In situ via Contact to hBN-Encapsulated Air-Sensitive Atomically Thin Semiconductors.

Establishing reliable electrical contacts to atomically thin materials is a prerequisite for both fundamental studies and applications yet remains a challenge. In particular, the development of contact techniques for air-sensitive monolayers has lagged behind, despite their unique properties and significant potential for applications. Here, we present a robust method to create contacts to device layers encapsulated within hexagonal boron nitride (hBN). This method uses plasma etching and metal deposition to create 'vias' in the hBN with graphene forming an atomically thin etch-stop. The resulting partially fluorinated graphene (PFG) protects the underlying device layer from air-induced degradation and damage during metal deposition. PFG is resistive in-plane but maintains high out-of-plane conductivity. The work function of the PFG/metal contact is tunable through the degree of fluorination, offering opportunities for contact engineering. Using the in situ via technique, we achieve ambipolar contact to air-sensitive monolayer 2H-molybdenum ditelluride (MoTe2) with more than 1 order of magnitude improvement in on-current density compared to previous literature. The complete encapsulation provides high reproducibility and long-term stability. The technique can be extended to other air-sensitive materials as well as air-stable materials, offering highly competitive device performance.

Kidney Function Biomarkers During Extreme Heat Exposure in Young and Older Adults.

This study investigates the effects of extreme heat exposure on kidney function using plasma-based biomarkers in young and older adults.

A rapid mixed-methods assessment of Libya's primary care system.

BACKGROUND: Libya has experienced decades of violent conflict that have severely disrupted health service delivery. The Government of National Unity is committed to rebuilding a resilient health system built on a platform of strong primary care. AIM: Commissioned by the government, we set out to perform a rapid assessment of the system as it stands and identify areas for improvement. DESIGN AND SETTING: We used a rapid applied policy explanatory-sequential mixed-methods design, working with Libyan data and Libyan policymakers, with supporting interview data from other primary care policymakers working across the Middle East and North Africa region. METHOD: We used the Primary Health Care Performance Initiative framework to structure our assessment. Review of policy documents and secondary analysis of WHO and World Bank survey data informed a series of targeted policymaker interviews. We used deductive framework analysis to synthesise our findings. RESULTS: We identified 11 key documents and six key policymakers to interview. Libya has strong policy commitments to providing good quality primary care, and a high number of health staff and facilities. Access to services and trust in providers is high. However, a third of facilities are non-operational; there is a marked skew towards axillary and administrative staff; and structural challenges with financing, logistics, and standards has led to highly variable provision of care. CONCLUSION: In reforming the primary care system, the government should consolidate leadership, clarify governance structures and systems, and focus on setting national standards for human resources for health, facilities, stocks, and clinical care.

ACR Appropriateness Criteria® Dizziness and Ataxia: 2023 Update.

Diagnostic evaluation of a patient with dizziness or vertigo is complicated by a lack of standardized nomenclature, significant overlap in symptom descriptions, and the subjective nature of the patient's symptoms. Although dizziness is an imprecise term often used by patients to describe a feeling of being off-balance, in many cases dizziness can be subcategorized based on symptomatology as vertigo (false sense of motion or spinning), disequilibrium (imbalance with gait instability), presyncope (nearly fainting or blacking out), or lightheadedness (nonspecific). As such, current diagnostic paradigms focus on timing, triggers, and associated symptoms rather than subjective descriptions of dizziness type. Regardless, these factors complicate the selection of appropriate diagnostic imaging in patients presenting with dizziness or vertigo. This document serves to aid providers in this selection by using a framework of definable clinical variants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

The use of sequential window acquisition of all theoretical fragment ion spectra (SWATH), a data-independent acquisition high-resolution mass spectrometry approach, in forensic toxicological regimes: A review.

Sequential window acquisition of all theoretical fragment ion spectra (SWATH) is a type of high-resolution mass spectrometry that uses data-independent acquisition. Compared with more targeted acquisition schemes, the power behind this data-independent acquisition technique comes from its ability to mitigate interferences via the use of SWATH acquisition windows (Q1 quadrupole isolation windows) while still obtaining all accurate mass information. However, consistent with high-resolution mass spectrometry techniques, its routine and high throughput implementation in forensic toxicology is limited due to the complex processing power required to effectively manage the large amount of acquired data. It is therefore pivotal to create an efficient and validated identification criterion that confidently reports suspected positive detections as a confirmational technique for final reporting. This review examines all publications that implemented SWATH in a forensic toxicological framework with suggestive best practices and commonly used criteria. Seventeen publications were reviewed for extraction, liquid chromatography and mass spectrometry parameters, and more specifically for all SWATH applicable characteristics including spray voltages, collision energies and spreads, mass error, isotopic ratio difference, retention time error, and library score thresholds. Notwithstanding the challenges SWATH implementation faces for a laboratory, the technique demonstrates its potential to be utilized in routine forensic toxicology testing regimes and aids in the detection of both common and emerging novel drugs simultaneously.

