Search

Abstract Wolverine distribution contracted along the southern periphery of its range in North America during the 19th and 20th centuries due primarily to human influences. This history, along with low densities, sensitivity to climate change, and concerns about connectivity among fragmented habitats spurred the recent US federal listing of threatened status and special concern status in Canada. To help inform large scale landscape connectivity, we collected 882 genetic samples genotyped at 19 microsatellite loci. We employed multiple statistical models to assess the landscape factors (terrain complexity, human disturbance, forest configuration, and climate) associated with wolverine genetic connectivity across 2.2 million km2 of southwestern Canada and the northwestern contiguous United States. Genetic similarity (positive spatial autocorrelation) of wolverines was detected up to 555 km and a high-to-low gradient of genetic diversity occurred from north-to-south. Landscape genetics analyses confirmed that wolverine genetic connectivity has been negatively influenced by human disturbance at broad scales and positively influenced by forest cover and snow persistence at fine- and broad–scales, respectively. This information applied across large landscapes can be used to guide management actions with the goal of maintaining or restoring population connectivity.

Abstract Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization’s Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment.

Rasmussen's encephalitis (RE) is a progressive inflammatory neurological process most commonly occurring in children characterized by drug-resistant focal epilepsy, hemiplegia, and cognitive decline, with brain atrophy and white matter changes typically localized to 1 hemisphere of the brain. Because the clinical course of RE is often indistinguishable from a variety of medical conditions, MRI has historically been the primary diagnostic tool. Here, we report both the clinical course and progression of neuroimaging findings of a 5-year-old female who had very subtle early cortical and white matter changes on MRI and was diagnosed with RE by correlating the clinical presentation, imaging, and electrographic findings.

Abstract Early peritoneal dialysis (PD)-related infection is a severe complication. This study investigated the relationship between patient–doctor contact (PDC) duration and early PD-related infection. In the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) Korea, incident dialysis patients receiving PD were divided into two groups based on PDC duration (

Abstract Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O2) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single‐blind randomized crossover design, 16 male military personnel (age, 25.3 ± 2.4 year, body mass, 86.2 ± 9.3 kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20 min; 0 m; 20.9% O2) and hypoxia (20 min; 6096 m, 9.7% O2) using a reduced O2 breathing device (ROBD). (R)‐3‐Hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME; 650 mg/kg, split dose given at 30 min prior to each exposure) or taste‐matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R‐βHB and glucose concentrations, cognitive performance and O2 saturation (SpO2) were collected throughout. KME ingestion increased blood R‐βHB concentration, which was rapid and sustained (>4 mM 30 min post; P

Abstract Acute ingestion of exogenous ketone supplements in the form of a (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate‐intensity exercise. In a single‐blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O2). The R‐BD R‐βHB KME (573 mg/kg) or a calorie‐ and taste‐matched placebo (∼50 g maltodextrin) were co‐ingested with 40 g of dextrose before exposure to hypoxia. The R‐βHB concentrations were rapidly elevated and sustained (>3 mM; P

Abstract Background Depression is the most diagnosed mental health condition among people living with HIV. Collaborative care is an effective intervention for depression, typically delivered in primary care settings. The HIV Translating Initiatives for Depression into Effective Solutions (HITIDES) clinical intervention involves a depression care team housed off-site that supports depression care delivery by HIV care providers. In a randomized controlled trial, HITIDES significantly improved depression symptoms for veterans living with HIV and delivered cost savings. However, no HIV clinics in the Veterans Health Administration (VHA) have implemented HITIDES; as such, it is unclear what implementation strategies are necessary to launch and sustain this intervention. Methods This hybrid type-3 effectiveness-implementation trial examines the implementation and effectiveness of HITIDES in 8 VHA HIV clinics randomly assigned to one of two implementation arms. Each arm uses a different implementation strategy package. Arm 1 includes an intervention operations guide; an on-site clinical champion who, with the help of a peer community of practice, will work with local clinicians and leadership to implement HITIDES at their site; and patient engagement in implementation tools. Arm 2 includes all strategies from Arm 1 with assistance from an external facilitator. The primary implementation outcomes is reach; secondary outcomes include adoption, implementation dose, depressive symptoms, and suicidal ideation. We will conduct a budget impact analysis of the implementation strategy packages. We hypothesize that Arm 2 will be associated with greater reach and adoption and that Arm 1 will be less costly. Discussion Preliminary work identified implementation strategies acceptable to veterans living with HIV and HIV care providers; however, the effectiveness and cost of these strategies are unknown. While the depression care team can deliver services consistently with high quality, the ability of the depression care team to engage with HIV care providers at sites is unknown. Findings from this study will be used to inform selection of implementation strategies for a broad rollout to enhance depression and suicide care for people living with HIV. Trial registration ClinicalTrials.gov ID: NCT05901272, Registered 10 May 2023, https://clinicaltrials.gov/study/NCT05901272

