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Abstract Idiopathic rapid eye movement sleep behaviour disorder (iRBD)—a Parkinson’s disease (PD) prodrome—might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1—the earliest-degenerating dopaminergic neurons in PD—and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson’s Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (p adj

Abstract Guilt is a negative emotion elicited by realizing one has caused actual or perceived harm to another person. One of guilt’s primary functions is to signal that one is aware of the harm that was caused and regrets it, an indication that the harm will not be repeated. Verbal expressions of guilt are often deemed insufficient by observers when not accompanied by nonverbal signals such as facial expression, gesture, posture, or gaze. Some research has investigated isolated nonverbal expressions in guilt, however none to date has explored multiple nonverbal channels simultaneously. This study explored facial expression, gesture, posture, and gaze during the real-time experience of guilt when response demands are minimal. Healthy adults completed a novel task involving watching videos designed to elicit guilt, as well as comparison emotions. During the video task, participants were continuously recorded to capture nonverbal behaviour, which was then analyzed via automated facial expression software. We found that while feeling guilt, individuals engaged less in several nonverbal behaviours than they did while experiencing the comparison emotions. This may reflect the highly social aspect of guilt, suggesting that an audience is required to prompt a guilt display, or may suggest that guilt does not have clear nonverbal correlates.

Background Globally alcohol consumption is a leading risk factor for premature death and disability and is associated with crime, social and economic consequences. Local communities may be able to play a role in addressing alcohol-related issues in their area. Objectives To evaluate the effectiveness and cost–benefit of an asset-based community development approach to reducing alcohol-related harm and understand the context and factors that enable or hinder its implementation. Design A mixed-methods evaluation. Area-level quasi-experimental trial analysed using four different evaluation methods (a stepped-wedge design where each area was a control until it entered the intervention, comparison to matched local/national controls and comparison to synthetic controls), alongside process and economic evaluations. Setting Ten local authorities in Greater Manchester, England. Participants The outcomes evaluation was analysed at an area level. Ninety-three lay persons representing nineareas completed questionnaires, with 12 follow-up interviews in five areas; 20 stakeholders representing ten areas were interviewed at baseline, with 17 follow-up interviews in eight areas and 26 members of the public from two areas attended focus groups. Interventions Professionals in a co-ordinator role recruited and supported lay volunteers who were trained to become alcohol health champions. The champion’s role was to provide informal, brief alcohol advice to the local population and take action to strengthen restrictions on alcohol availability. Main outcome measures Numbers of alcohol-related hospital admissions, accident and emergency attendances, ambulance call-outs, street-level crime and antisocial behaviour in the intervention areas (area size: 1600–5500 residents). Set-up and running costs were collected alongside process evaluation data exploring barriers and facilitators. Data sources Routinely collected quantitative data on outcome measures aggregated at the intervention area and matched control and synthetic control areas. Data from policy documents, licensing registers, meeting notes, invoices, time/cost diaries, training registers, questionnaires, interviews, reflective diaries and focus groups. Results The intervention rolled out in nine out of ten areas, seven of which ran for a full 12 months. Areas with better-established infrastructure at baseline were able to train more champions. In total, 123 alcohol health champions were trained (95 lay volunteers and 28 professionals): lay volunteers self-reported positive impact. Champions engaged in brief advice conversations more readily than taking action on alcohol availability. There were no consistent differences in the health and crime area-level indicators between intervention areas and controls, as confirmed by using three different analysis methods for evaluating natural experiments. The intervention was not found to be cost-beneficial. Limitations Although the sequential roll-out order of the intervention was randomised, the selection of the intervention areas was not. Self-reported impact may have been subject to social desirability bias due to the project’s high profile. Conclusions There was no measurable impact on health and crime outcomes. Possible explanations include too few volunteers trained, volunteers being unwilling to get involved in licensing decisions, or that the intervention has no direct impact on the selected outcomes. Future work Future similar interventions should use a coproduced community outcomes framework. Other natural experiment evaluations should use methodological triangulation to strengthen inferences about effectiveness. Trial registration This trial is registered as ISRCTN81942890. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/129/03) and is published in full in Public Health Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Alcohol consumption puts an individual’s health and social relationships at risk of harm. The more a person drinks, the more harmful it is. The harmful effects can place a burden on emergency services and hospitals. We wanted to find out whether community members can make a difference by taking action to address alcohol harm in their local area. What did we do? Local councils in Greater Manchester developed a project called Communities in Charge of Alcohol, where volunteers in targeted local areas were trained to become ‘alcohol health champions’. Alcohol health champions gave alcohol-related brief advice to people to help them drink less. They had a say about when, where and how alcohol is sold by reporting issues to their local council. We compared numbers of alcohol-related hospital admissions, accident and emergency attendances, ambulance call-outs and reports of crime and antisocial behaviour between areas that had alcohol health champions with other similar areas in England that did not. We calculated how much it costs to run and whether Communities in Charge of Alcohol could save society money. What did we find? Not as many volunteers came forward to become an alcohol health champion as hoped for. Those who did give alcohol-related brief advice to people. They preferred not to report issues about alcohol sales to their local council, either because it was too complicated or because they did not want to be called a ‘grass’. We did not find levels of alcohol harm changed in the Communities in Charge of Alcohol areas. Because of this, we could not demonstrate that Communities in Charge of Alcohol could save society money. What does this mean? Getting involved in alcohol licensing decisions needs to be made easier for communities, with more anonymity, through the support of professionals. More work needs to be done to understand whether giving brief advice can reduce alcohol harm in whole communities. Scientific summary Background The availability of, and access to, alcohol is a key determinant of alcohol harm, and powers exist within the Licensing Act 2003 of England and Wales that enable the public to influence the local sale and supply of alcohol. At an individual level, implementing programmes to promote early risk identification and brief advice have the potential to reduce alcohol consumption and prevent alcohol-related harm, but there is a dearth of evidence to determine the feasibility and effectiveness of lay people having a role. The Greater Manchester (GM) Combined Authority (GMCA) and Greater Manchester Health and Social Care Partnership (GMHSCP) designed a new programme, ‘Communities in Charge of Alcohol’ (CICA) in 2017 to train lay volunteers to become alcohol health champions (AHCs), who would be able to (1) give alcohol-related brief advice to individuals and (2) help communities influence alcohol availability and strengthen restrictions in alcohol risk environments. Overall aims To evaluate the effectiveness and cost–benefit of implementing a locally delivered AHC intervention and understand the context and factors that enable or hinder the intervention. Objectives Relating to the outcome evaluation: to determine the effect on area-level key health performance indicators: alcohol-related hospital admissions (narrow measure), weekend accident and emergency (A&E) attendances (Friday 3 p.m.–Sunday 3 p.m.), weekday A&E attendances (Monday–Friday 9 a.m.–5 p.m. each day), weekend ambulance call-outs (Friday 3 p.m.–Sunday 3 p.m.), weekday ambulance call-outs (Monday–Friday 9 a.m.–5 p.m. each day) to determine the effect on key crime indicators (street-level crime data) at the weekend (Friday 3 p.m.–Sunday 3 p.m.) and weekday (Monday–Friday 9 a.m.–5 p.m. each day) to determine the effect on key antisocial behaviour (ASB) indicators (police recorded calls for service were classified as ASB according to the National Standard for Incident Recording). Relating to the process evaluation: to explore policy context and variation in licensing practice, including any impact of devolution in GM to explore barriers and facilitators at key stages of the implementation of the intervention: recruitment of AHCs to initial training and cascade training, delivery of initial training and cascade training, use of skills beyond the training in AHC activity, retention of AHCs to explore responses to AHC training, modelling of health behaviours, perceptions of community cohesion and development to determine numbers of brief interventions applied and community awareness events organised/participated in to examine and quantify the amount and success of community involvement in licensing issues to determine whether there was a change in composite measures of alcohol availability. Relating to the economic evaluation: to identify set-up and running costs using a standardised costing exercise to resolve costs by sector (health, ambulance and police) before, during and after set-up to quantify benefits due to reduced hospital admissions, ambulance call-outs, A&E use, crime and ASB. Methods Communities in Charge of Alcohol was a complex intervention already planned by the GMCA in 10 small local authority areas (~1600–5500 residents each) and was outside direct researcher control. Intervention areas were chosen by each local authority public health team as having high levels of alcohol harm in comparison to the rest of the local authority. All intervention areas were at the bottom of the deprivation index, in deprivation decile 1 or 2. Using a stepped-wedge design, researchers were able to randomise the order of roll-out of intervention areas to bring a quasi-experimental approach to the evaluation. Two additional evaluation designs were used in order to triangulate findings, namely comparison to matched controls and comparison to synthetic controls. Ethical approval was received from the University of Salford Research Ethics Committee on 17 May 2017 (reference number: HSR1617–135) and obtained from the University of Bristol on 16 May 2019 (reference number: 82762). Outcome evaluation data sources Routinely collected data at the lower-layer super output area (LSOA) level for intervention areas was compared with control areas. Data sources were as follows: alcohol-related hospital admissions data – Public Health England (now Office for Health Improvement and Disparities) accident and emergency department attendance data – NHS Digital ambulance call-out data – North West Ambulance Service reported crime and ASB data – GM Police. Analysis spanned a 10-year period (7 years pre intervention and a maximum of 3 years post implementation), ending in January 2020. Data were analysed using log-rate growth models and time series analyses to quantify the effect of the CICA programme on key performance indicators. Process evaluation data sources Pre-implementation phase document review of local Statements of Licensing Policy (n = 9), alcohol availability composite score of on- and off-licensed premises (n = 9 areas), roll-out preparatory meeting notes. Train-the-Trainer attendance registers by area (n = 5, representing 9 areas, attended by 48 lay participants and 25 professional participants). Cascade training attendance registers by area (n = 11, representing 7 areas, attended by 47 lay participants and 3 professional participants). Pre- and post-training questionnaires (n = 93 lay people, 98% response rate). Baseline interviews with stakeholders (n = 20) (initial implementation phase); interviews with lay volunteer AHCs (n = 5, representing 3 areas) within 3–6 months of initial training (implementation phase). Follow-up interviews (12 months) with stakeholders (n = 11, representing eight areas), licensing officers (n = 6, representing six areas) and lay volunteer AHCs (n = 7, representing four areas); follow-up questionnaires with AHCs (n = 11); focus groups with local residents (n = 3 groups, representing two areas, with a total of 26 participants). Economic evaluation data sources Time and transportation costs incurred during project meetings aggregated from meeting minutes and stakeholder time/cost diaries. Invoices for the design, development and delivery of training packages and accreditation fees. Invoices for the qualification and assessment fees, time and miscellaneous (transportation, room hire, catering, printing costs). AHC time and costs aggregated from volunteer diaries and stakeholder time/cost diaries. Invoices for engagement materials (AUDIT-C scratchcards). Greater Manchester Combined Authority research team’s (formerly New Economy) cost–benefit analysis (CBA) tool was populated using aggregated outcome evaluation data to resolve costs for each key performance indicator before, during and after CICA setup. Results Nine out of 10 local authorities rolled out the CICA intervention on their given start date: seven areas completed a full year, carrying out cascade training in the first 12 months, two areas withdrew at 6 and 9 months and one area withdrew in the pre-implementation phase. There were 118 [interquartile range (IQR): 60–205] alcohol-related hospital admissions per month per pre-intervention LSOA, rising to 134 (IQR: 67–203) post intervention. Some outcomes had very small counts at the LSOA level; notably, there were only 2 (IQR: 1–3) weekend crimes per month pre-intervention and 4 (IQR: 2–6) post intervention. The primary, stepped-wedge analyses provide weak evidence of an average increase in alcohol-related hospital admissions following the implementation of CICA of about 13%, corresponding to about 20 admissions weekly, although the confidence interval was wide, −1.98 to 31.39, and not statistically significant (p~0.09), while the analysis that made use of local controls suggested a bigger effect, at 16.4% (7.33–26.16, p