Frontline health workers' experiences of providing care for people living with non-communicable diseases during the COVID-19 pandemic in Ghana: a qualitative study.

BACKGROUND: The COVID-19 pandemic has significantly impacted frontline health workers. However, a neglected dimension of this discourse was the extent to which the pandemic impacted frontline healthcare workers providing non-communicable diseases (NCDs) care. This study aims to understand the experiences of healthcare workers with no prior exposure to pandemics who provided care to people living with NCDs (PLWNCDs). METHODS: A qualitative study design was employed, using a face-to-face in-depth interviews. Interviews were conducted in primary healthcare facilities in three administrative regions of Ghana, representing the Northern, Southern and Middle Belts. Only frontline health workers with roles in providing care for PLWNCDs were included. Purposive snowballing and convenience sampling methods were employed to select frontline health workers. An open-ended interview guide was used to facilitate data collection, and thematic content analysis was used to analyse the data. RESULTS: A total of 47 frontline health workers were interviewed. Overall, these workers experienced diverse patient-driven and organisational challenges. Patient-level challenges included a decline in healthcare utilisation, non-adherence to treatment, a lack of continuity, fear and stigma. At the organisational levels, there was a lack of medical logistics, increased infection of workers and absenteeism, increased workload and burnout, limited motivational packages and inadequate guidelines and protocols. Workers coped and responded to the pandemic by postponing reviews and consultations, reducing inpatient and outpatient visits, changing their prescription practices, using teleconsultation and moving to long-shift systems. CONCLUSION: This study has brought to the fore the experiences that adversely affected frontline health workers and, in many ways, affected the care provided to PLWNCDs. Policymakers and health managers should take these experiences into account in plans to mitigate the impact of future pandemics.

The surge of bromazolam-related fatalities replacing other novel designer benzodiazepines-related fatalities in San Francisco.

BACKGROUND AND AIM: Bromazolam, a novel designer benzodiazepine (NBD), exhibits potent sedative, hypnotic and anxiolytic effects, raising concerns regarding its potential for misuse and fatal outcomes, particularly when combined with opioids such as fentanyl. Despite limited documented fatalities globally, its use poses a significant threat, exacerbated by under-reporting and a lack of routine testing. This study analysed NBD-related deaths in a major US city over a 4-year period. METHODS: Analysis of accidental overdose deaths involving NBDs in San Francisco, CA, USA from 2020 to 2023, was performed utilizing medico-legal death investigations including comprehensive forensic toxicology, pathology and demographic information. San Francisco conducts thorough investigations into all non-natural and sudden unexpected deaths, including routine alcohol and drug testing of decedents under its jurisdiction, including etizolam, flualprazolam, flubromazolam and bromazolam analysis. RESULTS: There was a sudden surge in bromazolam-related deaths, with 44 fatalities documented in 2023, contrasting with relatively fewer deaths related to other NBDs. Bromazolam fatalities frequently involved co-ingestion with opioids, primarily fentanyl, and stimulants such as methamphetamine and cocaine. Demographic characteristics indicated a predominance of males, with a significant proportion lacking fixed addresses. Blood concentrations of bromazolam increased during the study period, suggesting heightened availability and/or purity in the community. CONCLUSION: There was a surge in bromazolam-related deaths during 2023 in San Francisco, CA, USA, contrasting with relatively stable numbers of deaths associated with other NBDs over the preceding years. The findings underscore the urgency for enhanced death investigation, testing and reporting to facilitate targeted harm reduction strategies for individuals at risk of bromazolam-related morbidity and mortality.

Barriers and Opportunities for WHO "Best Buys" Non-communicable Disease Policy Adoption and Implementation From a Political Economy Perspective: A Complexity Systematic Review.

