Search

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Primary cell culture is a powerful model system to address fundamental questions about organismal physiology at the cellular level, especially for species that are difficult, or impossible, to study under natural or semi-natural conditions. Due to their ease of use, primary fibroblast cultures are the dominant model system, but studies using both somatic and germ cells are also common. Using these models, genome evolution and phylogenetic relationships, the molecular and biochemical basis of differential longevities among species, and the physiological consequences of life history evolution have been studied in depth. With the advent of new technologies such as gene editing and the generation of induced pluripotent stem cells (iPSC), the field of molecular evolutionary physiology will continue to expand using both descriptive and experimental approaches.

Changes in predator–prey interactions are often implicated as drivers of major evolutionary change. A prominent example is the dramatic changes in shallow marine assemblages during the Mesozoic Marine Revolution (MMR) when major clades, including rhynchonelliform brachiopods, became restricted and less diverse. Currently, shallow-water temperate and polar brachiopods can be large, but in the tropics, they are small. By contrast, we demonstrate that throughout the Jurassic large brachiopods occurred in shallow sites, from polar to tropical latitudes, but are absent in later periods from tropical areas. These changes occurred in parallel in both major orders (Rhynchonellida and Terebratulida) and also independently within the two sub-ordinal lineages within the Terebratulida (terebratulinids and terebratellinids). Increases in both grazing and predation pressures associated with the MMR might account for this pattern. However, we note that many current environments support both large brachiopods and high densities of grazing species and suggest that the pattern fits more closely to the intensification of durophagous predation in shallow tropical waters.

What happened when eLife decided to eliminate accept/reject decisions after peer review?

Objectives To estimate the time required to undertake consultations according to BMJ’s 10-minute consultation articles.To quantify the tasks recommended in 10-minute consultation articles.To determine if, and to what extent, the time required and the number of tasks recommended have increased over the past 22 years.Design Analysis of estimations made by four general practitioners (GPs) of the time required to undertake tasks recommended in BMJ’s 10-minute consultation articles.Setting Primary care in the UK.Participants Four doctors with a combined total of 79 years of experience in the UK National Health Service following qualification as GPs.Main outcome measures Median minimum estimated consultation length (the estimated time required to complete tasks recommended for all patients) and median maximum estimated consultation length (the estimated time required to complete tasks recommended for all patients and the additional tasks recommended in specific circumstances). Minimum, maximum and median consultation lengths reported for each year and for each 5-year period.Results Data were extracted for 44 articles. The median minimum and median maximum estimated consultation durations were 15.7 minutes (IQR 12.6–20.9) and 28.4 minutes (IQR 22.4–33.8), respectively. A median of 17 tasks were included in each article. There was no change in durations required over the 22 years examined.Conclusions The approximate times estimated by GPs to deliver care according to 10-minute consultations exceed the time available in routine appointments. ‘10 minute consultations’ is a misleading title that sets inappropriate expectations for what GPs can realistically deliver in their routine consultations. While maintaining aspirations for high-quality care is appropriate, practice recommendations need to take greater account of the limited time doctors have to deliver routine care.

Purpose: To evaluate visuo-cognitive sequelae following blast-induced traumatic brain injury in a rat model. Methods: Rats were randomly assigned to one of four groups depending on the intensity/quantity of a blast received in a blast chamber: sham (no blast), low intensity (22 psi), medium intensity (26 psi), or three medium intensity blasts (26 psi × 3). After recovery, all subjects were given visual discrimination tasks of increasing complexity, until mastery. After behavioral training, visual function was assessed via spectral-domain optical coherence tomography and pattern electroretinogram, and the extent of retinal damage was quantified via immunohistochemistry of retinal ganglion cells. Results: None of the measures assessing visual function revealed significant differences as a function of blast intensity/quantity. Behavioral training did not disclose short-term effects of blast in general motivation or the development of anticipatory responding. No differences in general learning ability and the number of perseverative errors were observed. However, behavioral training found effects of blast in attentional function; relative to controls, subjects that received blasts were faster in learning to attend to informative (over non-informative) cues in the most difficult visual discrimination task. Conclusion: Blast exposure in rats resulted in increased attention following blast, with no appreciable deficits in visual function. These results are contrary to what is often reported for human clinical populations; as such, more research bridging methodological differences is necessary.