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance use or a marker of the inclination to engage in such behavior. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1000 participants. Behaviors and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.

Purpose: To use artificial intelligence to identify relationships between morphological characteristics of the Meibomian glands (MGs), subject factors, clinical outcomes, and subjective symptoms of dry eye. Methods: A total of 562 infrared meibography images were collected from 363 subjects (170 contact lens wearers, 193 non-wearers). Subjects were 67.2 % female and were 54.8 % Caucasian. Subjects were 18 years of age or older. A deep learning model was trained to take meibography as input, segment the individual MG in the images, and learn their detailed morphological features. Morphological characteristics were then combined with clinical and symptom data in prediction models of MG function, tear film stability, ocular surface health, and subjective discomfort and dryness. The models were analyzed to identify the most heavily weighted features used by the algorithm for predictions. Results: MG morphological characteristics were heavily weighted predictors for eyelid notching and vascularization, MG expressate quality and quantity, tear film stability, corneal staining, and comfort and dryness ratings, with accuracies ranging from 65 % to 99 %. Number of visible MG, along with other clinical parameters, were able to predict MG dysfunction, aqueous deficiency and blepharitis with accuracies ranging from 74 % to 85 %. Conclusions: Machine learning-derived MG morphological characteristics were found to be important in predicting multiple signs, symptoms, and diagnoses related to MG dysfunction and dry eye. This deep learning method illustrates the rich clinical information that detailed morphological analysis of the MGs can provide, and shows promise in advancing our understanding of the role of MG morphology in ocular surface health.

The Notch signaling pathway is evolutionarily conserved across metazoan species and plays key roles in many physiological processes. The Notch receptor is activated by two families of canonical ligands (Delta-like and Serrate/Jagged) where both ligands and receptors are single-pass transmembrane proteins usually with large extracellular domains, relative to their intracellular portions. Upon interaction of the core binding regions, presented on opposing cell surfaces, formation of the receptor/ligand complex initiates force-mediated proteolysis, ultimately releasing the transcriptionally-active Notch intracellular domain. This review focuses on structural features of the extracellular receptor/ligand complex, the role of post-translational modifications in tuning this complex, the contribution of the cell membrane to ligand function, and insights from acquired and genetic diseases.

Objective This study aims to determine the associations between specialty type and practice location at postgraduate year 10 (PGY10), matched with PGY5 and PGY8 work locations, and earlier rural exposure/experience.Design and setting A cohort study of medicine graduates from nine Australian universities.Participants 1220 domestic medicine graduates from the class of 2011.Outcome measures Practice location recorded by the Australian Health Practitioner Regulation Agency in PGY10; matched graduate movement between PGYs 5, 8 and 10 as classified by the Modified Monash Model, stratified by specialty type (predominantly grouped as general practitioner (GP) or non-GP).Results At PGY10, two-thirds (820/1220) had achieved fellowship. GPs were 2.8 times more likely to be in non-metropolitan practice (28% vs 12%; 95% CI 2.0 to 4.0, p

Background: Screening children for developmental disorders presents unique ethical and methodological challenges, particularly with disorders associated with high levels of shame and stigma. Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental condition resulting from prenatal alcohol exposure. The potential distress caused by informing parents that their child may have FASD has been cited as a significant barrier to conducting such studies. However, limited research has investigated the impact of screening for FASD on parents and children. Aims: This exploratory study aimed to examine the experiences of a small sample of parents participating in an active case ascertainment prevalence study screening for FASD in Greater Manchester, UK (ADD-GM study). Methods: Interviews were conducted with six parents, whose children aged 8–10 years, underwent screening (including three cases of FASD). Thematic analysis was performed on the collected data to identify key themes and patterns. Results: The analysis revealed that parents perceived participation in the study as worthwhile, and their children either enjoyed or were indifferent to the process of data collection. Parents of children identified with FASD reported that although the results were surprising, they did not find the experience overly distressing. Conclusion: The findings suggest that parents generally view participation positively and perceive limited negative impact. These insights contribute to a better understanding of the challenges and benefits associated with screening children for FASD.

