sorajja reported receiving research funding from Abbott Structural, Boston Scientific, Edwards Lifesciences, and Medtronic, and serving as a consultant to those companies and several others.

[email protected]

SNOWMASS, COLO. – Percutaneous mitral valve plication shows early promise as a primary therapy for severely symptomatic, drug-refractory hypertrophic obstructive cardiomyopathy (HOCM), Paul Sorajja, MD, said at the Annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

He and his coworkers at the Minneapolis Heart Institute developed the novel procedure and published the first experience in the world with it. But further study in a much larger patient population is needed before percutaneous mitral plication is ready for prime time as a treatment for symptomatic HOCM, according to Dr. Sorajja, director of the Center of Valve and Structural Heart Disease at the institute.

Surgical myectomy is the guideline-recommended standard for treatment of patients with disabling symptoms caused by left ventricular outflow tract obstruction in the setting of hypertrophic cardiomyopathy. Alcohol septal ablation is a widely utilized alternative in patients who are frail and elderly or otherwise high-risk surgical candidates, or who lack ready access to an experienced surgical myectomy center, where the best outcomes are achieved. But roughly 20% of patients evaluated for alcohol septal ablation don’t have a septal artery anatomy amenable to the procedure. Other patients are put off by the 10%-50% risk that they will require a permanent pacemaker after alcohol septal ablation, depending upon their baseline ECG. And a small percentage of well-chosen patients – less than 10% – will experience inadequate gradient relief following alcohol septal ablation. So there is room for a novel therapeutic approach.

A percutaneous mitral clip–based solution, while technically challenging, offers several advantages over surgical myectomy and alcohol septal ablation. It’s less invasive, doesn’t create a potentially arrhythmogenic ablation scar requiring a permanent pacemaker, and it targets the mitral valve directly, addressing the mitral regurgitation that causes the left ventricular outflow tract obstruction. In contrast, both surgical myectomy and alcohol septal ablation target the ventricular septum.

Dr. Sorajja summarized his experience to date with percutaneous mitral valve plication for symptomatic HOCM, which encompasses the six patients in the published study (J Am Coll Cardiol. 2016 Jun 21;67[24]:2811-8) and the four others treated since then. The procedure was completed with placement of a single MitraClip in 9 of 10 patients. One patient experienced cardiac tamponade, resulting in a halt of the procedure; in the other nine, the intervention eliminated systolic anterior motion and markedly decreased the intraoperative left ventricular outflow tract gradient and mitral regurgitation.

At 2-5 years of follow-up, all patients have improved from New York Heart Association functional class III preprocedurally to class I or II. One patient required alcohol septal ablation. High systolic left ventricular outflow tract velocities in excess of 4 cm/s have been documented via follow-up echocardiography in some patients, the significance of which is under study.

Dr. Sorajja reported receiving research funding from Abbott Structural, Boston Scientific, Edwards Lifesciences, and Medtronic, and serving as a consultant to those companies and several others.

[email protected]

Bees? Really?

This might be one of the weirdest thing we’ve ever seen. It’s definitely the weirdest thing this Taiwanese woman has ever seen, considering it’s BEES in her EYE.

William Jones-Warner/Getty Images

One more time, for the people in the back: BEES. IN. HER. EYE.

The unfortunate 29-year-old, identified as He, reported to a hospital with sharp eye pain that she assumed was from dirt in her eyes after a vigorous afternoon of gardening near a grave site. Upon close inspection, the hospital’s head of ophthalmology noticed “something that looked like insect legs” floating in her eye and carefully pulled them out. (Pause to dry heave.)

The eyeball intruders turned out to be “sweat bees,” which nest in fallen trees and are attracted to human perspiration. The bees flew into He’s eye and started drinking from her tear duct, which was overproducing because of the immense pain she was in. Miraculously, He’s eyeball and sight are intact, and she’s expected to make a full recovery. The bees are fine, too.

Oh, and in case you’re wondering, sweat bees live all over the world. We’re wearing goggles outside from now on.
 

