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Abstract Background Population growth and management in cervid species is dependent on reproductive ecology and factors influencing juvenile survival. Aspects of the female’s movement behavior likely affect juvenile survival and movement patterns of pregnant and lactating females differ from non-pregnant or non-lactating females. Explanations for these differing movement patterns include change in nutritional demands for the female, isolation during parturition, and predator avoidance. White-tailed deer (Odocoileus virginianus) are an important managed cervid and a better understanding of their reproductive ecology, including the relationships between resources, movement, and juvenile survival, can better inform management. Methods Our objective was to determine if biological factors, such as female age, fawn age, number of fawns, as well as characteristics of prepartum range affected the female’s postpartum daily movement or overlap of space used pre- and postpartum in Sussex County, Delaware, USA (2,420 km2). We collected GPS locations 2 weeks pre- and postpartum on 22 individual females from 2016 to 2017. In total, we recorded data from 263 days of postpartum movement for an average of 12 days/individual. We used a hierarchical modeling process to test biological factors and prepartum home range characteristics on two aspects of postpartum movement behavior, mean hourly displacements and daily use of prepartum home range. Results Mean hourly displacement decreased with increased female age and increased with number of known fawns alive and the female’s home range size prior to parturition. We found that as fawns aged the doe increased use of the prepartum home range. Conclusions Our results indicate that younger females are moving more than older females during lactation potentially to access higher quality habitat. This increased movement increases nutritional demand and may play a role in fawn survival. Females are more likely to use more of their prepartum home range as fawns age, a finding congruent with previous research. This differentiation in metric response (movement rate vs. space use) emphasizes the complexities of movement ecology and the importance of considering multiple dependent variables for complex behavior.

Firefighting is a physically demanding occupation that requires optimal fitness and coordination in addition to other physical and cognitive skills. When firefighters lack the physical fitness necessary to perform their duties, they put themselves and others in danger of injury and even death. The heavy, unbreathable personal protective equipment worn to shield firefighters from harmful conditions also promotes overall performance decrements via restricted range of motion as well as energy expenditure and heat-related fatigue. Firefighters are expected to carry other heavy loads, such as hose packs, tools, and victims, while working in hazardous environments. In addition to external load carriage, many firefighters also carry excess body fat that may contribute to poor physical fitness and performance. Therefore, it is imperative to incorporate training strategies to optimize load carriage and improve body composition for improved physical performance during emergencies. Thus, the aims of this narrative review are to (1) explore the impact of firefighter-specific issues on physical performance and safety and (2) identify strategies to assess and optimize occupational performance and safety. Plyometrics; resistance training; and exercise selection, volume, and intensity specifically for improving physical performance in firefighters will be discussed.

Infants at elevated likelihood of developing autism display differences in sensory reactivity, especially hyporeactivity, as early as 7 months of age, potentially contributing to a developmental cascade of autism symptoms. Caregiver responsiveness, which has been linked to positive social communication outcomes, has not been adequately examined with regard to infant sensory reactivity. This study examined the multiplicative impact of infant sensory hypo- and hyperreactivity on caregiver responsiveness to sensory reactivity and regulation cues in 43 infants at elevated likelihood of autism. Sensory hyperreactivity was found to moderate the association between sensory hyporeactivity and caregiver responsiveness, such that caregivers of infants with moderately high sensory hypo- and hyperreactivity demonstrated higher responsiveness.

Summary: Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107).

Background:. Concurrent panniculectomy with abdominal wall reconstruction (CP-AWR) as a single-stage operation has reported increased complications, but constant quality improvement can improve results. This study describes outcomes for 21 years, impacted by evidence-based-practice changes. Methods:. Prospectively maintained database was reviewed for CP-AWR and separated by surgery date: “early” (2002–2016) and “recent” (2017–2023). A 1:1 propensity-scored matching was performed based on age, tobacco use, body mass index (BMI), American Society of Anesthesiologists (ASA) score, wound class, and defect size. Results:. Of 701 CP-AWRs, 196 pairs matched. Match criteria were not significantly different between early and recent groups, except for BMI (34.6 ± 7.2 versus 32.1 ± 6.01 kg/m2; P = 0.001). Groups were comparable in sex and diabetes, but recent patients had fewer recurrent hernias (71.4% versus 56.1%; P = 0.002). Recent patients had more biologic (21.9% versus 49.0%; P < 0.001) and preperitoneal mesh (87.2% versus 97.4%; P = 0.005). Readmission and reoperation did not significantly differ, but length of stay (8.3 ± 6.7 versus 6.5 ± 3.4 d; P = 0.001) and wound complications decreased over time (50.5% versus 25.0%; P < 0.001). Hernia recurrence rates improved (6.6% versus 1.5%; P = 0.019), but follow-up was shorter (50.9 ± 52.8 versus 22.9 ± 22.6 months; P < 0.0001). Conclusions:. Despite patient complexity, outcomes of CP-AWR improved with implementation of evidence-based-practice changes in preoperative optimization, intraoperative technique, and postoperative care. This large dataset demonstrates the safety of a single-stage repair that should be part of hernia surgeons' repertoire.

Advancements in cell therapy have the potential to improve healthcare accessibility for eligible patients. However, there are still challenges in scaling production and reducing costs. These challenges involve various stakeholders such as the manufacturing facility, third-party logistics (3PL) company, and medical center. Proposed solutions tend to focus on individual companies rather than addressing the interconnectedness of the supply chain’s challenges. The challenges can be categorized as barriers from product characteristics, regulatory requirements, or lagging infrastructure. Each barrier affects multiple stakeholders, especially during a boundary event like product handover. Therefore, solutions that only consider the objectives of one stakeholder fail to address underlying problems. This review examines the interconnecting cell therapy supply chain challenges and how they affect the multiple stakeholders involved. The authors consider whether proposed solutions impact individual stakeholders or the entire supply chain and discuss the benefits of stakeholder coordination-focused solutions such as integrated technologies and information tracking. The review highlights how coordination efforts allow for the implementation of widely-supported cell therapy supply solutions such as decentralized manufacturing through stakeholder collaboration.