Abstract This study is to identify subgroups of DED patients with different tear cytokine profiles and compare their DED symptoms and signs among subgroups. Baseline tear cytokines (IL-1β, IL-6, IL-8, IL-10, IL-17A, IFN-γ and TNF-α) were measured using a magnetic bead assay. DED symptoms were assessed by Ocular Surface Disease Index (OSDI) and signs were assessed by corneal and conjunctival staining, tear break-up time (TBUT), Schirmer’s test, tear osmolarity and meibomian gland dysfunction (MGD). Latent profile analysis was performed to identify subgroups, and their scores of DED symptoms and signs were compared using generalized linear regression. Among 131 patients with total tear volume > 4 µl from both eyes, subgroup 1 (n = 23) significantly higher in IL-6 and IL-8 (all p

Abstract Acute respiratory distress syndrome (ARDS) alters the dynamics of lung inflation during mechanical ventilation. Repetitive alveolar collapse and expansion (RACE) predisposes the lung to ventilator-induced lung injury (VILI). Two broad approaches are currently used to minimize VILI: (1) low tidal volume (LVT) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LVT approach attempts to protect already open lung tissue from overdistension, while simultaneously resting collapsed tissue by excluding it from the cycle of mechanical ventilation. By contrast, the OLA attempts to reinflate potentially recruitable lung, usually over a period of seconds to minutes using higher PEEP used to prevent progressive loss of end-expiratory lung volume (EELV) and RACE. However, even with these protective strategies, clinical studies have shown that ARDS-related mortality remains unacceptably high with a scarcity of effective interventions over the last two decades. One of the main limitations these varied interventions demonstrate to benefit is the observed clinical and pathologic heterogeneity in ARDS. We have developed an alternative ventilation strategy known as the Time Controlled Adaptive Ventilation (TCAV) method of applying the Airway Pressure Release Ventilation (APRV) mode, which takes advantage of the heterogeneous time- and pressure-dependent collapse and reopening of lung units. The TCAV method is a closed-loop system where the expiratory duration personalizes VT and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (CRS) measured by the slope of the expiratory flow curve during passive exhalation. Two potentially beneficial features of TCAV are: (i) the expiratory duration is personalized to a given patient’s lung physiology, which promotes alveolar stabilization by halting the progressive collapse of alveoli, thereby minimizing the time for the reopened lung to collapse again in the next expiration, and (ii) an extended inspiratory phase at a fixed inflation pressure after alveolar stabilization gradually reopens a small amount of tissue with each breath. Subsequently, densely collapsed regions are slowly ratcheted open over a period of hours, or even days. Thus, TCAV has the potential to minimize VILI, reducing ARDS-related morbidity and mortality. Graphical Abstract

Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02/07/2019)

Abstract A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)–associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum.

Summary: The presence of a ‘magenstrasse’, a central ‘stomach road’ for flow and mixing of foods and drinks in the stomach had been predicted from hydrodynamic modelling. Here a magnetic resonance imaging (MRI) tagging technique was used to gain novel insights on the intragastric motion of breakfast porridges in 17 healthy humans. They consumed two similar breakfast porridge meals on separate days and tagging images with two different delay times were acquired 15 and 45 minutes postprandially, generating 128 data sets. Motion of the gastric contents was assessed by coefficient of variation (CoV) analysis across timeframes. The data showed that postprandial movement occurred already at the first imaging point after feeding. The motion of the gastric contents occurred along the central axis of the stomach appearing as a central ‘magenstrasse’ reaching the stomach body/fundus region in 73% of cases. Only in 10% of cases the displacement and smearing of the tag lines was detected close to the stomach walls. Seven % of data sets showed antegrade (towards the antrum) motion whilst a much larger percentage of motion was observed to be only retrograde (43%) or mixed antegrade and retrograde (50%). In conclusion, the MRI tagging method allowed novel insights into the movement of stomach contents using real model porridge meals and confirmed the existence of a central ‘stomach road’ for intragastric flow and mixing of food.

Abstract Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Degeneration in the substantia nigra (SN) pars compacta (SNc) underlies motor symptoms in Parkinson’s disease (PD). Currently, there are no neuroimaging biomarkers that are sufficiently sensitive, specific, reproducible, and accessible for routine diagnosis or staging of PD. Although iron is essential for cellular processes, it also mediates neurodegeneration. MRI can localize and quantify brain iron using magnetic susceptibility, which could potentially provide biomarkers of PD.We measured iron in the SNc, SN pars reticulata (SNr), total SN, and ventral tegmental area (VTA), using quantitative susceptibility mapping (QSM) and R2* relaxometry, in PD patients and age-matched healthy controls (HCs). PD patients, diagnosed within five years of participation and HCs were scanned at 3T (22 PD and 23 HCs) and 7T (17 PD and 21 HCs) MRI. Midbrain nuclei were segmented using a probabilistic subcortical atlas. QSM and R2* values were measured in midbrain subregions. For each measure, groups were contrasted, with Age and Sex as covariates, and receiver operating characteristic (ROC) curve analyses were performed with repeated k-fold cross-validation to test the potential of our measures to classify PD patients and HCs. Statistical differences of area under the curves (AUCs) were compared using the Hanley-MacNeil method (QSM versus R2*; 3T versus 7T MRI).PD patients had higher QSM values in the SNc at both 3T (padj = 0.001) and 7T (padj = 0.01), but not in SNr, total SN, or VTA, at either field strength. No significant group differences were revealed using R2* in any midbrain region at 3T, though increased R2* values in SNc at 7T MRI were marginally significant in PDs compared to HCs (padj = 0.052). ROC curve analyses showed that SNc iron measured with QSM, distinguished early PD patients from HCs at the single-subject level with good diagnostic accuracy, using 3T (mean AUC = 0.83, 95 % CI = 0.82–0.84) and 7T (mean AUC = 0.80, 95 % CI = 0.79–0.81) MRI. Mean AUCs reported here are from averages of tests in the hold-out fold of cross-validated samples. The Hanley-MacNeil method demonstrated that QSM outperforms R2* in discriminating PD patients from HCs at 3T, but not 7T. There were no significant differences between 3T and 7T in diagnostic accuracy of QSM values in SNc.This study highlights the importance of segmenting midbrain subregions, performed here using a standardized atlas, and demonstrates high accuracy of SNc iron measured with QSM at 3T MRI in identifying early PD patients. QSM measures of SNc show potential for inclusion in neuroimaging diagnostic biomarkers of early PD. An MRI diagnostic biomarker of PD would represent a significant clinical advance.