Flip it and reverse it

Imagine you’re back in your med school days, happily dissecting another cadaver. You pop the body open and … every organ is in the wrong place??

yanjf/Getty Images

That’s what some students at Oregon Health & Science University (OHSU) experienced recently. They discovered their body donor had a condition called situs inversus with levocardia – meaning, her heart was in the right place (hah), but all her abdominal organs were transposed right to left. The deceased woman was Rose Marie Bentley, who had died at the ripe old age of 99 without ever knowing she had this condition.

What makes her remarkable is barely anyone with this condition lives to adulthood. Professor Cam Walker of OHSU estimates the odds are 1 in 50 million, and there are only two other known cases of older patients who lived with situs inversus. After taking a look at their mother’s medical records, Bentley’s children noted that the surgeon who removed her appendix recorded its strange location, but no one raised any alarm.

Ms. Bentley lived a full and happy life, despite her organs being a mirror image of virtually everyone else’s anatomy. Some people are just special.

Turn that smile upside down

Service with a smile. Put on a happy face. Let a smile be your umbrella. Seems like good advice, but don’t let these cliches fool you. They are all examples of surface acting – hiding feelings of annoyance behind a mask of forced pleasantness – and they’re not really good for you. At least not if you work with the public and are required to be nice.

Koldunov/Getty Images

Investigators at Penn State University and the University at Buffalo looked at survey data from nurses, teachers, and people in food service and found that they were more likely to drink after work than those who did not interact with the public on a regular basis. “In these jobs, there’s also often money tied to showing positive emotions and holding back negative feelings. Money gives you a motivation to override your natural tendencies, but doing it all day can be wearing,” lead investigator Alicia Grandey said in a written statement.

Personality also plays a part. The risk of increased drinking is greater for surface actors who are more impulsive. And it is stronger still for impulsive people who “also worked in jobs where employees have one-time service encounters with customers, like a call center or coffee shop, rather than relationships, like health care or education,” the investigators said.

They suggested that businesses could give their employees more autonomy, but we’ve got another idea. There are lots of awards for real actors, so how about one for surface actors? They could call it the Oscar … Mayer. Best performance in serving a drive-thru customer who smoked a little too much marijuana. Creative achievement while helping a credit card applicant who still doesn’t understand after being told the same thing five times. Stunt coordination while helping a patient use a bedpan (the “turn the other cheek” award). Choreography to get out of bed every day to face the blank stares of sullen teenagers (the “Lord, give me strength” award). The “okay, we get the picture, you can stop with the awards” award.
 

That’s not the ice cream truck

Any story that starts with strange men in white, unmarked vans is never going to end well. Especially when that strange man is offering $20 in exchange for DNA samples.

visualspace/Getty Images

However, this is the situation that Louisville, Ky., finds itself in. According to WAVE3 News, the aforementioned men have been cruising the poorer neighborhoods of the city for a couple of months, offering money to anyone who belongs to Passport Health. Cheek swabs are collected, no questions are asked, and the person walks out with 20 extra dollars.

This is already shady territory, but to make things worse, Passport Health has denied any affiliation. And when asked by one of their customers, the men reported being with Freedom Health. The number the customer was given? Of course it didn’t work.

The cherry on top of the shady cake? According to a professor from the University of Louisville interviewed by WAVE3, the swabs can be used to test for only certain kinds of cancer, and those tests aren’t even commercially available yet. What, you mean this was all a scam? We’re shocked! SHOCKED!

[email protected]

Bees? Really?

This might be one of the weirdest thing we’ve ever seen. It’s definitely the weirdest thing this Taiwanese woman has ever seen, considering it’s BEES in her EYE.

William Jones-Warner/Getty Images

One more time, for the people in the back: BEES. IN. HER. EYE.

The unfortunate 29-year-old, identified as He, reported to a hospital with sharp eye pain that she assumed was from dirt in her eyes after a vigorous afternoon of gardening near a grave site. Upon close inspection, the hospital’s head of ophthalmology noticed “something that looked like insect legs” floating in her eye and carefully pulled them out. (Pause to dry heave.)

