Impact of Wildfires on Cardiovascular Health.

Wildfire smoke (WFS) is a mixture of respirable particulate matter, environmental gases, and other hazardous pollutants that originate from the unplanned burning of arid vegetation during wildfires. The increasing size and frequency of recent wildfires has escalated public and occupational health concerns regarding WFS inhalation, by either individuals living nearby and downstream an active fire or wildland firefighters and other workers that face unavoidable exposure because of their profession. In this review, we first synthesize current evidence from environmental, controlled, and interventional human exposure studies, to highlight positive associations between WFS inhalation and cardiovascular morbidity and mortality. Motivated by these findings, we discuss preventative measures and suggest interventions to mitigate the cardiovascular impact of wildfires. We then review animal and cell exposure studies to call attention on the pathophysiological processes that support the deterioration of cardiovascular tissues and organs in response to WFS inhalation. Acknowledging the challenges of integrating evidence across independent sources, we contextualize laboratory-scale exposure approaches according to the biological processes that they model and offer suggestions for ensuring relevance to the human condition. Noting that wildfires are significant contributors to ambient air pollution, we compare the biological responses triggered by WFS to those of other harmful pollutants. We also review evidence for how WFS inhalation may trigger mechanisms that have been proposed as mediators of adverse cardiovascular effects upon exposure to air pollution. We finally conclude by highlighting research areas that demand further consideration. Overall, we aspire for this work to serve as a catalyst for regulatory initiatives to mitigate the adverse cardiovascular effects of WFS inhalation in the community and alleviate the occupational risk in wildland firefighters.

Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.

The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.

Do Early Relapses Predict the Risk of Long-Term Relapsing Disease in an Adult and Paediatric Cohort with MOGAD?

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer-term relapse risk is unknown. Here, we investigate whether early relapses increase longer-term relapse risk in patients with MOGAD. METHODS: A retrospective analysis of 289 adult- and pediatric-onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. "Early relapses" were defined as attacks within the first 12 months from onset, with "very early relapses" defined within 30 to 90 days from onset and "delayed early relapses" defined within 90 to 365 days. "Long-term relapses" were defined as relapses beyond 12 months. Cox regression modeling and Kaplan-Meier survival analysis were used to estimate the long-term relapse risk and rate. RESULTS: Sixty-seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long-term relapses if any "early relapses" were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long-term relapses (HR = 2.64, p = 0.026). INTERPRETATION: The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long-term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric-onset disease. ANN NEUROL 2023;94:508-517.

Navigating challenges and workarounds: A qualitative study of healthcare and support workers' perceptions on providing care to people seeking sanctuary.

BACKGROUND: Healthcare and support workers play a pivotal role in delivering quality services and support to people seeking sanctuary who have experienced poor physical and mental health linked to previous trauma, relocation and loss of freedoms. However, they often encounter various challenges in their daily work, ranging from communication barriers to resource constraints. This qualitative study seeks to delve into the perspectives of healthcare and support workers' experience of workarounds, employed to overcome barriers to providing care. AIM: This study aims to describe healthcare providers', practitioners' and health and third sector support workers' views on barriers and workarounds to providing care for people seeking sanctuary, to inform policy and practice. DESIGN: A qualitative study was carried out using semi-structured telephone interviews. SETTING: This study focused on primary, secondary, community and specialist National Health Service (NHS) support services for people seeking sanctuary in Wales, United Kingdom (2018). METHOD: We interviewed 32 healthcare providers, practitioners and support workers employed by primary care and third sector organisations. Our approach involved obtaining verbal informed consent before digitally recording and transcribing all interviews. To analyse the data, we used the Four Levels of Change for Improving Quality model as a guiding framework for interpretation. RESULTS: Our study findings reveal that certain respondents expressed challenges in meeting the needs of people seeking sanctuary; notably, their experience of delivering care differed by care settings. Specifically, those involved in providing specialist NHS care believed that there was room for improvement. Mainstream primary, secondary and community health practitioners faced limitations due to resource constraints and lacked tailored information to address the unique circumstances and needs of sanctuary seekers. To address these gaps, workarounds emerged at both individual and local levels (team/departmental and organisational level). These included establishing informal communication channels between providers, fostering cross service collaboration to fill gaps and adapting existing services to enhance accessibility. CONCLUSION: Understanding healthcare providers', practitioners' and support workers' perspectives offers invaluable insights into ways to enhance healthcare delivery to sanctuary seekers. Acknowledging challenges and harnessing innovative workarounds can foster a more effective and compassionate service for this vulnerable population. PATIENT OR PUBLIC CONTRIBUTION: The HEAR study actively involved public contributors in the design, delivery and dissemination of the research. Two public contributors (S. M. and G. R.) who had personal experience of seeking asylum served as study co-applicants. They played pivotal roles in shaping the research by participating in its development and securing funding. Alongside other co-applicants, S. M. and G. R. formed the Research Management Group, overseeing study delivery. Their contributions extended to strategic decision-making and specific feedback at critical junctures, including participant recruitment, data collection, analysis and reporting. Additionally, S. M. and G. R. were instrumental in recruiting and supporting a team of peer researchers, enhancing respondent participation among people seeking sanctuary. To facilitate effective public involvement, we provided named contacts for support (A. K. and R. F.), research training, honoraria, reimbursement of expenses and accessible information in line with best practice.