Background. Freezing of gait (FOG) is an intractable motor symptom in Parkinson’s disease (PD) that increases fall risk and impairs the quality of life. FOG has been associated with anxiety, with experimental support for the notion that anxiety itself provokes FOG. We investigated the effect of acute anxiety reduction via alprazolam on FOG in PD. Methods. In ten patients with PD, FOG, and normal cognition, we administered 0.25 mg alprazolam in one session and placebo in another, in counterbalanced order. At each session, on separate days, patients walked on a pressure-sensitive walkway. Using Oculus Rift virtual-reality goggles, patients walked along a plank that appeared to be (a) level with the floor, in the low-anxiety condition or (b) raised high above the ground, in the high-anxiety conditions. In this way, we assessed the impacts of anxiety and alprazolam (i.e., anxiety reduction) on FOG frequency and other gait parameters. Results. FOG events appeared only in the high-anxiety conditions. Alprazolam significantly reduced subjective and objective measures of anxiety, as well as the prevalence of FOG (p=0.05). Furthermore, alprazolam improved swing time (p

Background: In comparison to the neurotypical population, individuals with fetal alcohol spectrum disorders (FASD) are over-represented in the criminal justice system (CJS). This study explores the perspectives of a small sample of individuals with FASD regarding the factors that predispose them to encounters with the CJS, and their experiences during investigative interviews. Methods: Semi-structured interviews were conducted with ten individuals with FASD, aged between 12 and 46 years old (mean age 20.1 years). Interviews were a combination of remote audio-recorded, video-recorded, and face-to-face interviews administered by parents/carers. NVivo was used to collate, organise, and explore data. Data were analysed by reflexive thematic analysis. Results: Three over-arching themes were generated from seven sub-themes: “personality/individual triggers to CJS encounters” which described vulnerabilities, such as a tendency to be impulsive and to accept suggestions, “encounters ‘fuelled’ by society” where examples of exploitation, police's aggressive approach and lack of knowledge were given. The final theme of “sense of self-awareness” demonstrated that participants had a sense of appreciation of their strengths and abilities. Conclusion: Individuals with FASD are highly vulnerable to, and within, encounters with the CJS. Procedural justice will benefit by employing alternative methods in dealing with situations where individuals with FASD may be involved, and in obtaining information via interviews from the FASD population.

BackgroundTo promote early childhood development (ECD), we require information not only on what needs to be addressed and on what effects can be achieved but also on effective delivery methods that can be adapted to local context. We describe design, implementation, and evaluation of a complex intervention to strengthen nurturing environment for young children.MethodsStudy participants were pregnant women and their children from birth to 2 years. We used design and redesign, implementation, and evaluation approaches for the study. We co-created curriculum and delivery plan with stakeholders, based on the theoretical framework, findings from formative research, and our preliminary work. We recruited 656 pregnant women and newborns, 326 (49.69%) from intervention and 330 (50.30%) from the control group. We conducted a cluster randomized controlled trial to evaluate the program’s effectiveness. The outcomes of children were assessed at 12 and 24 months.FindingsAt recruitment, study participants from both the study arms were similar in sociodemographic characteristics. We conducted 6,665 home visits, 25 toy-making workshops, and 65 caregiver-meetings. The initial examination of program data revealed gaps in quality and coverage of interventions. The intervention was redesigned based on feedback from stakeholders in community meetings. At recruitment, participants in both study groups had similar socio-demographics. We conducted 6,665 home visits, 25 toy workshops, and 65 caregiver meetings. Initial program data showed intervention quality and coverage gaps, leading to a redesign program based on community and stakeholder feedback. Post-re-designing, session quality improved, with program coverage rising from 32 to 98%. Male participation in home visits increased from 4.3 to 32.65%, and data errors reduced from 270 to 140 per month on average. At 24 months, program showed moderate–mild impact on ECD – cognitive (0.31, 95%CI: 0.13–0.48), language (0.2, 95%CI: 0.01–0.39), and socioemotional-development (0.19, 95%CI: 0.01–0.37), moderate effect on home-environment and mother–child interaction. 96% of women initiated breastfeed within one-hour of delivery, and exclusive-breastfeeding rate of 89.80%.InterpretationsThe study provides an evidence-based community centered ECD curriculum and implementation strategies to enhance service providers, and caregivers’ knowledge and skills for promoting ECD in low-resource settings with the potential to scale within existing Government Program.FundingThe trial was funded by the Saving Brains Round 5 Initiative of Grand Challenges Canada (Grant no. SB-1707-05084), and we are grateful for their ongoing support through online sessions and orientation workshops. The trial was also supported by the Indian Council of Medical Research (File No: 5/7/1693/CH/Adhoc/RBMCH-2020).

Correct fetal testis development underpins adult male fertility, and TGFβ superfamily ligands control key aspects of this process. Transcripts encoding one such ligand, activin A, are upregulated in testes after sex determination and remain high until after birth. Testis development requires activin signalling; mice lacking activin A (Inhba KO) display altered somatic and germ cell proliferation, disrupted cord elongation and altered steroid synthesis. In human pregnancies with pre-eclampsia, the foetus is inappropriately exposed to elevated activin A. To learn how this affects testis development, we examined mice lacking the potent activin inhibitor, inhibin, (Inha KO) at E13.5, E15.5 and PND0. At E13.5, testes appeared similar in WT and KO littermates, however E15.5 Inha KO testes displayed two germline phenotypes: (1) multinucleated germ cells within cords, and (2) germ cells outside of cords, both of which are documented following in utero exposure to endocrine disrupting phthalates in rodents. Quantitation of Sertoli and germ cells in Inha KO (modelling elevated activin A) and Inhba KO (low activin A) testes using immunofluorescence demonstrated activin A bioactivity determines the Sertoli/germ cell ratio. The 50% reduction in gonocytes in Inha KO testes at birth indicates unopposed activin A has a profound impact on embryonic germ cells. Whole testis RNAseq on Inha KO mice revealed most transcripts affected at E13.5 were present in Leydig cells and associated with steroid biosynthesis/metabolism. In agreement, androstenedione (A4), testosterone (T), and the A4:T ratio were reduced in Inha KO testes at E17.5, confirming unopposed activin A disrupts testicular steroid production. E15.5 testes cultured with either activin A and/or mono-2-ethylhexyl phthalate (MEHP) generated common histological and transcriptional outcomes affecting germline and Leydig cells, recapitulating the phenotype observed in Inha KO testes. Cultures with activin A and MEHP together provided evidence of common targets. Lastly, this study extends previous work focussed on the Inhba KO model to produce a signature of activin A bioactivity in the fetal testis. These outcomes show the potential for elevated activin A signalling to replicate some aspects of fetal phthalate exposure prior to the masculinization programming window, influencing fetal testis growth and increasing the risk of testicular dysgenesis.

Through a systematic reflection on the journey that transformed traditional state-run baby homes in Tajikistan from closed institutions into community-oriented Family and Child Support Centres (FCSC) we reveal key moments of change. This review describes how community consultation with local participants in a development project shifted responsibility and accountability from international to local ownership and how distributed leadership contributes to the decolonisation of social services. Based on these interviews we ask, ‘How do the innovations of a social development project become a fixed part of normal local social, cultural and political life; and, how do we know when a new normal is self-sustaining at a local level?’ This analysis builds on a network-mapping tool previously described in this journal. Our interviews show that each participant has taken a non-linear journey, building on the networks previously described, under the influence of activities and discussions that emerged throughout the project. We consider how a monitoring, evaluation, and learning process should be responsive over time to these influences, rather than be set at the start of the project. Using the themes that emerge from participants’ journeys, we apply a ‘measurement for change’ (M4C) approach that integrates Monitoring, Evaluation and Learning (MEL) into decision-making. The journey framework applied represents a systematic application of the M4C approach that gives us insight into where local ownership is responsible for the sustainable management of the intervention, and where continued partnership will further strengthen impact and accountability. The exercise has provided evidence of progress towards decolonisation and of the centring of local priorities in MEL and implementation processes.