The eyeball intruders turned out to be “sweat bees,” which nest in fallen trees and are attracted to human perspiration. The bees flew into He’s eye and started drinking from her tear duct, which was overproducing because of the immense pain she was in. Miraculously, He’s eyeball and sight are intact, and she’s expected to make a full recovery. The bees are fine, too.

Oh, and in case you’re wondering, sweat bees live all over the world. We’re wearing goggles outside from now on.
 

Flip it and reverse it

Imagine you’re back in your med school days, happily dissecting another cadaver. You pop the body open and … every organ is in the wrong place??

yanjf/Getty Images

That’s what some students at Oregon Health & Science University (OHSU) experienced recently. They discovered their body donor had a condition called situs inversus with levocardia – meaning, her heart was in the right place (hah), but all her abdominal organs were transposed right to left. The deceased woman was Rose Marie Bentley, who had died at the ripe old age of 99 without ever knowing she had this condition.

What makes her remarkable is barely anyone with this condition lives to adulthood. Professor Cam Walker of OHSU estimates the odds are 1 in 50 million, and there are only two other known cases of older patients who lived with situs inversus. After taking a look at their mother’s medical records, Bentley’s children noted that the surgeon who removed her appendix recorded its strange location, but no one raised any alarm.

Ms. Bentley lived a full and happy life, despite her organs being a mirror image of virtually everyone else’s anatomy. Some people are just special.

Turn that smile upside down

Service with a smile. Put on a happy face. Let a smile be your umbrella. Seems like good advice, but don’t let these cliches fool you. They are all examples of surface acting – hiding feelings of annoyance behind a mask of forced pleasantness – and they’re not really good for you. At least not if you work with the public and are required to be nice.

Koldunov/Getty Images

Investigators at Penn State University and the University at Buffalo looked at survey data from nurses, teachers, and people in food service and found that they were more likely to drink after work than those who did not interact with the public on a regular basis. “In these jobs, there’s also often money tied to showing positive emotions and holding back negative feelings. Money gives you a motivation to override your natural tendencies, but doing it all day can be wearing,” lead investigator Alicia Grandey said in a written statement.

Personality also plays a part. The risk of increased drinking is greater for surface actors who are more impulsive. And it is stronger still for impulsive people who “also worked in jobs where employees have one-time service encounters with customers, like a call center or coffee shop, rather than relationships, like health care or education,” the investigators said.

They suggested that businesses could give their employees more autonomy, but we’ve got another idea. There are lots of awards for real actors, so how about one for surface actors? They could call it the Oscar … Mayer. Best performance in serving a drive-thru customer who smoked a little too much marijuana. Creative achievement while helping a credit card applicant who still doesn’t understand after being told the same thing five times. Stunt coordination while helping a patient use a bedpan (the “turn the other cheek” award). Choreography to get out of bed every day to face the blank stares of sullen teenagers (the “Lord, give me strength” award). The “okay, we get the picture, you can stop with the awards” award.
 

That’s not the ice cream truck

Any story that starts with strange men in white, unmarked vans is never going to end well. Especially when that strange man is offering $20 in exchange for DNA samples.

visualspace/Getty Images

However, this is the situation that Louisville, Ky., finds itself in. According to WAVE3 News, the aforementioned men have been cruising the poorer neighborhoods of the city for a couple of months, offering money to anyone who belongs to Passport Health. Cheek swabs are collected, no questions are asked, and the person walks out with 20 extra dollars.

This is already shady territory, but to make things worse, Passport Health has denied any affiliation. And when asked by one of their customers, the men reported being with Freedom Health. The number the customer was given? Of course it didn’t work.

The cherry on top of the shady cake? According to a professor from the University of Louisville interviewed by WAVE3, the swabs can be used to test for only certain kinds of cancer, and those tests aren’t even commercially available yet. What, you mean this was all a scam? We’re shocked! SHOCKED!