Emission lines from Rydberg transitions are detected for the first time from a region close to the surface of Betelgeuse. The H30 α line is observed at 231.905 GHz, with an FWHM ∼42 km s ^−1 and extended wings. A second line at 232.025 GHz (FWHM ∼21 km s ^−1 ), is modeled as a combination of Rydberg transitions of abundant low first ionization potential metals. Both H30 α and the Rydberg combined line X30 α are fitted by Voigt profiles, and collisional broadening with electrons may be partly responsible for the Lorentzian contribution, indicating electron densities of a few 10 ^8 cm ^−3 . X30 α is located in a relatively smooth ring at a projected radius of 0.9× the optical photospheric radius R _⋆ , whereas H30 α is more clumpy, reaching a peak at ∼1.4 R _⋆ . We use a semiempirical thermodynamic atmospheric model of Betelgeuse to compute the 232 GHz (1.29 mm) continuum and line profiles making simple assumptions. Photoionized abundant metals dominate the electron density, and the predicted surface of continuum optical depth unity at 232 GHz occurs at ∼1.3 R _⋆ , in good agreement with observations. Assuming a Saha–Boltzmann distribution for the level populations of Mg, Si, and Fe, the model predicts that the X30 α emission arises in a region of radially increasing temperature and turbulence. Inclusion of ionized C and non-LTE effects could modify the integrated fluxes and location of emission. These simulations confirm the identity of the Rydberg transition lines observed toward Betelgeuse and reveal that such diagnostics can improve future atmospheric models.

We describe a computer-assisted program for conducting well-body assessments of children with neurodevelopmental disabilities attending a private special education school. Classroom instructors completed daily assessments to detect the presence of bodily injuries and other skin trauma, determine the need for medical treatment, and monitor healing status. Evaluations performed with the classroom instructors revealed that they implemented the program with high integrity and rated several procedural components favorably. Compared to "paper form" data recording, clinicians and supervisors judged the computer-assisted program to track student injuries more thoroughly and record student injuries more accurately. The importance of health monitoring among persons with neurodevelopmental disabilities, advantages of technology-based assessment methods, and practice considerations are discussed.

ABSTRACT: Accurate measurements of concentration and ruminal degradability of corn silage starch is necessary for formulation of diets that meet the energy requirements of dairy cows. Five corn silage hybrids ensiled for 0 (unfermented), 30, 60, 120, and 150 d were used to determine the effects of ensiling time on starch degradability of corn silage. In addition, the effects of grind size of silage samples on 7-h in vitro starch degradability and the relationship between in vitro, in situ and near-infrared reflectance spectroscopy (NIRS) starch degradability were studied. In situ disappearance of corn silage starch increased from 0 to 150 d of ensiling, primarily as a result of an increase in the washout or rapidly degraded fraction of starch, particularly during the first 60 d of ensiling. When analyzed in vitro and by NIRS, ensiling time increased corn silage starch degradability either linearly or to a greater extent during the first 2 mo of ensiling. Differences in in situ starch disappearance among corn silage hybrids were apparent during the first 2 mo of ensiling but were attenuated as silages aged. No differences among hybrids were detected using a 7-h in vitro starch digestibility approach. Results from the in vitro subexperiment indicate that 7-h in vitro starch degradability was increased by reducing grind size of corn silage from 4 to 1 mm, regardless of ensiling duration. Fine grinding corn silages samples (i.e., 1-mm sieve) allowed distinguishing low- from medium- and high-starch degradability rated hybrids. Correlations among in situ, in vitro and NIRS measurements for starch degradability were medium to high (r ≥0.57); however, agreement among methods was low (concordance correlation coefficient ≤0.15). In conclusion, ensiling time linearly increased degradation rate of corn silage resulting in greater in situ starch disappearance after 150 d of ensiling. Reductions in grind size from 4 to 1 mm resulted in greater in vitro starch degradability, regardless of ensiling duration. Strong correlation but low agreement between starch degradability methods suggest that absolute estimations of corn silage starch degradability will vary, but all methods can be used to assess the effect of ensiling time on starch degradability.

TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies.

Abstract Background Clostridioides difficile is a spore forming bacterial species and the major causative agent of nosocomial gastrointestinal infections. C. difficile spores are highly resilient to disinfection methods and to prevent infection, common cleaning protocols use sodium hypochlorite solutions to decontaminate hospital surfaces and equipment. However, there is a balance between minimising the use of harmful chemicals to the environment and patients as well as the need to eliminate spores, which can have varying resistance properties between strains. In this work, we employ TEM imaging and Raman spectroscopy to analyse changes in spore physiology in response to sodium hypochlorite. We characterize different C. difficile clinical isolates and assess the chemical’s impact on spores’ biochemical composition. Changes in the biochemical composition can, in turn, change spores’ vibrational spectroscopic fingerprints, which can impact the possibility of detecting spores in a hospital using Raman based methods. Results We found that the isolates show significantly different susceptibility to hypochlorite, with the R20291 strain, in particular, showing less than 1 log reduction in viability for a 0.5% hypochlorite treatment, far below typically reported values for C. difficile. While TEM and Raman spectra analysis of hypochlorite-treated spores revealed that some hypochlorite-exposed spores remained intact and not distinguishable from controls, most spores showed structural changes. These changes were prominent in B. thuringiensis spores than C. difficile spores. Conclusion This study highlights the ability of certain C. difficile spores to survive practical disinfection exposure and the related changes in spore Raman spectra that can be seen after exposure. These findings are important to consider when designing practical disinfection protocols and vibrational-based detection methods to avoid a false-positive response when screening decontaminated areas. Graphical Abstract