Abstract Background The aim of this national study was to explore the learning experiences of Australia’s medical students who trained rurally during the COVID-19 pandemic in 2020. Methods A cross-sectional, national multi-centre survey was conducted in 2020, through the Federation of Rural Australian Medical Educators (FRAME). Participants were medical students who had completed an extended Rural Clinical School (RCS) training placement (≥ 12 months). A bespoke set of COVID-19 impact questions were incorporated into the annual FRAME survey, to capture COVID-19-related student experiences in 2020. Pre-pandemic (2019 FRAME survey data) comparisons were also explored. Results FRAME survey data were obtained from 464 students in 2020 (51.7% response rate), compared with available data from 668 students in 2019 (75.6% response rate). Most students expressed concern regarding the pandemic’s impact on the quality of their learning (80%) or missed clinical learning (58%); however, students reported being well-supported by the various learning and support strategies implemented by the RCSs across Australia. Notably, comparisons to pre-pandemic (2019) participants of the general RCS experience found higher levels of student support (strongly agree 58.9% vs 42.4%, p

Abstract Background It is widely recognised that complex public health interventions roll out in distinct phases, within which external contextual factors influence implementation. Less is known about relationships with external contextual factors identified a priori in the pre-implementation phase. We investigated which external contextual factors, prior to the implementation of a community-centred approach to reducing alcohol harm called ‘Communities in Charge of Alcohol’ (CICA), were related to one of the process indicators: numbers of Alcohol Health Champions (AHCs) trained. Methods A mixed methods design was used in the pre-implementation phase of CICA. We studied ten geographic communities experiencing both high levels of deprivation and alcohol-related harm in the North West of England. Qualitative secondary data were extracted from pre-implementation meeting notes, recorded two to three months before roll-out. Items were coded into 12 content categories using content analysis. To create a baseline ‘infrastructure score’, the number of external contextual factors documented was counted per area to a maximum score of 12. Descriptive data were collected from training registers detailing training numbers in the first 12 months. The relationship between the baseline infrastructure score, external contextual factors, and the number of AHCs trained was assessed using non-parametric univariable statistics. Results There was a positive correlation between baseline infrastructure score and total numbers of AHCs trained (Rs = 0.77, p = 0.01). Four external contextual factors were associated with significantly higher numbers of lay people recruited and trained: having a health care provider to coordinate the intervention (p = 0.02); a pool of other volunteers to recruit from (p = 0.02); a contract in place with a commissioned service (p = 0.02), and; formal volunteer arrangements (p = 0.03). Conclusions Data suggest that there were four key components that significantly influenced establishing an Alcohol Health Champion programme in areas experiencing both high levels of deprivation and alcohol-related harm. There is added value of capturing external contextual factors a priori and then testing relationships with process indicators to inform the effective roll-out of complex interventions. Future research could explore a wider range of process indicators and outcomes, incorporating methods to rate individual factors to derive a mean score. Trial registration ISRCTN81942890, date of registration 12/09/2017.

Abstract A hallmark of ARDS is progressive shrinking of the ‘baby lung,’ now referred to as the ventilator-induced lung injury (VILI) ‘vortex.’ Reducing the risk of the VILI vortex is the goal of current ventilation strategies; unfortunately, this goal has not been achieved nor has mortality been reduced. However, the temporal aspects of a mechanical breath have not been considered. A brief expiration prevents alveolar collapse, and an extended inspiration can recruit the atelectatic lung over hours. Time-controlled adaptive ventilation (TCAV) is a novel ventilator approach to achieve these goals, since it considers many of the temporal aspects of dynamic lung mechanics.

While the prolific nature of many grass and herbaceous species in urban parks offers an opportunity to cultivate more biodiverse and dynamic grasslands, widespread maintenance practices and complex cultural, economic, and bureaucratic forces often result in the undervaluing and regular destruction of these plant species. The research described in this paper reimagines the way grassy landscapes are cared for and understood in urban environments. Located in an urban park in inner Sydney, Australia, and using design research methods of observation, physical care, storytelling and installation, the research proposes three “frames of care” to assist landscape architects and other spatial designers to engage with communities at a local level. The frames have the potential to expand collective understandings of grassland communities, test alternative maintenance practices, and better support urban biodiversity and seasonal flux. With acknowledgment to the complexities of urban sites such as these, experimental installation provided a promising space to meaningfully engage with the local community and build a foundation to generate greater reciprocity between humans and non-humans of the site.

Adult male fertility depends on spermatogonial stem cells (SSCs) which undergo either self-renewal or differentiation in response to microenvironmental signals. Activin A acts on Sertoli and Leydig cells to regulate key aspects of testis development and function throughout life, including steroid production. Recognising that activin A levels are elevated in many pathophysiological conditions, this study investigates effects of this growth factor on the niche that determines spermatogonial fate. Although activin A can promote differentiation of isolated spermatogonia in vitro, its impacts on SSC and spermatogonial function in vivo are unknown. To assess this, we examined testes of Inha KO mice, which feature elevated activin A levels and bioactivity, and develop gonadal stromal cell tumours as adults. The GFRA1+ SSC-enriched population was more abundant and proliferative in Inha KO compared to wildtype controls, suggesting that chronic elevation of activin A promotes a niche which supports SSC self-renewal. Intriguingly, clusters of GFRA1+/EOMES+/LIN28A– cells, resembling a primitive SSC subset, were frequently observed in tubules adjacent to tumour regions. Transcriptional analyses of Inha KO tumours, tubules adjacent to tumours, and tubules distant from tumour regions revealed disrupted gene expression in each KO group increased in parallel with tumour proximity. Modest transcriptional changes were documented in Inha KO tubules with complete spermatogenesis. Importantly, tumours displaying upregulation of activin responsive genes were also enriched for factors that promote SSC self-renewal, including Gdnf, Igf1, and Fgf2, indicating the tumours generate a supportive microenvironment for SSCs. Tumour cells featured some characteristics of adult Sertoli cells but lacked consistent SOX9 expression and exhibited an enhanced steroidogenic phenotype, which could arise from maintenance or acquisition of a fetal cell identity or acquisition of another somatic phenotype. Tumour regions were also heavily infiltrated with endothelial, peritubular myoid and immune cells, which may contribute to adjacent SSC support. Our data show for the first time that chronically elevated activin A affects SSC fate in vivo. The discovery that testis stromal tumours in the Inha KO mouse create a microenvironment that supports SSC self-renewal but not differentiation offers a strategy for identifying pathways that improve spermatogonial propagation in vitro.