Interventions, Barriers, and Proposed Solutions Associated With the Implementation of a Protocol That Uses Clinical Decision Support and a Stress Biomarker Test to Identify ICU Patients at High-Risk for Drug Associated Acute Kidney Injury.

BACKGROUND: Damage biomarkers are helpful in early identification of patients who are at risk of developing acute kidney injury (AKI). Investigations are ongoing to identify the optimal role of stress/damage biomarkers in clinical practice regarding AKI risk prediction, surveillance, diagnosis, and prognosis. OBJECTIVE: To determine the impact of utilizing a clinical decision support system (CDSS) to guide stress biomarker testing in intensive care unit (ICU) patients at risk for drug-induced acute kidney injury (D-AKI). METHODS: A protocol was designed utilizing a clinical decision support system (CDSS) alert to identify patients that were ordered 3 or more potentially nephrotoxic medications, suggesting risk for progressing to AKI from nephrotoxic burden. Once alerted to these high-risk patients, the pharmacist determined if action was needed by ordering a stress biomarker test, tissue inhibitor of metalloproteinase-2-insulin-like growth factor-binding protein 7 (TIMP-2•IGFBP7). If the biomarker test result was elevated, the pharmacist provided nephrotoxin stewardship recommendations to the team. Pharmacists recorded the response to the clinical decision support alert, ordering, and interpreting the TIMP-2•IGFBP7, and information regarding clinical interventions. An alert in conjunction with TIMP-2•IGFBP7 as a strategy for AKI risk prediction and stimulant for patient care management was assessed. In addition, barriers and solutions to protocol implementation were evaluated. RESULTS: There were 394 total activities recorded by pharmacists for 345 unique patients. Ninety-three (93/394; 23.6%) actionable alerts resulted in a TIMP-2•IGFBP7 test being ordered. Thirty-one TIMP-2•IGFBP7 results were >0.3 (31/81; 38.3%), suggesting a high-risk of progression to AKI, which prompted 191 pharmacist/team interventions. On average, there were 1.64 interventions per patient in the low-risk patients, 3.43 in high-risk patients, and 3.75 in the highest-risk patients. CONCLUSION AND RELEVANCE: Stress biomarkers can be used in conjunction with CDSS alerts to affect therapeutic decisions in ICU patients at high-risk for D-AKI.

Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease.

PRKN mutations are the most common recessive cause of Parkinson's disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson's disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 0.91 (0.58-1.38), P-value 0.76] or a parent with Parkinson's disease [odds ratio = 1.12 (0.94-1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson's disease [odds ratio = 1.29 (0.74-2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson's disease.

The cost of implementing the COVID-19 shielding policy in Wales.