Abstract Background Individuals on the autism spectrum commonly have differences from non-autistic people in expressing their emotions using communicative behaviors, such as facial expressions. However, it is not yet clear if this reduced expressivity stems from reduced physiological reactivity in emotional contexts or if individuals react internally, but do not show these reactions externally to others. We hypothesized that autism is characterized by a discordance between in-the-moment internal psychophysiological arousal and external communicative expressions of emotion. Methods Forty-one children on the autism spectrum and 39 non-autistic, typically developing (TD) children of two age groups (2–4 and 8–12 years) participated in a low-level stress task whilst wearing a wireless electrocardiogram. Children’s negative emotional expressions (facial, vocal, bodily) were coded following standardized protocols. Alexithymia traits were assessed using the Children’s Alexithymia Measure with school-aged children only. Data analyses involved ANOVAs, correlations, and sensitivity analyses. Results There were no group differences in physiological arousal (heart rate) or in communicative expressions of stress to the stress task. For TD preschoolers, physiological arousal during the stress task was associated with vocal expressions and for TD school-aged children, they were associated with facial and bodily expressions. By contrast, for children on the autism spectrum, physiological arousal during the stress tasks was not associated with communicative expressions across age groups. Conclusions Our findings suggest that children on the autism spectrum might experience emotional disconcordance, in that their physiological arousal does not align with their communicative expressions. Therefore, the internally experienced stress of children on the autism spectrum may be inadvertently missed by teachers and caregivers and, consequently, learning opportunities for teaching emotional communication and regulation may be also missed. Our results support the use of wearable biosensors to facilitate such interventions in children on the autism spectrum.

Background: Current treatment guidelines for infective endocarditis focus on left-sided infective endocarditis. Because right-sided infective endocarditis has different presentations and outcomes, it is crucial to further delineate surgical outcomes for isolated tricuspid valve endocarditis (TVE). Methods: This retrospective study reviewed 374 surgically treated patients with isolated TVE from January 2012 through April 2022 who underwent isolated tricuspid valve surgical procedures. Primary outcomes were in-hospital mortality, permanent pacemaker need, and postsurgical inotropic support. Results: The in-hospital mortality was 4% (n = 15). Patients with liver disease had 3.81-times higher odds of death vs no liver disease (odds ratio [OR], 3.81; 95% CI, 1.22-12.17). A pacemaker was required in 17% of patients without a prior pacemaker, which was 4.07 times the odds with tricuspid valve replacement (OR, 4.07; 95% CI, 1.72-11.60) vs tricuspid valve repair. Each yearly increase in patient age demonstrated lower odds of permanent pacemaker requirement by 7% (OR, 0.93; 95% CI, 0.89-0.97). The odds for postoperative inotropic support increased 2.55-times higher in patients receiving preoperative inotropic agents (OR, 2.55; 95% CI, 1.29-5.05), 2.27-times higher with renal failure (OR, 2.27; 95% CI, 1.38-3.74), and 86% higher in patients administered preoperative heparin (OR, 1.86; 95% CI, 1.14-3.02). Conclusions: Mortality of surgical treatment for TVE was 4%, with higher risks with liver disease. Tricuspid valve replacement was associated with higher odds for permanent pacemaker vs repair. Renal failure, preoperative inotropic support, and preoperative heparin were associated with higher odds for postoperative inotropic support. These findings further illustrate surgical outcomes with TVE.

Netherton syndrome (NS) is a rare autosomal recessive disorder that occurs due to a loss-of-function mutation in SPINK5; this loss results in significant inflammation, as well as perturbations of the skin barrier’s integrity and functionality. While it is unclear which inflammatory pathways contribute to the development of NS, recent studies have demonstrated the expression of interleukin (IL)-17/IL-36, as well as several Th2 cytokines. Consequently, immunohistochemistry (IHC) with IL-36 may serve as a potential tool for aiding the histopathological diagnosis of this condition. In this case series, we present two cases of NS and capture their immunostaining pattern with IL-36. Both cases demonstrated robust expression of IL-36. This finding bolsters the hypothesis that NS is partially driven by Th17 activation and suggests the potential utility of IL-36 IHC as part of the workup for this rare and diagnostically elusive entity. LEKTI IHC was negative in one biopsy, revealing a limitation of this stain in diagnosing NS.

Abstract A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.

Abstract 53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the ‘leaky’ DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

Abstract Ovarian function suppression (OFS) benefits young women with hormone receptor (HR)-positive breast cancer but they are at risk for ovarian function breakthrough. We assessed endocrine effects of gonadotropin-releasing hormone agonist (GnRHa) treatment in a prospective cohort of patients aged ≤ 40 years with HR-positive breast cancer. Plasma estradiol (E2), estrone, and follicule-stimulating hormone (FSH) levels were measured from blood samples drawn 1 and 4 years after diagnosis. Patient characteristics, invasive breast cancer-free survival (iBCFS), and overall survival (OS) were compared between those with and without E2 > 2.72 pg/mL during GnRHa treatment. Among eligible patients, 54.7% (46/84) and 60% (15/25) had E2 > 2.72 pg/mL at 1 and 4 years, respectively. Factors associated with E2 > 2.72 pg/mL at 1 year were no prior chemotherapy (P = 0.045) and tamoxifen use (P = 0.009). After a median follow-up of 7 years, among patients with stage I-III breast cancer (N = 74), iBCFS events were seen in 6 (8.1%) with E2 > 2.72 pg/mL and 5 (6.8%) with E2 ≤ 2.72 pg/mL (P = 0.893). Among patients with de novo metastatic breast cancer (N = 12), 6 (50%) with E2 > 2.72 pg/mL and 3 (25%) with E2 ≤ 2.72 pg/mL died during follow-up (P = 0.052). Larger studies exploring the clinical implications of incomplete E2 suppression by GnRHa are needed to ensure optimal OFS treatment strategies are being employed for this population.

