Structural basis of respiratory complex adaptation to cold temperatures.

In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ∼25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.

Characterizing visual processing deficits in cerebral adrenoleukodystrophy.

BACKGROUND AND OBJECTIVES: Cerebral adrenoleukodystrophy (CALD) can cause visual impairment, but early symptoms are often missed or misdiagnosed. The framework of cerebral visual impairment (CVI) distinguishes deficits in sensory detection ("lower order") from those of perception and interpretation ("higher order"). This study describes visual deficits in patients with CALD and higher order visual function assessed with a virtual reality (VR) interface combined with eye tracking. METHODS: A retrospective medical record review assessed the prevalence of visual deficits in patients with CALD, as well as lesion burden on brain MRI using the Loes MRI severity score. A VR-based task measured visual spatial processing performance in participants with CALD and controls. RESULTS: Out of 89 CALD patients, 69 % had at least one sign or symptom of visual impairment. Lower order deficits were seen in 56 % of patients, and higher order deficits were seen in 59 % of patients who underwent neuropsychological testing. Even in early stage disease (Loes MRI severity score ≤ 3), visual impairment was present in more than half of patients (58 %). On prospective VR-based assessment, the CALD group (n = 30) had impaired visual search performance (lower success rate and longer reaction time) compared with controls (n = 38). In both groups, there was a trend of worsening performance with increasing task difficulty. DISCUSSION: Higher order visual deficits, not just impairment of visual acuity, visual fields, or oculomotor function, are common in all stages of CALD. Beyond neuropsychological testing, VR-based functional testing allows for quantitative assessment of higher order visual perceptual deficits that are relevant to everyday tasks and may serve as an important marker of neurological decline.

Preventive Health Services Offered in a Sampling of US Emergency Departments, 2022-2023.

Introduction: In the United States, more chronic and preventive healthcare is being delivered in the emergency department (ED) setting. Understanding the availability of preventive health services in the ED setting is crucial. Our goal was to understand the availability of a subset of preventive health services in US EDs and explore how that has changed over time. Methods: In 2022-2023, using the National Emergency Department Inventory (NEDI)-USA, we surveyed a random 20% (1,064) sampling of all 5,613 US EDs. We asked directors of these EDs about the availability of and preference for 12 preventive health services, social worker availability, self-reported percentage of uninsured ED patients, and measures of ED crowding. We also asked about perceptions of barriers to implementing preventive health services in the ED. We used unadjusted and multivariable logistic regression models to compare service frequency in 2022-2023 to prior findings from 2008-2009 that represented a 5.7% random sampling of all EDs. Results: Among 302 responders to the 2022-2023 survey (5.4% random sampling, 28.4% response rate), 94% reported offering at least one preventive health service, with a median of five services. The most common service offered was intimate partner violence screening (83%), while the least common was routine HIV screening (19%). Seven services (eg, intimate partner violence, alcohol risk, and smoking cessation screening) had a higher odds of being offered in 2022-2023 than in 2008-2009; findings were unchanged in sensitivity analyses. A small proportion of directors opposed offering preventive health services. However, many expressed concerns that preventive health services in the ED would lead to longer lengths of stay (56%), increased costs to their ED (58%), a diversion of staff time from providing acute care (50%), or that their patients would not have access to adequate follow-up (49%). Conclusion: Nearly all EDs offer at least one preventive health service. Many offer multiple services; rates were higher than those identified in 2008-2009, in both unadjusted and multivariable models. Although limited by the response rate, this work provides the most recent and comprehensive snapshot of the type and frequency of a subset of preventive health services currently offered in US EDs.

Persistent elevation in incidence of pneumonia in children in England, 2023/24.

Since November 2023, the absolute number of attendances at emergency departments for pneumonia among children aged 5-14 years in England have been above expected levels for the time of year. This increased signal peaked during March 2024 but then persisted into early summer 2024 despite decreases in prevalence of seasonal respiratory pathogens. Record linkage between emergency department and laboratory databases points to this unusual activity being driven largely by Mycoplasma pneumoniae.

Reliability of Continuous Noninvasive Hemoglobin Monitoring in Healthy Participants During En Route Care Training.