BACKGROUND: The EVITE Immunity study investigated the effects of shielding Clinically Extremely Vulnerable (CEV) people during the COVID-19 pandemic on health outcomes and healthcare costs in Wales, United Kingdom, to help prepare for future pandemics. Shielding was intended to protect those at highest risk of serious harm from COVID-19. We report the cost of implementing shielding in Wales. METHODS: The number of people shielding was extracted from the Secure Anonymised Information Linkage Databank. Resources supporting shielding between March and June 2020 were mapped using published reports, web pages, freedom of information requests to Welsh Government and personal communications (e.g. with the office of the Chief Medical Officer for Wales). RESULTS: At the beginning of shielding, 117,415 people were on the shielding list. The total additional cost to support those advised to stay home during the initial 14 weeks of the pandemic was £13,307,654 (£113 per person shielded). This included the new resources required to compile the shielding list, inform CEV people of the shielding intervention and provide medicine and food deliveries. The list was adjusted weekly over the 3-month period (130,000 people identified by June 2020). Therefore the cost per person shielded lies between £102 and £113 per person. CONCLUSION: This is the first evaluation of the cost of the measures put in place to support those identified to shield in Wales. However, no data on opportunity cost was available. The true costs of shielding including its budget impact and opportunity costs need to be investigated to decide whether shielding is a worthwhile policy for future health emergencies.

Body image and psychosocial well-being among UK military personnel and veterans who sustained appearance-altering conflict injuries.

A modest but significant number of military personnel sustained injuries during deployments resulting in an altered-appearance (e.g., limb loss and/or scarring). Civilian research indicates that appearance-altering injuries can affect psychosocial wellbeing, yet little is known about the impact of such injuries among injured personnel. This study aimed to understand the psychosocial impact of appearance-altering injuries and possible support needs among UK military personnel and veterans. Semi-structured interviews with 23 military participants who sustained appearance-altering injuries during deployments or training since 1969 were conducted. The interviews were analyzed using reflexive thematic analysis, identifying six master themes. These themes indicate that in the context of broader recovery experiences, military personnel and veterans experience a variety of psychosocial difficulties related to their changed appearance. While some of these are consistent with evidence from civilians, military-related nuances in the challenges, protective experiences, coping approaches, and preferences for support are evident. Personnel and veterans with appearance-altering injuries may require specific support for adjusting to their changed appearance and related difficulties. However, barriers to acknowledging appearance concerns were identified. Implications for support provision and future research are discussed.

Skin conditions among pediatric dermatology outpatients in Botswana.

BACKGROUND: An understanding of the prevalence patterns of skin diseases in children in Botswana is needed to guide national dermatological policy development, training, and resource allocation to improve patient care. OBJECTIVE: To describe local skin disease patterns in children aged 0-18 years presenting for dermatologic care in Botswana. METHODS: A retrospective review of records from 1st January 2011 to 31st December 2016 was conducted at the outpatient dermatology clinic of Princess Marina Hospital (PMH) in Gaborone, Botswana and outreach clinic sites. RESULTS: There were 4413 pediatric visits constituting 18.6% of all dermatology visits. There was a slight male predominance of 1.2:1. The majority of disorders were noninfectious 80.1% (3537/4413) versus infectious 14.6% (645/4413), with 5.2% (231/4413) unclassified. In the noninfectious category, two-thirds were inflammatory, followed by disorders of nails, skin appendages, and pigmentary disorders. Atopic dermatitis was the most common inflammatory disorder. Over half of infectious skin diseases were viral, followed by fungal and bacterial disorders. In the HIV-related disorders, the majority were verrucae 94% (108/115) followed by Kaposi sarcoma. The nine most common skin diagnoses accounted for close to 70% of all skin diseases seen at the clinic, and these included atopic dermatitis (almost half of all cases), followed by verruca, acne, and vitiligo. CONCLUSION: There is a high burden of skin disorders in children in Botswana. In our cohort, a small number of skin conditions made up the vast majority of pediatric diagnoses. This information can be used to guide dermatology training and resource allocation to better manage these common diseases.

Novel Education Modules Addressing the Underrepresentation of Skin of Color in Dermatology Training.