Background: Autoantibodies to type I interferons have been identified in association with a variety of inflammatory and autoimmune diseases. Type I interferons have demonstrated inhibitory effects on mast cell proliferation and degranulation. Systemic mastocytosis (SM) is a disease characterized by increased mast cell burden and mediator release. Whether autoantibodies to type I interferon are present in the sera of patients with SM, and if so, whether they correlate with characteristics of disease, is unknown. Objective: The purpose of this study was to determine whether autoantibodies to type I interferons are observed in the sera of patients with SM, and if so, whether they correlate with biomarkers of disease severity. Methods: We analyzed sera from 89 patients with SM for concentrations of autoantibodies to type I interferon by using a multiplex particle-based assay and signal neutralization capacity by using a STAT1 activity assay and then compared these measurements with those in a database of information on 1284 healthy controls. Results: Our cohort was predominantly female (57.3%), with a median age of 56 years. Of the cohort members, 13 produced autoantibodies to IFN-β, 3 to IFN-ω, and 0 to IFN-α. None of the 13 sera demonstrated signal neutralization. Neither autoantibody concentration nor signaling inhibition measurements correlated with tryptase concentrations or D816V allele burden. Conclusion: Although a small subpopulation of patients with SM have autoantibodies to type I interferons, there was no correlation between autoantibody production and signaling inhibition. These data are consistent with the conclusion that autoantibodies to type I interferon do not play a significant role in the pathogenesis or severity of SM.

IntroductionSystemic lupus erythematosus is a multi-faceted autoimmune disorder of complex etiology. Pre-pubertal onset of pediatric systemic lupus erythematosus (pSLE) is uncommon and should raise suspicion for a genetic driver of disease. Autosomal recessive p40phox deficiency is a rare immunologic disorder characterized by defective but not abolished NADPH oxidase activity with residual production of reactive oxygen species (ROS) by phagocytic cells.Case presentationWe report the case of a now 18-year-old female with pSLE onset at 7 years of age. She presented with recurrent fever and malar rash. Aspects of her immune dysregulation over time have included typical pSLE features including production of autoantibodies, hematologic manifestations, and hypocomplementemia, as well as chronic suppurative skin lesions and recurrent infections. Genetic analysis revealed biallelic pathogenic variants in NCF4 resulting in p40phox deficiency. Comprehensive NADPH oxidase activity studies confirmed significantly decreased production of reactive oxygen species, confirming the cellular phenotype seen in p40phox deficient patients.ConclusionsHere, we present a patient with pSLE harboring biallelic variants in NCF4. Our patient represents a unique clinical presentation of severe onset autoimmunity in the setting of a rare inborn error of immunity affecting NADPH oxidase activity. This case underscores the need to consider genetic causes of pSLE in cases of pre-pubertal onset and atypical disease.

ObjectivePatients with pathogenic variants in the GATA Binding Protein 2 (GATA2), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with GATA2 haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males.MethodsA 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with GATA2 haploinsufficiency followed at the National Institutes of Health. Student’s t-test and Mann-Whitney U test or Fisher’s exact test were used to compare differences in continuous or categorical variables, respectively. Spearman’s rho coefficient was employed for correlations.ResultsOf 68 patients with GATA2 haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from GATA2 haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males.ConclusionFemales with GATA2 haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. GATA2 haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.

Climate simulation uncertainties arise from internal variability, model structure, and external forcings. Model intercomparisons (such as the Coupled Model Intercomparison Project; CMIP) and single-model large ensembles have provided insight into uncertainty sources. Under the Community Earth System Model (CESM) project, large ensembles have been performed for CESM2 (a CMIP6-era model) and CESM1 (a CMIP5-era model). We refer to these as CESM2-LE and CESM1-LE. The external forcing used in these simulations has changed to be consistent with their CMIP generation. As a result, differences between CESM2-LE and CESM1-LE ensemble means arise from changes in both model structure and forcing. Here we present new ensemble simulations which allow us to separate the influences of these model structural and forcing differences. Our new CESM2 simulations are run with CMIP5 forcings equivalent to those used in the CESM1-LE. We find a strong influence of historical forcing uncertainty due to aerosol effects on simulated climate. For the historical period, forcing drives reduced global warming and ocean heat uptake in CESM2-LE relative to CESM1-LE that is counteracted by the influence of model structure. The influence of the model structure and forcing vary across the globe, and the Arctic exhibits a distinct signal that contrasts with the global mean. For the 21st century, the importance of scenario forcing differences (SSP3–7.0 for CESM2-LE and RCP8.5 for CESM1-LE) is evident. The new simulations presented here allow us to diagnose the influence of model structure on 21st century change, despite large scenario forcing differences, revealing that differences in the meridional distribution of warming are caused by model structure. Feedback analysis reveals that clouds and their impact on shortwave radiation explain many of these structural differences between CESM2 and CESM1. In the Arctic, albedo changes control transient climate evolution differences due to structural differences between CESM2 and CESM1.

Abstract The space weather effects at the Earth's magnetosphere are mostly driven by the solar wind that carries the interplanetary magnetic field (IMF). In this paper, we use 2 years of data in the solar wind from lunar orbiting ARTEMIS and MMS spacecraft upstream of the Earth's bow shock to study the structure of the IMF. We determine the lag times of IMF structures and their dependence on spacecraft positions by conducting an information theory analysis and comparing it with two traditional analysis methods: cross‐correlation (CC) analysis and minimum variance of magnetic field analysis (MVAB). For the events with long time intervals (i.e., >4 hr) and with small‐spatial separation between the MMS and ARTEMIS along the yGSM‐direction (i.e.,

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

ABSTRACT Mycobacterium abscessus (Mab) affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, Mab poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with β-lactamase inhibitors [BLIs—avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical Mab isolates and ATCC19977 (MIC50 and MIC90 ≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log10 CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log10 for sulopenem-CXM and AVI and ~4 Log10 for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; LdtMab1–LdtMab4), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with LdtMab2–LdtMab4, DDC, and PBP B and CXM with LdtMab2 and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and LdtMab2 after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring and the establishment of a thioester bond linking the LdtMab2 with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat Mab.IMPORTANCETreating infections from Mycobacterium abscessus (Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination β-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a “step down” to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.

