Women and girls' participation in haemophilia clinical trials.

KEY POINTS: women and girls were infrequently represented in haemophilia clinical trials intentional recruitment strategies are needed for haemophilia trials to be more inclusive of women and girls.

Predictors of Health in Substance Use Disorder Recovery: Economic Stability in Residential Aftercare Environments.

The exit from active substance use presents barriers to achieving and maintaining health, especially as individuals lack the economic resources to afford healthcare access. Treatment settings that strengthen resources may support stability in recovery and influence health. Analyzing a sample of recovery home residents over two years (N = 494), the current study assessed individually held resources (e.g., wages, employment) and the average economic conditions of a resident's house (e.g., house employment rate) to understand their association with self-reported health status. Employment status, but not wages or transportation access, was associated with reported health scores. The average employment rate of a recovery home was also positively correlated with the health of its residents. Results indicate the need to address employment and other economic issues which plague recovering individuals. Community aftercare settings may offer such a pathway through affordable housing, employment opportunities, and supportive relationships.

Immunoproteomic discovery of Mycobacterium bovis antigens, including the surface lipoprotein Mpt83 as a T cell antigen useful for vaccine development.

Tuberculosis (TB) is one of the leading causes of death from infectious diseases, killing approximately 1.3 million people worldwide in 2022 alone. The current vaccine for TB contains a live attenuated bacterium, Mycobacterium bovis BCG (Bacille Calmette-Guérin). The BCG vaccine is highly effective in preventing severe forms of childhood TB but does not protect against latent infection or disease in older age groups. A new or improved BCG vaccine for prevention of pulmonary TB is urgently needed. In this study, we infected murine bone marrow derived dendritic cells from C57BL/6 mice with M. bovis BCG followed by elution and identification of BCG-derived MHC class I and class II-bound peptides using tandem mass spectrometry. We identified 1436 MHC-bound peptides of which 94 were derived from BCG. Fifty-five peptides were derived from MHC class I molecules and 39 from class II molecules. We tested the 94 peptides for their immunogenicity using IFN- γ ELISPOT assay with splenocytes purified from BCG immunized mice and 10 showed positive responses. Seven peptides were derived from MHC II and three from MHC class I. In particular, MHC class II binding peptides derived from the mycobacterial surface lipoprotein Mpt83 were highly antigenic. Further evaluations of these immunogenic BCG peptides may identify proteins useful as new TB vaccine candidates.

Development of the coreHEM mental health patient-reported outcome measure - A novel mental health outlook measure for people with haemophilia.

INTRODUCTION: Currently, no quality-of-life instrument exists that captures the full experience of the mental health outlook (MHO), a coreHEM core outcome, in people with haemophilia, including the potential transformational experience of receiving gene therapy. AIM: To describe the methods used to develop a content validated patient-reported outcome measure (PROM) that measures MHO for people with haemophilia. METHODS: A conceptual framework, developed from a literature/evidence review, was used to create an interview guide and draft a questionnaire. Males aged 15 or older with severe/moderate haemophilia were eligible to participate in concept elicitation or cognitive debriefing interviews. The conceptual framework was refined based on a thematic analysis of concept elicitation interviews and PROM items were developed from the conceptual framework. Cognitive debriefing sessions that prioritised relevance and understanding of the PROM were held in two rounds; items were updated iteratively. RESULTS: A conceptual framework with five domains (stigma, anxiety, depression, life interference and identity) was constructed from over 300 identified MHO concepts. Fifty-three participants took part in interviews. After 32 concept elicitation interviews, the framework was updated by including eight new sub-concepts and eliminating two. Updates to the questionnaire included items added or removed and improved wording. The final coreHEM MHO PROM has 26 questions in two sections (general mental health associated with haemophilia, and a gene therapy section). CONCLUSIONS: The instrument is content-validated and can be used as an exploratory outcome. MHO scores can be measured and compared to give more insight into patient quality of life.

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study.

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.

Effect of posture on position of subcutaneous implantable cardioverter-defibrillator.