Purpose: To evaluate how increasing age is associated with dry eye disease (DED) signs and symptoms in the Dry Eye Assessment and Management (DREAM) study. This study was undertaken to better understand how DED signs and symptoms differ across decades of life with goals to help assess detection and treatment of DED. Design: Secondary analysis of the DREAM study. Subjects: One hundred twenty, 140, 185, and 90 participants aged < 50, 50 to 59, 60 to 69, and ≥ 70 years, respectively. Methods: We performed a secondary analysis of data from the DREAM study, a multicenter randomized clinical trial, to evaluate the effect of omega-3 fatty acid supplementation for the treatment of DED. At baseline, 6 months, and 12 months follow-up, participants underwent an assessment of DED symptoms and signs using Ocular Surface Disease Index, Brief Pain Inventory, tear break-up time (TBUT) (in seconds), Schirmer test with anesthesia (mm/5 minutes), conjunctival staining, corneal staining, meibomian gland dysfunction evaluation, and tear osmolarity (mOsm/l). Multivariable generalized linear regression models were used to compare DED symptoms and signs across the 4 age groups among all participants and by sex. Main Outcome Measures: Scores of DED symptoms, individual signs, and composite scores of DED signs. Results: Among 535 patients with DED, increasing age was significantly associated with worse TBUT (P = 0.01), corneal staining (P < 0.001), a composite severity score of DED signs (P = 0.007), and tear osmolarity (P = 0.001). Similar significant differences were found across 4 age groups of 334 women in TBUT, corneal staining score, composite severity score of DED signs, and tear osmolarity (all P < 0.05) but not in men. Conclusion: We found that corneal staining, TBUT, tear osmolarity, and a composite severity score of DED signs were significantly more severe with increasing age in women but not in men; worsening symptoms did not increase with increasing age. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Methane from livestock is a significant source of greenhouse gas emissions. Under the UN Framework Convention on Climate Change (UNFCCC), Annex I countries’ National Inventories report emissions from cattle as enteric or from manure management at ratios of between 3:1 and 9:1 depending on country and cattle type. Field research generally supports the inventories’ assumptions about enteric emissions, but these ratios have focused interest on enteric emissions and diverted attention away from those from manure management. Official calculations about manure management emissions factors are more varied than those for enteric emissions and evidence from field measurements suggests inventories may be underestimating manure management emissions especially in the dairy sector. This paper has three objectives. First, it reviews the science underpinning the international framework for estimating methane emissions from manure management. Second, it presents data from two dairy farms in south-west England where measured emissions of methane from slurry storage facilities are found to be four to five times greater than the assumptions in the UK’s inventory. If these measurements were representative of the UK, the implication is that total methane emissions from the UK dairy herd would be over 40% greater than the level reported to the UNFCCC and the proportion of total methane emissions from dairy cows arising from manure management would be almost a half rather than less than a quarter. Finally, the paper assesses the potential value if methane were captured from slurry storage facilities. Its value as a biogas is estimated to be £500 million per year for the UK dairy industry (at forecourt diesel prices). The paper concludes that the scale of emissions and the potential economic value of lost biogas are sufficient to warrant urgent research and action to reduce emissions from manure management with the beneficial prospect that a valuable new income stream for farm businesses could also be realised.

Abstract Background Cigarette smoking cessation has been described as the world’s most important public health intervention. Electronic cigarettes are a relatively new tool for assisting smoking cessation but there is a lack of data on their efficacy. This article reports on a pharmacy supported e-cigarette smoking cessation intervention undertaken in a metropolitan area in the north of England. Methods Longitudinal mixed-methods evaluation incorporating analysis of secondary data, interviews with service users, and interviews with service providers at 3-month and 12-month follow-up, with an additional text message survey of service users at 12-month follow-up. Results The four-week follow-up data suggest that for every twenty people given an e-cigarette, six quit smoking tobacco and three people cut their cigarette intake by more than five cigarettes per day. Long-term follow-up results were positive but only a small number of participants were still engaged with the study at 12 months. Service users and providers spoke positively about the combination of e-cigarettes and pharmacy support. Conclusions E-cigarette distribution combined with pharmacy support appears to be an agreeable and effective intervention for smoking cessation, but further data are needed on long-term quit rates and health effects.

ABSTRACT: Objectives: We evaluated antibiotic resistance among intraocular isolates obtained from presumed endophthalmitis cases collected from 2009 through 2020 in the Antibiotic Resistance Monitoring in Ocular micRoorganisms (ARMOR) study, the only ongoing nationwide surveillance study tracking in vitro resistance in ocular pathogens. Methods: Presumed endophthalmitis isolates obtained from the aqueous humour and vitreous humour were collected from participating centres, and minimum inhibitory concentrations were determined and interpreted per Clinical and Laboratory Standards Institute methods and available breakpoints. Results: A total of 307 presumed endophthalmitis isolates (aqueous humour, n = 88; vitreous humour, n = 219) were obtained from 43 clinical sites, including 188 coagulase-negative staphylococci (CoNS), 61 Staphylococcus aureus, 31 Streptococcus pneumoniae, 14 Pseudomonas aeruginosa, and 13 Haemophilus influenzae isolates. Of the CoNS isolates, 47.9% (90/188) were methicillin resistant, 58.0% (109/188) were azithromycin resistant, and 46.3% (87/188) were ciprofloxacin resistant. Of the S. aureus isolates, 45.9% (28/61) were methicillin resistant, 57.4% (35/61) were azithromycin resistant, and 44.3% (27/61) were ciprofloxacin resistant. Multidrug resistance (MDR; i.e., resistance to ≥3 antibiotic classes) was prevalent among staphylococci, particularly methicillin-resistant strains, of which >70% exhibited MDR. Resistance among S. pneumoniae isolates was notable for azithromycin and penicillin, each 38.7% (12/31), and for polymyxin B among P. aeruginosa 100.0% (14/14), whereas no resistance was observed for H. influenzae isolates to the antibiotics tested. Conclusion: In vitro antibiotic resistance was common among presumed endophthalmitis isolates collected in the ARMOR surveillance study. These data could inform antibiotic selection for infection prophylaxis and/or treatment of intraocular infections.

BackgroundEffective and real-time data analytics plays an essential role in understanding gaps and improving the quality and coverage of complex public health interventions. Studies of public health information systems identify problems with data quality, such as incomplete records and untimely reporting. Effective data collection and real-time analysis systems for rapid-cycle learning are necessary to monitor public health programs and take timely evidence-based decisions. Early childhood development (ECD) programs are very diverse. Rapid-cycle evaluation and learning (REAL) guides the implementation process of such complex interventions in real time. Stepping stones was one such early childhood development program implemented in Central India.ObjectiveThe objective was to improve the delivery of complex, integrated public health interventions for early childhood development in remote areas of rural India.MethodologyThe program was developed according to the principles of inclusion and community-centeredness, which can be tested quickly and iteratively. To enhance the decision-making process and improve delivery and coverage, the core team implemented an information system for rapid-cycle learning. We developed performance indicators and a performance measurement matrix after defining the specific needs. Following that, we trained staff to collect complete data using electronic data collection tools and transfer it the same day to the server for quality review and further analysis. A variety of data/information was triangulated to address the gaps in intervention delivery, and those decisions were subsequently implemented.ResultsWe observed that the quality of data collection improved, and errors were reduced by 50% in the third quarter. The quality of the narrative was also enhanced; it became more elaborate and reflective. Sharing their field output in meetings and improving the quality of the narrative enhanced the self-reflection skills of field staff and consequently improved the quality of the intervention delivery. Refresher training and mentoring by supervisors helped to improve the data quality over time.ConclusionRapid-cycle evaluation and learning (REAL) can be implemented in resource-limited settings to improve the quality and coverage of integrated intervention in early childhood. It nurtures a reinforcing ecosystem that integrates providers, community, and family perspectives and guides interactions among stakeholders by integrating data from all available sources.

Abstract On 11th March 2020, the UK government announced plans for the scaling of COVID-19 testing, and on 27th March 2020 it was announced that a new alliance of private sector and academic collaborative laboratories were being created to generate the testing capacity required. The Cambridge COVID-19 Testing Centre (CCTC) was established during April 2020 through collaboration between AstraZeneca, GlaxoSmithKline, and the University of Cambridge, with Charles River Laboratories joining the collaboration at the end of July 2020. The CCTC lab operation focussed on the optimised use of automation, introduction of novel technologies and process modelling to enable a testing capacity of 22,000 tests per day. Here we describe the optimisation of the laboratory process through the continued exploitation of internal performance metrics, while introducing new technologies including the Heat Inactivation of clinical samples upon receipt into the laboratory and a Direct to PCR protocol that removed the requirement for the RNA extraction step. We anticipate that these methods will have value in driving continued efficiency and effectiveness within all large scale viral diagnostic testing laboratories.