Abstract Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends far from the active site. We leverage our library to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.

A better understanding of modifiable psychological processes that could reduce pathways to violent radicalization (VR) would greatly aid researchers, providers, policy makers, and individuals at risk for VR. Cognitive fusion, the tendency for behavior to be overly regulated and influenced by one’s thoughts and feelings, and a common intervention target within Acceptance and Commitment Therapy (ACT), may be one such fulcrum. Participants, recruited via gateway snowball sampling, were 233 young adults drawn from five communities in North America as part of Wave 4 of the Somali Youth Longitudinal Study. Utilizing moderation and mediation path analysis in MPlus, the study examined the relations between cognitive fusion, VR, and three important variables associated with VR risk: post traumatic stress symptoms, experiences of daily discrimination, and perceptions of a just government. Findings supported that higher levels of cognitive fusion were directly related to greater openness to VR. Additionally, higher levels of cognitive fusion statistically mediated the link between both daily discrimination and openness to VR as well as between post traumatic stress symptoms and openness to VR. Findings also highlighted that cognitive fusion and perceptions of a just government interacted such that openness to VR was highest in individuals who had low perceptions of a just government and had high levels of cognitive fusion. Results of this study provide preliminary evidence of the potential role of high cognitive fusion in the pathways to VR and further evidence for its potential integration as a target domain within deradicalization efforts.

Abstract This review aims at providing an extensive discussion of modern constraints relevant for dense and hot strongly interacting matter. It includes theoretical first-principle results from lattice and perturbative QCD, as well as chiral effective field theory results. From the experimental side, it includes heavy-ion collision and low-energy nuclear physics results, as well as observations from neutron stars and their mergers. The validity of different constraints, concerning specific conditions and ranges of applicability, is also provided.

Objective The objective is to externally validate and assess the opportunity to update the Canadian COVID-19 Mortality Score (CCMS) to predict in-hospital mortality among consecutive non-palliative COVID-19 patients infected with Omicron subvariants at a time when vaccinations were widespread.Design This observational study validated the CCMS in an external cohort at a time when Omicron variants were dominant. We assessed the potential to update the rule and improve its performance by recalibrating and adding vaccination status in a subset of patients from provinces with access to vaccination data and created the adjusted CCMS (CCMSadj). We followed discharged patients for 30 days after their index emergency department visit or for their entire hospital stay if admitted.Setting External validation cohort for CCMS: 36 hospitals participating in the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN). Update cohort for CCMSadj: 14 hospitals in CCEDRRN in provinces with vaccination data.Participants Consecutive non-palliative COVID-19 patients presenting to emergency departments.Main outcome measures In-hospital mortality.Results Of 39 682 eligible patients, 1654 (4.2%) patients died. The CCMS included age, sex, residence type, arrival mode, chest pain, severe liver disease, respiratory rate and level of respiratory support and predicted in-hospital mortality with an area under the curve (AUC) of 0.88 (95% CI 0.87 to 0.88) in external validation. Updating the rule by recalibrating and adding vaccination status to create the CCMSadj changed the weights for age, respiratory status and homelessness, but only marginally improved its performance, while vaccination status did not. The CCMSadj had an AUC of 0.91 (95% CI 0.89 to 0.92) in validation. CCMSadj scores of 15 had observed mortality of >56.8%.Conclusions The CCMS remained highly accurate in predicting mortality from Omicron and improved marginally through recalibration. Adding vaccination status did not improve the performance. The CCMS can be used to inform patient prognosis, goals of care conversations and guide clinical decision-making for emergency department patients with COVID-19.

Introduction There are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methods We tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed

# Background and Purpose The prevalence of arm pain in youth baseball players is high with approximately half reporting arm pain during the season, and the number of ulnar collateral ligament reconstructions in youth baseball players is increasing. Few studies have examined the relationship between shoulder strength and passive range of motion (ROM) with arm pain (either shoulder or elbow pain) during throwing, especially in athletes in early adolescence. The purpose of this study was to determine the relationship between shoulder ROM and strength and the presence of arm pain during throwing in youth baseball players. It was hypothesized that less internal rotation (IR) ROM, less total rotational ROM, and lower IR and external rotation (ER) strength would be associated with arm pain. # Study Design Observational cohort study # Methods Sixty-five youth male baseball players between the ages of 12-15 were enrolled. Shoulder strength (ER, IR, ER/IR strength ratio, scaption) and passive ROM (ER, IR, flexion, horizontal adduction) were collected prior to the start of the spring 2021 baseball season. Players self-reported their arm pain frequency during throwing as never, rarely, sometimes, often, or always. The relationship between reported arm pain frequency during throwing and shoulder ROM and strength measurements was examined. # Results ER (ρ= -0.289, p=0.020) and IR strength (ρ= -0.262, p=0.035) were weakly and negatively correlated with reports of arm pain during throwing. No other clinical variables were associated with reports of arm pain (p ≥ 0.124) # Conclusion In youth baseball players, greater IR and ER strength were associated with less arm pain frequency during throwing, while ROM was not associated with arm pain frequency. Future research should explore these variables prospectively to determine if changes in ROM and strength are related to the development of arm pain in youth baseball players. # Level of Evidence 3