[email protected]

Bees? Really?

This might be one of the weirdest thing we’ve ever seen. It’s definitely the weirdest thing this Taiwanese woman has ever seen, considering it’s BEES in her EYE.

William Jones-Warner/Getty Images

One more time, for the people in the back: BEES. IN. HER. EYE.

The unfortunate 29-year-old, identified as He, reported to a hospital with sharp eye pain that she assumed was from dirt in her eyes after a vigorous afternoon of gardening near a grave site. Upon close inspection, the hospital’s head of ophthalmology noticed “something that looked like insect legs” floating in her eye and carefully pulled them out. (Pause to dry heave.)

The eyeball intruders turned out to be “sweat bees,” which nest in fallen trees and are attracted to human perspiration. The bees flew into He’s eye and started drinking from her tear duct, which was overproducing because of the immense pain she was in. Miraculously, He’s eyeball and sight are intact, and she’s expected to make a full recovery. The bees are fine, too.

Oh, and in case you’re wondering, sweat bees live all over the world. We’re wearing goggles outside from now on.
 

Flip it and reverse it

Imagine you’re back in your med school days, happily dissecting another cadaver. You pop the body open and … every organ is in the wrong place??

yanjf/Getty Images

That’s what some students at Oregon Health & Science University (OHSU) experienced recently. They discovered their body donor had a condition called situs inversus with levocardia – meaning, her heart was in the right place (hah), but all her abdominal organs were transposed right to left. The deceased woman was Rose Marie Bentley, who had died at the ripe old age of 99 without ever knowing she had this condition.

What makes her remarkable is barely anyone with this condition lives to adulthood. Professor Cam Walker of OHSU estimates the odds are 1 in 50 million, and there are only two other known cases of older patients who lived with situs inversus. After taking a look at their mother’s medical records, Bentley’s children noted that the surgeon who removed her appendix recorded its strange location, but no one raised any alarm.

Ms. Bentley lived a full and happy life, despite her organs being a mirror image of virtually everyone else’s anatomy. Some people are just special.

Turn that smile upside down

Service with a smile. Put on a happy face. Let a smile be your umbrella. Seems like good advice, but don’t let these cliches fool you. They are all examples of surface acting – hiding feelings of annoyance behind a mask of forced pleasantness – and they’re not really good for you. At least not if you work with the public and are required to be nice.

Koldunov/Getty Images

Investigators at Penn State University and the University at Buffalo looked at survey data from nurses, teachers, and people in food service and found that they were more likely to drink after work than those who did not interact with the public on a regular basis. “In these jobs, there’s also often money tied to showing positive emotions and holding back negative feelings. Money gives you a motivation to override your natural tendencies, but doing it all day can be wearing,” lead investigator Alicia Grandey said in a written statement.

Personality also plays a part. The risk of increased drinking is greater for surface actors who are more impulsive. And it is stronger still for impulsive people who “also worked in jobs where employees have one-time service encounters with customers, like a call center or coffee shop, rather than relationships, like health care or education,” the investigators said.

They suggested that businesses could give their employees more autonomy, but we’ve got another idea. There are lots of awards for real actors, so how about one for surface actors? They could call it the Oscar … Mayer. Best performance in serving a drive-thru customer who smoked a little too much marijuana. Creative achievement while helping a credit card applicant who still doesn’t understand after being told the same thing five times. Stunt coordination while helping a patient use a bedpan (the “turn the other cheek” award). Choreography to get out of bed every day to face the blank stares of sullen teenagers (the “Lord, give me strength” award). The “okay, we get the picture, you can stop with the awards” award.
 

That’s not the ice cream truck

Any story that starts with strange men in white, unmarked vans is never going to end well. Especially when that strange man is offering $20 in exchange for DNA samples.

visualspace/Getty Images

However, this is the situation that Louisville, Ky., finds itself in. According to WAVE3 News, the aforementioned men have been cruising the poorer neighborhoods of the city for a couple of months, offering money to anyone who belongs to Passport Health. Cheek swabs are collected, no questions are asked, and the person walks out with 20 extra dollars.

