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IntroductionPrevious evidence indicates that gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of cytosolic Ca2+ in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca2+ signals can offer insight into the pathophysiological disruptions taking place in hypoxia-related perinatal cerebrovascular disease. This study aimed to determine the extent to which gestational hypoxia disrupts local Ca2+ sparks and whole-cell Ca2+ signals and coupling with BKCa channel activity.MethodsConfocal imaging of cytosolic Ca2+ and recording BKCa currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (∼140 days of gestation) from ewes held at low- (700 m) and high-altitude (3,801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 μM ryanodine (Ry), to block RyR mediated Ca2+ release.ResultsMembrane depolarization increased Ry-sensitive Ca2+ spark frequency in normoxic and LTH groups along with BKCa activity. LTH reduced Ca2+ spark and whole-cell Ca2+ activity and induced a large leftward shift in the voltage-dependence of BKCa current activation. The influence of LTH on the spatial and temporal aspects of Ca2+ sparks and whole-cell Ca2+ responses varied.DiscussionOverall, LTH attenuates Ca2+ signaling while increasing the coupling of Ca2+ sparks to BKCa activity; a process that potentially helps maintain oxygen delivery to the developing brain.

BackgroundExperience-based knowledge and value considerations of health professionals, citizens, and patients are essential to formulate public health and clinical guidelines that are relevant and applicable to medical practice. Conventional methods for incorporating such knowledge into guideline development often involve a limited number of representatives and are considered to be time-consuming. Including experiential knowledge can be crucial during rapid guidance production in response to a pandemic but it is difficult to accomplish. ObjectiveThis proof-of-concept study explored the potential of artificial intelligence (AI)–based methods to capture experiential knowledge and value considerations from existing data channels to make these insights available for public health guideline development. MethodsWe developed and examined AI-based methods in relation to the COVID-19 vaccination guideline development in the Netherlands. We analyzed Dutch messages shared between December 2020 and June 2021 on social media and on 2 databases from the Dutch National Institute for Public Health and the Environment (RIVM), where experiences and questions regarding COVID-19 vaccination are reported. First, natural language processing (NLP) filtering techniques and an initial supervised machine learning model were developed to identify this type of knowledge in a large data set. Subsequently, structural topic modeling was performed to discern thematic patterns related to experiences with COVID-19 vaccination. ResultsNLP methods proved to be able to identify and analyze experience-based knowledge and value considerations in large data sets. They provide insights into a variety of experiential knowledge that is difficult to obtain otherwise for rapid guideline development. Some topics addressed by citizens, patients, and professionals can serve as direct feedback to recommendations in the guideline. For example, a topic pointed out that although travel was not considered as a reason warranting prioritization for vaccination in the national vaccination campaign, there was a considerable need for vaccines for indispensable travel, such as cross-border informal caregiving, work or study, or accessing specialized care abroad. Another example is the ambiguity regarding the definition of medical risk groups prioritized for vaccination, with many citizens not meeting the formal priority criteria while being equally at risk. Such experiential knowledge may help the early identification of problems with the guideline’s application and point to frequently occurring exceptions that might initiate a revision of the guideline text. ConclusionsThis proof-of-concept study presents NLP methods as viable tools to access and use experience-based knowledge and value considerations, possibly contributing to robust, equitable, and applicable guidelines. They offer a way for guideline developers to gain insights into health professionals, citizens, and patients’ experience-based knowledge, especially when conventional methods are difficult to implement. AI-based methods can thus broaden the evidence and knowledge base available for rapid guideline development and may therefore be considered as an important addition to the toolbox of pandemic preparedness.