Background Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known.Objectives To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors.Methods In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health.Results From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86).Conclusion Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need.Trail registration number ISRCTN10980107.

Background: Health disparities are pervasive in surgical care. Particularly racial and socioeconomic inequalities have been demonstrated in emergency general surgery outcomes, but less so in elective abdominal wall reconstruction (AWR). The goal of this study was to evaluate the disparities in referrals to a tertiary hernia center.Methods: A prospectively maintained hernia database was queried for patients who underwent open ventral hernia (OVHR) or minimally invasive surgical (MISR) repair from 2011 to 2022 with complete insurance and address information. Patients were divided by home address into in-state (IS) and out-of-state (OOS) referrals as well as by operative technique. Demographic data and outcomes were compared. Standard and inferential statistical analyses were performed.Results: Of 554 patients, most were IS (59.0%); 334 underwent OVHR, and 220 underwent MISR. IS patients were more likely to undergo MISR (OVHR: 45.6% vs. 81.5%, laparoscopic: 38.2% vs. 14.1%, robotic: 16.2% vs. 4.4%; p < 0.001) when compared to OOS referrals. Of OVHR patients, 44.6% were IS and 55.4% were OOS. Patients’ average age and BMI, sex, ASA score, and insurance payer were similar between IS and OOS groups. IS patients were more often Black (White: 77.9% vs. 93.5%, Black: 16.8% vs. 4.3%; p < 0.001). IS patients had more smokers (12.1% vs. 3.2%; p = 0.001), fewer recurrent hernias (45.0% vs. 69.7%; p < 0.001), and smaller defects (155.7 ± 142.2 vs. 256.4 ± 202.9 cm2; p < 0.001). Wound class, mesh type, and rate of fascial closure were similar, but IS patients underwent fewer panniculectomies (13.4% vs. 34.1%; p < 0.001), component separations (26.2% vs. 51.4%; p < 0.001), received smaller mesh (744.2 ± 495.6 vs. 975.7 ± 442.3 cm2; p < 0.001), and had shorter length-of-stay (4.8 ± 2.0 vs. 7.0 ± 5.5 days; p < 0.001). There was no difference in wound breakdown, seroma requiring intervention, hematoma, mesh infection, or recurrence; however, IS patients had decreased wound infections (2.0% vs. 8.6%; p = 0.009), overall wound complications (11.4% vs. 21.1%; p = 0.016), readmissions (2.7% vs. 13.0%; p = 0.001), and reoperations (3.4% vs. 11.4%; p = 0.007). Of MISR patients, 80.9% were IS and 19.1% were OOS. In contrast to OVHR, MISR IS and OOS patients had similar demographics, preoperative characteristics, intraoperative details, and postoperative outcomes.Conclusion: Although there were no differences in referred patients for MISR, this study demonstrates the racial disparities that exist among our IS and OOS complex, open AWR patients. Awareness of these disparities can help clinicians work towards equitable access to care and equal referrals to tertiary hernia centers.

Abstract Adhesives play a crucial role in many industries, including medicine, construction, and electronics. In the medical field, additives may be incorporated into adhesives to enhance drug delivery or prevent infection. This study explored the effects of two antimicrobial ceragenin (CSA) additives, CSA-44 and CSA-131, on the shear strength of a polyacrylate pressure sensitive adhesive. Strength of the adhesive bond was determined by lap shear tests. The adhesive formulation with CSA-131 exhibited significantly higher shear strength, 84.5 N, compared to the formulation with CSA-44 or the neat adhesive, 22.5 and 19.5 N, respectively. Preliminary analysis suggests that the longer hydrocarbon chains in CSA-131 enhance van der Waals forces, leading to improved adhesion to the nonpolar substrate. These findings shed light on possible molecular design principles for optimizing the properties of adhesive formulations. Article highlights Two antimicrobial additives were shown to have no negative impact on the performance of a medical adhesive. One additive, CSA-131, improved the shear strength of the adhesive formulation relative to the neat adhesive. Differences in shear strength of the adhesive formulation are likely linked to the molecular structure of the additives.

Background/Objectives: Firefighters are exposed to a high level of stress as they often perform physically challenging work in hazardous environments while responsible for rescuing and keeping those around them safe. To add to this stress, they are also required to work in heavy, unbreathable personal protective equipment which promotes dehydration. These occupational demands paired with dehydration may lead to increased core temperatures, cardiac strain, and overall risk for sudden cardiac events. Thus, it is important to include hydration assessments and determine fluid needs when firefighters are on shift to ensure their personal safety as well as the safety of those around them by optimizing physical performance by maintaining adequate hydration. Therefore, the purpose of this review is to identify markers of hydration, classifications of hydration status, current hydration recommendations, and hydration interventions that may contribute to the overall clarity of hydration protocols that may optimize performance and health of firefighters. In addition, the impact of common medications, exercise training, and health conditions on hydration status related to firefighters will be discussed. Methods: A comprehensive literature search was conducted to discuss the purpose statements. Results: Hydration recommendations for firefighters include (1) assessing hydration status with multiple measurements including body mass, urine specific gravity and thirst sensation, and (2) following general hydration recommendations on rest days and exercise hydration protocols during firefighting activities which may be altered according to hydration status measurements. Conclusion: Randomized controlled trials in firefighters are needed to determine the impact of maintaining adequate hydration on health markers.

IntroductionNontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature.Materials and methodsBetween January 1995 and December 2020, six cases were identified. Records were reviewed for demographic, clinical, and radiological characteristics. A MEDLINE search found previously reported cases. Data were extracted, followed by statistical analysis to compare two groups [cases with slow-growing mycobacteria (SGM) vs. those with rapidly growing mycobacteria (RGM)] and evaluate for predictors of survival. NIH cases were evaluated for clinical and radiological characteristics. Cases from the literature were reviewed to determine the differences between SGM and RGM cases and to identify predictors of survival.ResultsSix cases from NIH were identified (age 41 ± 13, 83% male). Five cases were caused by SGM [Mycobacterium avium complex (MAC) n = 4; Mycobacterium haemophilum n = 1] and one due to RGM (Mycobacterium abscessus). Underlying immune disorders were identified only in the SGM cases [genetic (n = 2), HIV (n = 1), sarcoidosis (n = 1), and anti-interferon-gamma antibodies (n = 1)]. All cases were diagnosed using tissue analysis. A literature review found 81 reports on 125 cases (SGM n = 85, RGM n = 38, non-identified n = 2). No immune disorder was reported in 26 cases (21%). Within SGM cases, the most common underlying disease was HIV infection (n = 55, 65%), and seizures and focal lesions were more common. In RGM cases, the most common underlying condition was neurosurgical intervention or implants (55%), and headaches and meningeal signs were common. Tissue-based diagnosis was used more for SGM than RGM (39% vs. 13%, p = 0.04). Survival rates were similar in both groups (48% SGM and 55% in RGM). Factors associated with better survival were a solitary CNS lesion (OR 5.9, p = 0.01) and a diagnosis made by CSF sampling only (OR 9.9, p = 0.04).DiscussionNTM infections cause diverse neurological manifestations, with some distinctions between SGM and RGM infections. Tissue sampling may be necessary to establish the diagnosis, and an effort should be made to identify an underlying immune disorder.

We report the case of a 1-week-old male born full-term, who had two inconclusive severe combined immunodeficiency (SCID) newborn screens and developed scalp cellulitis and Escherichia coli bacteremia. He did not pass early confirmatory hearing screens. Initial blood counts and lymphocyte flow cytometry revealed profound neutropenia and lymphopenia with a T-/B-/NK- phenotype. Red blood cell adenosine deaminase 1 activity was within normal limits. A presumptive diagnosis of reticular dysgenesis was considered. Granulocyte colony-stimulating factor was started, but there was no improvement in neutrophil counts. Subsequent lymphocyte flow cytometry at around 4 weeks of age demonstrated an increase in T-, B- and NK-cell numbers, eliminating suspicion for SCID and raising concern for congenital neutropenia and bone marrow failure syndromes. Genetic testing revealed a novel variant in RAC2 [c.181C>A (p.Gln61Lys)] (Q61K). RAC2, a Ras-related GTPase, is the dominant RAC protein expressed in hematopoietic cells and is involved with various downstream immune-mediated responses. Pathogenic RAC2 variants show significant phenotypic heterogeneity (spanning from neutrophil defects to combined immunodeficiency) across dominant, constitutively activating, dominant activating, dominant negative, and autosomal recessive subtypes. Given the identification of a novel variant, functional testing was pursued to evaluate aberrant pathways described in other RAC2 pathogenic variants. In comparison to wild-type RAC2, the Q61K variant supported elevated superoxide production under both basal and PMA-stimulated conditions, increased PAK1 binding, and enhanced plasma membrane ruffling, consistent with other dominant, constitutively active mutations. This case highlights the diagnostic challenge associated with genetic variants identified via next-generation sequencing panels and the importance of functional assays to confirm variant pathogenicity.

Not available.

ABSTRACT Mice that lack the genes for IL-27, or the IL-27 receptor, and infected with Toxoplasma gondii develop T cell-mediated pathology. Here, studies were performed to determine the impact of endogenous IL-27 on the immune response to T. gondii in wild-type (WT) mice. Analysis of infected mice revealed the early production of IL-27p28 by a subset of Ly6Chi, inflammatory monocytes, and sustained IL-27p28 production at sites of acute and chronic infection. Administration of anti-IL-27p28 prior to infection resulted in an early (day 5) increase in levels of macrophage and granulocyte activation, as well as enhanced effector T cell responses, as measured by both cellularity, cytokine production, and transcriptional profiling. This enhanced acute response led to immune pathology, while blockade during the chronic phase of infection resulted in enhanced T cell responses but no systemic pathology. In the absence of IL-27, the enhanced monocyte responses observed at day 10 were a secondary consequence of activated CD4+ T cells. Thus, in WT mice, IL-27 has distinct suppressive effects that impact innate and adaptive immunity during different phases of this infection.IMPORTANCEThe molecule IL-27 is critical in limiting the immune response to the parasite Toxoplasma gondii. In the absence of IL-27, a lethal, overactive immune response develops during infection. However, when exactly in the course of infection this molecule is needed was unclear. By selectively inhibiting IL-27 during this parasitic infection, we discovered that IL-27 was only needed during, but not prior to, infection. Additionally, IL-27 is only needed in the active areas in which the parasite is replicating. Finally, our work found that a previously unstudied cell type, monocytes, was regulated by IL-27, which contributes further to our understanding of the regulatory networks established by this molecule.

Abstract Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity.

This crossover randomized controlled trial examined the acute psychological effects of a bout of moderate-intensity continuous aerobic exercise (MICE) and a bout of high-intensity functional exercise (HIFE), relative to a no-exercise sedentary control (SED), in participants (N = 21; 15 f; 24.7 ± 9.3 years) with subsyndromal post-traumatic stress disorder (PTSD). Affective state (Energy, Tiredness, Tension, Calmness) was assessed before (Pre), immediately after (Post 0), 20-min after (Post 20), and 40-min after (Post 40) each condition. Affective valence was assessed during each condition, and exercise enjoyment was assessed at Post 0. Enjoyment was significantly greater following HIFE and MICE relative to SED. Energy was significantly increased Post 0 HIFE and MICE but decreased Post 0 SED. Tension was reduced following all conditions and was significantly lower at Post 40 relative to Pre for HIFE, MICE, and SED. Tiredness was significantly reduced at Post 40 relative to Pre following MICE only, while Calmness was significantly lower at Post 40 relative to Pre following MICE and SED. Overall, both exercise conditions were enjoyed to a greater extent than the control, but MICE may provide greater psychological benefits with respect to Calmness and Tiredness. This study is among the first to assess acute changes in affective states relative to various exercise modes in individuals living with subsyndromal PTSD.