INTRODUCTION: Current standards for hemoglobin monitoring during air transports of U.S. combat wounded are invasive and intermittent. Fielded pulse co-oximeters can noninvasively measure total hemoglobin, but this parameter is not currently utilized. The primary objective of this study was to assess the percentage of vital sign measurements with successful capture of total noninvasive hemoglobin measurement using spectrophotometry-based technology for Hb (SpHb) measurements in healthy participants during training flights. Secondary objectives were to assess the feasibility of a novel electronic data capture mechanism from usual patient movement items and perform a pilot analysis of SpHb changes in healthy participants during transitions from ground to air transport. METHODS: We conducted a feasibility study enrolling healthy participants who had hemodynamic monitoring during usual U.S. Air Force Critical Care Air Transport (CCAT) flight training exercises from 2022 to 2023. Usual CCAT monitoring equipment and currently used Masimo Rainbow® pulse co-oximeters had the capability to measure SpHb. After each training exercise, the study team wirelessly downloaded case files from patient monitors utilizing the Battlefield Assisted Trauma Distributed Observation Kit (BATDOKTM) Case Downloader application. We then calculated point and precision estimates for the percentage of time for successful SpHb capture during the exercise and compared this to pulse oximetry (SpO2) capture. An a priori precision analysis for percentage of flight-time with successful SpHb data capture and descriptive statistics were performed. This study received Exempt Determination by the 59th Medical Wing IRB. RESULTS: We analyzed 26 records with mean monitoring durations of 94.5 [59.3-119.9] minutes during ground phases and 78.0 [59.9-106.5] minutes during flight phases. SpHb measures were successfully captured for 97.7% (n = 4,620) of possible ground measurements and 97.2% (n = 3,973) of possible in-flight measurements compared to 99.5% ground and 98.2% in-flight capture for SpO2. Mean intervals of missing SpHb data were 2 ± 5 minutes on the ground and 4 ± 6 minutes in-flight. Mean SpHb increased by 0.93 ± 0.96 g/dL during the ground phase, but had minimal changes during ascent, cruising altitude or descent. The BATDOKTM Case downloader completed transfer for all files. CONCLUSION: Masimo Rainbow® SpHb pulse co-oximeters reliably captured continuous, noninvasive hemoglobin measurements using usual CCAT patient movement items in healthy participants during both ground and flight training. The BATDOKTM Case Downloader successfully imported case files from CCAT patient monitors. Mean SpHb measures had a small increase during the ground phase of monitoring followed by minimal changes when transitioning to flight altitude.

Exogenous photocatalyst-free aryl radical generation from diaryliodonium salts and use in metal-catalyzed C-H arylation.

We demonstrate (1) detectable halogen bonding is not critical for enabling light-driven radical generation from diaryliodonium salts and (2) radicals generated by this route can be captured by transition-metals for C-H arylation reactions. These results are the first step toward developing new metal-catalyzed aryl radical couplings without exogenous photocatalysts.

Estimating the size and scope of the academic emergency physician workforce.

BACKGROUND: Academic emergency medicine (EM) is foundational to the EM specialty through the development of new knowledge and clinical training of resident physicians. Despite recent increased attention to the future of the EM workforce, no evaluations have specifically characterized the U.S. academic EM workforce. We sought to estimate the national proportion of emergency physicians (EPs) identified as academic and the proportion of emergency department (ED) visits that take place at academic sites. METHODS: We performed a cross-sectional analysis of EPs and EDs using data from the American Hospital Association, the Centers for Medicare & Medicaid Services, and Doximity's Residency Navigator. EPs were identified as "academic" if they were affiliated with at least one facility determined to be academic, defined as EDs officially designated by the Accreditation Council for Graduate Medical Education (ACGME) as clinical training sites at accredited EM residency programs. Our primary outcomes were to estimate the national proportion of EPs identified as academic and the proportion of ED visits performed at academic sites. RESULTS: Our analytic sample included 26,937 EPs practicing clinically across 4920 EDs and providing care during 130,471,386 ED visits. Among EPs, 11,720 (43.5%) were identified as academic, and among EDs, 635 (12.9%) were identified as academic sites, including 585 adult/general sites, 45 pediatric-specific sites, and 10 sites affiliated with the Department of Veterans Affairs. In 2021, academic EDs provided care for 42,794,106 ED visits or 32.8% of all ED visits nationally. CONCLUSIONS: Approximately four in 10 EPs practice in at least one clinical training site affiliated with an ACGME-accredited EM residency program, and approximately one in three ED visits nationally occur in these academic EDs. We encourage further work using alternative definitions of an academic EPs and EDs, along with longitudinal research to identify trends in the workforce's composition.