ObjectivesWe aim to assess the pooled incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) in clinical trials and real-world studies of chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancy and compare the incidences among different agents.MethodsThe PubMed, Embase, and Web of Science databases were searched for clinical trials and real-world studies. An inverse-variance weighting model was used to calculate pooled incidences and subgroup analyses. Multivariable analysis was conducted using binomial-normal modeling.ResultsSeventy-five trials comprising 3,184 patients were included. The overall pooled incidence was 26.9% (95% CI, 21.7–32.7%) for all-grade and 10.5% (95% CI, 8.1–13.6%) for high-grade ICANS. In subgroup analysis, cohorts with anti-CD19 drugs had significantly higher ICANS incidences than cohorts with other agents. The multivariable analysis demonstrated higher odds of ICANS in anti-CD19 drug studies for high-grade (OR, 4.6) compared to anti-BCMA drug studies. In 12 real-world studies, studies used axicabtagene ciloleucel with CD28 (54.0% all-grade, 26.4% high-grade) exhibited significantly higher rates of all-grade and high-grade ICANS than studies using tisagenlecleucel with 4-1BB (17.2% all-grade, 6.1% high-grade).ConclusionsThe overall incidences of ICANS with CAR T-cell therapy were 26.9% for all-grade and 10.5% for high-grade. Compared with other agents, patients with anti-CD19 drugs had a significantly increased risk of developing high-grade ICANS. Therefore, careful monitoring of ICANS should be considered for patients undergoing CAR T-cell therapy.

The past several decades have seen rapid advances in diagnosis and treatment of cardiovascular diseases and stroke, enabled by technological breakthroughs in imaging, genomics, and physiological monitoring, coupled with therapeutic interventions. We now face the challenge of how to (1) rapidly process large, complex multimodal and multiscale medical measurements; (2) map all available data streams to the trajectories of disease states over the patient's lifetime; and (3) apply this information for optimal clinical interventions and outcomes. Here we review new advances that may address these challenges using digital twin technology to fulfill the promise of personalized cardiovascular medical practice. Rooted in engineering mechanics and manufacturing, the digital twin is a virtual representation engineered to model and simulate its physical counterpart. Recent breakthroughs in scientific computation, artificial intelligence, and sensor technology have enabled rapid bidirectional interactions between the virtual‐physical counterparts with measurements of the physical twin that inform and improve its virtual twin, which in turn provide updated virtual projections of disease trajectories and anticipated clinical outcomes. Verification, validation, and uncertainty quantification builds confidence and trust by clinicians and patients in the digital twin and establishes boundaries for the use of simulations in cardiovascular medicine. Mechanistic physiological models form the fundamental building blocks of the personalized digital twin that continuously forecast optimal management of cardiovascular health using individualized data streams. We present exemplars from the existing body of literature pertaining to mechanistic model development for cardiovascular dynamics and summarize existing technical challenges and opportunities pertaining to the foundation of a digital twin.

Abstract While extreme weather events are often localized, the potential effects on global forests can be far reaching due to the interconnected nature of forest product markets. To better understand these dynamics, this study leverages historical forest‐based wind damage data in the United States and applies this information as shocks within a global forest sector outlook model. A large, localized wind event modeled as a shock to the US South creates a one‐time increase of 18.7 million m3 from salvage harvest operations, equal to over 4% of national harvest. This crowds out traditional harvest activities, leading to downward pressure on prices in the short run, followed by a persistent effect that could take approximately 25 years to dissipate from markets. Average annual wind damage contributes downward pressure on roundwood prices between 1% and 4% in the United States, and this effect is distributed to other countries. The findings suggest that large, localized shocks reverberate across regions and wood product markets due to their interconnected supply chains and trade patterns, and these impacts have important temporal dynamics. Another key result is that the magnitude of these effects are offset by endogenous market reactions in other markets. In other words, unaffected regions change their harvesting patterns in order to compensate for changes in the availability of fiber, shedding light on the importance of capturing global channels as large shocks materialize in changes in market dynamics internationally. Monte Carlo simulations suggest a wide confidence band on salvage harvest rates and prices.

Cardiac allografts suffer diastolic dysfunction early post-heart transplantation (HTx) due to ischemic injury, however the natural course of diastology recovery post HTx remains unknown (Tallaj et al., 2007 [1]). We retrospectively reviewed 60 adult HTx patients between 2015 and 2021 at a single site. Invasive hemodynamics and echocardiograms were obtained at 2 weeks and 1, 3, 6, and 12 months post-HTx. RA strain by 2D feature tracking was compared to intracardiac pressure measurements. In all patients, we observed normalization of RV and RA filling pressures by post-operative week 12 and recovery of diastolic dysfunction by month 6. There was an inverse correlation between RV end-diastolic pressure and RA contractile (r = −0.192, p