Abstract Numerical modeling of ice sheet motion and hence projections of global sea level rise require information about the evolving subglacial environment, which unfortunately remains largely unknown due to its difficulty of access. Here we advance such subglacial observations by reporting multi‐year observations of seismic tremor likely associated with glacier sliding at Helheim Glacier. This association is confirmed by correlation analysis between tremor power and multiple environmental forcings on different timescales. Variations of the observed tremor power indicate that different factors affect glacial sliding on different timescales. Effective pressure may control glacial sliding on long (seasonal/annual) timescales, while tidal forcing modulates the sliding rate and tremor power on short (hourly/daily) timescales. Polarization results suggest that the tremor source comes from an upstream subglacial ridge. This observation provides insights on how different factors should be included in ice sheet modeling and how their timescales of variability play an essential role.

Background Context: Virtual reality (VR) reduces pain through visual and auditory distraction without narcotic-related side effects or dependency. Cognitive behavioral therapy (CBT) improves pain-related disability and quality of life, but patient access remains a challenge. We hypothesized that in-home weekly CBT coordinated with daily use of a proprietary VR toolkit will reduce pain, anxiety, and depression for patients with non-operative chronic cervical and lumbar spondylitic pain with and without radiculopathy. Methods: A total of 145 patients with chronic spondylitic pain (63 cervical, 46 noradicular lumbar, 36 radicular lumbar) were enrolled into a guided 14-week VR+CBT program (Vx Therapy) consisting of weekly encounters with a trained therapist and 50 modules. Pain/anxiety severity scores and time to pain recurrence were recorded prospectively by patients. PROMIS measures of overall daily pain intensity, behavior, interference, anxiety, and depression were recorded at baseline and conclusion of the program. Results: A total of 52% of the 145 patients were male. The average (SD) age of the cohort was 51 (10.7) years (range: 24–76 years). Mean score for all PROMIS domains were significantly improved after 14 weeks of Vx Therapy (pain intensity 36±24 vs. 28±21, interference 39±25 vs. 24±21, behavior 35±21 vs. 25±16, anxiety 51±28 vs. 41±26, depression 58±32 vs. 48±32) for the entire cohort and each diagnosis group. Virtual reality acutely reduced pain on average by 33% (4.5±2.5 vs. 6.7±2.2, p

BackgroundDelta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid found in small amounts naturally in the cannabis plant; it can also be synthetically produced in larger quantities from hemp-derived cannabidiol. Most states permit the sale of hemp and hemp-derived cannabidiol products; thus, hemp-derived delta-8 THC products have become widely available in many state hemp marketplaces, even where delta-9 THC, the most prominently occurring THC isomer in cannabis, is not currently legal. Health concerns related to the processing of delta-8 THC products and their psychoactive effects remain understudied. ObjectiveThe goal of this study is to implement a novel topic modeling approach based on transformers, a state-of-the-art natural language processing architecture, to identify and describe emerging trends and topics of discussion about delta-8 THC from social media discourse, including potential symptoms and adverse health outcomes experienced by people using delta-8 THC products. MethodsPosts from January 2008 to December 2021 discussing delta-8 THC were isolated from cannabis-related drug forums on Reddit (Reddit Inc), a social media platform that hosts the largest web-based drug forums worldwide. Unsupervised topic modeling with state-of-the-art transformer-based models was used to cluster posts into topics and assign labels describing the kinds of issues being discussed with respect to delta-8 THC. Results were then validated by human subject matter experts. ResultsThere were 41,191 delta-8 THC posts identified and 81 topics isolated, the most prevalent being (1) discussion of specific brands or products, (2) comparison of delta-8 THC to other hemp-derived cannabinoids, and (3) safety warnings. About 5% (n=1220) of posts from the resulting topics included content discussing health-related symptoms such as anxiety, sleep disturbance, and breathing problems. Until 2020, Reddit posts contained fewer than 10 mentions of delta-8-THC for every 100,000 cannabis posts annually. However, in 2020, these rates increased by 13 times the 2019 rate (to 99.2 mentions per 100,000 cannabis posts) and continued to increase into 2021 (349.5 mentions per 100,000 cannabis posts). ConclusionsOur study provides insights into emerging public health concerns around delta-8 THC, a novel substance about which little is known. Furthermore, we demonstrate the use of transformer-based unsupervised learning approaches to derive intelligible topics from highly unstructured discussions of delta-8 THC, which may help improve the timeliness of identification of emerging health concerns related to new substances.

ABSTRACTBackground Mycobacterium abscessus subspecies massiliense (M. massiliense) is increasingly recognized as an emerging bacterial pathogen, particularly in cystic fibrosis (CF) patients and CF centres’ respiratory outbreaks. We characterized genomic and phenotypic changes in 15 serial isolates from two CF patients (1S and 2B) with chronic pulmonary M. massiliense infection leading to death, as well as four isolates from a CF centre outbreak in which patient 2B was the index case.Results Comparative genomic analysis revealed the mutations affecting growth rate, metabolism, transport, lipids (loss of glycopeptidolipids), antibiotic susceptibility (macrolides and aminoglycosides resistance), and virulence factors. Mutations in 23S rRNA, mmpL4, porin locus and tetR genes occurred in isolates from both CF patients. Interestingly, we identified two different spontaneous mutation events at the mycobacterial porin locus: a fusion of two tandem porin paralogs in patient 1S and a partial deletion of the first porin paralog in patient 2B. These genomic changes correlated with reduced porin protein expression, diminished 14C-glucose uptake, slower bacterial growth rates, and enhanced TNF-α induction in mycobacteria-infected THP-1 human cells. Porin gene complementation of porin mutants partly restored 14C-glucose uptake, growth rate and TNF-α levels to those of intact porin strains.Conclusions We hypothesize that specific mutations accumulated and maintained over time in M. massiliense, including mutations shared among transmissible strains, collectively lead to more virulent, host adapted lineages in CF patients and other susceptible hosts.