BACKGROUND: Improving the adoption and implementation of policies to curb non-communicable diseases (NCDs) is a major challenge for better global health. The adoption and implementation of such policies remain deficient in various contexts, with limited insights into the facilitating and inhibiting factors. These policies have traditionally been treated as technical solutions, neglecting the critical influence of political economy dynamics. Moreover, the complex nature of these interventions is often not adequately incorporated into evidence for policy-makers. This study aims to systematically review and evaluate the factors affecting NCD policy adoption and implementation. METHODS: We conducted a complex systematic review of articles discussing the adoption and implementation of World Health Organization's (WHO's) "best buys" NCD policies. We identified political economy factors and constructed a causal loop diagram (CLD) program theory to elucidate the interplay between factors influencing NCD policy adoption and implementation. A total of 157 papers met the inclusion criteria. RESULTS: Our CLD highlights a central feedback loop encompassing three vital variables: (1) the ability to define, (re)shape, and pass appropriate policy into law; (2) the ability to implement the policy (linked to the enforceability of the policy and to addressing NCD local burden); and (3) ability to monitor progress, evaluate and correct the course. Insufficient context-specific data impedes the formulation and enactment of suitable policies, particularly in areas facing multiple disease burdens. Multisectoral collaboration plays a pivotal role in both policy adoption and implementation. Effective monitoring and accountability systems significantly impact policy implementation. The commercial determinants of health (CDoH) serve as a major barrier to defining, adopting, and implementing tobacco, alcohol, and diet-related policies. CONCLUSION: To advance global efforts, we recommend focusing on the development of robust accountability, monitoring, and evaluation systems, ensuring transparency in private sector engagement, supporting context-specific data collection, and effectively managing the CDoH. A system thinking approach can enhance the implementation of complex public health interventions.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P=0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG in both adipocyte differentiation and placental angiogenesis. NOS3, NRK, and ADAMTS8 (fetal and maternal-acting) have been implicated in both placental function and hypertension. Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors.

Mutant FOXO1 controls an oncogenic network via enhancer accessibility.

Transcriptional dysregulation is a hallmark of diffuse large B cell lymphoma (DLBCL), as transcriptional regulators are frequently mutated. However, our mechanistic understanding of how normal transcriptional programs are co-opted in DLBCL has been hindered by a lack of methodologies that provide the temporal resolution required to separate direct and indirect effects on transcriptional control. We applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated (mFOXO1) in DLBCL. The combination of rapid degradation of mFOXO1, nascent transcript detection, and assessment of chromatin accessibility allowed us to identify the direct targets of mFOXO1. mFOXO1 was required to maintain accessibility at specific enhancers associated with multiple oncogenes, and mFOXO1 degradation impaired RNA polymerase pause-release at some targets. Wild-type FOXO1 appeared to weakly regulate many of the same targets as mFOXO1 and was able to complement the degradation of mFOXO1 in the context of AKT inhibition.

A genetic screen identifies a role for oprF in Pseudomonas aeruginosa biofilm stimulation by subinhibitory antibiotics.

Biofilms are surface-associated communities of bacteria that grow in a self-produced matrix of polysaccharides, proteins, and extracellular DNA (eDNA). Sub-minimal inhibitory concentrations (sub-MIC) of antibiotics induce biofilm formation, potentially as a defensive response to antibiotic stress. However, the mechanisms behind sub-MIC antibiotic-induced biofilm formation are unclear. We show that treatment of Pseudomonas aeruginosa with multiple classes of sub-MIC antibiotics with distinct targets induces biofilm formation. Further, addition of exogenous eDNA or cell lysate failed to increase biofilm formation to the same extent as antibiotics, suggesting that the release of cellular contents by antibiotic-driven bacteriolysis is insufficient. Using a genetic screen for stimulation-deficient mutants, we identified the outer membrane porin OprF and the ECF sigma factor SigX as important. Similarly, loss of OmpA - the Escherichia coli OprF homolog - prevented sub-MIC antibiotic stimulation of E. coli biofilms. Our screen also identified the periplasmic disulfide bond-forming enzyme DsbA and a predicted cyclic-di-GMP phosphodiesterase encoded by PA2200 as essential for biofilm stimulation. The phosphodiesterase activity of PA2200 is likely controlled by a disulfide bond in its regulatory domain, and folding of OprF is influenced by disulfide bond formation, connecting the mutant phenotypes. Addition of reducing agent dithiothreitol prevented sub-MIC antibiotic biofilm stimulation. Finally, activation of a c-di-GMP-responsive promoter follows treatment with sub-MIC antibiotics in the wild-type but not an oprF mutant. Together, these results show that antibiotic-induced biofilm formation is likely driven by a signaling pathway that translates changes in periplasmic redox state into elevated biofilm formation through increases in c-di-GMP.

