Joseph Rigdon

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial

Importance Alternate-day fasting has become increasingly popular, yet, to date, no long-term randomized clinical trials have evaluated its efficacy. Objective To compare the effects of alternate-day fasting vs daily calorie restriction on weight loss, weight maintenance, and risk indicators for cardiovascular disease. Design, Setting, and Participants A single-center randomized clinical trial of obese adults (18 to 64 years of age; mean body mass index, 34) was conducted between October 1, 2011, and January 15, 2015, at an academic institution in Chicago, Illinois. Interventions Participants were randomized to 1 of 3 groups for 1 year: alternate-day fasting (25% of energy needs on fast days; 125% of energy needs on alternating “feast days”), calorie restriction (75% of energy needs every day), or a no-intervention control. The trial involved a 6-month weight-loss phase followed by a 6-month weight-maintenance phase. Main Outcomes and Measures The primary outcome was change in body weight. Secondary outcomes were adherence to the dietary intervention and risk indicators for cardiovascular disease. Results Among the 100 participants (86 women and 14 men; mean [SD] age, 44 [11] years), the dropout rate was highest in the alternate-day fasting group (13 of 34 [38%]), vs the daily calorie restriction group (10 of 35 [29%]) and control group (8 of 31 [26%]). Mean weight loss was similar for participants in the alternate-day fasting group and those in the daily calorie restriction group at month 6 (–6.8% [95% CI, –9.1% to –4.5%] vs –6.8% [95% CI, –9.1% to –4.6%]) and month 12 (–6.0% [95% CI, –8.5% to –3.6%] vs –5.3% [95% CI, –7.6% to –3.0%]) relative to those in the control group. Participants in the alternate-day fasting group ate more than prescribed on fast days, and less than prescribed on feast days, while those in the daily calorie restriction group generally met their prescribed energy goals. There were no significant differences between the intervention groups in blood pressure, heart rate, triglycerides, fasting glucose, fasting insulin, insulin resistance, C-reactive protein, or homocysteine concentrations at month 6 or 12. Mean high-density lipoprotein cholesterol levels at month 6 significantly increased among the participants in the alternate-day fasting group (6.2 mg/dL [95% CI, 0.1-12.4 mg/dL]), but not at month 12 (1.0 mg/dL [95% CI, –5.9 to 7.8 mg/dL]), relative to those in the daily calorie restriction group. Mean low-density lipoprotein cholesterol levels were significantly elevated by month 12 among the participants in the alternate-day fasting group (11.5 mg/dL [95% CI, 1.9-21.1 mg/dL]) compared with those in the daily calorie restriction group. Conclusions and Relevance Alternate-day fasting did not produce superior adherence, weight loss, weight maintenance, or cardioprotection vs daily calorie restriction. Trial Registration clinicaltrials.gov Identifier: NCT00960505

Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association With Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial

Importance Dietary modification remains key to successful weight loss. Yet, no one dietary strategy is consistently superior to others for the general population. Previous research suggests genotype or insulin-glucose dynamics may modify the effects of diets. Objective To determine the effect of a healthy low-fat (HLF) diet vs a healthy low-carbohydrate (HLC) diet on weight change and if genotype pattern or insulin secretion are related to the dietary effects on weight loss. Design, Setting, and Participants The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized clinical trial included 609 adults aged 18 to 50 years without diabetes with a body mass index between 28 and 40. The trial enrollment was from January 29, 2013, through April 14, 2015; the date of final follow-up was May 16, 2016. Participants were randomized to the 12-month HLF or HLC diet. The study also tested whether 3 single-nucleotide polymorphism multilocus genotype responsiveness patterns or insulin secretion (INS-30; blood concentration of insulin 30 minutes after a glucose challenge) were associated with weight loss. Interventions Health educators delivered the behavior modification intervention to HLF (n = 305) and HLC (n = 304) participants via 22 diet-specific small group sessions administered over 12 months. The sessions focused on ways to achieve the lowest fat or carbohydrate intake that could be maintained long-term and emphasized diet quality. Main Outcomes and Measures Primary outcome was 12-month weight change and determination of whether there were significant interactions among diet type and genotype pattern, diet and insulin secretion, and diet and weight loss. Results Among 609 participants randomized (mean age, 40 [SD, 7] years; 57% women; mean body mass index, 33 [SD, 3]; 244 [40%] had a low-fat genotype; 180 [30%] had a low-carbohydrate genotype; mean baseline INS-30, 93 &mgr;IU/mL), 481 (79%) completed the trial. In the HLF vs HLC diets, respectively, the mean 12-month macronutrient distributions were 48% vs 30% for carbohydrates, 29% vs 45% for fat, and 21% vs 23% for protein. Weight change at 12 months was −5.3 kg for the HLF diet vs −6.0 kg for the HLC diet (mean between-group difference, 0.7 kg [95% CI, −0.2 to 1.6 kg]). There was no significant diet-genotype pattern interaction (P = .20) or diet-insulin secretion (INS-30) interaction (P = .47) with 12-month weight loss. There were 18 adverse events or serious adverse events that were evenly distributed across the 2 diet groups. Conclusions and Relevance In this 12-month weight loss diet study, there was no significant difference in weight change between a healthy low-fat diet vs a healthy low-carbohydrate diet, and neither genotype pattern nor baseline insulin secretion was associated with the dietary effects on weight loss. In the context of these 2 common weight loss diet approaches, neither of the 2 hypothesized predisposing factors was helpful in identifying which diet was better for whom. Trial Registration clinicaltrials.gov Identifier: NCT01826591

Randomization inference for treatment effects on a binary outcome

Two methods are developed for constructing randomization-based confidence sets for the average effect of a treatment on a binary outcome. The methods are nonparametric and require no assumptions about random sampling from a larger population. Both of the resulting 1 - α confidence sets are exact in the sense that the probability of containing the true treatment effect is at least 1 - α. Both types of confidence sets are also guaranteed to have width no greater than one. In contrast, a previously proposed asymptotic confidence interval is not exact and may have width greater than 1. The first approach combines Bonferroni-adjusted prediction sets for the attributable effects in the treated and untreated. The second method entails inverting a permutation test. Simulations are presented comparing the two randomization-based confidence sets with the asymptotic interval as well as the standard Wald confidence interval and a commonly used exact interval for the difference in binomial proportions. Results show for small to moderate sample sizes that the permutation confidence set attains the narrowest width on average among the methods that maintain nominal coverage. Extensions that allow for stratifying on categorical baseline covariates are also discussed.

The interplay between immune maturation, age, chronic viral infection and environment

BackgroundThe worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses.ResultsOur results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies.ConclusionsOur data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.

Supplemental Nutrition Assistance Program (SNAP) Participation and Health Care Expenditures Among Low-Income Adults

Importance Food insecurity is associated with high health care expenditures, but the effectiveness of food insecurity interventions on health care costs is unknown. Objective To determine whether the Supplemental Nutrition Assistance Program (SNAP), which addresses food insecurity, can reduce health care expenditures. Design, Setting, and Participants This is a retrospective cohort study of 4447 noninstitutionalized adults with income below 200% of the federal poverty threshold who participated in the 2011 National Health Interview Survey (NHIS) and the 2012-2013 Medical Expenditure Panel Survey (MEPS). Exposures Self-reported SNAP participation in 2011. Main Outcomes and Measures Total health care expenditures (all paid claims and out-of-pocket costs) in the 2012-2013 period. To test whether SNAP participation was associated with lower subsequent health care expenditures, we used generalized linear modeling (gamma distribution, log link, with survey design information), adjusting for demographics (age, gender, race/ethnicity), socioeconomic factors (income, education, Social Security Disability Insurance disability, urban/rural), census region, health insurance, and self-reported medical conditions. We also conducted sensitivity analyses as a robustness check for these modeling assumptions. Results A total of 4447 participants (2567 women and 1880 men) were enrolled in the study, mean (SE) age, 42.7 (0.5) years; 1889 were SNAP participants, and 2558 were not. Compared with other low-income adults, SNAP participants were younger (mean [SE] age, 40.3 [0.6] vs 44.1 [0.7] years), more likely to have public insurance or be uninsured (84.9% vs 67.7%), and more likely to be disabled (24.2% vs 10.6%) (P < .001 for all). In age- and gender-adjusted models, health care expenditures between those who did and did not participate in SNAP were similar (difference,

Burnout in the neonatal intensive care unit and its relation to healthcare-associated infections.

34; 95% CI, −

Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer

1097 to

Factors Associated With Provider Burnout in the NICU

1165). In fully adjusted models, SNAP was associated with lower estimated annual health care expenditures (−

Benefit and harm of intensive blood pressure treatment: Derivation and validation of risk models using data from the SPRINT and ACCORD trials

1409; 95% CI, −