BACKGROUND: Representative images of pathology in patients with skin of color are lacking in most medical education resources. This particularly affects training in dermatology, which relies heavily on the use of images to teach pattern recognition. The presentation of skin pathology can vary greatly among different skin tones, and this lack of representation of dark skin phototypes challenges providers' abilities to provide quality care to patients of color.In Botswana and other countries in sub-Saharan Africa, this challenge is further compounded by limited resources and access to dermatologists. There is a need for improved and accessible educational resources to train medical students and local medical providers in basic skin lesion description and diagnosis. OBJECTIVES: We examined whether online Perceptual and Adaptive Learning Modules (PALMs) composed of representative dark skin images could efficiently train University of Botswana medical students to more accurately describe and diagnose common skin conditions in their community. METHODS: Year 4 and 5 medical students voluntarily completed PALMs that teach skin morphology, configuration, and distribution terminology and diagnosis of the most common dermatologic conditions in their community. Pre-tests, post-tests and delayed-tests assessed knowledge acquisition and retention. RESULTS: PALMs training produced statistically significant (P < .0001) improvements in accuracy and fluency with large effect sizes (1.5, 3.7) and good retention after a 12.5-21-week median delay. Limitations were a self-selected group of students, a single institution, slow internet connections, and high drop-out rates. CONCLUSIONS: Overall, population-specific PALMs are a useful tool for efficient development of pattern recognition in skin disease description and diagnosis.

A Web-based Lifestyle Intervention for Cancer Survivors: Feasibility and Acceptability of SurvivorSHINE.

Assess the feasibility, acceptability, and preliminary efficacy of a healthy lifestyle website, SurvivorSHINE ( www.survivorshine.org ), for cancer survivors using a mixed-methods approach. Formative research included a comprehensive literature review and four focus groups on website preferences with diagnosis-diverse cancer survivors (N = 17). Their feedback informed a web adaptation of a telephone counseling and mailed-print lifestyle intervention previously found effective for cancer survivors. The resulting web-based intervention was examined in a 3-week, single-arm trial among 41 cancer survivors. Assessments of physical activity, diet, body weight, and knowledge related to exercise and diet guidelines for cancer survivors occurred at baseline and 3 weeks later, along with exit interviews. Themes from focus groups indicated cancer survivors' desire for easy-to-use, interactive web-based platforms to access credible diet and exercise information. The study sample was recruited within 12 months, and study retention was high (85.4%). Participants showed significant pre- to post-test improvements in diet and exercise knowledge (t = 5.31, p < .0001) and physical activity (t = 2.40, p = .02). Improvements in body weight and some dietary components (red meat, alcohol) were observed, but did not reach statistical significance. Results support the feasibility and acceptability of SurvivorSHINE. The significant increases in healthy lifestyle knowledge and physical activity found in the current study are promising, but a larger, randomized-controlled trial is needed to determine efficacy.

Association Between Hospital Outbreaks and Hand Hygiene: Insights from Electronic Monitoring.

BACKGROUND: Hand hygiene (HH) is an important patient safety measure linked to the prevention of health care-associated infection, yet how outbreaks affect HH performance has not been formally evaluated. METHODS: A controlled, interrupted time series was performed across 5 acute-care academic hospitals using group electronic monitoring. This system captures 100% of all hand sanitizer and soap dispenser activations via a wireless signal to a wireless hub; the number of activations is divided by a previously validated estimate of the number of daily HH opportunities per patient bed, multiplied by the hourly census of patients on the unit. Daily HH adherence 60 days prior and 90 days following outbreaks on inpatient units was compared to control units not in outbreaks over the same period, using a Poisson regression model adjusting for correlations within hospitals and units. Predictors of HH improvement were assessed in this multivariate model. RESULTS: In the 60 days prior to outbreaks, units destined for outbreaks had significantly lower HH adherence compared to control units (incidence rate ratio [IRR], 0.91; 95% confidence interval [CI], .90-.93; P < .0001). Following an outbreak, the HH adherence among the outbreak units increased above that of the controls (IRR, 1.04; 95% CI, 1.02-1.06; P < .0001). Greater improvements were noted for outbreaks on surgical units, for outbreaks involving antibiotic-resistant organisms and enteric pathogens, and in those outbreaks where health-care workers became ill. CONCLUSIONS: Hospital outbreaks tend to occur in units with lower HH adherence and are associated with rapid improvements in HH performance. Group electronic monitoring of HH could be used to develop novel, prospective feedback interventions designed to avert hospital outbreaks.