BACKGROUND: The PRAETORIAN score was developed as an alternative for defibrillation testing after subcutaneous implantable cardioverter-defibrillator implantation to assess 3 aspects of implant position on a bidirectional chest radiograph. The score is validated on a standard standing chest radiograph with arms elevated in the lateral view. OBJECTIVE: We aimed to evaluate the effect of different anatomic positions on the PRAETORIAN score. METHODS: Thirty patients with a subcutaneous implantable cardioverter-defibrillator underwent standard posterior-anterior and lateral chest radiography, including additional lateral views in 2 positions: standing with arms down and supine with arms alongside the body. PRAETORIAN score and weighted κ coefficient were calculated for each position. RESULTS: In 8 of 30 patients, the PRAETORIAN score was ≥90 in standard position. The agreement in PRAETORIAN score was substantial (κ = 0.677) for the position with the arms down and fair (κ = 0.399) for the supine position. With the arms down, the PRAETORIAN score decreased in 10 patients (33%), 4 of whom changed to a lower risk category. In supine position, the PRAETORIAN score decreased in 16 patients (53%), 7 of whom changed to a lower risk category, 1 from high to low risk. CONCLUSION: A supine or arms-down position during chest radiography can result in lower PRAETORIAN scores and underestimation of associated risk on defibrillation testing failure. This emphasizes the importance of correct anatomic positioning (arms up) during chest radiography when the PRAETORIAN score is used.

The U.S. Army Aeromedical Research Laboratory Virtual Reality Vection System.

INTRODUCTION: Vection is a stationary individual's illusory experience of self-motion. This illusory self-motion is operationally important for aviation, particularly military aviation, since vection is a dramatic example of spatial disorientation (SD), which is an individual's failure to correctly sense the aircraft's position, motion, and/or attitude with respect to the fixed coordinate system of the Earth's surface and its gravitational vertical. Notably, SD is a major cause of fatal aviation mishaps, and the visual system is particularly prone to provoking vection. This article describes the Virtual Reality Vection System (VRVS), which uses computer-controlled virtual reality technology to induce vection under controlled conditions for training, demonstration, testing, and research. MATERIALS AND METHODS: The VRVS enables the precise specification of the number and appearance of visual stimulus elements intended to generate vection, including photorealistic images. The VRVS can present visual stimuli on any OpenXR-capable virtual reality headset. The VRVS currently records 2 types of behavioral responses, button presses to indicate the presence and duration of vection and the voltage of a handheld linear potentiometer to indicate the presence, duration, and magnitude of vection. RESULTS: An approved test plan helped guide, organize, document, and validate the VRVS during its development. Under this plan, a pair of tests guided hardware and software development of the VRVS system. Although the first test verified the ability of the VRVS to generate and measure vection, it also demonstrated that the VRVS can quickly manipulate the visual stimuli from one trial to the next so that the VRVS can support complex experimental designs. The second test used these capabilities to verify that the VRVS can characterize vection in a more analytic fashion using a masking paradigm. Specifically, the test assessed whether random stimulus elements injected into the vection-inducing stimulus disrupted vection in a quantifiable fashion. This work opens the door to studies that characterize the necessary and sufficient visual elements for vection-based SD. DISCUSSION: The VRVS is currently used to research, develop, test, and evaluate mitigation strategies targeting vection-related SD in degraded visual environments. Similarly, the VRVS is supporting research to develop methods to predict individual differences in visually induced motion sickness susceptibilities. The VRVS is currently being integrated with a precision motor-controlled rotating Barany chair for multisensory studies. It should be noted that since the VRVS was developed to support United States Army Aeromedical Research Laboratory projects, it is an Army product representing government intellectual property and may be freely available to other government institutions.

Hypertension and Ventilatory Responses During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND).

BACKGROUND: A high minute ventilation/rate of carbon dioxide production (V̇E/V̇co2) slope during exercise is prognostic for cardiovascular death. Recent data indicate that adults with either controlled or untreated primary hypertension, but not those with uncontrolled hypertension, exhibit a higher V̇E/V̇co2 slope during exercise. However, the sample sizes were modest. Therefore, we used the Fitness Registry and the Importance of Exercise National Database to determine whether adults with hypertension, particularly those with controlled or untreated hypertension, exhibit higher V̇E/V̇co2 slopes compared with adults without hypertension. METHODS AND RESULTS: Using the Fitness Registry and the Importance of Exercise National Database, we isolated primary hypertension by excluding those with any disease other than hypertension or taking any medications other than antihypertension medications. We also excluded current smokers and those with obesity. The V̇E/V̇co2 slope was determined during a peak cycling exercise test. All data are presented as median [interquartile range]. We compared groups using linear regression adjusted for age, male/female, and body mass index. The characteristics of the entire sample (n=4109) were age, 42 [18] years; 48% women; body mass index, 26 [4] kg/m2. The V̇E/V̇co2 slope did not differ between adults with hypertension (n=1940; 24.7 [3.7]) compared with those without hypertension (n=2169; 24.9 [3.8]) (hypertension versus no hypertension, P=0.31; overall model: R2=0.07, F4,4104=73.0; P<0.001). Further, the V̇E/V̇co2 slope did not differ between adults with medication-controlled hypertension (n=107; 24.4 [3.0]), untreated hypertension (n=1626; 24.8 [3.9]), uncontrolled hypertension (n=207; 24.8 [3.0]), or those without hypertension (n=2169; 24.9 [3.8]) (hypertension subgroup versus no hypertension, P≥0.06; overall model: R2=0.07, F6,4102=49.6, P<0.001). CONCLUSIONS: Primary hypertension is not associated with V̇E/V̇co2 slope in the Fitness Registry and the Importance of Exercise National Database.

