Denis Rybin

Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial

IMPORTANCE Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294671.

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10−9, OR = 1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P = 1.3×10−8, OR = 1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P = 3.2×10−14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10−16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.

Randomized Controlled Trial of a Personalized Cellular Phone Reminder System to Enhance Adherence to Antiretroviral Therapy

Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 ± 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue.

Trends and Factors Associated With Infant Bed Sharing, 1993-2010: The National Infant Sleep Position Study

IMPORTANCE A strong association between infant bed sharing and sudden infant death syndrome or unintentional sleep-related death in infants has been established. Occurrences of unintentional sleep-related deaths among infants appear to be increasing. OBJECTIVES To determine the trends and factors associated with infant bed sharing from 1993 through 2010, including the association of physician advice on bed sharing. DESIGN National Infant Sleep Position study conducted with annual telephone surveys. SETTING The 48 contiguous states. PARTICIPANTS Nighttime caregivers of infants born within 7 months of each survey administration. Approximately 1000 interviews were completed annually. MAIN OUTCOMES AND MEASURES Infant bed sharing as a usual practice. RESULTS Of 18 986 participants, 11.2% reported an infant sharing a bed as a usual practice. Bed sharing increased from 1993 (6.5%) to 2010 (13.5%). Although bed sharing increased significantly among white respondents from 1993 to 2000 (P < .001), the increase from 2001 to 2010 was not significant (P = .48). Black and Hispanic respondents reported an increase in bed sharing throughout the study period, with no difference between the earlier and later periods (P = .63 and P = .77, respectively). After accounting for the study year, factors associated with increase in infant bed sharing as a usual practice included maternal educational level of less than high school compared with college or greater (adjusted odds ratio, 1.42 [95% CI, 1.12-1.79]); black (3.47 [2.97-4.05]), Hispanic (1.33 [1.10-1.61]), and other (2.46 [2.03-2.97]) maternal race or ethnicity compared with white race; household income of less than

Identifying prescription opioid use disorder in primary care: diagnostic characteristics of the Current Opioid Misuse Measure (COMM).

20,000 (1.69 [1.44-1.99]) and

Trends and factors associated with infant sleeping position: the national infant sleep position study, 1993-2007

20,000 to

Barriers to Following the Supine Sleep Recommendation Among Mothers at Four Centers for the Women, Infants, and Children Program

50,000 (1.29 [1.14-1.45]) compared with greater than

Web intervention for OEF/OIF veterans with problem drinking and PTSD symptoms: A randomized clinical trial

50,000; living in the West (1.61 [1.38-1.88]) or the South (1.47 [1.30-1.66]) compared with the Midwest; infants younger than 8 weeks (1.45 [1.21-1.73]) or ages 8 to 15 weeks (1.31 [1.17-1.45]) compared with 16 weeks or older; and being born prematurely compared with full-term (1.41 [1.22-1.62]). Almost 46% of the participants reported talking to a physician about bed sharing. Compared with those who did not receive advice from a physician, those who reported their physicians had a negative attitude were less likely to have the infant share a bed (adjusted odds ratio, 0.66 [95% CI, 0.53-0.82]), whereas a neutral attitude was associated with increased bed sharing (1.38 [1.05-1.80]). CONCLUSIONS AND RELEVANCE Our finding of a continual increase in bed sharing throughout the study period among black and Hispanic infants suggests that the current American Academy of Pediatrics recommendation about bed sharing is not universally followed. The factors associated with infant bed sharing may be useful in evaluating the impact of a broad intervention to change behavior.

Weight-Based, Insulin Dose–Related Hypoglycemia in Hospitalized Patients With Diabetes

&NA; The Current Opioid Misuse Measure (COMM), a self‐report assessment of past‐month aberrant medication‐related behaviors, has been validated in specialty pain management patients. The performance characteristics of the COMM were evaluated in primary care (PC) patients with chronic pain. It was hypothesized that the COMM could identify patients with prescription drug use disorder (PDD). English‐speaking adults awaiting PC visits at an urban, safety‐net hospital, who had chronic pain and had received any opioid analgesic prescription in the past year, were administered the COMM. The Composite International Diagnostic Interview served as the “gold standard,” using DSM‐IV criteria for PDD and other substance use disorders (SUDs). A receiver operating characteristic (ROC) curve demonstrated the COMM’s diagnostic test characteristics. Of the 238 participants, 27 (11%) met DSM‐IV PDD criteria, whereas 17 (7%) had other SUDs, and 194 (82%) had no disorder. The mean COMM score was higher in those with PDD than among all others (ie, those with other SUDs or no disorder, mean 20.4 [SD 10.8] vs 8.4 [SD 7.5], P < .0001). A COMM score of ⩾13 had a sensitivity of 77% and a specificity of 77% for identifying patients with PDD. The area under the ROC curve was 0.84. For chronic pain patients prescribed opioids, the development of PDD is an undesirable complication. Among PC patients with chronic pain‐prescribed prescription opioids, the COMM is a promising tool for identifying those with PDD. Among primary care patients with chronic pain‐prescribed opioids, the validated Current Opioid Misuse Measure (COMM) is a promising tool for identifying patients with prescription opioid use disorder.