HIV testing at visits to US emergency departments: 2021 update.

In this updated cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey, we found that among the 2.5 million more weighted emergency department (ED) visits in 2021 compared with 2020, there was an insignificant increase in HIV testing per ED visit in 2021 compared with 2020 (0.81% to 0.86%). This suggests HIV testing during ED visits did not increase in line with rebounding visit volumes after the pandemic nadir.

Metabolite profiles of medulloblastoma for rapid and non-invasive detection of molecular disease groups.

BACKGROUND: The malignant childhood brain tumour, medulloblastoma, is classified clinically into molecular groups which guide therapy. DNA-methylation profiling is the current classification 'gold-standard', typically delivered 3-4 weeks post-surgery. Pre-surgery non-invasive diagnostics thus offer significant potential to improve early diagnosis and clinical management. Here, we determine tumour metabolite profiles of the four medulloblastoma groups, assess their diagnostic utility using tumour tissue and potential for non-invasive diagnosis using in vivo magnetic resonance spectroscopy (MRS). METHODS: Metabolite profiles were acquired by high-resolution magic-angle spinning NMR spectroscopy (MAS) from 86 medulloblastomas (from 59 male and 27 female patients), previously classified by DNA-methylation array (WNT (n = 9), SHH (n = 22), Group3 (n = 21), Group4 (n = 34)); RNA-seq data was available for sixty. Unsupervised class-discovery was performed and a support vector machine (SVM) constructed to assess diagnostic performance. The SVM classifier was adapted to use only metabolites (n = 10) routinely quantified from in vivo MRS data, and re-tested. Glutamate was assessed as a predictor of overall survival. FINDINGS: Group-specific metabolite profiles were identified; tumours clustered with good concordance to their reference molecular group (93%). GABA was only detected in WNT, taurine was low in SHH and lipids were high in Group3. The tissue-based metabolite SVM classifier had a cross-validated accuracy of 89% (100% for WNT) and, adapted to use metabolites routinely quantified in vivo, gave a combined classification accuracy of 90% for SHH, Group3 and Group4. Glutamate predicted survival after incorporating known risk-factors (HR = 3.39, 95% CI 1.4-8.1, p = 0.025). INTERPRETATION: Tissue metabolite profiles characterise medulloblastoma molecular groups. Their combination with machine learning can aid rapid diagnosis from tissue and potentially in vivo. Specific metabolites provide important information; GABA identifying WNT and glutamate conferring poor prognosis. FUNDING: Children with Cancer UK, Cancer Research UK, Children's Cancer North and a Newcastle University PhD studentship.

Structural basis of respiratory complexes adaptation to cold temperatures.

In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain (1, 2). Yet, the structural basis of respiratory complex adaptation to cold remains elusive. Herein we combined thermoregulatory physiology and cryo-EM to study endogenous respiratory supercomplexes exposed to different temperatures. A cold-induced conformation of CI:III 2 (termed type 2) was identified with a ∼25° rotation of CIII 2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting different catalytic states which favor electron transfer. Large-scale supercomplex simulations in lipid membrane reveal how unique lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations and biochemical analyses unveil the mechanisms and dynamics of respiratory adaptation at the structural and energetic level.

Estimates of HIV testing at visits to United States emergency departments.