Joint health and pain in the changing hemophilia treatment landscape.

INTRODUCTION: Hemophilia is an inherited bleeding disorder. Bleeding, and in particular joint hemorrhage results in chronic arthropathy and disability. Acute and chronic pain are frequent and limit activity and participation and result in decreased health-related quality of life. Remarkable progress has been made in the diagnosis and treatment of hemophilia but bleeding continues to prove recalcitrant to currently available treatments and joint disease remains problematic. Physiotherapy and pain management are mainstays of current multidisciplinary integrated care of people with hemophilia (PWH). The focus of this review is on preservation of joint health in the era of new and innovative therapies. AREAS COVERED: A search of the PubMed Central was conducted on 1 February 2024 using the MeSH Major Topic terms identified as keywords for the manuscript. This review will highlight what is known and unknown about joint bleeding and arthropathy, including insights on pain as a related complication. EXPERT OPINION: Recent advances in therapeutic interventions aimed at promoting healthy joints in PWH will be discussed, including both the pharmacological treatment landscape and related strategies to promote joint health.

Impact of Catheter-Drawn Blood Cultures on Patient Management: A Multicenter, Retrospective Cohort Study.

Background: Nosocomial bloodstream infections associated with intravascular catheters pose significant financial burden, morbidity, and mortality. There is much debate about whether or not blood cultures should be drawn through central venous catheters, and while guidelines advocate for catheter-drawn cultures when catheter infection is suspected, there is variable practice in this regard. Methods: We performed a retrospective cohort study assessing episodes of positive catheter-drawn blood cultures with concomitant negative percutaneously-drawn cultures in tertiary care hospitals in the United States and Spain. Results: We identified 143 episodes in 122 patients meeting inclusion criteria. Thirty percent of such episodes revealed growth of potential pathogens such as Staphylococcus aureus. Overall, 21% of follow-up percutaneously-drawn blood cultures obtained within 48 hours revealed growth of the same microbe after an episode of positive catheter-drawn blood cultures with negative concomitant percutaneously-drawn cultures (33% when potential pathogens were isolated; 16% when common skin contaminants were isolated). Patients with cultures growing pathogenic organisms were more likely to receive targeted antimicrobial therapy and have their catheters removed sooner. Conclusions: Many episodes of positive catheter-drawn blood cultures with concomitant negative percutaneously-drawn cultures lead to growth from percutaneously-drawn follow-up blood cultures. Thus, such initial discordant results should not be disregarded. Our findings advocate for a nuanced approach to blood culture interpretation, emphasizing the value of catheter-drawn blood cultures in clinical decision making and management.

Canadian Stroke Best Practice Recommendations, 7th Edition: Cerebral Venous Thrombosis, 2024.

The 7th edition of the Canadian Stroke Best Practice Recommendations (CSBPR) is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners, and intended to drive healthcare excellence, improved outcomes and more integrated health systems. This edition includes a new module on the management of cerebral venous thrombosis (CVT). Cerebral venous thrombosis is defined as thrombosis of the veins of the brain, including the dural venous sinuses and/or cortical or deep veins. Cerebral venous thrombosis is a rare but potentially life-threatening type of stroke, representing 0.5-1.0% of all stroke admissions. The reported rates of CVT are approximately 10-20 per million and appear to be increasing over time. The risk of CVT is higher in women and often associated with oral contraceptive use and with pregnancy and the puerperium. This guideline addresses care for adult individuals who present to the healthcare system with current or recent symptoms of CVT. The recommendations cover the continuum of care from diagnosis and initial clinical assessment of symptomatic CVT, to acute treatment of symptomatic CVT, post-acute management, person-centered care, special considerations in the long-term management of CVT, including pregnancy and considerations related to CVT in special circumstances such as trauma and vaccination. This module also includes supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.