Intercropping using mixtures of dryland crop species for grain or seed production was investigated in southern Australia across a range of rainfall zones over three years. The objective was to understand the productivity and profitability of intercropping in extensive, high-input grain cropping systems. Previous research has shown large productivity benefits of mixtures; however, few farmers practice intercropping in Australia, and an analysis of profitability is needed to support future potential adoption. Experimental results showed strong mixture responses (in terms of yield, value and land equivalence), but not all were profitable compared to an equivalent share of monoculture crops (as measured by gross margins). The most promising mixtures were those containing high-value crops (canola) and legumes (field pea or faba bean) at the wetter sites where the additional gross margin over equivalent monoculture crops ranged from $12/ha to $576/ha. Mixtures containing highly competitive crops (wheat or barley) were generally unprofitable. Mixtures involving cereals were doubly disadvantaged by the aggressiveness of these lower-value crops in the mixtures we examined and the high grain separation costs post-harvest. Cost reduction in mixture systems involving high-value crops that are synergistic (grain legumes) should provide enduring opportunities for intercropping in southern Australia.

Background: Cardiovascular disease CVD), the leading cause of death in the U.S., is a particular problem for African Americans (AAs). Church-based health interventions are effective in reducing CVD risk, yet few have been successfully disseminated. This paper describes the model development, preliminary health outcomes, and lessons learned from the Health for Hearts United (HHU) dissemination trial which evolved from the longitudinal Reducing CVD Risk Study in a two-county area in North Florida. Community-based participatory research approaches and the socio-ecological model guided the study. Methods: Data for this paper were from health leaders (n = 25) in the first six churches investigated, and the outreach participants (n = 86) they engaged. Health leaders completed survey items (daily servings of fruits/vegetables [F/V], fat consumption [FAT], and daily minutes of physical activity [PA]) and clinical measures (body mass index [BMI]; waist, hip and abdomen circumferences; and systolic and diastolic blood pressure [BP]). For outreach participants, a brief CVD Awareness Quiz was administered. Data were analyzed using description statistics, Pearson correlations, and repeated measures analysis of variance. Results: Findings showed that the dissemination model was implemented by 100% of the churches, and resulted in health outcomes changes for health leaders (significant increases between pre- and post-test in F/V; significant decreases in FAT, BMI, abdomen circumference, with educational level and marital status as selected significant covariates) and in a significant increase in CVD awareness for outreach participants. Lessons learned are discussed. Although preliminary, the results suggest that the HHU dissemination model has promise for reducing CVD risk in AA's.

Introduction: Mutations and misfolding of membrane proteins are associated with various disorders, hence they make suitable targets in proteomic studies. However, extraction of membrane proteins is challenging due to their low abundance, stability, and susceptibility to protease degradation. Given the limitations in existing protocols for membrane protein extraction, the aim of this investigation was to develop a protocol for a high yield of membrane proteins for isolated Natural Killer (NK) cells. This will facilitate genetic analysis of membrane proteins known as transient receptor potential melastatin 3 (TRPM3) ion channels in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) research.Methods: Two protocols, internally identified as Protocol 1 and 2, were adapted and optimized for high yield protein extraction. Protocol 1 utilized ultrasonic and salt precipitation, while Protocol 2 implemented a detergent and chloroform/methanol approach. Protein concentrations were determined by the Pierce Bicinchoninic Acid (BCA) and the Bio-Rad DC (detergent compatible) protein assays according to manufacturer’s recommendation. Using Protocol 2, protein samples were extracted from NK cells of n = 6 healthy controls (HC) and n = 4 ME/CFS patients. In silico tryptic digest and enhanced signature peptide (ESP) predictor were used to predict high-responding TRPM3 tryptic peptides. Trypsin in-gel digestion was performed on protein samples loaded on SDS-PAGE gels (excised at 150–200 kDa). A liquid chromatography-multiple reaction monitoring (LC-MRM) method was optimized and used to evaluate the detectability of TRPM3 n = 5 proteotypic peptides in extracted protein samples.Results: The detergent-based protocol protein yield was significantly higher (p < 0.05) compared with the ultrasonic-based protocol. The Pierce BCA protein assay showed more reproducibility and compatibility compared to the Bio-Rad DC protein assay. Two high-responding tryptic peptides (GANASAPDQLSLALAWNR and QAILFPNEEPSWK) for TRPM3 were detectable in n = 10 extracted protein samples from NK cells isolated from HC and ME/CFS patients.Conclusion: A method was optimized for high yield protein extraction from human NK cells and for the first time TRPM3 proteotypic peptides were detected using LC-MRM. This new method provides for future research to assess membrane protein structural and functional relationships, particularly to facilitate proteomic investigation of TRPM3 ion channel isoforms in NK cells in both health and disease states, such as ME/CFS.

Abstract ELTD1/ADGRL4 is an adhesion GPCR with an important role in angiogenesis. We recently identified a role for ELTD1 in wound repair and inflammation. Activation of ELTD1 in endothelial cells results in a type II EMT to myofibroblast‐like cells that have enhanced angiogenic ability. Furthermore, expression of Eltd1 in murine breast cancer cells increases tumour growth by increasing blood vessel size and perfusion and by creating an immunosuppressive microenvironment. As extracellular vesicles (EVs) are known to be involved in vascular development, growth and maturation we investigated the composition and functional effects of the EVs isolated from ELTD1 expressing cells to elucidate their role in these processes. A highly glycosylated form of the extracellular domain (ECD) of ELTD1 is readily incorporated into EVs. Using mass spectrometry‐based proteomics we identified proteins that are enriched in ELTD1‐EVs and are involved in haemostasis and immune responses. ELTD1 enriched EVs were pro‐angiogenic in vivo and in vitro and the presence of the ECD alone induced endothelial sprouting. In endothelial cells experiencing laminar flow, ELTD1 levels were reduced in the EVs when they are quiescent, showing a relationship between ELTD1 and the activation state of the endothelium. Using FACS, we detected a significant increase in vesicular ELTD1 in the plasma of patients with preeclampsia, a condition characterized by endothelial dysfunction. These data confirm a role for ELTD1 in wound repair and inflammation and reveal its potential as a biomarker of vessel dysfunction.

Objective While greater body mass index (BMI) is associated with increased risk of developing atrial fibrillation (AF), the impact of BMI on outcomes in newly diagnosed AF is unclear. We examine the influence of BMI on outcomes and whether this is modified by sex and evaluate the effect of non-vitamin K oral anticoagulants (NOACs) in patients with high BMI.Methods GARFIELD-AF is a prospective registry of 52 057 newly diagnosed AF patients. The study population comprised 40 482 participants: 703 underweight (BMI

Abstract Background The prevalence of obesity is disproportionately high among African Americans in the Southern US. More information is needed about factors that influence participation in nutrition and physical activity programs to promote healthy weight. Objective The purpose of this study is to explore the weight management perceptions of young to middle aged adult African Americans. Methods The Church Bridge Project intervention participants were recruited for two focus groups. Qualitative data were recorded, transcribed and a thematic content analysis was conducted to identify major themes. Results Barriers included technology learning curve/burden and competing priorities. Facilitators included support, limited cost, convenience, and health. Participants perceived the term “weight management” program as overwhelming and defeating. Conclusion The Church Bridge Project model confirmed social support and disease prevention as key factors for weight management. Further work should substantiate social support as a key factor to guide minority health efforts.