Multisectoral action to address noncommunicable diseases: lessons from three country case studies.

Introduction: Multisectoral action is a central component of the global response to the rising prevalence of non-communicable diseases (NCDs). In this paper we aimed to unpack the definition of multisectoral action and provide an overview of the historical context, challenges, and recommendations alongside three country case studies: salt reduction in the UK, tobacco legislation in Nigeria, and regulation of edible oils in Iran. Methods: We used an iterative review process to select three country case studies from a list of 20 potential cases previously identified by WHO. At our third round of review we unanimously agreed to focus on salt reduction in the UK, tobacco regulation in Nigeria, and edible oil regulation in Iran as these represented rich cases on diverse risk factors from three different world regions that we felt offered important lessons. We conducted literature reviews to identify further data for each case study. Results: Across the three studies a number of important themes emerged. We found that multisectoral approaches demand the often difficult reconciliation of competing and conflicting values and priorities. Across our three chosen cases, commercial interests and free trade agreements were the most common obstacles to successful multisectoral strategies. We found that early consultative stakeholder engagement and strong political and bureaucratic leadership were necessary for success. Discussion: The complex multi-rooted nature of NCDs requires a multisectoral approach, but the inevitable conflicts that this entails requires careful navigation.

Analysis of over 250 novel synthetic opioids and xylazine by LC-MS-MS in blood and urine.

Novel Synthetic Opioids (NSO) are frequently found in postmortem (PM) and human performance (HP) forensic toxicology casework, resulting in impairment and fatal overdoses. Developing a broad NSO method benefits public health, as it can be used to identify trends in potent opioid use to develop risk management programs. This project aimed to design a comprehensive, rapid and routine method for the selective analysis of over 250 novel synthetic opioids in blood and urine. This method rapidly extracted 150 µL of blood or urine via protein precipitation followed by size-exclusion filtration, evaporation and reconstitution. Separation and data acquisition were achieved on a 12 min LC-MS-MS method using an F5 column. Data processing was expedited with a custom built-in query created in-house that automated processing and enhanced quality assurance. Validation according to ASB/ANSI Standard 036 was performed and applicability of the method was assessed using proficiency test and authentic casework samples. Assessed in blood and urine qualitatively were 261 unique analytes including fentanyl analogs (fentalogs), nitazenes and other miscellaneous synthetic opioids. As 59 isomeric target analytes were placed into groups due to co-elution, there were 202 distinct acquired targets or target - groups. To demonstrate applicability, 27 proficiency test blood samples received over an approximate 4-year period were analyzed with 126 expected results assessed comprising 25 unique target analytes. Additionally, 617 fatal accidental overdoses within San Francisco in 2022 were retroactively analyzed by this method with almost 10% of cases containing a new NSO substance(s). Such trends and NSO substances were previously unknown in this community.

Atomic Defect Quantification by Lateral Force Microscopy.

Atomic defects in two-dimensional (2D) materials impact electronic and optoelectronic properties, such as doping and single photon emission. An understanding of defect-property relationships is essential for optimizing material performance. However, progress in understanding these critical relationships is hindered by a lack of straightforward approaches for accurate, precise, and reliable defect quantification on the nanoscale, especially for insulating materials. Here, we demonstrate that lateral force microscopy (LFM), a mechanical technique, can observe atomic defects in semiconducting and insulating 2D materials under ambient conditions. We first improve the sensitivity of LFM through consideration of cantilever mechanics. With the improved sensitivity, we use LFM to locate atomic-scale point defects on the surface of bulk MoSe2. By directly comparing LFM and conductive atomic force microscopy (CAFM) measurements on bulk MoSe2, we demonstrate that point defects observed with LFM are atomic defects in the crystal. As a mechanical technique, LFM does not require a conductive pathway, which allows defect characterization on insulating materials, such as hexagonal boron nitride (hBN). We demonstrate the ability to observe intrinsic defects in hBN and defects introduced by annealing. Our demonstration of LFM as a mechanical defect characterization technique applicable to both conductive and insulating 2D materials will enable routine defect-property determination and accelerate materials research.

Sex Differences in Sympathetic Responses to Lower-Body Negative Pressure.