Maculopapillary Bundle Degeneration in Optic Neuropathies.

PURPOSE OF REVIEW: Degeneration of the maculopapillary bundle (MPB) is a prominent feature in a spectrum of optic neuropathies. MPB-selective degeneration is seen in specific conditions, such as nutritional and toxic optic neuropathies, Leber hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA). Despite their distinct etiologies and clinical presentations, which encompass variations in age of incidence and monocular or binocular onset, these disorders share a core molecular mechanism: compromised mitochondrial homeostasis. This disruption is characterized by dysfunctions in mitochondrial metabolism, biogenesis, and protein synthesis. This article provides a comprehensive understanding of the MPB's role in optic neuropathies, emphasizing the importance of mitochondrial mechanisms in the pathogenesis of these conditions. RECENT FINDINGS: Optical coherence tomography studies have characterized the retinal nerve fiber layer changes accompanying mitochondrial-affiliated optic neuropathies. Selective thinning of the temporal optic nerve head is preceded by thickening in early stages of these disorders which correlates with reductions in macular ganglion cell layer thinning and vascular atrophy. A recently proposed mechanism underpinning the selective atrophy of the MPB involves the positive feedback of reactive oxygen species generation as a common consequence of mitochondrial dysfunction. Additionally, new research has revealed that the MPB can undergo degeneration in the early stages of glaucoma, challenging the historically held belief that this area was not involved in this common optic neuropathy. A variety of anatomical risk factors influence the propensity of glaucomatous MPB degeneration, and cases present distinct patterns of ganglion cell degeneration that are distinct from those observed in mitochondria-associated diseases. This review synthesizes clinical and molecular research on primary MPB disorders, highlighting the commonalities and differences in their pathogenesis. KEY POINTS (BOX): 1. Temporal degeneration of optic nerve fibers accompanied by cecocentral scotoma is a hallmark of maculopapillary bundle (MPB) degeneration. 2. Mechanisms of MPB degeneration commonly implicate mitochondrial dysfunction. 3. Recent research challenges the traditional belief that the MPB is uninvolved in glaucoma by showing degeneration in the early stages of this common optic neuropathy, yet with features distinct from other MPB-selective neuropathies. 4. Reactive oxygen species generation is a mechanism linking mitochondrial mechanisms of MPB-selective optic neuropathies, but in-vivo and in-vitro studies are needed to validate this hypothesis.

Fifteen years of subcutaneous implantable cardioverter-defibrillator therapy: Where do we stand, and what will the future hold?

The subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as a feasible alternative to the transvenous ICD in the treatment of ventricular tachyarrhythmias in patients without indications for pacing or cardiac resynchronization therapy. Since its introduction, numerous innovations have been made and clinical experience has been gained, leading to its adoption in current practice and preference in certain populations. Moreover, emerging technologies like the extravascular ICD and the combination of the S-ICD with the leadless pacemaker offer new possibilities for the future. These advancements underscore the evolving role of the S-ICD in management of ventricular tachyarrhythmias. This review outlines implantation considerations, patient selection, and troubleshooting advancements in the last 15 years and provides insights into future perspectives.

Unraveling the link between cardiorespiratory fitness and cancer: a state-of-the-art review.

Cardiorespiratory fitness (CRF) not only reflects an individual's capacity to perform physical activities but also encapsulates broader effects on the basic biology of aging. This review aims to summarize the evidence on the influence of CRF on overall and site-specific cancer risks. It delves into the biological mechanisms through which CRF may exert its effects, explores the clinical implications of these findings, identifies gaps in the current evidence base, and suggests directions for future research. The synthesis of findings reveals that higher CRF levels (general threshold of > 7 METs) are consistently associated with a reduced risk of a range of cancers, including head and neck, lung, breast, gastrointestinal, particularly pancreatic and colorectal, bladder, overall cancer incidence and mortality, and potentially stomach and liver, bile duct, and gall bladder cancers. These inverse associations between CRF and cancer risk do not generally differ across age groups, sex, race, or adiposity, suggesting a universal protective effect of CRF. Nonetheless, evidence linking CRF with skin, mouth and pharynx, kidney, and endometrial cancers is limited and inconclusive. Conversely, higher CRF levels may be potentially linked to an increased risk of prostate cancer and hematological malignancies, such as leukemia and myeloma, although the evidence is still not conclusive. CRF appears to play a significant role in reducing the risk of several cancers through various biological mechanisms, including inflammation reduction, immune system enhancement, hormonal regulation, and metabolic improvements. Overall, enhancing CRF through regular physical activity offers a vital, accessible strategy for reducing cancer risk and extending the health span. Future research should aim to fill the existing evidence gaps regarding specific cancers and elucidate the detailed dose-response relationships between CRF levels and cancer risk. Studies are also needed to elucidate the causal relationships and mechanistic pathways linking CRF to cancer outcomes.

