Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191

EQUIP: Implementing chronic care principles and applying formative evaluation methods to improve care for schizophrenia: QUERI Series

<p>Abstract</p> <p>Background</p> <p>This paper presents a case study that demonstrates the evolution of a project entitled "Enhancing QUality-of-care In Psychosis" (EQUIP) that began approximately when the U.S. Department of Veterans Affairs' Quality Enhancement Research Initiative (QUERI), and implementation science were emerging. EQUIP developed methods and tools to implement chronic illness care principles in the treatment of schizophrenia, and evaluated this implementation using a small-scale controlled trial. The next iteration of the project, EQUIP-2, was further informed by implementation science and the use of QUERI tools.</p> <p>Methods</p> <p>This paper reports the background, development, results and implications of EQUIP, and also describes ongoing work in the second phase of the project (EQUIP-2). The EQUIP intervention uses implementation strategies and tools to increase the adoption and implementation of chronic illness care principles. In EQUIP-2, these strategies and tools are conceptually grounded in a stages-of-change model, and include clinical and delivery system interventions and adoption/implementation tools. Formative evaluation occurs in conjunction with the intervention, and includes developmental, progress-focused, implementation-focused, and interpretive evaluation.</p> <p>Results</p> <p>Evaluation of EQUIP provided an understanding of quality gaps <it>and </it>how to address related problems in schizophrenia. EQUIP showed that solutions to quality problems in schizophrenia differ by treatment domain and are exacerbated by a lack of awareness of evidence-based practices. EQUIP also showed that improving care requires creating resources for physicians to help them easily implement practice changes, plus intensive education as well as product champions who help physicians use these resources. Organizational changes, such as the addition of care managers and informatics systems, were shown to help physicians with identifying problems, making referrals, and monitoring follow-up. In EQUIP-2, which is currently in progress, these initial findings were used to develop a more comprehensive approach to implementing and evaluating the chronic illness care model.</p> <p>Discussion</p> <p>In QUERI, small-scale projects contribute to the development and enhancement of hands-on, action-oriented service-directed projects that are grounded in current implementation science. This project supports the concept that QUERI tools can be useful in implementing complex care models oriented toward evidence-based improvement of clinical care.</p