Abstract Data from commercial off-the-shelf (COTS) wearables leveraged with machine learning algorithms provide an unprecedented potential for the early detection of adverse physiological events. However, several challenges inhibit this potential, including (1) heterogeneity among and within participants that make scaling detection algorithms to a general population less precise, (2) confounders that lead to incorrect assumptions regarding a participant’s healthy state, (3) noise in the data at the sensor level that limits the sensitivity of detection algorithms, and (4) imprecision in self-reported labels that misrepresent the true data values associated with a given physiological event. The goal of this study was two-fold: (1) to characterize the performance of such algorithms in the presence of these challenges and provide insights to researchers on limitations and opportunities, and (2) to subsequently devise algorithms to address each challenge and offer insights on future opportunities for advancement. Our proposed algorithms include techniques that build on determining suitable baselines for each participant to capture important physiological changes and label correction techniques as it pertains to participant-reported identifiers. Our work is validated on potentially one of the largest datasets available, obtained with 8000+ participants and 1.3+ million hours of wearable data captured from Oura smart rings. Leveraging this extensive dataset, we achieve pre-symptomatic detection of COVID-19 with a performance receiver operator characteristic (ROC) area under the curve (AUC) of 0.725 without correction techniques, 0.739 with baseline correction, 0.740 with baseline correction and label correction on the training set, and 0.777 with baseline correction and label correction on both the training and the test set. Using the same respective paradigms, we achieve ROC AUCs of 0.919, 0.938, 0.943 and 0.994 for the detection of self-reported fever, and 0.574, 0.611, 0.601, and 0.635 for detection of self-reported shortness of breath. These techniques offer improvements across almost all metrics and events, including PR AUC, sensitivity at 75% specificity, and precision at 75% recall. The ring allows continuous monitoring for detection of event onset, and we further demonstrate an improvement in the early detection of COVID-19 from an average of 3.5 days to an average of 4.1 days before a reported positive test result.

Abstract In this study, we explore the utilization of penalized likelihood estimation for the analysis of sparse photon counting data obtained from distributed target lidar systems. Specifically, we adapt the Poisson Total Variation processing technique to cater to this application. By assuming a Poisson noise model for the photon count observations, our approach yields denoised estimates of backscatter photon flux and related parameters. This facilitates the processing of raw photon counting signals with exceptionally high temporal and range resolutions (demonstrated here to 50 Hz and 75 cm resolutions), including data acquired through time-correlated single photon counting, without significant sacrifice of resolution. Through examination involving both simulated and real-world 2D atmospheric data, our method consistently demonstrates superior accuracy in signal recovery compared to the conventional histogram-based approach commonly employed in distributed target lidar applications.

Abstract Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.

Abstract We estimated the operating characteristics of ICD-10 code U07.1, introduced by the World Health Organization in 2020, to identify lab-confirmed SARS-CoV-2. CCEDRRN is a national research registry of adults (March 2020–August 2021) with suspected/confirmed SARS-CoV-2 identified in Canadian emergency departments (EDs) using chart review (symptoms, clinical information, and lab test results including SARS-CoV-2 polymerase chain reaction, PCR results). CCEDRRN data were linked to administrative hospitalization discharge and ED ICD-10 diagnostic codes (accessed centrally via the Canadian Institute for Health Information). We identified ICD-10 diagnostic codes in CCEDRRN participants. We defined lab-confirmed SARS-CoV-2 based on at least one positive PCR in the 0–14 days before the ED presentation and/or during hospitalization (in those admitted from ED). We performed separate analyses for CCEDRRN participants discharged from ED and those hospitalized from the ED. Additional analyses were stratified by province, sex, age, and (for hospitalized patients) timing of the first PCR test. The sensitivity of ICD-10 code U07.1 for a positive SARS-CoV-2 test was 93.6% (95% CI 93.0–94.1%) in those hospitalized from ED and 83.0% (95% CI 82.1–83.9%) in those discharged from the ED. Sensitivity was similar across provinces and demographics, but in each stratified analysis, values were higher in those hospitalized versus those discharged from ED. The ICD-10 diagnostic code for U07.1 within administrative data identified most lab-confirmed SARS-CoV-2 within persons hospitalized from ED, although a significant number of cases discharged from ED were missed. This should be considered when using administrative data for research and public health planning.

Motor vehicle crashes are a leading cause of death in the United States, and disproportionately impact communities of color. Replacing human control with automated vehicles (AVs) holds the potential to reduce crashes and save lives. The benefits of AVs, including automated shuttles, buses, or cars could extend beyond safety to include improvements in congestion, reductions in emissions, and increased access to mobility, particularly for vulnerable populations. However, AVs have not attained the level of public trust that has been expected, given their potential to save lives and increase access to mobility. Public opinion surveys have highlighted safety and security concerns as reasons for this lack of confidence. In this study, we present the findings of an experiment we conducted to actively shift mindsets on AVs toward advancing health equity. We demonstrate through a nationally representative sample of 2265 U.S. adults that the public support for AVs can be improved by expanding their scope of application to include advancing social benefit. The survey began with questions on respondent's support for AVs based on a priori knowledge and beliefs. Consistent with prior surveys, baseline support (strong support and some degree of support) was low at 26.4% (95% confidence interval 24.0?29.0). After introducing information about how AVs could be used to provide mobility for older adults, those with limited income, or the vision-impaired, respondents were asked to reassess their support for AVs. Support significantly increased to include the majority of respondents. By prioritizing the deployment of AVs to serve individuals and communities in greatest need of mobility, AVs would not only demonstrate compelling social value by reducing disparities but would also gain widespread public support among the U.S. public.