Background: The effects of climate change are seen with a rise of extreme weather and climate events (EWCEs) which lead to the closures of many healthcare facilities, such as community pharmacies. Pharmacists in community pharmacies are seen as the most accessible healthcare professional to the public and are responsible for the continued delivery of care to patients. However, amid closures due to EWCEs and the emergence of pharmacy deserts, there is decreased access to pharmacies and a disruption of care. Objective: It is important to address the preparedness and accessibility of pharmacies post-EWCEs to guide future research and policy. Additionally, to tackle health disparities that arise due to pharmacy deserts, the populations most affected by a decreased access to pharmacies should be identified. We conducted a scoping review to assess the preparedness and accessibility of pharmacies post-EWCEs and to identify populations most affected by pharmacy deserts. Methods: We searched PubMed, Embase, and Web of Science from January 1, 2012 to September 30, 2022 and included all English-language, peer-reviewed primary literature that examined the preparedness and accessibility of community pharmacies in the United States post-EWCEs and addressed disparities within pharmacy deserts. Studies meeting these criteria were screened of their titles and abstracts by the first author and discrepancies were resolved with co-authors. We used Covidence for data extraction. Results: A total of 472 studies were identified (196 duplicates removed) and after screening, 53 studies were assessed for eligibility. The results of included publications (N = 26) showed that pharmacists and pharmacies are not equipped with the necessary emergency protocols which could lead to decreased access of pharmacies in the wake of EWCEs. Pharmacy deserts disproportionately affect residents living in rural, lower income, and Black/African American and Hispanic/Latino neighborhoods. The lack of preparedness of pharmacies post-EWCEs could worsen medication access. Conclusion: This scoping review addresses challenges impacting pharmacies and patients post-EWCEs and within pharmacy deserts. In times of increased need, these challenges implicate the well-being of communities affected by EWCEs by breaking the continuum of care and access to medications. Here we offer suggestions for future research and directions for policy change.

Purpose The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study.Participants UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40–69 enrolled in 2006–2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs.Findings to date UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes.Future plans The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022–2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia.

Abstract Background Individuals with bipolar disorder (BD) are increasingly turning to smartphone applications (apps) for health information and self-management support. While reviews have raised concerns regarding the effectiveness and safety of publicly available apps for BD, apps surveyed may not reflect what individuals with BD are using. The present study had two aims: first, to characterize the use of health apps to support mood and sleep amongst people with BD, and second, to evaluate the quality, safety and functionality of the most commonly used self-management apps. Methods A web-based survey was conducted to explore which apps people with BD reported using to support self-management of mood and sleep. The characteristics of the most commonly nominated apps were described using a standardized framework, including their privacy policy, clinical foundations, and functionality. Results Respondents (n = 919) were 77.9% female with a mean age of 36.9 years. 41.6% of participants (n = 382) reported using a self-management app to support mood or sleep. 110 unique apps were nominated in relation to mood, and 104 unique apps nominated in relation to sleep; however, most apps were only mentioned once. The nine most frequently nominated apps related to mood and sleep were subject to further evaluation. All reviewed apps offered a privacy policy, however user control over data was limited and the complexity of privacy policies was high. Only one app was developed for BD populations. Half of reviewed apps had published peer-reviewed evidence to support their claims of efficacy, but little research was specific to BD. Conclusion Findings illustrate the potential of smartphone apps to increase the reach of psychosocial interventions amongst people with BD. Apps were largely created by commercial developers and designed for the general population, highlighting a gap in the development and dissemination of evidence-informed apps for BD. There may be risks in using generic health apps for BD self-management; clinicians should enquire about patients’ app use to foster conversations about their particular benefits and limitations.

Abstract Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10−7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7–58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

Abstract Background Engaging youth throughout the research process improves research quality and outcomes. Youth advisory groups provide one way for youth to express their opinions on relevant issues. Objective This study aimed to identify research‐ and health‐related youth advisory groups (‘groups’) in Canada and understand the best practices of these groups. Methods Google searches and supplementary methods were used to identify relevant groups in Canada. Group information was extracted from websites or through interviews with key informants. Results We identified 40 groups. Groups were commonly part of a hospital/healthcare facility, nonprofit/health organization or research group. The majority focused on a specific content area, most commonly, mental health. Over half the groups advised on health services. Members' ages ranged from 9 to 35 years. The number of members ranged from 5 to 130. Interviews (n = 12) identified seven categories relating to group practices: (a) group purpose/objectives, (b) group development, (c) group operations, (d) group structure, (e) adult involvement, (f) membership and recruitment and (g) group access. Challenges and facilitators to the success of groups were described within the following themes: (a) retaining engagement, (b) creating a safe environment and (c) putting youth in positions of influence. Advice and recommendations were provided regarding the development of a new group. Conclusion This study provides a comprehensive overview of research‐ and health‐related youth advisory groups in Canada. This information can be used to identify groups that stakeholders could access as well as inform the development of a new group. Patient or Public Contribution Youth advisory group representatives were interviewed as part of the study.

Cell death is a critical process in health and disease, yet available markers record later stages of cell death once a cell has already begun to decompose. Here the authors show the use of a genetically encoded calcium indicator that demarcates an irreversible stage of cell death earlier than previously possible.