ABSTRACT: Yeast culture and phytonutrients are dietary supplements with distinct modes of action, and they may have additive effects on the performance of dairy cattle. The objective of this study was to investigate the effects of a preparation of phytonutrients and a yeast culture from Saccharomyces cerevisiae on lactational performance, total-tract digestibility of nutrients, urinary nitrogen losses, energy metabolism markers, and blood cells in dairy cows. Thirty-six mid-lactation Holstein cows (10 primiparous and 26 multiparous) were used in an 8-wk randomized complete block design experiment with a 2-wk covariate period, 2 wk for adaptation to the diets, and a 4-wk experimental period for data and samples collection. Following a 2-wk covariate period, cows were blocked by days in milk, parity, and milk yield and randomly assigned to 1 of 3 treatments (12 cows per treatment): basal diet supplemented with 14 g/cow per day yeast culture (YC; S. cerevisiae), basal diet supplemented with 1.0 g/cow per day phytonutrients (PN; 5.5% cinnamaldehyde, 9.5% eugenol, and 3.5% capsicum oleoresin), or basal diet supplemented with a combination of YC and PN (YCPN). Treatments were top-dressed once daily on the total mixed ration at time of feeding. Dry matter intake, milk yield, and feed efficiency were not affected by treatments. Milk composition and energy-corrected milk yield were also not affected by supplementation of YC, PN, and YCPN. There were no differences in intake or total-tract digestibility of dietary nutrients among treatments. Compared with YC, the PN and YCPN treatments tended to decrease the proportion of short-chain fatty acids in milk fat. There was an additive effect of YC and PN supplementation on urinary urea nitrogen (UUN) excretion relative to total nitrogen intake. Cows fed a diet supplemented with YCPN had lower UUN excretion than cows in YC and tended to have lower UUN excretion compared with PN. Blood monocytes count and percentage were decreased in cows fed PN and YCPN diets compared with YC. Treatments did not affect concentrations of blood β-hydroxybutyrate and total fatty acids. Overall, lactational performance, digestibility of nutrients, energy metabolism markers, and blood cells were not affected by YC, PN, or YCPN supplementation. A combination of PN and YC had an additive effect on nitrogen excretion in dairy cows.

Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5–10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH−/− PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental.

We describe recent spectroscopic observations of red giant stars made by the Space Telescope Imaging Spectrograph (STIS) instrument on board the Hubble Space Telescope, which has provided spatially resolved observations of the warm chromospheric winds that predominate for early K to mid-M giants. The H i Ly α lines of a set of 11 red giants observed with the STIS/E140M echelle grating are first analyzed to ascertain wind H i column densities and total wind mass-loss rates. The M giants have estimated mass-loss rates of $\dot{M}=(14\mbox{--}86)\times {10}^{-11}$ M _⊙ yr ^−1 , while the K giants with detected wind absorption have weaker winds with $\dot{M}=(1.5\mbox{--}2.8)\times {10}^{-11}$ M _⊙ yr ^−1 . We use long-slit spectra of H i Ly α for two particular red giants, α Tau (K5 III) and γ Cru (M3.5 III), to study the spatial extent of the Ly α emission. From these data we estimate limits for the extent of detectable emission, which are r = 193 R _* for γ Cru and r = 44 R _* for α Tau. The cross-dispersion emission profiles in the STIS echelle spectra of the larger sample of red giants also show evidence for spatial resolution, not only for H i Ly α but for other lines with visible wind absorption, such as Fe ii , Mg ii , Mg i , O i , and C ii . We characterize the nature of these spatial signatures. The spatial extent is far more apparent for the M giants than for the K giants, consistent with the stronger winds found for the M giants from the Ly α analysis.

Many persons with intellectual and developmental disabilities are at risk for injury and physical harm due to unsafe environmental conditions. The present study addressed safety practices among care providers responsible for preventing access to hazardous materials among residential students living in two group homes. In a multiple baseline across settings design, the care providers were first exposed to visual cues intended to prompt access-prevention followed by visual cuing combined with graphic feedback. Care providers in one of the group homes demonstrated a high level of safety practices during baseline which continued throughout both intervention phases. In the second group home, a lower level of safety practices in baseline increased during the visual cuing intervention and remained stable with the addition of graphic feedback. The study demonstrates the contribution of behavioral assessment and intervention toward training and performance management of safety practices by residential care providers.