Abstract Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) that can present across the age spectrum, highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Desmopressin is a synthetic analog of the endogenous peptide hormone arginine vasopressin, or antidiuretic hormone. The drug was initially developed in 1967 with the intention of creating a molecule that could treat central diabetes insipidus, a condition characterized by a deficiency of ADH and results in the production of large volumes of dilute urine (Zaoral et al., 1967). In the years since, therapeutic use of desmopressin has expanded beyond central diabetes insipidus to include the treatment of many other conditions, notably nocturnal polyuria in children with enuresis (bed wetting), adult nocturia, congenital bleeding disorders, and more. The purpose of the present narrative review is to recount the history of desmopressin, review its key therapeutic indications, and discuss important pharmacologic and pharmacokinetic considerations of this medication.

Background: Removal of zero-COVID restrictions in China led to a surge in COVID-19 cases. In response, countries imposed restrictions on Chinese travelers. However, border policies imposed may not have been informed by accurate data and may not have provided substantial benefits. Methods: We analyzed quarantines sufficient to prevent additional in-country transmission for February 13–19, 2023 based on World Health Organization (WHO) and self-reported infections to estimate prevalence. Results: We have shown that self-reported prevalence data indicated more stringent border restrictions compared to WHO-published prevalence statistics. No travel restrictions were required for Singapore, South Korea, and Japan so that infections would not be greater than with complete border closure. However, a 1-, 2-, and 3-day quarantine were indicated for England, Germany, and Scotland respectively. A 10-, 13-, and 14-day quarantine were required for Italy, France, and the Philippines, respectively, to prevent an increase in within-country infections due to travel. Vietnam and Thailand required a complete border shutdown. Conclusion: Our results demonstrated the necessity for accurate and timely reporting of pandemic statistics to prevent an increase in viral spread. Through the minimum quarantine analysis, countries can use science to determine policy, minimize international friction, and improve the cost-efficiency of interventions.

Abstract Objective To report the first steps of a project to automate and optimize scheduling of multidisciplinary consultations for patients with longstanding dizziness utilizing artificial intelligence. Study Design Retrospective case review. Setting Quaternary referral center. Methods A previsit self‐report questionnaire was developed to query patients about their complaints of longstanding dizziness. We convened an expert panel of clinicians to review diagnostic outcomes for 98 patients and used a consensus approach to retrospectively determine what would have been the ideal appointments based on the patient's final diagnoses. These results were then compared retrospectively to the actual patient schedules. From these data, a machine learning algorithm was trained and validated to automate the triage process. Results Compared with the ideal itineraries determined retrospectively with our expert panel, visits scheduled by the triage clinicians showed a mean concordance of 70%, and our machine learning algorithm triage showed a mean concordance of 79%. Conclusion Manual triage by clinicians for dizzy patients is a time‐consuming and costly process. The formulated first‐generation automated triage algorithm achieved similar results to clinicians when triaging dizzy patients using data obtained directly from an online previsit questionnaire.

Introduction Determining aetiology of severe illness can be difficult, especially in settings with limited diagnostic resources, yet critical for providing life-saving care. Our objective was to describe the accuracy of antemortem clinical diagnoses in young children in high-mortality settings, compared with results of specific postmortem diagnoses obtained from Child Health and Mortality Prevention Surveillance (CHAMPS).Methods We analysed data collected during 2016–2022 from seven sites in Africa and South Asia. We compared antemortem clinical diagnoses from clinical records to a reference standard of postmortem diagnoses determined by expert panels at each site who reviewed the results of histopathological and microbiological testing of tissue, blood, and cerebrospinal fluid. We calculated test characteristics and 95% CIs of antemortem clinical diagnostic accuracy for the 10 most common causes of death. We classified diagnostic discrepancies as major and minor, per Goldman criteria later modified by Battle.Results CHAMPS enrolled 1454 deceased young children aged 1–59 months during the study period; 881 had available clinical records and were analysed. The median age at death was 11 months (IQR 4–21 months) and 47.3% (n=417) were female. We identified a clinicopathological discrepancy in 39.5% (n=348) of deaths; 82.3% of diagnostic errors were major. The sensitivity of clinician antemortem diagnosis ranged from 26% (95% CI 14.6% to 40.3%) for non-infectious respiratory diseases (eg, aspiration pneumonia, interstitial lung disease, etc) to 82.2% (95% CI 72.7% to 89.5%) for diarrhoeal diseases. Antemortem clinical diagnostic specificity ranged from 75.2% (95% CI 72.1% to 78.2%) for diarrhoeal diseases to 99.0% (95% CI 98.1% to 99.6%) for HIV.Conclusions Antemortem clinical diagnostic errors were common for young children who died in areas with high childhood mortality rates. To further reduce childhood mortality in resource-limited settings, there is an urgent need to improve antemortem diagnostic capability through advances in the availability of diagnostic testing and clinical skills.