OBJECTIVES: Emergency department-based HIV testing rates are historically low, but recent testing trends surrounding the COVID-19 pandemic and launch of the Ending the HIV Epidemic (EHE) initiative are unknown. The objective of the study is to estimate recent trends in the proportion of emergency department visits that included HIV testing. METHODS: We performed a cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey (NHAMCS), a weighted nationally representative survey of US emergency departments, from 2014 to 2020. Given EHE's focus on several rural Southern jurisdictions as well as populations disproportionately affected by HIV, we stratified by characteristics including US region and visit-listed race and ethnicity. RESULTS: The proportion of emergency department visits that included HIV testing increased from 2014 (0.6%) to 2018 (1.1%) but was lower in 2019 and 2020 (0.8%). Compared with other regions, the South had the lowest rates of testing in both 2019 (0.6%) and 2020 (0.5%); testing rates in the nonmetropolitan South remained 0.1% or less across all years. Testing rates for emergency department visits by persons who identified as Hispanic/Latino were highest in 2018 (2.2%) but were sharply lower in 2019 and 2020 (0.8%). CONCLUSION: After a small but insufficient increase in emergency department-based HIV testing since 2014, rates decreased between 2018 and 2019 and were stable between 2019 and 2020. Overall, very few emergency department visits during our entire study period included an HIV test, and there were persistently low rates of HIV testing for populations prioritized in national efforts and during visits in rural jurisdictions in the South.

Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.

Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.

Comparison of US emergency departments by HIV priority jurisdiction designation: A case for geographically targeted screening in teaching hospitals.

The Ending the HIV Epidemic (EHE) Initiative targets a subset of United States (US) priority jurisdictions hardest hit by HIV. It remains unclear which emergency departments (EDs) are the most appropriate targets for EHE-related efforts. To explore this, we used the 2001-2019 National Emergency Department Inventories (NEDI)-USA as a framework to characterize all US EDs, focusing on those in priority jurisdictions and those affiliated with a teaching hospital. We then incorporate multivariable regression to explore the association between ED characteristics and location in an HIV priority jurisdiction. Further, to provide context on the communities these EDs serve, demographic and socioeconomic information and sexually transmitted infection case rate data were included. This reflected 2019 US Census Bureau data on age, race, ethnicity, and proportion uninsured and living in poverty along with 2001-2019 Centers for Disease Control and Prevention case rate data on chlamydia, gonorrhea, and syphilis. We found that EDs in priority jurisdictions (compared to EDs not in priority jurisdictions) more often served populations emphasized in HIV-related efforts (i.e., Black or African American or Hispanic or Latino populations), communities with higher proportions uninsured and living in poverty, and counties with higher rates of chlamydia, gonorrhea, and syphilis. Further, of the groups studied, EDs with teaching hospital affiliations had the highest visit volumes and had steady visit volume growth. In regression, ED annual visit volume was associated with an increased odds of an ED being located in a priority jurisdiction. Our results suggest that geographically targeted screening for HIV in a subset of US priority jurisdiction EDs with a teaching hospital affiliation could be an efficient means to reach vulnerable populations and reduce the burden of undiagnosed HIV in the US.

Altered neural oscillations underlying visuospatial processing in cerebral visual impairment.

Visuospatial processing deficits are commonly observed in individuals with cerebral visual impairment, even in cases where visual acuity and visual field functions are intact. Cerebral visual impairment is a brain-based visual disorder associated with the maldevelopment of central visual pathways and structures. However, the neurophysiological basis underlying higher-order perceptual impairments in this condition has not been clearly identified, which in turn poses limits on developing rehabilitative interventions. Using combined eye tracking and EEG recordings, we assessed the profile and performance of visual search on a naturalistic virtual reality-based task. Participants with cerebral visual impairment and controls with neurotypical development were instructed to search, locate and fixate on a specific target placed among surrounding distractors at two levels of task difficulty. We analysed evoked (phase-locked) and induced (non-phase-locked) components of broadband (4-55 Hz) neural oscillations to uncover the neurophysiological basis of visuospatial processing. We found that visual search performance in cerebral visual impairment was impaired compared to controls (as indexed by outcomes of success rate, reaction time and gaze error). Analysis of neural oscillations revealed markedly reduced early-onset evoked theta [4-6 Hz] activity (within 0.5 s) regardless of task difficulty. Moreover, while induced alpha activity increased with task difficulty in controls, this modulation was absent in the cerebral visual impairment group identifying a potential neural correlate related to deficits with visual search and distractor suppression. Finally, cerebral visual impairment participants also showed a sustained induced gamma response [30-45 Hz]. We conclude that impaired visual search performance in cerebral visual impairment is associated with substantial alterations across a wide range of neural oscillation frequencies. This includes both evoked and induced components suggesting the involvement of feedforward and feedback processing as well as local and distributed levels of neural processing.