INTRODUCTION: Trauma-induced hemorrhage is a leading cause of death in prehospital settings. Experimental data demonstrate that females have a lower tolerance to simulated hemorrhage (i.e., central hypovolemia). However, the mechanism(s) underpinning these responses are unknown. Therefore, this study aimed to compare autonomic cardiovascular responses during central hypovolemia between the sexes. We hypothesized that females would have a lower tolerance and smaller increase in muscle sympathetic nerve activity (MSNA) to simulated hemorrhage. METHODS: Data from 17 females and 19 males, aged 19-45 yr, were retrospectively analyzed. Participants completed a progressive lower-body negative pressure (LBNP) protocol to presyncope to simulate hemorrhagic tolerance with continuous measures of MSNA and beat-to-beat hemodynamic variables. We compared responses at baseline, at two LBNP stages (-40 and -50 mmHg), and at immediately before presyncope. In addition, we compared responses at relative percentages (33%, 66%, and 100%) of hemorrhagic tolerance, calculated via the cumulative stress index (i.e., the sum of the product of time and pressure at each LBNP stage). RESULTS: Females had lower tolerance to central hypovolemia (female: 561 ± 309 vs male: 894 ± 304 min·mmHg [time·LBNP]; P = 0.003). At LBNP -40 and -50 mmHg, females had lower diastolic blood pressures (main effect of sex: P = 0.010). For the relative LBNP analysis, females exhibited lower MSNA burst frequency (main effect of sex: P = 0.016) accompanied by a lower total vascular conductance (sex: P = 0.028; main effect of sex). CONCLUSIONS: Females have a lower tolerance to central hypovolemia, which was accompanied by lower diastolic blood pressure at -40 and -50 mmHg LBNP. Notably, females had attenuated MSNA responses when assessed as relative LBNP tolerance time.

Spontaneous exciton dissociation in transition metal dichalcogenide monolayers.

Since the seminal work on MoS2, photoexcitation in atomically thin transition metal dichalcogenides (TMDCs) has been assumed to result in excitons, with binding energies order of magnitude larger than thermal energy at room temperature. Here, we reexamine this foundational assumption and show that photoexcitation of TMDC monolayers can result in a substantial population of free charges. Performing ultrafast terahertz spectroscopy on large-area, single-crystal TMDC monolayers, we find that up to ~10% of excitons spontaneously dissociate into charge carriers with lifetimes exceeding 0.2 ns. Scanning tunneling microscopy reveals that photocarrier generation is intimately related to mid-gap defects, likely via trap-mediated Auger scattering. Only in state-of-the-art quality monolayers, with mid-gap trap densities as low as 109 cm-2, does intrinsic exciton physics start to dominate the terahertz response. Our findings reveal the necessity of knowing the defect density in understanding photophysics of TMDCs.

NF1 deficiency drives metabolic reprogramming in ER+ breast cancer.

OBJECTIVE: NF1 is a tumor suppressor gene and its protein product, neurofibromin, is a negative regulator of the RAS pathway. NF1 is one of the top driver mutations in sporadic breast cancer such that 27 % of breast cancers exhibit damaging NF1 alterations. NF1 loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)+ breast cancer metastasis and endocrine resistance. Individuals with Neurofibromatosis type 1 (NF) - a disorder caused by germline NF1 mutations - have an increased risk of dying from breast cancer [1-4]. NF-related breast cancers are associated with decreased overall survival compared to sporadic breast cancer. Despite numerous studies interrogating the role of RAS mutations in tumor metabolism, no study has comprehensively profiled the NF1-deficient breast cancer metabolome to define patterns of energetic and metabolic reprogramming. The goals of this investigation were (1) to define the role of NF1 deficiency in estrogen receptor-positive (ER+) breast cancer metabolic reprogramming and (2) to identify potential targeted pathway and metabolic inhibitor combination therapies for NF1-deficient ER + breast cancer. METHODS: We employed two ER+ NF1-deficient breast cancer models: (1) an NF1-deficient MCF7 breast cancer cell line to model sporadic breast cancer, and (2) three distinct, Nf1-deficient rat models to model NF-related breast cancer [1]. IncuCyte proliferation analysis was used to measure the effect of NF1 deficiency on cell proliferation and drug response. Protein quantity was assessed by Western Blot analysis. We then used RNAseq to investigate the transcriptional effect of NF1 deficiency on global and metabolism-related transcription. We measured cellular energetics using Agilent Seahorse XF-96 Glyco Stress Test and Mito Stress Test assays. We performed stable isotope labeling and measured [U-13C]-glucose and [U-13C]-glutamine metabolite incorporation and measured total metabolite pools using mass spectrometry. Lastly, we used a Bliss synergy model to investigate NF1-driven changes in targeted and metabolic inhibitor synergy. RESULTS: Our results revealed that NF1 deficiency enhanced cell proliferation, altered neurofibromin expression, and increased RAS and PI3K/AKT pathway signaling while constraining oxidative ATP production and restricting energetic flexibility. Neurofibromin deficiency also increased glutamine influx into TCA intermediates and dramatically increased lipid pools, especially triglycerides (TG). Lastly, NF1 deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis. CONCLUSIONS: NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies.