Neurodevelopmental disorders (NDDs) are complex conditions characterized by heterogeneous clinical profiles and symptoms that arise in infancy and childhood. NDDs are often attributed to a complicated interaction between genetic risk and environmental factors, suggesting a need for preclinical models reflecting the combined impact of heritable susceptibility and environmental effects. A notable advantage of “two-hit” models is the power to reveal underlying vulnerability that may not be detected in studies employing only genetic or environmental alterations. In this review, we summarize existing literature that investigates detrimental interactions between prenatal stress (PNS) and genes associated with NDDs, with a focus on behavioral phenotyping approaches in mouse models. A challenge in determining the overall role of PNS exposure in genetic models is the diversity of approaches for inducing stress, variability in developmental timepoints for exposure, and differences in phenotyping regimens across laboratories. Identification of optimal stress protocols and critical windows for developmental effects would greatly improve the use of PNS in gene × environment mouse models of NDDs.

eLife has published a special issue containing articles that examine how cancer prevention, control, care and survivorship were impacted by the COVID-19 pandemic.

Abstract Objective Obesity in pregnancy and gestational diabetes (GDM) increase cardiometabolic disease risk but are difficult to disentangle. This study aimed to test the hypothesis that 4–10 years after a pregnancy complicated by overweight/obesity and GDM (OB‐GDM), women and children would have greater adiposity and poorer cardiometabolic health than those with overweight/obesity (OB) or normal weight (NW) and no GDM during the index pregnancy. Methods In this cross‐sectional study, mother‐child dyads were stratified into three groups based on maternal health status during pregnancy (OB‐GDM = 67; OB = 76; NW = 76). Weight, height, waist and hip circumferences, and blood pressure were measured, along with fasting glucose, insulin, HbA1c, lipids, adipokines, and cytokines. Results Women in the OB and OB‐GDM groups had greater current adiposity and poorer cardiometabolic health outcomes than those in the NW group (p

Abstract Background Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3 WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. Methods We recorded sleep behavior in developing Shank3 ΔC/ΔC , Shank3 WT/ΔC , and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3 WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. Results Male and female Shank3 ΔC/ΔC mice slept significantly less than wild-type and Shank3 WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3 WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3 WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3 WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3 WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. Limitations This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. Conclusion Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

Marine gastropod shells have thickened over the past 130 years on the southern North Sea coast as local environmental conditions counteracted global ocean acidification, suggest analyses of a 130-year record of dog whelk morphology.

Abstract The external surface microornament of the glass scallops Catillopecten natalyae and malyutinae is made by calcitic spiny projections consisting of a stem that later divides into three equally spaced and inclined branches (here called aerials). C. natalyae contains larger and smaller aerials, whereas C. malyutinae only secreted aerials of the second type. A remarkable feature is that aerials within each type are fairly similar in size and shape and highly co-oriented, thus constituting a most sophisticated microornament. We demonstrate that aerials are single crystals whose morphology is strongly controlled by the crystallography, with the stem being parallel to the c-axis of calcite, and the branches extending along the edges of the {104} calcite rhombohedron. They grow epitaxially onto the foliated prisms of the outer shell layer. The co-orientation of the prisms explains that of the aerials. We have developed a model in which every aerial grows within a periostracal pouch. When this pouch reaches the growth margin, the mantle initiates the production of the aerial. Nevertheless, later growth of the aerial is remote, i.e. far from the contact with the mantle. We show how such an extremely sophisticated microornament has a morphology and co-orientation which are determined by crystal growth.

Lower limb cortical and trabecular bone varies with human behavior, leading to suggestions that activity level decreases have contributed to a more gracile skeleton. Similar trends are likely present in calcaneal morphology due to its locomotor role during heel strike. Such relationships exist in calcaneal trabecular structure; however, they have yet to be investigated in external morphology. Here entire external calcaneal shape is analyzed among three human populations that vary in subsistence strategy, activity level, and footwear use (n = 93) to investigate how calcaneal morphology varies relative to these factors. Calcanei were either surface scanned or micro-CT scanned. Calcaneal external shape was analyzed using a sliding semilandmark analysis with 1,007 semilandmarks. Semilandmarks were allowed to slide along tangent vectors or planes to minimize the bending energy of the thin plate spline interpolation function relative to an updated Procrustes average. Final landmark configurations underwent a Generalized Procrustes Analysis. Shape variation of Procrustes coordinates was summarized using principal components analysis (PCA). Procrustes distances between the average calcaneus of each population were calculated, and resampling statistics run to test for significant differences. The three populations exhibit significantly different calcaneal morphologies (p