Evaluation of CI electrode position from imaging: comparison of an automated technique with the established manual method.

BACKGROUND: A manual evaluation of the CI electrode position from CT and DVT scans may be affected by diagnostic errors due to cognitive biases. The aim of this study was to compare the CI electrode localization using an automated method (image-guided cochlear implant programming, IGCIP) with the clinically established manual method. METHODS: This prospective experimental study was conducted on a dataset comprising N=50 subjects undergoing cochlear implantation with a Nucleus® CI532 or CI632 Slim Modiolar electrode. Scalar localization, electrode-to-modiolar axis distances (EMD) and angular insertion depth (aDOI) were compared between the automated IGCIP tool and the manual method. Two raters made the manual measurements, and the interrater reliability (±1.96·SD) was determined as the reference for the method comparison. The method comparison was performed using a correlation analysis and a Bland-Altman analysis. RESULTS: Concerning the scalar localization, all electrodes were localized both manually and automatically in the scala tympani. The interrater differences ranged between ±0.2 mm (EMD) and ±10° (aDOI). There was a bias between the automatic and manual method in measuring both localization parameters, which on the one hand was smaller than the interrater variations. On the other hand, this bias depended on the magnitude of the EMD respectively aDOI. A post-hoc analysis revealed that the deviations between the methods were likely due to a different selection of mid-modiolar axis. CONCLUSIONS: The IGCIP is a promising tool for automated processing of CT and DVT scans and has useful functionality such as being able to segment the cochlear using post-operative scans. When measuring EMD, the IGCIP tool is superior to the manual method because the smallest possible distance to the axis is determined depending on the cochlear turn, whereas the manual method selects the helicotrema as the reference point rigidly. Functionality to deal with motion artifacts and measurements of aDOI according to the consensus approach are necessary, otherwise the IGCIP is not unrestrictedly ready for clinical use.

Unfilled in emergency medicine: An analysis of the 2022 and 2023 Match by program accreditation, ownership, and geography.

Background: The two most recent National Resident Matching Program (NRMP) Match cycles saw a high number of initially unfilled emergency medicine (EM) residency positions. We sought to identify the risk of EM residency program characteristics including accreditation duration, primary clinical site ownership status, and geography pertaining to not initially filling all positions. Methods: We performed a repeated cross-sectional observational study of EM residency programs participating in the 2022 and 2023 NRMP Match cycles and used publicly available data from the NRMP, the Accreditation Council for Graduate Medical Education, the Centers for Medicare & Medicaid Services, and the U.S. Department of Housing and Urban Development. Our primary outcome was the proportion of EM residency programs that did not initially fill positions, with analyses stratified by accreditation duration (>5 or ≤5 years), primary clinical site ownership status, and geographic core-based statistical areas (CBSAs). Results: A total of 219 of 2921 (7.5%) positions in the 2022 Match and 554 of 3010 (18.4%) positions in the 2023 Match were initially unfilled. Over the 2-year period, EM residency programs accredited within the past 5 years had more than double the risk (relative risk [RR] 2.08, 95% confidence interval [CI] 1.69-2.57, chi-square p < 0.001) of not filling all positions compared to those accredited more than 5 years previously. EM residency programs with a primary clinical site under for-profit ownership had a 50% greater risk of not filling all positions when compared to those under nonprofit or governmental ownership (RR 1.50, 95% CI 1.14-1.98, chi-square p = 0.009). In 2023, several CBSAs had a high number of both offered and unfilled positions. Conclusions: EM residency programs accredited within the past 5 years or those with a primary clinical site under for-profit ownership had a greater risk of not filling all positions within the past two Match cycles.

Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.

Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.