3b-hydroxy-5a-androst-1-en-17-one Increases Testosterone Bioavailability Through Downregulation of Sex Hormone Binding Globulin Protein

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Aperture effects on Star Formation Rate, Metallicity and Reddening

(Abridged) We use 101 galaxies selected from the Nearby Field Galaxy Survey (NFGS) to investigate the effect of aperture size on the star formation rate, metallicity and reddening determinations for galaxies. We compare the star formation rate, metallicity and reddening derived from nuclear spectra to those derived from integrated spectra. For apertures capturing <20% of the B(26) light, the differences between nuclear and global metallicity, extinction and star formation rate are substantial. We calculate an `expected' star formation rate using our nuclear spectra and apply the commonly-used aperture correction method. The expected star formation rate overestimates the global value for early type spirals, with large scatter for all Hubble types, particularly late types. The differences between the expected and global star formation rates probably result from the assumption that the distributions of the emission-line gas and the continuum are identical. We discuss the implications of these results for metallicity-luminosity relations and star formation history studies based on fiber spectra. To reduce systematic and random errors from aperture effects, we recommend selecting samples with fibers that capture >20% of the galaxy light. For the Sloan Digital Sky Survey and the 2dFGRS, redshifts z>0.04 and z>0.06 are required, respectively, to ensure a covering fraction >20% for galaxies similar to the average size, type, and luminosity observed in our sample. Higher luminosity samples and samples containing many late-type galaxies require a larger minimum redshift to ensure that >20% of the galaxy light is enclosed by the fiber.Comment: 19 pages, 11 figures, 5 tables. Accepted for publication in the PAS

The complete genome sequence and comparative genome analysis of the high pathogenicity Yersinia enterocolitica strain 8081

The human enteropathogen, Yersinia enterocolitica, is a significant link in the range of Yersinia pathologies extending from mild gastroenteritis to bubonic plague. Comparison at the genomic level is a key step in our understanding of the genetic basis for this pathogenicity spectrum. Here we report the genome of Y. enterocolitica strain 8081 (serotype 0:8; biotype 1B) and extensive microarray data relating to the genetic diversity of the Y. enterocolitica species. Our analysis reveals that the genome of Y. enterocolitica strain 8081 is a patchwork of horizontally acquired genetic loci, including a plasticity zone of 199 kb containing an extraordinarily high density of virulence genes. Microarray analysis has provided insights into species-specific Y. enterocolitica gene functions and the intraspecies differences between the high, low, and nonpathogenic Y. enterocolitica biotypes. Through comparative genome sequence analysis we provide new information on the evolution of the Yersinia. We identify numerous loci that represent ancestral clusters of genes potentially important in enteric survival and pathogenesis, which have been lost or are in the process of being lost, in the other sequenced Yersinia lineages. Our analysis also highlights large metabolic operons in Y. enterocolitica that are absent in the related enteropathogen, Yersinia pseudotuberculosis, indicating major differences in niche and nutrients used within the mammalian gut. These include clusters directing, the production of hydrogenases, tetrathionate respiration, cobalamin synthesis, and propanediol utilisation. Along with ancestral gene clusters, the genome of Y. enterocolitica has revealed species-specific and enteropathogen-specific loci. This has provided important insights into the pathology of this bacterium and, more broadly, into the evolution of the genus. Moreover, wider investigations looking at the patterns of gene loss and gain in the Yersinia have highlighted common themes in the genome evolution of other human enteropathogens

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.</p

Report of Working Group on Widely Distributed Stocks (WGWIDE).

As a consequence of the impact of the COVID pandemic on international travel which prevented the traditional meeting from taking place, the Working Group on Widely Distributed Stocks (WGWIDE) met online via WebEx hosted by ICES. Prior to the 2020 meeting, the generic ToRs for species and regional working groups were re-prioritised by ACOM to allow the WG to focus primarily on those ToRs most applicable to the provision of advice. WGWIDE reports on the status and considerations for management of Northeast Atlantic mackerel, blue whiting, Western and North Sea horse mackerel, Northeast Atlantic boarfish, Norwegian springspawning herring, striped red mullet (Subareas 6, 8 and Divisions 7.a-c, e-k and 9.a), and red gurnard (Subareas 3, 4, 5, 6, 7, and 8) stocks. Northeast Atlantic (NEA) Mackerel. This stock is highly migratory and widely distributed throughout the Northeast Atlantic with significant fisheries is most ICES subareas. A diverse range of fleets from smaller artisanal, handline vessels to large (100m+) factory freezer vessels and modern RSW trawlers and purse seiners take part in what is one of the most valuable European fisheries. The assessment conducted in 2020 is an update assessment, based on the configuration agreed during the most recent inter-benchmark exercise in 2019 and incorporates the most recent data available from sampling of the commercial catch in 2019, the final 2019 egg survey SSB estimate, an updated recruitment index and tagging time series along with 2020 survey data from the IESSNS swept area survey. Advice is given based on stock reference points which were updated during a management strategy evaluation carried out in 2020. Following a strong increase from 2007 to 2014, SSB has been declining although it remains well above MSY Btrigger. Fishing mortality has been below FMSY since 2016. There have been a number of large year classes since 2001 with above average recruitment over much of the most recent decade. Blue Whiting. This pelagic gadoid is widely distributed in the eastern part of the North Atlantic. The 2020 update assessment followed the protocol from the most recent inter-benchmark in 2016 and used preliminary catch data from 2020. Due to the cancellation of the 2020 acoustic survey, this data was not available. The effect on the assessment was minimal and limited to increases in uncertainty of the terminal year estimates. The SSB continues to decrease from the most recent maximum in 2017 mainly due to below average recruitment since 2017, although it remains above MSY Btrigger. Fishing mortality has been above FMSY since 2014. Norwegian Spring Spawning Herring. This is one of the largest herring stocks in the world. It is highly migratory, spawning along the Norwegian coast and feeding throughout much of the Norwegian Sea. The 2020 assessment is based on an implementation of the XSAM assessment model introduced at the benchmark in 2016. This years’ assessment indicates that the stock is continuing to decline from the peak in 2008 of 7Mt to just above MSY Btrigger due to successive years of average or below average recruitment. Catch advice for 2021 is given on the basis of the agreed management plan and represents a substantial increase over the 2020 advice due to an upward revision in the estimate of the 2016 year-class which is considered to be the most significant year-class since 2004