Genomic Epidemiology of Carbapenemase-Producing Enterobacterales at a Hospital System in Toronto, Ontario, Canada, 2007 to 2018.

At a hospital system (H1) in Ontario, Canada, we investigated whether whole-genome sequencing (WGS) altered initial epidemiological interpretation of carbapenemase-producing Enterobacterales (CPE) transmission. We included patients with CPE colonization/infection identified by population-based surveillance from October 2007 to August 2018 who received health care at H1 in the year before/after CPE detection. H1 reported epidemiological transmission clusters. We combined single nucleotide variant (SNV) analysis, plasmid characterization, and epidemiological data. Eighty-five patients were included. H1 identified 7 epidemiological transmission clusters, namely, A to G, involving 24/85 (28%) patients. SNV analysis confirmed transmission clusters C, D, and G and identified two additional cases belonging to cluster A. One was a travel-related case that was the likely index case (0 to 6 SNVs from other isolates); this case stayed on the same unit as the initially presumed index case 4 months prior to detection of the initially presumed index case on another unit. The second additional case occupied a room previously occupied by 5 cluster A cases. Plasmid sequence analysis excluded a case from cluster A and identified clusters E and F as possibly two parts of a single cluster. SNV analysis also identified a case without direct epidemiologic links that was 18 to 21 SNVs away from cluster B, suggesting possible undetected interhospital transmission. SNV and plasmid sequence analysis identified cases belonging to transmission clusters that conventional epidemiology missed and excluded other cases. Implementation of routine WGS to complement epidemiological transmission investigations has the potential to improve prevention and control of CPE in hospitals.

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

Introduction of Group Electronic Monitoring of Hand Hygiene on Inpatient Units: A Multicenter Cluster Randomized Quality Improvement Study.

BACKGROUND: The current approach to measuring hand hygiene (HH) relies on human auditors who capture <1% of HH opportunities and rapidly become recognized by staff, resulting in inflation in performance. Group electronic monitoring is a validated method of measuring HH adherence, but data demonstrating the clinical impact of this technology are lacking. METHODS: A stepped-wedge cluster randomized quality improvement study was performed on 26 inpatient medical and surgical units across 5 acute care hospitals in Ontario, Canada. The intervention involved daily HH reporting as measured by group electronic monitoring to guide unit-led improvement strategies. The primary outcome was monthly HH adherence (percentage) between baseline and intervention. Secondary outcomes included transmission of antibiotic-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and other healthcare-associated infections. RESULTS: After adjusting for the correlation within inpatient units and hospitals, there was a significant overall improvement in HH adherence associated with the intervention (incidence rate ratio [IRR], 1.73 [95% confidence interval {CI}, 1.47-1.99]; P < .0001). Monthly HH adherence relative to the intervention increased from 29% (1 395 450/4 544 144) to 37% (598 035/1 536 643) within 1 month, followed by consecutive incremental increases up to 53% (804 108/1 515 537) by 10 months (P < .0001). There was a trend toward reduced healthcare-associated transmission of MRSA (IRR, 0.74 [95% CI, .53-1.04]; P = .08). CONCLUSIONS: The introduction of a system for group electronic monitoring led to rapid, significant improvements in HH performance within a 2-year period. This method offers significant advantages over direct observation for measurement and improvement of HH.

The effect of white matter signal abnormalities on default mode network connectivity in mild cognitive impairment.

Regions within the default mode network (DMN) are particularly vulnerable to Alzheimer's disease pathology and mechanisms of DMN disruption in mild cognitive impairment (MCI) are still unclear. White matter lesions are presumed to be mechanistically linked to vascular dysfunction whereas cortical atrophy may be related to neurodegeneration. We examined associations between DMN seed-based connectivity, white matter lesion load, and cortical atrophy in MCI and cognitively healthy controls. MCI showed decreased functional connectivity (FC) between the precuneus-seed and bilateral lateral temporal cortex (LTC), medial prefrontal cortex (mPFC), posterior cingulate cortex, and inferior parietal lobe compared to those with controls. When controlling for white matter lesion volume, DMN connectivity differences between groups were diminished within bilateral LTC, although were significantly increased in the mPFC explained by significant regional associations between white matter lesion volume and DMN connectivity only in the MCI group. When controlling for cortical thickness, DMN FC was similarly decreased across both groups. These findings suggest that white matter lesions and cortical atrophy are differentially associated with alterations in FC patterns in MCI. Associations between white matter lesions and DMN connectivity in MCI further support at least a partial but important vascular contribution to age-associated neural and cognitive impairment.