Abstract Hundreds of genes have been associated with autism spectrum disorder (ASD), including loss-of-function mutations in chromodomain helicase DNA binding protein 8 (Chd8). Environmental factors also are implicated in autism risk and have the potential to exacerbate phenotypes in genetically sensitized backgrounds. Here we investigate transcriptional and behavioral phenotypes in a Chd8 haploinsufficient (Chd8 V986*/+) mouse line exposed to the pesticide deltamethrin (DM) from conception to postnatal day 22. Vehicle-exposed Chd8 V986*/+ mice displayed ASD-associated phenotypes, including anxiety-like behavior and altered sociability, replicating a previous study with this mouse line. A core set of genes was altered in Chd8 V986*/+ mice at multiple ages, including Usp11, Wars2, Crlf2, and Eglf6, and proximity ligation data indicated direct binding of CHD8 to the 5’ region of these genes. Moreover, oligodendrocyte and neurodegenerative transcriptional phenotypes were apparent in 12 and 18 month old Chd8 V986*/+ mice. Following DM exposure, the mutant mice displayed an exacerbated phenotype in the elevated plus maze, and genes associated with vascular endothelial cells were downregulated in the cerebral cortex of older Chd8 V986*/+ animals. Our study reveals a gene x environment interaction with a Chd8 haploinsufficient mouse line and points to the importance of investigating phenotypes in ASD animal models across the lifespan.

ABSTRACT: As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN‐designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity‐focused investigators and next‐step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.

Human papillomavirus (HPV) infection is responsible for many cancers in both women and men. Cervical cancer, caused by HPV, is the fourth most common cancer among women worldwide, even though it is one of the most preventable cancers. Prevention efforts include HPV vaccination, however these programs remain nascent in many countries. In 2020 the World Health Assembly adopted the Global Strategy for cervical cancer elimination including a goal to fully vaccinate 90% of girls with the HPV vaccine by the age of 15. However, very few countries have reached even 70% coverage. Increased vaccine availability in the future may allow the opportunity to vaccinate more people. This could add to the feasibility of introducing gender-neutral HPV vaccination programs. Adopting a gender-neutral HPV vaccine approach will reduce HPV infections transmitted among the population, combat misinformation, minimize vaccine-related stigma, and promote gender equity. We propose approaching programmatic research through a gender-neutral lens to reduce HPV infections and cancers and promote gender equality. In order to design more effective policies and programs, a better understanding of the perspectives of clients, clinicians, community leaders, and policy-makers is needed. A clear, multi-level understanding of these stakeholders' views will facilitate the development of target policy and programs aimed at addressing common barriers and optimizing uptake. Given the benefit of developing gender-neutral HPV vaccination programs to eliminate cervical cancer and address other HPV associated cancers, we must build knowledge through implementation research around this topic to inform policy-makers and funders for future policy shifts.

Preterm human infants often show periodic breathing (PB) or apnea of prematurity (AOP), breathing patterns which are accompanied by intermittent hypoxia (IH). We examined cause-effect relationships between transient IH and reduced facial bone growth using a rat model. Neonatal pups from 14 timed pregnant Sprague-Dawley rats were randomly assigned to an IH condition, with oxygen altering between 10% and 21% every 4 min for 1 h immediately after birth, or to a litter-matched control group. The IH pups were compared with their age- and sex-matched control groups in body weight (WT), size of facial bones and nor-epinephrine (NE) levels in blood at 3, 4, and 5-weeks. Markedly increased activity of osteoclasts in sub-condylar regions of 3-week-old IH-treated animals appeared, as well as increased numbers of sympathetic nerve endings in the same region of tissue sections. Male IH-pups showed significantly higher levels of NE levels in sera at 3, 4 as well as 5-week-old time points. NE levels in 4- and-5-week-old female pups did not differ significantly. Intercondylar Width, Mandible Length and Intermolar Width measures consistently declined after IH insults in 3- and 4-week-old male as well as female animals. Three-week-old male IH-pups only showed a significantly reduced (p < 0.05) body weight compared to those of 3-week controls. However, female IH-pups were heavier than age-matched controls at all 3 time-points. Trabecular bone configuration, size of facial bones, and metabolism are disturbed after an IH challenge 1 h immediately after birth. The findings raise the possibility that IH, introduced by breathing patterns such as PB or AOP, induce significantly impaired bone development and metabolic changes in human newborns. The enhanced NE outflow from IH exposure may serve a major role in deficient bone growth, and may affect bone and other tissue influenced by that elevation.