Over the last few decades, reliance on point-of-use (POU) treatment for removing actual or perceived contaminants in drinking water has increased within the United States. Understanding POU treatment removal performance, and accurately estimating metals exposure at the tap, is critical for understanding POU water treatment device effectiveness and potential reductions in contaminant exposure. Previous bench-scale efforts have documented significant removal of dissolved Pb using faucet-mounted POU filters; however, limited efforts have challenged these filters with extreme water quality conditions which are more common in homes reliant on private well water. Characterization of typical rates of metals uptake by POU filters would support: improved exposure estimates and predictions, a better understanding of long-term filter performance under different conditions, and identification of conditions where POU use is recommended. In the current study, standard faucet-mount activated carbon POU filters were tested in a laboratory setting in order to: 1) determine removal of Pb, Cu, and Fe under low and high concentration conditions designed to reflect previous observations of residential water quality; and 2) evaluate the effectiveness of an acid flow-through procedure in recovering metals from used POU filters exposed to varying concentrations of Pb, Cu, and Fe. Although the filters tested here successfully removed Pb and Cu from waters of both high and low-level concentrations (>91% removal), Fe removal varied considerably. The acid flow-through procedure yielded mixed results: while 25.1-70.4% of influent Pb mass was recovered, recovery of Cu and Fe from the dosed filters was unpredictable. This was attributed in part to leaching from the filter media itself; in addition to Cu and Fe, concentrations of several other elements (e.g., Ti, Si, Al) increased and appeared to leach from control filters during the acid flow-through procedure. Given these results, alternative methods for assessing uptake of metals to POU filters should be explored.

Iliocaval venous obstruction presents a significant danger to patients with increased risk for deep vein thromboses, wounds, and lower extremity edema. Iliocaval venous obstruction arises from many causes, one of which is congenital deformity of the inferior vena cava. Here we present a 39-year-old man with complex congenital cardiac disease with interruption of the infrahepatic, left-sided, inferior vena cava who presented with nonhealing left leg wounds and edema. He was found to have left common iliac vein occlusion and underwent balloon venoplasty and self-expanding stent placement, which demonstrated mid-term patency of the stent and healing of leg wounds.

Purpose Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women’s Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population.Participants The YWS enrolled 1302 women newly diagnosed with stages 0–IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints.Findings to date Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors.Future plans With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer.Trial registration number NCT01468246.

Introduction Critically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting.Methods and analysis A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity.Ethics and dissemination This study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial.Trial registration number Australian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Abstract Introduction Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post‐treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone. Materials and Methods We performed whole‐transcriptome and small non‐coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC). Results We identified 12 novel saliva and serum miRNAs and a panel of unique miRNA and mRNA signatures, significantly differentially expressed in OSCC patients relative to HC (log2 fold change: 2.6–26.8; DE: 0.02–0.000001). We utilized a combined panel of the 10 top‐deregulated miRNAs and mRNAs and evaluated their putative diagnostic potential (>87% sensitivity; 100% specificity), recommending seven of them for further validation. We also identified unique saliva and serum miRNAs associated with OSCC and smoking history (OSCC smokers vs. never‐smokers or HC: log2 fold change: 22–23; DE: 0.00003–0.000000001). Functional and pathway analyses indicated interactions between the discovered OSCC‐related non‐invasive miRNAs and mRNAs and their targets, through PI3K/AKT/mTOR signaling. Conclusion Our data support our hypothesis that using paired saliva and serum from the same individuals and deep sequencing analyses can provide unique combined mRNA and miRNA signatures associated with canonical pathways that may have a diagnostic advantage relative to saliva or serum alone and may be useful for clinical testing. We believe this data will contribute to effective preventive care by post‐treatment monitoring of patients, as well as suggesting potential targets for therapeutic approaches.

Abstract Seismic anisotropy is a powerful tool to map deformation processes in the deep Earth. Below 660 km, however, observations are scarce and conflicting. In addition, the underlying crystal scale mechanisms, leading to microstructures and crystal orientations, remain poorly constrained. Here, we use multigrain X‐ray diffraction in the laser‐heated diamond anvil cell to investigate the orientations of hundreds of grains in pyrolite, a model composition of the Earth's mantle, at in situ pressure and temperature. Bridgmanite in pyrolite exhibits three regimes of microstructures, due to transformation and deformation at low and high pressure. These microstructures result in predictions of 1.5%–2% shear wave splitting between 660 and 2,000 km with reversals in fast S‐wave polarization direction at about 1,300 km depth. Anisotropy can develop in pyrolite at lower mantle conditions, but pressure has a significant impact on the plastic behavior of bridgmanite, and hence seismic observations, which may explain conflicting anisotropy observations.

This study pairs a recently developed regulatory framework for Chile with a regional case study in Aysén to highlight systems-level pinch points and synergies for the future application of a circular economy framework for construction demolition waste (CE-CDW) management. A qualitative coding process called purposive text analysis was used to extract, aggregate, and structurally analyze causal connections between factors impacting CE-CDW derived from 15 semi-structured interviews with relevant stakeholders in Aysén. Findings highlight recommendations for future CE-CDW policy and practice centering on well-structured and enforceable laws and regulations that can undergird effective stakeholder collaboration, market competitiveness, and infrastructure development.

This study developed a random forest approach for downscaling the coarse-resolution (36 km) soil moisture measured by The National Aeronautics and Space Administration (NASA) Soil Moisture Active Passive (SMAP) mission to 1 km spatial resolution, utilizing airborne remotely sensed data (radar backscatter and radiometer retrieved soil moisture), vegetation characteristics (normalized difference vegetation index), soil properties, topography, and ground soil moisture measurements from before the launch of SMAP for training a random forest model. The 36 km SMAP soil moisture product was then downscaled by the trained model to 1 km resolution using the information from SMAP. The downscaled soil moisture was evaluated using airborne retrieved soil moisture observations and ground soil moisture measurements. Considering the airborne retrieved soil moisture as a reference, the results demonstrated that the proposed random forest model could downscale the SMAP radiometer product to 1 km resolution with a correlation coefficient of 0.97, unbiased Root Mean Square Error of 0.048 m3 m−3 and bias of 0.016 m3 m−3. Accordingly, the downscaled soil moisture captured the spatial and temporal heterogeneity and demonstrated the potential of the proposed machine learning model for soil moisture downscaling.