Major planktonic lifeforms such as diatoms, dinoflagellates, meroplankton and holoplankton have recently shown significant and alarming changes in abundance - mainly downwards trends - around the northwest European shelf. This has major implications for food web connections and for ecosystem services including seafood provision and carbon storage. We have quantified these changes in abundance for 2006–2019/20 using a Plankton Index (PI) and show that the scale of spatial aggregation is critical to the ability of the PI to detect change, understand causal mechanisms, and provide advice to policymakers.We derived PI statistics in the Celtic and North Seas from data from the Continuous Plankton Recorder survey offshore and England’s Environment Agency inshore using three sets of spatial units: (i) Ecohydrodynamic (EHD) units based on hydro-biogeochemical modelling, (ii) ‘COMP4′ areas based on cluster analysis of satellite data for chlorophyll a and primary productivity, and (iii) English coastal and estuarine Water Framework Directive (WFD) waterbodies. For the largest scale areas, the EHD units (median size 87,000 km2), we find greater change in plankton communities than previously reported, suggesting that these shifts have continued and possibly intensified in recent years. The smaller-scale COMP4 areas (median size 6,700 km2) appear to encompass more spatially coherent changes in plankton community structure than EHD units; at this scale PI values indicate community shifts of greater magnitude. These COMP4 areas provide a reasonable compromise scale for linking offshore plankton communities to large-scale drivers of change such as climate warming. For inshore plankton communities, larger changes are detected at the smaller WFD waterbody scale (median size 11 km2). This scale allows direct links to coastal management measures and is more suitable for linking to land-sourced pressures.Recent integration of the UK’s OSPAR and WFD plankton monitoring data management enables the exploration of changes across spatial scales to develop a holistic understanding of ecosystem health. Regional-sea scale derivation of the PI for coastal waters provides a clear indication that changes are occurring, at least in phytoplankton communities, while localised PI statistics offer an additional layer of information which can be an important tool for linking to localised drivers of change including coastal anthropogenic pressures. Broadscale inshore zooplankton monitoring is needed to evaluate the coastal plankton community holistically; zooplankton communities offshore are also changing but these changes cannot currently be linked to coastal processes. Layering information across spatial scales provides a breadth of system-level understanding beyond what any one typology can provide.

Abstract Objectives The Anal Cancer High-grade squamous intraepithelial lesions (HSIL) Outcomes Research (ANCHOR) Health-Related Symptom Index (A-HRSI) is a 25-item measure that assesses physical symptoms and impacts, and psychological symptoms. To promote generalizability and equity in the capture of these concepts in Spanish-speaking participants, we linguistically validated a Spanish version of A-HRSI. Methods Following independent forward translation and reconciliation of A-HRSI from English to Spanish, two rounds of cognitive interviews were completed with ANCHOR participants who had been diagnosed with anal HSIL in the prior nine months and preferred delivery of their healthcare in Spanish. Interviews were coded to highlight any items and concepts that were reported as being difficult for any reason by ≥ 3 participants, with such items revised during a research team panel discussion and tested in a second round of interviews if applicable. Results Seventeen participants representing 8 nationalities were enrolled (Round 1 n=10, Round 2 n=7); 7 participants reported not completing high school (41.2%). No difficulties were reported with respect to the theoretical concepts measured by A-HRSI. We made modifications to the Spanish translation of eight items and two response option terms in cases where participants had difficulty understanding a term, experienced problems in discriminating between terms, or preferred the use of an alternative term to represent the concept(s). Conclusion The Spanish version of A-HRSI is a linguistically valid tool that can be used to assess physical symptoms, impacts, and psychological symptoms related to anal HSIL. Plain English Summary Language is a tremendous barrier to enrolling patients to clinical trials. The anal cancer high-grade squamous intraepithelial lesions (HSIL) outcomes research [ANCHOR] trial is a randomized clinical trial that recently established that the treatment of anal HSIL, versus active monitoring, is effective in reducing incidence of anal cancer in persons living with HIV (PLWH). The ANCHOR Health-Related Symptom Index (A-HRSI) is a 25-item patient-reported outcomes measure that was developed to assess physical symptoms, physical impacts, and psychological symptoms related to anal HSIL. As approximately 10% of ANCHOR participants preferred the delivery of their healthcare in Spanish, the purpose of the present study was to linguistically validate a Spanish version of A-HRSI. Based on feedback from interviews with 17 participants from the ANCHOR trial who had been diagnosed with anal HSIL in the prior nine months and preferred delivery of their healthcare in Spanish, we made modifications to the Spanish translation of eight items and two response option terms in cases where participants had difficulty understanding a term, experienced problems in discriminating between terms, or preferred the use of an alternative term to represent the concept(s). The Spanish version of A-HRSI is a linguistically valid tool that can be used to assess physical symptoms, impacts, and psychological symptoms related to anal HSIL as part of clinical trials or routine care.

Abstract Background Anti GM-CSF autoantibodies (aAb) have been related to acquired pulmonary alveolar proteinosis (PAP) and described in cases of severe infections such as cryptococcosis and nocardiosis in previously healthy subjects. Whether there are different anti-GM-CSF autoantibodies corresponding to these phenotypes is unclear. Therefore, we examined anti-GM-CSF autoantibodies to determine whether amount or neutralizing activity could distinguish between groups. Methods Plasma samples gathered in the National Institute of Health from patients with anti GM-CSF aAb and either PAP (n = 15), cryptococcal meningitis (n = 15), severe nocardiosis (n = 5) or overlapping phenotypes (n = 6) were compared. The relative amount of aAb was assessed using a particle-based approach, reported as a mouse monoclonal anti-human GM-CSF as standard curve and expressed in an arbitrary Mouse Monoclonal Antibody Unit (MMAU). The neutralizing activity of the plasma was assessed by inhibition of GM-CSF-induced intracellular phospho-STAT5 (pSTAT5) in monocytes. Results Anti-GM-CSF aAb relative amounts were higher in PAP patients compared to those with cryptococcosis (mean 495 ± 464 MMAU vs 197 ± 159 MMAU, p = 0.02); there was no difference with patients with nocardiosis (430 ± 493 MMAU) nor between the two types of infections. The dilution of plasma resulting in 50% inhibition of GM-CSF-induced pSTAT5 (approximate IC50) did not vary appreciably across groups of patients (1.6 ± 3.1%, 3.9 ± 6% and 1.8 ± 2.2% in PAP patients, cryptococcosis and nocardiosis patients, respectively). Nor was the concentration of GM-CSF necessary to induce 50% of maximal GM-CSF-induced pSTAT5 in the presence of 10 MMAU of anti-GM-CSF aAb (EC50). When studying longitudinal samples from patients with PAP or disseminated nocardiosis, the neutralizing effect of anti-GM-CSF aAb was relatively constant over time despite targeted treatments and variations in aAb levels. Conclusions Despite different clinical manifestations, anti-GM-CSF antibodies were similar across PAP, cryptococcosis and nocardiosis. Underlying host genetics and functional analyses may help further differentiate the biology of these conditions.