Abstract Cognitive side effects of anticholinergic medications in older adults are well documented. Whether these poor cognitive outcomes are observed in children has not been systematically investigated. We aimed to conduct a systematic review and meta-analysis on the associations between anticholinergic medication use and cognitive performance in children. Systematic review was conducted using Medline, PsychInfo, and Embase, identifying studies testing cognitive performance relative to the presence versus absence of anticholinergic medication(s) in children. We assessed effects overall, as well as relative to drug class, potency (low and high), cognitive domain, and duration of administration. The systematic search identified 46 articles suitable for meta-analysis. For the most part, random effects meta-analyses did not identify statistically significant associations between anticholinergic exposure and cognitive performance in children; the one exception was a small effect of anticholinergic anti-depressants being associated with better cognitive function (Hedges’ g = 0.24, 95% CI 0.06–0.42, p = 0.01). Anticholinergic medications do not appear to be associated with poor cognitive outcomes in children, as they do in older adults. The discrepancy in findings with older adults may be due to shorter durations of exposure in children, differences in study design (predominantly experimental studies in children rather than predominantly epidemiological in older adults), biological ageing (e.g. blood brain barrier integrity), along with less residual confounding due to minimal polypharmacy and comorbidity in children.

Abstract Background Only a small proportion of anterior cruciate ligament (ACL) tears are diagnosed on initial healthcare consultation. Current clinical guidelines do not acknowledge that primary point-of-care practitioners rely more heavily on a clinical history than special clinical tests for diagnosis of an ACL tear. This research will assess the accuracy of combinations of patient-reported variables alone, and in combination with clinician-generated variables to identify an ACL tear as a preliminary step to designing a primary point-of-care clinical decision support tool. Methods Electronic medical records (EMRs) of individuals aged 15–45 years, with ICD-9 codes corresponding to a knee condition, and confirmed (ACL+) or denied (ACL−) first-time ACL tear seen at a University-based Clinic between 2014 and 2016 were eligible for inclusion. Demographics, relevant diagnostic indicators and ACL status based on orthopaedic surgeon assessment and/or MRI reports were manually extracted. Descriptive statistics calculated for all variables by ACL status. Univariate between group comparisons, clinician surveys (n = 17), availability of data and univariable logistic regression (95%CI) were used to select variables for inclusion into multivariable logistic regression models that assessed the odds (95%CI) of an ACL-tear based on patient-reported variables alone (consistent with primary point-of-care practice), or in combination with clinician-generated variables. Model performance was assessed by accuracy, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (95%CI). Results Of 1512 potentially relevant EMRs, 725 were included. Participant median age was 26 years (range 15–45), 48% were female and 60% had an ACL tear. A combination of patient-reported (age, sport-related injury, immediate swelling, family history of ACL tear) and clinician-generated (Lachman test result) variables were superior for ACL tear diagnosis [accuracy; 0.95 (90,98), sensitivity; 0.97 (0.88,0.98), specificity; 0.95 (0.82,0.99)] compared to the patient-reported variables alone [accuracy; 84% (77,89), sensitivity; 0.60 (0.44,0.74), specificity; 0.95 (0.89,0.98)]. Conclusions A high proportion of individuals without an ACL tear can be accurately identified by considering patient-reported age, injury setting, immediate swelling and family history of ACL tear. These findings directly inform the development of a clinical decision support tool to facilitate timely and accurate ACL tear diagnosis in primary care settings.

The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick’s original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single-cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by t YAP1/TEAD1 and TGF-β2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.