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.

BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

Physical health composite and risk of cancer mortality in the REasons for Geographic and Racial Differences in Stroke Study.

It is unclear how resting myocardial workload, as indexed by baseline measures of rate-pressure product (RPP) and physical activity (PA), is associated with the overall risk of cancer mortality. We performed prospective analyses among 28,810 men and women from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We used a novel physical health (PH) composite index and categorized participants into one of four groups based on combinations from self-reported PA and RPP: 1) No PA and High RPP; 2) No PA and Low RPP; 3) Yes PA and High RPP; and 4) Yes PA and Low RPP. We examined the association between baseline PH composite and cancer mortality adjusted for potential confounders using Cox regression. A total of 1191 cancer deaths were observed over the 10-year observation period, with the majority being lung (26.87%) and gastrointestinal (21.49%) cancers. Even after controlling for sociodemographics, health behaviors, baseline comorbidity score, and medications, participants with No PA and High RPP had 71% greater risk of cancer mortality when compared to participants with PA and Low RPP (adjusted HR: 1.71, 95% CI: 1.42-2.06). These associations persisted after examining BMI, smoking, income, and gender as effect modifiers and all-cause mortality as a competing risk. Poorer physical health composite, including the novel RPP metric, was associated with a nearly 2-fold long-term risk of cancer mortality. The physical health composite has important public health implications as it provides a measure of risk beyond traditional measure of obesity and physical activity.

Care-pathways for patients presenting to emergency ambulance services with self-harm: national survey.

BACKGROUND: Self-harm is among the top five causes of acute hospital admissions and ambulance clinicians are often the first point of contact. However, the Emergency Department (ED) may not be the most appropriate place of care and little is known about the existence or nature of alternative pathways available to UK ambulance services. This survey describes the current management pathways used by ambulance services for patients who have self-harmed. METHODS: A structured questionnaire was sent to all UK ambulance services by email and followed up by telephone in 2018. Three independent researchers (two clinical) coded responses which were analysed thematically. RESULTS: All 13 UK ambulance services responded to the survey: nine by email and four by telephone interview. Two services reported a service-wide protocol for managing people presenting with self-harm, with referral to mental health crisis team available as an alternative to conveyance to ED, following on-scene psychosocial assessment. Four services reported local pathways for managing mental health patients which included care of patients who had self-harmed. Four services reported being in the process of developing pathways for managing mental health patients. Six services reported no service-wide nor local pathways for managing self-harm patients. No robust evaluation of new care models was reported. CONCLUSION: Practice in ambulance services in the UK is variable, with a minority having a specific clinical pathway for managing self-harm, with an option to avoid ED. New pathways for patients who have self-harmed must be evaluated in terms of safety, clinical and cost-effectiveness.

Sonic hedgehog acts cell-autonomously on muscle precursor cells to generate limb muscle diversity.

How muscle diversity is generated in the vertebrate body is poorly understood. In the limb, dorsal and ventral muscle masses constitute the first myogenic diversification, as each gives rise to distinct muscles. Myogenesis initiates after muscle precursor cells (MPCs) have migrated from the somites to the limb bud and populated the prospective muscle masses. Here, we show that Sonic hedgehog (Shh) from the zone of polarizing activity (ZPA) drives myogenesis specifically within the ventral muscle mass. Shh directly induces ventral MPCs to initiate Myf5 transcription and myogenesis through essential Gli-binding sites located in the Myf5 limb enhancer. In the absence of Shh signaling, myogenesis is delayed, MPCs fail to migrate distally, and ventral paw muscles fail to form. Thus, Shh production in the limb ZPA is essential for the spatiotemporal control of myogenesis and coordinates muscle and skeletal development by acting directly to regulate the formation of specific ventral muscles.