Burn size and environmental conditions modify thermoregulatory responses to exercise in burn survivors.

This project tested the hypothesis that burn survivors can perform mild/moderate-intensity exercise in temperate and hot environments without excessive elevations in core body temperature. Burn survivors with low (23 ± 5%TBSA; N = 11), moderate (40 ± 5%TBSA; N = 9), and high (60 ± 8%TBSA; N = 9) burn injuries performed 60 minutes of cycle ergometry exercise (72 ± 15 watts) in a 25°C and 23% relative humidity environment (ie, temperate) and in a 40°C and 21% relative humidity environment (ie, hot). Absolute gastrointestinal temperatures (TGI) and changes in TGI (ΔTGI) were obtained. Participants with an absolute TGI of >38.5°C and/or a ΔTGI of >1.5°C were categorized as being at risk for hyperthermia. For the temperate environment, exercise increased ΔTGI in all groups (low: 0.72 ± 0.21°C, moderate: 0.42 ± 0.22°C, and high: 0.77 ± 0.25°C; all P < .01 from pre-exercise baselines), resulting in similar absolute end-exercise TGI values (P = .19). Importantly, no participant was categorized as being at risk for hyperthermia, based upon the aforementioned criteria. For the hot environment, ΔTGI at the end of the exercise bout was greater for the high group when compared to the low group (P = .049). Notably, 33% of the moderate cohort and 56% of the high cohort reached or exceeded a core temperature of 38.5°C, while none in the low cohort exceeded this threshold. These data suggest that individuals with a substantial %TBSA burned can perform mild/moderate intensity exercise for 60 minutes in temperate environmental conditions without risk of excessive elevations in TGI. Conversely, the risk of excessive elevations in TGI during mild/moderate intensity exercise in a hot environment increases with the %TBSA burned.

Exertional Heat Stroke Survival at the Falmouth Road Race: 180 New Cases With Expanded Analysis.

CONTEXT: A high number of exertional heat stroke (EHS) cases occur during the Falmouth Road Race. OBJECTIVES: To extend previous analyses of EHS cases during the Falmouth Road Race by assessing or describing (1) EHS and heat exhaustion (HE) incidence rates, (2) EHS outcomes as they relate to survival, (3) the effect of the environment on these outcomes, and (4) how this influences medical provider planning and preparedness. DESIGN: Descriptive epidemiologic study. SETTING: Falmouth Road Race. PATIENTS OR OTHER PARTICIPANTS: Patients with EHS or HE admitted to the medical tent. MAIN OUTCOME MEASURE(S): We obtained 8 years (2012 to 2019) of Falmouth Road Race anonymous EHS and HE medical records. Meteorologic data were collected and analyzed to evaluate the effect of environmental conditions on the heat illness incidence (exertional heat illness [EHI] = EHS + HE). The EHS treatment and outcomes (ie, cooling time, survival, and discharge outcome), number of HE patients, and wet bulb globe temperature (WBGT) for each race were analyzed. RESULTS: A total of 180 EHS and 239 HE cases were identified. Overall incidence rates per 1000 participants were 2.07 for EHS and 2.76 for HE. The EHI incidence rate was 4.83 per 1000 participants. Of the 180 EHS cases, 100% survived, and 20% were transported to the emergency department. The WBGT was strongly correlated with the incidence of both EHS (r2 = 0.904, P = .026) and EHI (r2 = 0.912, P = .023). CONCLUSIONS: This is the second-largest civilian database of EHS cases reported. When combined with the previous dataset of EHS survivors from this race, it amounts to 454 EHS cases resulting in 100% survival. The WBGT remained a strong predictor of EHS and EHI cases. These findings support 100% survival from EHS when patients over a wide range of ages and sexes are treated with cold-water immersion.

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.