BackgroundProviding parents with resources that aid in the identification and management of acute childhood illnesses helps those parents feel better equipped to assess their children’s health and significantly changes parental health-seeking behaviors. Some of these resources are limited by accessibility and scalability. Remote locations and staffing limitations create challenges for parents aiming to access their child’s health information. Mobile health apps offer a scalable, accessible solution for improving health literacy by enabling access to health information through mobile devices. ObjectiveThe aim of our study is to create an inventory of acute childhood illness apps that are available to North American parents and caregivers, assess their quality, and identify the areas in which future apps can be improved. MethodsWe conducted an environmental scan to identify and summarize app information for parents and digital health researchers. The Google and Apple app marketplaces were used as search platforms. We built a list of search terms and searched the platforms for apps targeted at parents and related to acute pediatric illnesses in the United States and Canada. We assessed apps meeting the inclusion criteria using the Mobile App Rating Scale (MARS), a validated tool for assessing the quality of health apps. The MARS examines apps on 5 subscales: engagement, functionality, aesthetics, information quality, and subjective quality. Data were analyzed by MARS subscale averages and individual item scores. ResultsOverall, 650 unique apps were screened, and 53 (8.2%) were included. On a scale of 1-5, apps had an average engagement score of 2.82/5 (SD 0.86), functionality score of 3.98/5 (SD 0.72), aesthetics score of 3.09/5 (SD 0.87), information quality score of 2.73/5 (SD 1.32), and subjective quality score of 2.20/5 (SD 0.79). On the same scale of 1-5, app scores ranged from 2.2/5 to 4.5/5 (mean 3.2, SD 0.6). The top 3 MARS-scored apps were Baby and Child First Aid (4.5/5), Ada (4.5/5), and HANDi Paediatric (4.2/5). Taken together, the top 3 apps covered topics of emergency pediatric first aid, identification of (and appropriate response to) common childhood illnesses, a means of checking symptoms, and a means of responding to emergency situations. There was a lack of Canadian-based app content available to parents in both marketplaces; this space was filled with content originating primarily in the United Kingdom and the United States. In addition, published evidence of the impact of the included apps was poor: of 53 apps, only 5 (9%) had an evidence base showing that the app had been trialed for usability or efficacy. ConclusionsThere is a need for evidence-based acute childhood illness apps of Canadian origin. This environmental scan offers a comprehensive picture of the health app landscape by examining trends in acute childhood illness apps that are readily available to parents and by identifying gaps in app design.

Objective There is contrasting evidence on the relationship between socioeconomic status (SES) and age-related macular degeneration (AMD), the most common cause of visual impairment (VI) in developed countries. This study examines the relationship between SES, cardiovascular risk factors and self-reported AMD.Methods and analysis Over 500000 people participated in the UK Biobank study from 2006 to 2019, with sociodemographic data and clinical measurements collected using standardised procedures. Visual acuity was measured in 117907 participants with VI defined as LogMAR ≤0.3. We used logistic regression to examine the cross-sectional associations between SES and self-reported AMD.Results Self-reported AMD was available for 133339 participants aged 50 and older. People reporting AMD had higher academic qualifications, lower income, were unable to work due to disability, have higher BMI, diabetes and vascular heart disease after adjusting for age and sex. In a multivariable analysis, higher income was protective of AMD and economic inactivity due to disability increased the odds of AMD (2.02, 95% CI 1.13 to 3.61). Both associations were independent of cardiovascular factors, but was no longer significant after adjusting for VI.Conclusions The association between education, employment and household income with AMD was independent of cardiovascular risk factors.

Viruses interact with their hosts via secreted and membrane-bound proteins to affect host immune responses and virulence. Here the authors contribute to our understanding of this relationship with an extracellular interaction map of human and adenoviral E3 immunomodulatory proteins.

Nature Communications 7: Article number: 11473 (2016); Published: 5 May 2016; Updated: 21 August 2017 In Supplementary Fig. 3 of this Article, the sequence given for CR1B_HAdV-D19a in the alignment shown is incorrect, and should have been identical to that listed for CR1B_HAdV-D37. A correct versionof Supplementary Fig.

Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however, the regulatory strategies underlying each factor’s effective recruitment to specific promoter and/or enhancer regions are not fully understood. Here, we identify an unexpected regulatory mechanism by which promoter-specific binding, and therefore function, of peroxisome proliferator-activator receptor γ (PPARγ) in adipocytes requires G protein suppressor 2 (GPS2) to prime the local chromatin environment via inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2. Integration of genome-wide profiling data indicates that the pioneering activity of GPS2/KDM4A is required for PPARγ-mediated regulation of a specific transcriptional program, including the lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). Hence, our findings reveal that GPS2 exerts a biologically important function in adipose tissue lipid mobilization by directly regulating ubiquitin signaling and indirectly modulating chromatin remodeling to prime selected genes for activation.

Divergence in gene regulation can play a major role in evolution. Here, we used a phylogenetic framework to measure mRNA profiles in 15 yeast species from the phylum Ascomycota and reconstruct the evolution of their modular regulatory programs along a time course of growth on glucose over 300 million years. We found that modules have diverged proportionally to phylogenetic distance, with prominent changes in gene regulation accompanying changes in lifestyle and ploidy, especially in carbon metabolism. Paralogs have significantly contributed to regulatory divergence, typically within a very short window from their duplication. Paralogs from a whole genome duplication (WGD) event have a uniquely substantial contribution that extends over a longer span. Similar patterns occur when considering the evolution of the heat shock regulatory program measured in eight of the species, suggesting that these are general evolutionary principles.

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure.