Reprints and permissions information is available at www.nature.com/reprints. Data availability All sequencing data from this study have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) and are accessible through the GEO Series accession code GSE122713. All other relevant data are available from the corresponding author on request.

Background A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting. Methods Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study ( N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models. Results Overweight/Class-I (25- < 35 kg/m 2 ) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1–0.71; p -value = 0.008 ) and progressive disease (adjusted-HR:0.43; 95%CI:0.19–0.95; p -value: 0.038 ) compared to normal-weight (18.5- < 25 kg/m 2 ). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1–1.77; p -value: 0.238) for OS and 1 (95%CI:0.34–2.94; p -value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HR males :0.11; 95%CI:0.03–0.4; adjusted-HR females : 0.56; 95%CI:0.16–1.89 ; p -value interaction : 0.044 ); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15–1.24; p -value interaction : 0.020 ), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy ( n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts. Conclusions The findings support the existence of an “obesity paradox” restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 block...

Introduction: Rising antibiotic resistance may negatively affect the health and cost of care for patients. This study aimed to determine the impact of antibiotic resistance on costs and health consequences for patients. Methodology: A one-year observational study was conducted at Christian Medical College, Vellore, a tertiary care hospital, on patients admitted into medical wards with a preliminary diagnosis of suspected sepsis. Patients with confirmed bacteremia were analysed in two groups -resistant and susceptible -based on susceptibility of causative bacteria to the empiric antibiotics administered. Clinical data and details about costs incurred were collected from hospital records. Costs and health consequences were compared using Mann-Whitney U test and Fisher's exact test. For median difference in costs, 95% bootstrap confidence interval was determined. Results: Overall, 220 patients were included. The median difference between resistant and susceptible groups in overall costs, antibiotic costs, and pharmacy costs was rupees (INR)/USD 41,993/700 (p = 0.001), 8,315/139 (p < 0.001) and 21,492/358 (p < 0.001), respectively. Health consequences such as intensive care admissions, complications, mortality, and length of stay were significantly higher in the resistant group as compared to susceptible group: 44% vs. 21% (p < 0.001), 56% vs. 37% (p = 0.006), 12% vs. 2% (p = 0.011), and 14 vs. 11 days (p = 0·027), respectively. Conclusions: Antibiotic resistance has a significant impact on cost and health consequences. These findings provide a key message for policymakers and other stakeholders to initiate feasible strategies to tackle resistance and reduce the burden.

IntroductionAntibiotic pressure contributes to rising antibiotic resistance. Policy guidelines encourage rational prescribing behavior, but effectiveness in containing antibiotic use needs further assessment. This study therefore assessed the patterns of antibiotic use over a decade and analyzed the impact of different modes of guideline development and dissemination on inpatient antibiotic use.MethodsAntibiotic use was calculated monthly as defined daily doses (DDD) per 100 bed days for nine antibiotic groups and overall. This time series compared trends in antibiotic use in five adjacent time periods identified as ‘Segments,’ divided based on differing modes of guideline development and implementation: Segment 1– Baseline prior to antibiotic guidelines development; Segment 2– During preparation of guidelines and booklet dissemination; Segment 3– Dormant period with no guidelines dissemination; Segment 4– Booklet dissemination of revised guidelines; Segment 5– Booklet dissemination of revised guidelines with intranet access. Regression analysis adapted for segmented time series and adjusted for seasonality assessed changes in antibiotic use trend.ResultsOverall antibiotic use increased at a monthly rate of 0.95 (SE = 0.18), 0.21 (SE = 0.08) and 0.31 (SE = 0.06) for Segments 1, 2 and 3, stabilized in Segment 4 (0.05; SE = 0.10) and declined in Segment 5 (−0.37; SE = 0.11). Segments 1, 2 and 4 exhibited seasonal fluctuations. Pairwise segmented regression adjusted for seasonality revealed a significant drop in monthly antibiotic use of 0.401 (SE = 0.089; p<0.001) for Segment 5 compared to Segment 4. Most antibiotic groups showed similar trends to overall use.ConclusionUse of overall and specific antibiotic groups showed varied patterns and seasonal fluctuations. Containment of rising overall antibiotic use was possible during periods of active guideline dissemination. Wider access through intranet facilitated significant decline in use. Stakeholders and policy makers are urged to develop guidelines, ensure active dissemination and enable accessibility through computer networks to contain antibiotic use and decrease antibiotic pressure.