Adoption of electronic identification ear tags (EID) and DNA testing by commercial range sheep producers in the Western United States has been low, despite the availability of these technologies for over a decade. Jointly, these technologies offer an approach to provide individual animal performance data to improve flock health, genetic and reproductive management. This project involved a collaboration with five California sheep producers representing a broad geographic range, varying levels of pre-project EID adoption, and diverse operational practices. Tissue samples were collected from, and ear EIDs were placed in, a total of 2,936 rams and their potential lambs. We partnered with a commercial packing company, Superior Farms, to genotype the animals. Superior Farms used a targeted genotyping panel to assign parentage, and link individual animal identification (ID) to camera-graded carcass measurements. This enabled the collection of individual progeny carcass data and provided insight into sire performance, providing for the within-flock identification of prolific sires that were producing lambs with significantly more saleable meat as compared to their flock mates. Overall, almost 91% of lambs were successfully matched to their sire, and prolificacy ranging from 0-135 lambs per ram. There was as much as an $80 difference in the average edible product from camera-graded carcasses derived from lamb groups sired by different rams. A partial budget analysis modeling investment in an EID system coupled with an autodrafter and scale to collect individual weights and improve labor efficiency during processing, and a sheep flip chute to improve worker safety during foot trimmings, yielded a greater than 7:1 return on investment over a five-year time frame. Ideally, the data collection enabled by EIDs and DNA testing would feed into data-driven genetic evaluation programs to enable selection for more productive and profitable animals, and allow the US sheep industry to accelerate the rate of genetic improvement.

Abstract We conducted a systematic review on the impacts of natural causes of variation or changes in flow magnitude (resulting from climatic variability and broad‐scale drivers such as climate‐induced change) on fish abundance and biomass in temperate regions. Following our systematic review protocol (Birnie‐Gauvin et al., 2021), we examined commercially published and grey literature originally identified during a recent systematic map process (Rytwinski et al., 2020) and a systematic search update. Articles were screened using an a priori eligibility criteria, with consistency checks performed at the title and abstract, and full text screening stages. All eligible articles were assessed for study validity. A narrative synthesis included all available evidence (300 studies from 219 articles), and meta‐analyses (1863 datasets from 193 studies) were conducted where appropriate. Most studies were conducted in the United States (65%) on genera in the Salmonidae and Leuciscidae families (29% and 28%, respectively), and mainly investigated variation in flow magnitude, followed by droughts and floods. We found that fish abundance and biomass responses to changes in natural flow magnitude were mainly negative, but analyses do not support clear generalizable signals across all contexts (e.g. types of changes in flow magnitude, taxa, locations). When exploring reasons for heterogeneity in effect sizes, we found a detectable effect of intervention type on average fish abundance within the first year of the natural change in flow magnitude, with floods and droughts associated with overall negative responses. However, these patterns were more variable when considering between‐year variation or specific taxonomic responses. Our results suggest that while immediate responses were more apparent and relatively consistent within specific types of natural events, fish populations may recover after such events (i.e. ≥2 years post‐natural event); however, most studies were short in duration (

Several subjective and direct methods have been used to measure and assess sleep patterns and problems among children and youth with autism spectrum disorder (ASD). In this paper, we describe the design, operating functions, and application of a computer-assisted system of sleep monitoring and data recording to improve measurement integrity of overnight care providers at a residential school. Descriptive and longitudinal evaluation conducted over a four-year evaluation period revealed that care providers averaged 91% implementation integrity with the system. A subsequent social validity assessment through survey questionnaire found that care providers uniformly rated the system as easy to learn, understand, and implement. We discuss the advantages of the system for sleep measurement and assessment of children and youth who have ASD and receive services in residential-care settings.

Adult molluscs produce shells with diverse morphologies and ornamentations, different colour patterns and microstructures. The larval shell, however, is a phenotypically more conserved structure. How do developmental and evolutionary processes generate varying diversity at different life-history stages within a species? Using live imaging, histology, scanning electron microscopy and transcriptomic profiling, we have described shell development in a heteroconchian bivalve, the Antarctic clam, Laternula elliptica, and compared it to adult shell secretion processes in the same species. Adult downstream shell genes, such as those encoding extracellular matrix proteins and biomineralization enzymes, were largely not expressed during shell development. Instead, a development-specific downstream gene repertoire was expressed. Upstream regulatory genes such as transcription factors and signalling molecules were largely conserved between developmental and adult shell secretion. Comparing heteroconchian data with recently reported pteriomorphian larval shell development data suggests that, despite being phenotypically more conserved, the downstream effectors constituting the larval shell ‘tool-kit’ may be as diverse as that of adults. Overall, our new data suggest that a larval shell formed using development-specific downstream effector genes is a conserved and ancestral feature of the bivalve lineage, and possibly more broadly across the molluscs.