Although author and teacher Penny Kittle has shifted from working with high school students to college freshman, she notes in this piece that they are not that different. They still show up the first day of class as "nonbelievers" needing to be "nudged" toward the love for books that she forges through her sensitive context building and unflagging personal identity as a reader. It is Penny Kittle's hope for each one of them that they will embrace by the semester's close the hallmarks of a literacy classroom -- sustained reading, engaged response, coaching conversations, high expectations, thinking, empathy, joy -- and they do.

This study examined perceptions of and experiences during the COVID-19 pandemic among 489 faculty from four public universities in the southeast United States. Data were collected via an online survey during the Fall 2020 semester, when campuses re-opened after closing in March. Two thirds of faculty perceived the severity of COVID-19 as severe, and their greatest concerns related to preventive behaviors, the possibility of a virus resurgence, and concern for the health of family/friends. The majority reported frequently engaging in COVID-19-preventing behaviors, which was highest among female and older faculty, and those with higher perceived severity and concern for personally contracting the virus. Over half of respondents reported teaching and scholarly activities were negatively impacted by the pandemic; most notable barriers to productivity included anxiety/stress and a distracted home environment. The study adds to the research on university faculty during the pandemic and aligns with research on the adult population.

This study employed a critical inquiry paradigm to explore the significance of equity and social justice in teaching qualitative methodologies and methods to graduate students. Graduate students of multiple minoritized identities and a faculty member conducted a two-year inquiry into the research apprenticeship experience, including the stages of student-led conceptualization, data collection, analysis, international conference presentation, and publication. The study investigated the experiences of the faculty and students as well as the responsibilities of the institution against the backdrop of historical and contemporary pandemics. Consequently, we problematized hidden curriculum and unconscious assumptions to suggest research course design sequencing improvements. The findings emphasize the impact of these experiences on qualitative research teaching and learning practices and institutional responsibility to graduate student research apprenticeships. The Graduate Research Apprenticeship Nested Design Pathway is presented as a tool that institutions worldwide can adapt and implement to serve the complex needs of their students.

In the pursuit of science, competitive ideas and debate are necessary means to attain knowledge and expose our ignorance. To quote Murray Gell-Mann (1969 Nobel Prize laureate in Physics): “Scientific orthodoxy kills truth”. In mechanical ventilation, the goal is to provide the best approach to support patients with respiratory failure until the underlying disease resolves, while minimizing iatrogenic damage. This compromise characterizes the philosophy behind the concept of “lung protective” ventilation. Unfortunately, inadequacies of the current conceptual model–that focuses exclusively on a nominal value of low tidal volume and promotes shrinking of the “baby lung” - is reflected in the high mortality rate of patients with moderate and severe acute respiratory distress syndrome. These data call for exploration and investigation of competitive models evaluated thoroughly through a scientific process. Airway Pressure Release Ventilation (APRV) is one of the most studied yet controversial modes of mechanical ventilation that shows promise in experimental and clinical data. Over the last 3 decades APRV has evolved from a rescue strategy to a preemptive lung injury prevention approach with potential to stabilize the lung and restore alveolar homogeneity. However, several obstacles have so far impeded the evaluation of APRV’s clinical efficacy in large, randomized trials. For instance, there is no universally accepted standardized method of setting APRV and thus, it is not established whether its effects on clinical outcomes are due to the ventilator mode per se or the method applied. In addition, one distinctive issue that hinders proper scientific evaluation of APRV is the ubiquitous presence of myths and misconceptions repeatedly presented in the literature. In this review we discuss some of these misleading notions and present data to advance scientific discourse around the uses and misuses of APRV in the current literature.

The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in studies of mice. Hence any ongoing use of testosterone as a marker of Leydig cell function in fetal testes is inappropriate. By interrogating new scRNAseq data from human fetal testes, we demonstrate this situation is also likely to be true in humans. This has implications for understanding how disruptions to either or both Leydig and Sertoli cells during the in utero masculinization programming window may contribute to the increasing incidence of hypospadias, cryptorchidism, testicular germ cell tumours and adult infertility. We recently discovered that activin A levels directly govern androgen production in mouse Sertoli cells, because the enzymes that drive the conversion of the precursor androgen androstenedione to generate testosterone are produced exclusively in Sertoli cells in response to activin A. This minireview addresses the implications of this growing understanding of how in utero exposures affect fetal masculinization for future research on reproductive health, including during programming windows that may ultimately be relevant for organ development in males and females.

Alcohol misuse during adolescence (AAM) has been associated with disruptive development of adolescent brains. In this longitudinal machine learning (ML) study, we could predict AAM significantly from brain structure (T1-weighted imaging and DTI) with accuracies of 73 -78% in the IMAGEN dataset (n∼1182). Our results not only show that structural differences in brain can predict AAM, but also suggests that such differences might precede AAM behavior in the data. We predicted 10 phenotypes of AAM at age 22 using brain MRI features at ages 14, 19, and 22. Binge drinking was found to be the most predictable phenotype. The most informative brain features were located in the ventricular CSF, and in white matter tracts of the corpus callosum, internal capsule, and brain stem. In the cortex, they were spread across the occipital, frontal, and temporal lobes and in the cingulate cortex. We also experimented with four different ML models and several confound control techniques. Support Vector Machine (SVM) with rbf kernel and Gradient Boosting consistently performed better than the linear models, linear SVM and Logistic Regression. Our study also demonstrates how the choice of the predicted phenotype, ML model, and confound correction technique are all crucial decisions in an explorative ML study analyzing psychiatric disorders with small effect sizes such as AAM.

Activin A, a TGFβ superfamily member, is important for normal testis development through its actions on Sertoli cell development. Our analyses of altered activin A mouse models indicated gonocyte abnormalities, implicating activin A as a key determinant of early germline formation. Whether it acts directly or indirectly on germ cells is not understood. In humans, the fetal testis may be exposed to abnormally elevated activin A levels during preeclampsia, maternal infections, or following ingestion of certain medications. We hypothesized that this may impact fetal testis development and ultimately affect adult fertility. Germ cells from two mouse models of altered activin bioactivity were analysed. RNA-Seq of gonocytes purified from E13.5 and E15.5 Inhba KO mice (activin A subunit knockout) identified 46 and 44 differentially expressed genes (DEGs) respectively, and 45 in the E13.5 Inha KO (inhibin alpha subunit knockout; increased activin A) gonocytes. To discern direct effects of altered activin bioactivity on germline transcripts, isolated E13.5 gonocytes were cultured for 24h with activin A or with the activin/Nodal/TGFβ inhibitor, SB431542. Gonocytes responded directly to altered signalling, with activin A promoting a more differentiated transcript profile (increased differentiation markers Dnmt3l, Nanos2 and Piwil4; decreased early germ cell markers Kit and Tdgf1), while SB431542 had a reciprocal effect (decreased Nanos2 and Piwil4; increased Kit). To delineate direct and indirect effects of activin A exposure on gonocytes, whole testes were cultured 48h with activin A or SB431542 and collected for histological and transcript analyses, or EdU added at the end of culture to measure germ and Sertoli cell proliferation using flow cytometry. Activin increased, and SB431542 decreased, Sertoli cell proliferation. SB431542-exposure resulted in germ cells escaping mitotic arrest. Analysis of FACS-isolated gonocytes following whole testis culture showed SB431542 increased the early germ cell marker Kit, however there was a general reduction in the impact of altered activin A bioavailability in the normal somatic cell environment. This multifaceted approach identifies a capacity for activin A to directly influence fetal germ cell development, highlighting the potential for altered activin A levels in utero to increase the risk of testicular pathologies that arise from impaired germline maturation.