Visual Function Measurements in Eyes With Diabetic Retinopathy: An Expert Opinion on Available Measures.

Clinical Relevance: Visual function impairment from diabetic retinopathy can have a considerable impact on patient's quality of life. Best-corrected visual acuity (BCVA) is most commonly used to assess visual function and guide clinical trials. However, BCVA is affected late in the disease process, is not affected in early disease, and does not capture some of the visual disturbances described by patients with diabetes. The goal of this report is to evaluate the relationship between diabetic retinal disease (DRD) and visual function parameters to determine which if any of them may be used in a future DRD staging system. Methods: The visual functions working group was 1 of 6 areas of DRD studied as part of the DRD staging system update, a project of the Mary Tyler Moore Vision Initiative. The working group identified 12 variables of possible interest, 7 of which were judged to have sufficient preliminary data to suggest an association with DR to warrant further review: microperimetry, static automated perimetry, electroretinogram (ERG) oscillatory potentials, flicker ERG, low luminance visual acuity (LLVA), contrast sensitivity (CS), and BCVA. The objective field analyzer (OFA) was added after subsequent in-person workshops. Results: Currently, the only visual function test available for immediate use is BCVA; the remaining tests are either promising (within 5 years) or have potential (>5 years) use. Besides BCVA, most visual function tests had a limited role in current clinical care; however, LLVA, CS, flicker ERG, and OFA demonstrated potential for screening and research purposes. Conclusions: Although current visual function tests are promising, future prospective studies involving patients with early and more advanced retinopathy are necessary to determine if these tests can be used clinically or as endpoints for clinical studies. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Chronic Use of Antihypertensive Medications and Peak Exercise Blood Pressure in Adult Men and Women from the BALL ST Cohort.

PURPOSE: To determine if individuals chronically (>1 yr) prescribed antihypertensive medications have a normal BP response to peak exercise compared with unmedicated individuals. METHODS: Participants included 2555 adults from the Ball State Adult Fitness Longitudinal Lifestyle STudy cohort who performed a peak treadmill exercise test. Participants were divided into groups by sex and antihypertensive medication status. Individuals prescribed antihypertensive medications for >1 yr were included. Exaggerated and blunted SBP within each group was categorized using the Fitness Registry and the Importance of Exercise: A National Database (FRIEND) and absolute criteria as noted by the American Heart Association. RESULTS: The unmedicated group had a greater prevalence ( P < 0.05) of blunted SBP responses, whereas the medicated group had a higher prevalence ( P < 0.05) of exaggerated SBP responses using both the FRIEND and absolute criteria. Peak SBP was higher ( P < 0.01) in medicated compared with unmedicated participants in the overall cohort when controlling for age and sex, but not after controlling for resting SBP ( P = 0.613), risk factors ( P = 0.104), or cardiorespiratory fitness ( P = 0.191). When men and women were assessed independently, peak SBP remained higher in the medicated women after controlling for age and resting SBP ( P = 0.039), but not for men ( P = 0.311). Individuals on beta-blockers had a higher peak SBP even after controlling for age, sex, risk factors, and cardiorespiratory fitness ( P = 0.022). CONCLUSIONS: Individuals on antihypertensive medications have a higher peak SBP response to exercise. Given the prognostic value of exaggerated peak SBP, control of exercise BP should be considered in routine BP assessment and in the treatment of hypertension.

Should Blood Cultures Be Drawn Through an Indwelling Catheter?