Abstract Cofilin family proteins have essential roles in remodeling the cytoskeleton through filamentous actin depolymerization and severing. The short, unstructured N-terminal region of cofilin is critical for actin binding and harbors the major site of inhibitory phosphorylation. Atypically for a disordered sequence, the N-terminal region is highly conserved, but specific aspects driving this conservation are unclear. Here, we screen a library of 16,000 human cofilin N-terminal sequence variants for their capacity to support growth in S. cerevisiae in the presence or absence of the upstream regulator LIM kinase. Results from the screen and biochemical analysis of individual variants reveal distinct sequence requirements for actin binding and regulation by LIM kinase. LIM kinase recognition only partly explains sequence constraints on phosphoregulation, which are instead driven to a large extent by the capacity for phosphorylation to inactivate cofilin. We find loose sequence requirements for actin binding and phosphoinhibition, but collectively they restrict the N-terminus to sequences found in natural cofilins. Our results illustrate how a phosphorylation site can balance potentially competing sequence requirements for function and regulation.

Abstract Mitochondrial cytochrome c maturation (CCM) requires heme attachment via distinct pathways termed systems I and III. The mosaic distribution of these systems in Archaeplastida raises questions about the genetic mechanisms and evolutionary forces promoting repeated evolution. Here, we show a recurrent shift from ancestral system I to the eukaryotic-specific holocytochrome c synthase (HCCS) of system III in 11 archaeplastid lineages. Archaeplastid HCCS is sufficient to rescue mutants of yeast system III and Arabidopsis system I. Algal HCCS mutants exhibit impaired growth and respiration, and altered biochemical and metabolic profiles, likely resulting from deficient CCM and reduced cytochrome c-dependent respiratory activity. Our findings demonstrate that archaeplastid HCCS homologs function as system III components in the absence of system I. These results elucidate the evolutionary trajectory and functional divergence of CCM pathways in Archaeplastida, providing insight into the causes, mechanisms, and consequences of repeated cooption of an entire biological pathway.

Goal: This paper introduces an automated post-traumatic stress disorder (PTSD) screening tool that could potentially be used as a self-assessment or inserted into routine medical visits to aid in PTSD diagnosis and treatment. Methods: With an emotion estimation algorithm providing arousal (excited to calm) and valence (pleasure to displeasure) levels through discourse, we select regions of the acoustic signal that are most salient for PTSD detection. Our algorithm was tested on a subset of data from the DVBIC-TBICoE TBI Study, which contains PTSD Check List Civilian (PCL-C) assessment scores. Results: Speech from low-arousal and positive-valence regions provide the highest discrimination for PTSD. Our model achieved an AUC (area under the curve) of 0.80 in detecting PCL-C ratings, outperforming models with no emotion filtering (AUC = 0.68). Conclusions: This result suggests that emotion drives the selection of the most salient temporal regions of an audio recording for PTSD detection.

P-band radiometry has been demonstrated to have a deeper sensing depth than L-band, making the consideration of multilayer microwave interactions necessary. In addition, the scattering and phase interference effects are different at the P-band, requiring a reconsideration of the need for coherent models. However, the impact remains to be clarified, and understanding the validity and limitations of these models at both L- and P-bands is crucial for their refinement and application. Therefore, two general categories of microwave emission models, including two stratified coherent models (Njoku and Wilhite) and four incoherent models (conventional tau-omega model and three multilayer models being zero-order, first-order, and incoherent solution), were intercompared for the first time on the same dataset. This evaluation utilized observations of L- and P-bands radiometry under different land cover conditions from a tower-based experiment in Victoria, Australia. Model estimations of brightness temperature (TB) were consistent with measurements, with the lowest root mean square error (RMSE) at P-band V-polarization under corn (2 K) and the highest RMSE at L-band H-polarization under bare soil (13 K). Coherent models performed slightly better than incoherent models under bare soil (3 K less RMSE), while the opposite was true under vegetated soil conditions (1 K less RMSE). Coherent and incoherent models showed maximum differences (3 K at P-band and 2 K at L-band), correlating strongly with soil moisture variations at 0–10 cm. Findings suggest that coherent and incoherent models performed similarly; thus, incoherent models may be preferable for estimating TB at L- and P-bands due to reduced computational complexity.

Abstract Despite increased Atlantic hurricane risk, projected trends in hurricane frequency in the warming climate are still highly uncertain, mainly due to short instrumental record that limits our understanding of hurricane activity and its relationship to climate. Here we extend the record to the last millennium using two independent estimates: a reconstruction from sedimentary paleohurricane records and a statistical model of hurricane activity using sea surface temperatures (SSTs). We find statistically significant agreement between the two estimates and the late 20th century hurricane frequency is within the range seen over the past millennium. Numerical simulations using a hurricane-permitting climate model suggest that hurricane activity was likely driven by endogenous climate variability and linked to anomalous SSTs of warm Atlantic and cold Pacific. Volcanic eruptions can induce peaks in hurricane activity, but such peaks would likely be too weak to be detected in the proxy record due to large endogenous variability.