Introduction: Altered signaling or function of acetylcholine (ACh) has been reported in various neurological diseases, including Alzheimer’s disease, Tourette syndrome, epilepsy among others. Many neurons that release ACh also co-transmit the neurotransmitter gamma-aminobutyrate (GABA) at synapses in the hippocampus, striatum, substantia nigra, and medial prefrontal cortex (mPFC). Although ACh transmission is crucial for higher brain functions such as learning and memory, the role of co-transmitted GABA from ACh neurons in brain function remains unknown. Thus, the overarching goal of this study was to investigate how a systemic loss of GABA co-transmission from ACh neurons affected the behavioral performance of mice.Methods: To do this, we used a conditional knock-out mouse of the vesicular GABA transporter (vGAT) crossed with the ChAT-Cre driver line to selectively ablate GABA co-transmission at ACh synapses. In a comprehensive series of standardized behavioral assays, we compared Cre-negative control mice with Cre-positive vGAT knock-out mice of both sexes.Results: Loss of GABA co-transmission from ACh neurons did not disrupt the animal’s sociability, motor skills or sensation. However, in the absence of GABA co-transmission, we found significant alterations in social, spatial and fear memory as well as a reduced reliance on striatum-dependent response strategies in a T-maze. In addition, male conditional knockout (CKO) mice showed increased locomotion.Discussion: Taken together, the loss of GABA co-transmission leads to deficits in higher brain functions and behaviors. Therefore, we propose that ACh/GABA co-transmission modulates neural circuitry involved in the affected behaviors.

Physician-scientists have epitomized the blending of deep, rigorous impactful curiosity with broad attention to human health for centuries. While we aspire to prepare all physicians with an appreciation for these skills, those who apply them to push the understanding of the boundaries of human physiology and disease, to advance treatments, and to increase our knowledge base in the arena of human health can fulfill an essential space for our society, economies, and overall well-being. Working arm in arm with basic and translational scientists as well as expert clinicians, as peers in both groups, this career additionally serves as a bridge to facilitate the pace and direction of research that ultimately impacts health. Globally, there are remarkable similarities in challenges in this career path, and in the approaches employed to overcome them. Herein, we review how different countries train physician-scientists and suggest strategies to further bolster this career path.

Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods: Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results: Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions: The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.

Phenotypic plasticity represents an important first-line organism response to newly introduced or changing environmental constraints. Knowledge about structural responses to environmental stressors could thus be an essential measure to predict species and ecosystem responses to a world in change. In this study, we combined morphometric analyses with environmental modelling to identify direct shape responses of the predatory gastropod Nucella lapillus to large-scale variability in sea surface temperature and the carbonate system. Our models suggest that the state of the carbonate system and, more specifically, the substrate inhibitor ratio ([HCO3−][H+]−1) (SIR) has a dominant effect on the shell shape of this intertidal muricid. Populations in regions with a lower SIR tend to form narrower shells with a higher spire to body whorl ratio, whereas populations in areas with a higher SIR form wider shells with a much lower spire to body whorl ratio. These results indicate that a widespread phenotypic response of N. lapillus to continuing ocean acidification can be expected, potentially altering the phenotypic response pattern to predator or wave exposure regimes with profound implications for North Atlantic rocky shore communities.

Summary: Background: Arab American women have preferred women physicians of their own culture in the past. The primary aim of this study is to determine the current influence of religion/culture among MENA women and their preferences for physicians of same sex, culture, and religion on the avoidance and uncomfortableness of routine and women's health exams. Methods: A cross sectional community survey including religiosity and the importance of physician matched sex, culture, and religion was completed. Outcome measures were avoidance of a routine physical exam, or a women's health exam because of religious/cultural issues; and the uncomfortableness of the women's health exam. Linear regression modeling was used to evaluate the association between outcomes and potential predictors, with significance assessed using a bootstrap method. Findings: The responses of 97 MENA women 30–65 years old showed that MENA women agreed that they would avoid routine health exams because of religious/cultural issues if their physician was of the same religion or culture as they were (p

BackgroundThe clinical presentation of COVID-19 suggests altered breathing control - tachypnoea, relative lack of dyspnoea, and often a discrepancy between severity of clinical and radiological findings. Few studies characterize and analyse the contribution of breathing drivers and their ventilatory and perceptual responses.AimTo establish the prevalence of inappropriate ventilatory and perceptual response in COVID-19, by characterizing the relationships between respiratory rate (RR), dyspnoea and arterial blood gas (ABG) in a cohort of COVID-19 patients at presentation to hospital, and their post-Covid respiratory sequelae at follow-up.MethodsWe conducted a retrospective cohort study including consecutive adult patients admitted to hospital with confirmed COVID-19 between 1st March 2020 and 30th April 2020. In those with concurrent ABG, RR and documented dyspnoea status on presentation, we documented patient characteristics, disease severity, and outcomes at hospital and 6-week post-discharge.ResultsOf 492 admissions, 194 patients met the inclusion criteria. Tachypnoea was present in 75% pronounced (RR>30) in 36%, and persisted during sleep. RR correlated with heart rate (HR) (r = 0.2674), temperature (r = 0.2824), CRP (r = 0.2561), Alveolar-arterial (A-a) gradient (r = 0.4189), and lower PaO2/FiO2 (PF) ratio (r = −0.3636). RR was not correlated with any neurological symptoms. Dyspnoea was correlated with RR (r = 0.2932), A-a gradient (r = 0.1723), and lower PF ratio (r = −0.1914), but not correlated with PaO2 (r = −0.1095), PaCO2 (r = −0.0598) or any recorded neurological symptom except for altered consciousness. Impaired ventilatory homeostatic control of pH/PaCO2 [tachypnoea (RR>20), hypocapnia (PaCO2 7.45)] was observed in 29%. This group, of which 37% reported no dyspnoea, had more severe respiratory disease (A-a gradient 38.9 vs. 12.4 mmHg; PF ratio 120 vs. 238), and higher prevalence of anosmia (21 vs. 15%), dysgeusia (25 vs. 12%), headache (33 vs. 23%) and nausea (33 vs. 14%) with similar rates of new anxiety/depression (26 vs. 23%), but lower incidence of past neurological or psychiatric diagnoses (5 vs. 21%) compared to appropriate responders. Only 5% had hypoxia sufficiently severe to drive breathing (i.e. PaO2