The potential for multiyear prediction of impactful Earth system change remains relatively underexplored compared to shorter (subseasonal to seasonal) and longer (decadal) timescales. In this study, we introduce a new initialized prediction system using the Community Earth System Model version 2 (CESM2) that is specifically designed to probe potential and actual prediction skill at lead times ranging from 1 month out to 2 years. The Seasonal-to-Multiyear Large Ensemble (SMYLE) consists of a collection of 2-year-long hindcast simulations, with four initializations per year from 1970 to 2019 and an ensemble size of 20. A full suite of output is available for exploring near-term predictability of all Earth system components represented in CESM2. We show that SMYLE skill for El Niño–Southern Oscillation is competitive with other prominent seasonal prediction systems, with correlations exceeding 0.5 beyond a lead time of 12 months. A broad overview of prediction skill reveals varying degrees of potential for useful multiyear predictions of seasonal anomalies in the atmosphere, ocean, land, and sea ice. The SMYLE dataset, experimental design, model, initial conditions, and associated analysis tools are all publicly available, providing a foundation for research on multiyear prediction of environmental change by the wider community.

Ecological predictions are necessary for testing whether processes hypothesized to regulate species population dynamics are generalizable across time and space. In order to demonstrate generalizability, model predictions should be transferable in one or more dimensions, where transferability is the successful prediction of responses outside of the model data bounds. While much is known as to what makes spatially-oriented models transferable, there is no general consensus as to the spatio-temporal transferability of ecological time series models. Here, we examine whether the intrinsic predictability of a time series, as measured by its complexity, could limit such transferability using an exceptional long-term dataset of Adélie penguin breeding abundance time series collected at 24 colonies around Antarctica. For each colony, we select a suite of environmental variables from the Community Earth System Model, version 2 to predict population growth rates, before assessing how well these environmentally-dependent population models transfer temporally and how reliably temporal signals replicate through space. We show that weighted permutation entropy (WPE), a model-free measure of intrinsic predictability recently introduced to ecology, varies spatially across Adélie penguin populations, perhaps in response to stochastic environmental events. We demonstrate that WPE can strongly limit temporal predictive performance, although this relationship could be weakened if intrinsic predictability is not constant over time. Lastly, we show that WPE can also limit spatial forecast horizon, which we define as the decay in spatial predictive performance with respect to the physical distance between focal colony and predicted colony. Irrespective of intrinsic predictability, spatial forecast horizons for all Adélie penguin breeding colonies included in this study are surprisingly short and our population models often have similar temporal and spatial predictive performance compared to null models based on long-term average growth rates. For cases where time series are complex, as measured by WPE, and the transferability of biologically-motivated mechanistic models are poor, we advise that null models should instead be used for prediction. These models are likely better at capturing more generalizable relationships between average growth rates and long-term environmental conditions. Lastly, we recommend that WPE can provide valuable insights when evaluating model performance, designing sampling or monitoring programs, or assessing the appropriateness of preexisting datasets for making conservation management decisions in response to environmental change.

PurposeThough copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.MethodsWe performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.ResultsOf the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.ConclusionPairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

Several agri-environment schemes aim to improve pollinator diversity and abundance, including the sowing of wildflower areas. These seed mixes are often either low in floral diversity and target few pollinator species (mainly social bees), or high in floral diversity but with limited evidence of good establishment of the component species. In order to support a greater diversity of wild bees in farmland, we need more diverse seed mixes, containing species shown to support a wide diversity of insect pollinators, with good establishment and long flowering periods. Here we trialled two typical seed mixes, a low-diversity Fabaceae-heavy mix (FAB) and a more diverse wildflower mix (WF), against two novel wildflower mixes, one based on literature sources (LT), and one based on first-hand surveys of pollinator attraction to flowers growing on a wildflower farm (WB). Both new mixes were focussed on plants attractive to wild bee species. Replicated field plots were set up on two farms and monitored over three years. Our novel wildflower mixes had higher floral diversity and abundance than the FAB mix, and began flowering earlier, reaching their floral peak before the FAB mix, potentially providing forage for a broader range of pollinators or those with earlier flight seasons. The high floral abundance in LT and WB was driven by annuals in the first year, and then multiple perennials in the second and third year. We identified five perennials from four families (Daucus carota, Leucanthemum vulgare, Geranium pyrenaicum, Lotus corniculatus and Trifolium hybridum) that established well on both farms, are known to be attractive to a diversity of bee species, and thus could be considered as providing a more taxonomically diverse base for creating future mixes. However, the mixes provided few floral resources in April (needed by early-flying wild bees), and more research is required in this area.