Female mice may have exacerbated catabolic signalling response compared to male mice during development and progression of disuse atrophy

Background: Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well-established model of hindlimb unloading (HU). Methods: One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism). Results: Both males and females lost ~30% of tibialis anterior cross-sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross-sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24-48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4-fold greater content in females compared with ~2-fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes. Conclusions: These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy

Delirium in older COVID-19 patients:Evaluating risk factors and outcomes

Objectives: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. Methods: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. Results: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3–33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1–22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40–1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71–4.72] p < 0.001), but not in multivariable analyses. Conclusions: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty

Comparing Dutch Case management care models for people with dementia and their caregivers: The design of the COMPAS study

<p>Abstract</p> <p>Background</p> <p>Dementia care in the Netherlands is shifting from fragmented, ad hoc care to more coordinated and personalised care. Case management contributes to this shift. The linkage model and a combination of intensive case management and joint agency care models were selected based on their emerging prominence in the Netherlands. It is unclear if these different forms of case management are more effective than usual care in improving or preserving the functioning and well-being at the patient and caregiver level and at the societal cost. The objective of this article is to describe the design of a study comparing these two case management care models against usual care. Clinical and cost outcomes are investigated while care processes and the facilitators and barriers for implementation of these models are considered.</p> <p>Design</p> <p>Mixed methods include a prospective, observational, controlled, cohort study among persons with dementia and their primary informal caregiver in regions of the Netherlands with and without case management including a qualitative process evaluation. Inclusion criteria for the cohort study are: community-dwelling individuals with a dementia diagnosis who are not terminally-ill or anticipate admission to a nursing home within 6 months and with an informal caregiver who speaks fluent Dutch. Person with dementia-informal caregiver dyads are followed for two years. The primary outcome measure is the Neuropsychiatric Inventory for the people with dementia and the General Health Questionnaire for their caregivers. Secondary outcomes include: quality of life and needs assessment in both persons with dementia and caregivers, activity of daily living, competence of care, and number of crises. Costs are measured from a societal perspective using cost diaries. Process indicators measure the quality of care from the participant’s perspective. The qualitative study uses purposive sampling methods to ensure a wide variation of respondents. Semi-structured interviews with stakeholders based on the theoretical model of adaptive implementation are planned.</p> <p>Discussion</p> <p>This study provides relevant insights into care processes, description of two case management models along with clinical and economic data from persons with dementia and caregivers to clarify important differences in two case management care models compared to usual care.</p

Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM): cluster randomised controlled trial.

OBJECTIVE To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. DESIGN Cluster randomised controlled trial. SETTING 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. PARTICIPANTS 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). INTERVENTION Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person's prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. MAIN OUTCOME MEASURE Primary outcome was first drug related hospital admission within 12 months. RESULTS 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 v 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 v 203 deaths). CONCLUSIONS Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes. TRIAL REGISTRATION ClinicalTrials.gov NCT02986425

A Thalamocortical Neural Mass Model of the EEG during NREM Sleep and Its Response to Auditory Stimulation

Few models exist that accurately reproduce the complex rhythms of the thalamocortical system that are apparent in measured scalp EEG and at the same time, are suitable for large-scale simulations of brain activity. Here, we present a neural mass model of the thalamocortical system during natural non-REM sleep, which is able to generate fast sleep spindles (12–15 Hz), slow oscillations (<1 Hz) and K-complexes, as well as their distinct temporal relations, and response to auditory stimuli. We show that with the inclusion of detailed calcium currents, the thalamic neural mass model is able to generate different firing modes, and validate the model with EEG-data from a recent sleep study in humans, where closed-loop auditory stimulation was applied. The model output relates directly to the EEG, which makes it a useful basis to develop new stimulation protocols