There is no practical way to definitively diagnose a catheter-related bloodstream infection in situ if blood cultures are only obtained percutaneously unless there is the rare occurrence of purulent drainage from a central venous catheter insertion site. That is why the Infectious Diseases Society of America guidelines for diagnosis and management of catheter-related bloodstream infections and Infectious Diseases Society of America guidelines for evaluation of fever in critically ill patients both recommend drawing blood cultures from a central venous catheter and percutaneously if the catheter is a suspected source of infection. However, central venous catheter-drawn blood cultures may be more likely to be positive reflecting catheter hub, connector, or intraluminal colonization, and many hospitals in the United States discourage blood culture collection from catheters in an effort to reduce reporting of central-line associated bloodstream infections to the Centers for Disease Control and Prevention. As such, clinical decisions are made regarding catheter removal or other therapeutic interventions based on incomplete and potentially inaccurate data. We urge clinicians to obtain catheter-drawn blood cultures when the catheter may be the source of suspected infection.

Examining the Influence of Cognitive Load and Environmental Conditions on Autonomic Nervous System Response in Military Aircrew: A Hypoxia-Normoxia Study.

Executing flight operations demand that military personnel continuously perform tasks that utilize low- and high-order cognitive functions. The autonomic nervous system (ANS) is crucial for regulating the supply of oxygen (O2) to the brain, but it is unclear how sustained cognitive loads of different complexities may affect this regulation. Therefore, in the current study, ANS responses to low and high cognitive loads in hypoxic and normoxic conditions were evaluated. The present analysis used data from a previously conducted, two-factor experimental design. Healthy subjects (n = 24) aged 19 to 45 years and located near Fort Novosel, AL, participated in the parent study. Over two, 2-h trials, subjects were exposed to hypoxic (14.0% O2) and normoxic (21.0% O2) air while simultaneously performing one, 15-min and one, 10-min simulation incorporating low- and high-cognitive aviation-related tasks, respectively. The tests were alternated across five, 27-min epochs; however, only epochs 2 through 4 were used in the analyses. Heart rate (HR), HR variability (HRV), and arterial O2 saturation were continuously measured using the Warfighter MonitorTM (Tiger Tech Solutions, Inc., Miami, FL, USA), a previously validated armband device equipped with electrocardiographic and pulse oximetry capabilities. Analysis of variance (ANOVA) regression models were performed to compare ANS responses between the low- and high-cognitive-load assessments under hypoxic and normoxic conditions. Pairwise comparisons corrected for familywise error were performed using Tukey's test within and between high and low cognitive loads under each environmental condition. Across epochs 2 through 4, in both the hypoxic condition and the normoxic condition, the high-cognitive-load assessment (MATB-II) elicited heightened ANS activity, reflected by increased HR (+2.4 ± 6.9 bpm) and decreased HRV (-rMSSD: -0.4 ± 2.7 ms and SDNN: -13.6 ± 14.6 ms). Conversely, low cognitive load (ADVT) induced an improvement in ANS activity, with reduced HR (-2.6 ± 6.3 bpm) and increased HRV (rMSSD: +1.8 ± 6.0 ms and SDNN: vs. +0.7 ± 6.3 ms). Similar observations were found for the normoxic condition, albeit to a lower degree. These within-group ANS responses were significantly different between high and low cognitive loads (HR: +5.0 bpm, 95% CI: 2.1, 7.9, p < 0.0001; rMSSD: -2.2 ms, 95% CI: -4.2, -0.2, p = 0.03; SDNN: -14.3 ms, 95% CI: -18.4, -10.1, p < 0.0001) under the hypoxic condition. For normoxia, significant differences in ANS response were only observed for HR (+4.3 bpm, 95% CI: 1.2, 7.4, p = 0.002). Lastly, only high cognitive loads elicited significant differences between hypoxic and normoxic conditions but just for SDNN (-13.3 ms, 95% CI, -17.5, -8.9, p < 0.0001). Our study observations suggest that compared to low cognitive loads, performing high-cognitive-load tasks significantly alters ANS activity, especially under hypoxic conditions. Accounting for this response is critical, as military personnel during flight operations sustain exposure to high cognitive loads of unpredictable duration and frequency. Additionally, this is likely compounded by the increased ANS activity consequent to pre-flight activities and anticipation of combat-related outcomes.

Loss-of-function variants affecting the STAGA complex component SUPT7L cause a developmental disorder with generalized lipodystrophy.

Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts. In addition, we found altered expression of genes encoding DNA repair pathway components. This pathway was further investigated and an increased rate of DNA damage was detected in proband-derived fibroblasts and genome-edited HeLa cells. Finally, we performed transient overexpression of wildtype SUPT7L in both cellular systems, which normalizes the number of DNA damage events. Our findings suggest SUPT7L as a novel disease gene and underline the link between genome instability and progeroid phenotypes.