Intermittent and ephemeral channels are a critical component of the global hydrologic network. The dominant feature in dryland environments, ephemeral channel transmission loss facilitates aquifer recharge. Characterizing flow intermittency improves groundwater storage estimates; however, limited gauging of intermittent systems impedes this understanding. This research develops an improved classification for surface flow, optimized for ephemeral systems using linear discriminant function analysis and remotely sensed imagery. It further applies this methodology to assess temporal and spatial flow patterns across the Souss channel, an ungauged, ephemeral system in central Morocco. Linear discriminant function analysis demonstrates high predictive accuracy for Landsat imagery, with significantly improved classification success as compared to the Modified Normalized Difference Water Index. Application to the Souss channel from 1984 to 2022 points to a decreasing trend in flow frequency. Despite this change, flow events remain concentrated within the wet season, critical for regional aquifer recharge. Spatial flow characteristics further support sustained infiltration, with the majority of events focused within the upstream channel section during both dry and wet seasons. Decreased occurrence moving downstream highlights the likely impact of additional factors such as transmission loss, evapotranspiration, and agricultural abstraction contributing to channel intermittency.

In the high-latitude Arctic, wintertime sea ice and snow insulate the relatively warmer ocean from the colder atmosphere. While the climate warms, wintertime Arctic surface heat fluxes remain dominated by the insulating effects of snow and sea ice covering the ocean until the sea ice thins enough or sea ice concentrations decrease enough to allow for direct ocean–atmosphere heat fluxes. The Community Earth System Model version 1 Large Ensemble (CESM1-LE) simulates increases in wintertime conductive heat fluxes in the ice-covered Arctic Ocean by ∼ 7–11 W m−2 by the mid-21st century, thereby driving an increased warming of the atmosphere. These increased fluxes are due to both thinning sea ice and decreasing snow on sea ice. The simulations analyzed here use a sub-grid-scale ice thickness distribution. Surface heat flux estimates calculated using grid-cell mean values of sea ice thicknesses underestimate mean heat fluxes by ∼16 %–35 % and overestimate changes in conductive heat fluxes by up to ∼36 % in the wintertime Arctic basin even when sea ice concentrations remain above 95 %. These results highlight how wintertime conductive heat fluxes will increase in a warming world even during times when sea ice concentrations remain high and that snow and the distribution of snow significantly impact large-scale calculations of wintertime surface heat budgets in the Arctic.

Abstract The Tibetan Plateau (TP) is known as one of the most sensitive regions to climate change, and it has experienced accelerated warming in recent decades. However, to what degree the TP warming amplification relates to remote forcing such as sea ice loss in the Arctic sea ice remains unclear. Here, we found that the decline of sea ice concentration over the Barents-Kara Sea (BKS) could account for 18–32% of the winter warming over the TP by comparing observational data and ensemble experiments from an atmospheric general circulation model. The reduced BKS sea ice and resultant upward turbulent heat fluxes can intensify a Rossby wave train propagating equatorward to the TP. As a result, the enhanced southwesterlies towards the TP strengthen the warm advection over most parts of the TP and lead to TP warming. In addition, an atmospheric teleconnection between the Arctic and the TP also exists in the interannual variability. That is, a tripole mode in air temperature, with warm centers in the Arctic and TP but a cold center in the mid-high latitudes of the Eurasian continent in between. Our results imply that the BKS sea ice loss could intensify such a tripole mode and thus enhancing the winter TP warming.

The melting of sea ice floes from the edges (lateral melting) results in open-water formation and subsequently increases absorption of solar shortwave energy. However, lateral melt plays a small role in the sea ice mass budget in both hemispheres in most climate models. This is likely influenced by the simple parameterization of lateral melting in sea ice models that are constrained by limited observations. Here we use a coupled climate model (CESM2.0) to assess the sensitivity of modeled sea ice state to the lateral melt parameterization in preindustrial and 2×CO2 runs. The runs explore the implications of how lateral melting is parameterized and structural changes in how it is applied. The results show that sea ice is sensitive both to the parameters determining the effective lateral melt rate and the nuances in how lateral melting is applied to the ice pack. Increasing the lateral melt rate is largely compensated for by decreases in the basal melt rate but still results in a significant decrease in sea ice concentration and thickness, particularly in the marginal ice zone. Our analysis suggests that this is tied to the increased efficiency of lateral melting at forming open water during the summer melt season, which drives the majority of the ice–albedo feedback. The more seasonal Southern Hemisphere ice cover undergoes larger relative reductions in sea ice concentration and thickness for the same relative increase in lateral melt rate, likely due to the hemispheric differences in the role of the sea-ice–upper-ocean coupling. Additionally, increasing the lateral melt rate under a 2×CO2 forcing, where sea ice is thinner, results in a smaller relative change in sea ice mean state but suggests that open-water-formation feedbacks are likely to steepen the decline to ice-free summer conditions. Overall, melt processes are more efficient at forming open water in thinner ice scenarios (as we are likely to see in the future), suggesting the importance of accurately representing thermodynamic evolution. Revisiting model parameterizations of lateral melting with observations will require finding new ways to represent salient physical processes.

Summary: Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research.

IntroductionAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and poikiloderma in association with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) are rare inherited syndromes resulting from biallelic pathogenic variants in AIRE and heterozygous pathogenic variants in FAM111B, respectively. The clinical diagnosis of APECED and POIKTMP rely on the development of two or more characteristic disease manifestations that define the corresponding syndromes. We discuss the shared and distinct clinical, radiographic, and histological features between APECED and POIKTMP presented in our patient case and describe his treatment response to azathioprine for POIKTMP-associated hepatitis, myositis, and pneumonitis.MethodsThrough informed consent and enrollment onto IRB-approved protocols (NCT01386437, NCT03206099) the patient underwent a comprehensive clinical evaluation at the NIH Clinical Center alongside exome sequencing, copy number variation analysis, autoantibody surveys, peripheral blood immunophenotyping, and salivary cytokine analyses.ResultsWe report the presentation and evaluation of a 9-year-old boy who was referred to the NIH Clinical Center with an APECED-like clinical phenotype that included the classic APECED dyad of CMC and hypoparathyroidism. He was found to meet clinical diagnostic criteria for POIKTMP featuring poikiloderma, tendon contractures, myopathy, and pneumonitis, and exome sequencing revealed a de novo c.1292T>C heterozygous pathogenic variant in FAM111B but no deleterious single nucleotide variants or copy number variants in AIRE.DiscussionThis report expands upon the available genetic, clinical, autoantibody, immunological, and treatment response information on POIKTMP.