This is already shady territory, but to make things worse, Passport Health has denied any affiliation. And when asked by one of their customers, the men reported being with Freedom Health. The number the customer was given? Of course it didn’t work.

The cherry on top of the shady cake? According to a professor from the University of Louisville interviewed by WAVE3, the swabs can be used to test for only certain kinds of cancer, and those tests aren’t even commercially available yet. What, you mean this was all a scam? We’re shocked! SHOCKED!

[email protected]

Women with factor XI (FXI) deficiency, particularly those with a history of bleeding and low plasmatic FXI levels, are at risk of experiencing obstetric and gynecologic hemorrhage, according to a retrospective analysis.

“[W]hile spontaneous bleeding episodes are unusual, FXI-deficient patients tend to bleed excessively after trauma or surgery, especially when highly fibrinolytic tissues are involved, such as rhino/oropharyngeal and genitourinary mucosa,” wrote Carlos Bravo-Perez, MD, of Universidad de Murcia in Spain, along with his colleagues. The report is in Medicina Clínica. “Menstruation, pregnancy and birth labour constitute intrinsic haemostatic challenges for FXI deficient women,” they noted.

The researchers conducted a retrospective analysis of 95 women with FXI deficiency. Cohort data was collected over a period of 20 years (1994 to 2014) from the city of Yecla, Spain.

Clinical information obtained included blood group, age, sex, aPTT ratio, and FXI coagulant levels, among others. The team completed a comprehensive molecular and biochemical analysis on all study patients.

“Surgical interventions and postoperative bleeding were recorded, as well as the use of antihemorrhagic prophylaxis or treatment,” the researchers wrote.

Bleeding occurred in 27.4% of women with FXI deficiency, with the majority of events being a single episode. The team reported that 52.5% of hemorrhagic events were provoked by surgical, obstetric, or dental procedures, while 47.5% were spontaneous bleeding events.

Among women who experienced bleeding events, 73.1% were gynecologic or obstetric hemorrhagic episodes. These included abnormal uterine bleeding, postpartum hemorrhage, excessive bleeding after a miscarriage, and bleeding after gynecologic surgery.

Overall, the proportion of abnormal uterine bleeding was 12.6%, the proportion of postpartum hemorrhage was 6.6%, and the proportion of gynecologic postoperative hemorrhage was 16%.

While the proportion of these bleeding events is higher than what has been observed in the general population, it is lower than what has been reported in other reviews for women with FXI deficiency, the researchers noted.

They also found that a positive history of bleeding and low plasmatic FXI levels were associated with a higher prevalence of gynecologic or obstetric bleeding.

The study was funded by Fundación Española de Trombosis y Hemostasia and Sociedad Española de Hematología y Hemoterapia in Spain. The authors reported having no conflicts of interest.

SOURCE: Bravo-Perez C et al. Med Clin (Barc). 2019 Mar 26. doi: 10.1016/j.medcli.2019.01.029.

Women with factor XI (FXI) deficiency, particularly those with a history of bleeding and low plasmatic FXI levels, are at risk of experiencing obstetric and gynecologic hemorrhage, according to a retrospective analysis.

“[W]hile spontaneous bleeding episodes are unusual, FXI-deficient patients tend to bleed excessively after trauma or surgery, especially when highly fibrinolytic tissues are involved, such as rhino/oropharyngeal and genitourinary mucosa,” wrote Carlos Bravo-Perez, MD, of Universidad de Murcia in Spain, along with his colleagues. The report is in Medicina Clínica. “Menstruation, pregnancy and birth labour constitute intrinsic haemostatic challenges for FXI deficient women,” they noted.

The researchers conducted a retrospective analysis of 95 women with FXI deficiency. Cohort data was collected over a period of 20 years (1994 to 2014) from the city of Yecla, Spain.

