Context Nicotine administration transiently improves many neurobiological and cognitive functions in schizophrenia. It is not yet clear which nAChR subtype(s) is responsible for these seemingly pervasive nicotinic effects in schizophrenia. Objective α4β2 is a key nAChR subtype for nicotinic actions. We investigated the effect of varenicline, a relatively specific α4β2 partial agonist/antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. Design double-blind, parallel, randomized, placebo controlled trial in schizophrenia patients to examine effects of varenicline on biomarkers at short-term (2 week) and long-term (8 week), using a slow titration and moderate dosing strategy for retaining α4β2 specific effect while minimizing side effects. Setting Outpatients. Participants 69 smoking and nonsmoking patients randomized; 64 completed week 2; 59 completed week 8. Intervention(s) varenicline. Main Outcome Measure(s) prepulse inhibition, sensory gating, antisaccade, spatial working memory, eyetracking, processing speed, and sustained attention. Results Moderate dose of varenicline 1) reduced P50 sensory gating deficit after a long-term (p=0.006) but not short-term treatment; significant in nonsmokers but not in smokers; 2) reduced startle reactivity (p=0.015) regardless of baseline smoking status; and 3) improved executive function by reducing antisaccade error rate (p=0.034) regardless of smoking status. Moderate dose varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit, processing speed, or sustained attention by Connor’s CPT. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration, 1 mg daily dose. Conclusions Moderate dose varenicline has a unique treatment profile on core schizophrenia related biomarkers. Further development is warranted for specific nAChR compounds and dosing/duration strategy to target subgroup of schizophrenia patients with specific biological deficits. ClinicalTrials.gov Identifier: NCT00492349

In contrast with other developed nations, life expectancy is decreasing in the United States, in part due to increasing mortality from alcohol-associated liver disease (ALD). Up-to-date estimates of ALD mortality are necessary for setting public health priorities to reverse this concerning trend. We therefore aimed to assess current (2017) estimates of ALD mortality and temporal trends from 1999 to 2017. METHODS:Using national data from the Centers for Disease Control and Prevention, we analyzed stratified ALD mortality rates between 1999 and 2017. We determined the age-adjusted death rates, stratified by sex and categorized by age, race/ethnicity, urbanization, and census region. We also identified statistically significant changes in the annual rate difference (ARD), annual percentage change (APC), and average APC in ALD mortality. RESULTS:In 2017, mortality from ALD was higher than any other year since 1999 with age-adjusted rates of 13.1 per 100,000 (95% confidence interval [CI] 12.9-13.3) in men and 5.6 per 100,000 (95% CI 5.4-5.7) in women. Mortality was highest among men and women who were middle aged, Native American, and from rural areas. Since 2006, ALD mortality has increased in almost every age group and race with the exception of non-Hispanic black men. Absolute increases in mortality rates have been particularly pronounced in Native American women (2005-2017 ARD 0.8, 95% CI 0.6-0.9), non-Hispanic/white men (2006-2017 ARD 0.4, 95% CI 0.3-0.4), and non-Hispanic/white women (2013-2017 ARD 0.4, 95% CI 0.3-0.5). DISCUSSION:Mortality from ALD is increasing over time in most demographic groups. Increased effort is needed to develop targeted public health strategies to address high and increasing ALD mortality.

Aim To examine whether sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors are associated with a higher risk of lower‐extremity amputation than dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors and sulphonylureas. Methods We conducted a retrospective cohort study, using the MarketScan Commercial Claims and Encounters Database (2013‐2015), to compare the incidence of lower‐extremity amputation (LEA) between initiators of SGLT2 inhibitors and initiators of two second‐line drugs, DPP‐4 inhibitors and sulphonylureas (SUs). We estimated crude incidence rates (IRs) and adjusted hazard ratios (aHR), with 95% confidence intervals (CIs), before and after propensity‐score weighting. We additionally conducted sensitivity analyses using a comparator group of all non‐metformin, non‐SGLT2 inhibitor glucose‐lowering drugs, as previous studies used this approach. Results In a cohort of 328 150 individuals aged 18 to 64 years, the IR of LEA ranged from 1.5 to 2.4 per 1000 person‐years. In as‐treated analysis, the estimated hazard of LEA was increased among SGLT2 inhibitor initiators compared to DPP‐4 inhibitor initiators (aHR 1.69, 95% CI 1.20‐2.38), but not compared to SU initiators (aHR 1.02, 95% CI 0.67‐1.55) or non‐metformin, non‐SGLT2 inhibitor initiators (aHR 1.02, 95% CI 0.54‐1.93). Results were consistent in intention‐to‐treat analysis and across a number of sensitivity analyses. Conclusions Among commercially insured patients in the United States, our results suggest that initiation of SGLT2 inhibitors may increase the risk of LEA compared to initiation of DPP‐4 inhibitors. Contrasting results when comparing SGLT2 inhibitor initiators to DPP‐4 inhibitor and SU initiators highlight the importance of choosing appropriate comparator drugs when addressing comparative effectiveness and safety questions that can inform clinical decision‐making.

A health department-based, mailed FIT program targeting Medicaid beneficiaries was feasible. Including a FIT kit resulted in greater screening completion than a reminder letter alone. Further research is needed to understand the comparative cost-effectiveness of these interventions.