Background: Using screen counts, women 50–64 years old have lower cancer screening rates for cervical and colorectal cancers (CRC) than all other age ranges. This paper aims to present woman-centric cervical cancer and CRC screenings to determine the predictor of being up-to-date for both. Methods: We used the Behavioral Risk Factor Surveillance System (BRFSS), an annual survey to guide health policy in the United States, to explore the up-to-date status of dual cervical cancer and CRC screening for women 50–64 years old. We categorized women into four mutually exclusive categories: up-to-date for dual-screening, each single screen, or neither screen. We used multinomial multivariate regression modeling to evaluate the predictors of each category. Results: Among women ages 50–64 years old, dual-screening was reported for 58.2% (57.1–59.4), cervical cancer screening alone (27.1% (26.0–28.2)), CRC screening alone (5.4% (4.9–5.9)), and neither screen (9.3% (8.7–9.9)). Age, race, education, income, and chronic health conditions were significantly associated with dual-screening compared to neither screen. Hispanic women compared to non-Hispanic White women were more likely to be up-to-date with cervical cancer screening than dual-screening (adjusted odds ratio [aOR] = 1.39 (1.10, 1.77)). Compared to younger women, those 60–64 years are significantly more likely to be up-to-date with CRC screening than dual-screening (aOR = 1.75 (1.30, 2.35)). Conclusions: Screening received by each woman shows a much lower rate of dual-screening than prior single cancer screening rates. Addressing dual-screening strategies rather than single cancer screening programs for women 50–64 years may increase both cancer screening rates. Funding: This work was supported by NIH through the Michigan Institute for Clinical and61 Health Research UL1TR002240 and by NCI through The University of Michigan Rogel Cancer62 Center P30CA046592 grants.

The jet-flow overpressure chamber (OPC) has been previously reported as a model of blast-mediated traumatic brain injury (bTBI). However, rigorous characterization of the features of this injury apparatus shows that it fails to recapitulate exposure to an isolated blast wave. Through combined experimental and computational modeling analysis of gas-dynamic flow conditions, we show here that the jet-flow OPC produces a collimated high-speed jet flow with extreme dynamic pressure that delivers a severe compressive impulse. Variable rupture dynamics of the diaphragm through which the jet flow originates also generate a weak and infrequent shock front. In addition, there is a component of acceleration-deceleration injury to the head as it is agitated in the headrest. Although not a faithful model of free-field blast exposure, the jet-flow OPC produces a complex multi-modal model of TBI that can be useful in laboratory investigation of putative TBI therapies and fundamental neurophysiological processes after brain injury.

During the COVID-19 pandemic, the Summer Food Service Program (SFSP) was allowed to operate in untraditional non-summer months to ensure children did not lose access to free and reduced-priced nutritious meals when schools were mandated to close in the United States. This study assessed the impact of the pandemic on the operations and experiences of Summer Food Service Program (SFSP) sponsors in the state of Maryland during the COVID-19 pandemic in 2020 (Phase I) and 2021 (Phase II). This study used a multiphase explanatory sequential mixed methods design with qualitative prioritization. Maryland SFSP sponsors completed an online survey (Phase I: n = 27, Phase II: n = 30), and semi-structured in-depth interviews were conducted with a subset of sponsors who completed the survey (Phase I: n = 12, Phase II: n = 7). Inductive and deductive analyses were used for qualitative data, and descriptive statistics were used for quantitative data. The COVID-19 pandemic caused SFSP sponsors to change their operations. Sponsors were primarily concerned about staff safety/burnout and decreased participation. Sponsors perceived waivers implemented by the United States Department of Agriculture to be crucial in enabling them to serve meals to children during the pandemic. The findings from our study support advocacy efforts to permanently implement waivers and provide free school meals for all children.