Clinical information obtained included blood group, age, sex, aPTT ratio, and FXI coagulant levels, among others. The team completed a comprehensive molecular and biochemical analysis on all study patients.

“Surgical interventions and postoperative bleeding were recorded, as well as the use of antihemorrhagic prophylaxis or treatment,” the researchers wrote.

Bleeding occurred in 27.4% of women with FXI deficiency, with the majority of events being a single episode. The team reported that 52.5% of hemorrhagic events were provoked by surgical, obstetric, or dental procedures, while 47.5% were spontaneous bleeding events.

Among women who experienced bleeding events, 73.1% were gynecologic or obstetric hemorrhagic episodes. These included abnormal uterine bleeding, postpartum hemorrhage, excessive bleeding after a miscarriage, and bleeding after gynecologic surgery.

Overall, the proportion of abnormal uterine bleeding was 12.6%, the proportion of postpartum hemorrhage was 6.6%, and the proportion of gynecologic postoperative hemorrhage was 16%.

While the proportion of these bleeding events is higher than what has been observed in the general population, it is lower than what has been reported in other reviews for women with FXI deficiency, the researchers noted.

They also found that a positive history of bleeding and low plasmatic FXI levels were associated with a higher prevalence of gynecologic or obstetric bleeding.

The study was funded by Fundación Española de Trombosis y Hemostasia and Sociedad Española de Hematología y Hemoterapia in Spain. The authors reported having no conflicts of interest.

SOURCE: Bravo-Perez C et al. Med Clin (Barc). 2019 Mar 26. doi: 10.1016/j.medcli.2019.01.029.

Women with factor XI (FXI) deficiency, particularly those with a history of bleeding and low plasmatic FXI levels, are at risk of experiencing obstetric and gynecologic hemorrhage, according to a retrospective analysis.

“[W]hile spontaneous bleeding episodes are unusual, FXI-deficient patients tend to bleed excessively after trauma or surgery, especially when highly fibrinolytic tissues are involved, such as rhino/oropharyngeal and genitourinary mucosa,” wrote Carlos Bravo-Perez, MD, of Universidad de Murcia in Spain, along with his colleagues. The report is in Medicina Clínica. “Menstruation, pregnancy and birth labour constitute intrinsic haemostatic challenges for FXI deficient women,” they noted.

The researchers conducted a retrospective analysis of 95 women with FXI deficiency. Cohort data was collected over a period of 20 years (1994 to 2014) from the city of Yecla, Spain.

Clinical information obtained included blood group, age, sex, aPTT ratio, and FXI coagulant levels, among others. The team completed a comprehensive molecular and biochemical analysis on all study patients.

“Surgical interventions and postoperative bleeding were recorded, as well as the use of antihemorrhagic prophylaxis or treatment,” the researchers wrote.

Bleeding occurred in 27.4% of women with FXI deficiency, with the majority of events being a single episode. The team reported that 52.5% of hemorrhagic events were provoked by surgical, obstetric, or dental procedures, while 47.5% were spontaneous bleeding events.

Among women who experienced bleeding events, 73.1% were gynecologic or obstetric hemorrhagic episodes. These included abnormal uterine bleeding, postpartum hemorrhage, excessive bleeding after a miscarriage, and bleeding after gynecologic surgery.

Overall, the proportion of abnormal uterine bleeding was 12.6%, the proportion of postpartum hemorrhage was 6.6%, and the proportion of gynecologic postoperative hemorrhage was 16%.

While the proportion of these bleeding events is higher than what has been observed in the general population, it is lower than what has been reported in other reviews for women with FXI deficiency, the researchers noted.

They also found that a positive history of bleeding and low plasmatic FXI levels were associated with a higher prevalence of gynecologic or obstetric bleeding.

The study was funded by Fundación Española de Trombosis y Hemostasia and Sociedad Española de Hematología y Hemoterapia in Spain. The authors reported having no conflicts of interest.

SOURCE: Bravo-Perez C et al. Med Clin (Barc). 2019 Mar 26. doi: 10.1016/j.medcli.2019.01.029.