Computing evolutionary distinctiveness indices in large scale analysis

We present optimal linear time algorithms for computing the Shapley values and 'heightened evolutionary distinctiveness' (HED) scores for the set of taxa in a phylogenetic tree. We demonstrate the efficiency of these new algorithms by applying them to a set of 10,000 reasonable 5139-species mammal trees. This is the first time these indices have been computed on such a large taxon and we contrast our finding with an ad-hoc index for mammals, fair proportion (FP), used by the Zoological Society of London's EDGE programme. Our empirical results follow expectations. In particular, the Shapley values are very strongly correlated with the FP scores, but provide a higher weight to the few monotremes that comprise the sister to all other mammals. We also find that the HED score, which measures a species' unique contribution to future subsets as function of the probability that close relatives will go extinct, is very sensitive to the estimated probabilities. When they are low, HED scores are less than FP scores, and approach the simple measure of a species' age. Deviations (like the Solendon genus of the West Indies) occur when sister species are both at high risk of extinction and their clade roots deep in the tree. Conversely, when endangered species have higher probabilities of being lost, HED scores can be greater than FP scores and species like the African elephant Loxondonta africana, the two solendons and the thumbless bat Furipterus horrens can move up the rankings. We suggest that conservation attention be applied to such species that carry genetic responsibility for imperiled close relatives. We also briefly discuss extensions of Shapley values and HED scores that are possible with the algorithms presented here

Signaling in Secret: Pay-for-Performance and the Incentive and Sorting Effects of Pay Secrecy

Key Findings: Pay secrecy adversely impacts individual task performance because it weakens the perception that an increase in performance will be accompanied by increase in pay; Pay secrecy is associated with a decrease in employee performance and retention in pay-for-performance systems, which measure performance using relative (i.e., peer-ranked) criteria rather than an absolute scale (see Figure 2 on page 5); High performing employees tend to be most sensitive to negative pay-for- performance perceptions; There are many signals embedded within HR policies and practices, which can influence employees’ perception of workplace uncertainty/inequity and impact their performance and turnover intentions; and When pay transparency is impractical, organizations may benefit from introducing partial pay openness to mitigate these effects on employee performance and retention

Standardizing data reporting in the research community to enhance the utility of open data for SARS-CoV-2 wastewater surveillance

SARS-CoV-2 RNA detection in wastewater is being rapidly developed and adopted as a public health monitoring tool worldwide. With wastewater surveillance programs being implemented across many different scales and by many different stakeholders, it is critical that data collected and shared are accompanied by an appropriate minimal amount of meta-information to enable meaningful interpretation and use of this new information source and intercomparison across datasets. While some databases are being developed for specific surveillance programs locally, regionally, nationally, and internationally, common globally-adopted data standards have not yet been established within the research community. Establishing such standards will require national and international consensus on what meta-information should accompany SARS-CoV-2 wastewater measurements. To establish a recommendation on minimum information to accompany reporting of SARS-CoV-2 occurrence in wastewater for the research community, the United States National Science Foundation (NSF) Research Coordination Network on Wastewater Surveillance for SARS-CoV-2 hosted a workshop in February 2021 with participants from academia, government agencies, private companies, wastewater utilities, public health laboratories, and research institutes. This report presents the primary two outcomes of the workshop: (i) a recommendation on the set of minimum meta-information that is needed to confidently interpret wastewater SARS-CoV-2 data, and (ii) insights from workshop discussions on how to improve standardization of data reporting

Short-Term Striatal Gene Expression Responses to Brain-Derived Neurotrophic Factor Are Dependent on MEK and ERK Activation

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. CONCLUSIONS: These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression

Wastewater surveillance for bacterial targets: current challenges and future goals

Wastewater-based epidemiology (WBE) expanded rapidly in response to the COVID-19 pandemic. As the public health emergency has ended, researchers and practitioners are looking to shift the focus of existing wastewater surveillance programs to other targets, including bacteria. Bacterial targets may pose some unique challenges for WBE applications. To explore the current state of the field, the National Science Foundation-funded Research Coordination Network (RCN) on Wastewater Based Epidemiology for SARS-CoV-2 and Emerging Public Health Threats held a workshop in April 2023 to discuss the challenges and needs for wastewater bacterial surveillance. The targets and methods used in existing programs were diverse, with twelve differentdifferentdifferenttargets and nine different methods listed. Discussions during the workshop highlighted the challenges in adapting existing programs and identified research gaps in four key areas: choosing new targets, relating bacterial wastewater data to human disease incidence and prevalence, developing methods, and normalizing results. To help with these challenges and research gaps, the authors identified steps the larger community can take to improve bacteria wastewater surveillance. This includes developing data reporting standards and method optimization and validation for bacterial programs. Additionally, more work is needed to understand shedding patterns for potential bacterial targets to better relate wastewater data to human infections. Wastewater surveillance for bacteria can help provide insight into the underlying prevalence in communities, but much work is needed to establish these methods

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Effectiveness of individualized physiotherapy on pain and functioning compared to a standard exercise protocol in patients presenting with clinical signs of subacromial impingement syndrome. A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Shoulder impingement syndrome is a common musculoskeletal complaint leading to significant reduction of health and disability. Physiotherapy is often the first choice of treatment although its effectiveness is still under debate. Systematic reviews in this field highlight the need for more high quality trials to investigate the effectiveness of physiotherapy interventions in patients with subacromial impingement syndrome.</p> <p>Methods/Design</p> <p>This randomized controlled trial will investigate the effectiveness of individualized physiotherapy in patients presenting with clinical signs and symptoms of subacromial impingement, involving 90 participants aged 18-75. Participants are recruited from outpatient physiotherapy clinics, general practitioners, and orthopaedic surgeons in Germany. Eligible participants will be randomly allocated to either individualized physiotherapy or to a standard exercise protocol using central randomization.</p> <p>The control group will perform the standard exercise protocol aiming to restore muscular deficits in strength, mobility, and coordination of the rotator cuff and the shoulder girdle muscles to unload the subacromial space during active movements. Participants of the intervention group will perform the standard exercise protocol as a home program, and will additionally be treated with individualized physiotherapy based on clinical examination results, and guided by a decision tree. After the intervention phase both groups will continue their home program for another 7 weeks.</p> <p>Outcome will be measured at 5 weeks and at 3 and 12 months after inclusion using the shoulder pain and disability index and patients' global impression of change, the generic patient-specific scale, the average weekly pain score, and patient satisfaction with treatment. Additionally, the fear avoidance beliefs questionnaire, the pain catastrophizing scale, and patients' expectancies of treatment effect are assessed. Participants' adherence to the protocol, use of additional treatments for the shoulder, direct and indirect costs, and sick leave due to shoulder complaints will be recorded in a shoulder log-book.</p> <p>Discussion</p> <p>To our knowledge this is the first trial comparing individualized physiotherapy based on a defined decision making process to a standardized exercise protocol. Using high-quality methodologies, this trial will add evidence to the limited body of knowledge about the effect of physiotherapy in patients with SIS.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN86900354</p