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Residual stress poses significant risks to the life management of key engineering components in nuclear fusion reactors. It is often induced within the narrow heat-affected zone (HAZ) during remote laser welding, essential for maintaining and assembling in-vessel components. Residual stress interacts with high temperatures, degrading mechanical properties and altering fracture mechanisms. Establishing a correlative methodology with microstructures to investigate these stresses and understand their effects on mechanical properties within the narrow HAZ is crucial for extending the reactor's lifetime. In this study, advanced residual stress measurements, including plasma-focused ion beam and digital image correlation, were employed to reveal heterogeneous stress distribution, discovering the peak tensile residual stress of 150 MPa at the interface of the fusion zone (FZ) and HAZ, and peak compressive residual stress of 550 MPa within HAZ. The residual stress effects on micro-hardness are quantitatively evaluated, showing a 25% hardening effect at HAZ/BM interface and a 10% softening effects at fusion line. The deformation mechanism is further analysed using tensile testing, where the residual stress effects were prominent in the low-stress field, reducing 6.5% strain evolution, while microstructures reinforced the material in the high-stress field. At elevated temperatures, the joint exhibited a significant reduction from 532 MPa to 345 MPa for yield strength and from 12 % to 8 % for elongation, with distinct fracture mechanisms observed through fractography compared to its behaviour at room temperature. These findings provide critical insights into enhancing laser welding processing and maintaining the structural integrity of in-service nuclear fusion reactor components.

Summary: Monoclonal antibodies have potential as rapidly developable agents for treatment and prevention of emerging viruses. The ACTIV-2 trial randomized persons with mild-moderate COVID-19 to the monoclonal antibody combination tixagevimab/cilgavimab via intramuscular injection (600 mg IM) or infusion (300 mg IV) versus placebo. We present final safety and laboratory outcomes; primary outcomes were previously reported. The analyzed IM group included 214 participants, and the IV group, 106 participants. Adverse events were not different between treatment and placebo. The half-life of both components was >90 days for IM or 75 days for IV. New anti-drug antibodies were about 3 times more likely in active vs. placebo recipients. SARS-CoV-2 neutralizing antibodies increased 157-fold at 7 days and 127-fold at 1 month (IM-treated) but were less robust in IV participants. These data can inform future development of monoclonal antibodies against SARS-CoV-2 and other viruses, even if this intervention is of low utility for contemporary SARS-CoV-2 variants.

A recently introduced quantitative susceptibility mapping (QSM) technique, χ-separation, offers the capability to separate paramagnetic (χpara) and diamagnetic (χdia) susceptibility distribution within the brain. In-vivo high-resolution mapping of iron and myelin distribution, estimated by χ-separation, could provide a deeper understanding of brain substructures, assisting the investigation of their functions and alterations. This can be achieved using 7T MRI, which benefits from a high signal-to-noise ratio and susceptibility effects. However, applying χ-separation at 7T presents difficulties due to the requirement of an R2 map, coupled with issues such as high specific absorption rate (SAR), large B1 transmit field inhomogeneities, and prolonged scan time. To address these challenges, we developed a novel deep neural network, R2PRIMEnet7T, designed to convert a 7T R2* map into a 3T R2′ map. Building on this development, we present a new pipeline for χ-separation at 7T, enabling us to generate high-resolution χ-separation maps from multi-echo gradient-echo data. The proposed method is compared with alternative pipelines, such as an end-to-end network and linearly-scaled R2′, and is validated against χ-separation maps at 3T, demonstrating its accuracy. The 7T χ-separation maps generated by the proposed method exhibit similar contrasts to those from 3T, while 7T high-resolution maps offer enhanced clarity and detail. Quantitative analysis confirms that the proposed method surpasses the alternative pipelines. The proposed method results well delineate the detailed brain structures associated with iron and myelin. This new pipeline holds promise for analyzing iron and myelin concentration changes in various neurodegenerative diseases through precise structural examination.

Rationale & Objective: Equations for estimated glomerular filtration rate (eGFR) have previously included a coefficient for African American race. We evaluated and compared risk of incident stroke and dementia between old and new equations of eGFR for African American and non-African American participants. Study Design: Prospective observational study. Setting & Participants: Baseline values were collected from 6,814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort between 2000 and 2002. Participants were followed up until 2018. The analytic sample consisted of 6,646 participants (mean [SD] age 62 [10] years; 53% female; 39% White, 27% African American, 12% Chinese American, and 22% Hispanic/Latino). Exposure: eGFR equation from 2021 based on serum creatinine and cystatin C levels without race. Outcome: Incident stroke and dementia. Analytical Approach: Cox proportional regression adjusting for demographic, lifestyle, and clinical variables was performed to estimate associations between different eGFR measures and risk of incident stroke and dementia. Results: During a median follow-up period of 17 years, 349 (5.3%) participants experienced an incident stroke event, and 574 (8.6%) participants experienced incident dementia. In the fully adjusted model, overall participants with eGFR 90 mL/min/1.73 m2 were at significantly increased risk of dementia (HR, 95% CI: 1.73, 1.21-2.45). A lower eGFR was not significantly associated with incident stroke (1.30, 0.75-2.24). African American participants tended to be reclassified to a lower group of eGFR in the new equations, whereas non-African American participants were reclassified to a higher group of eGFR. When comparing older versus newer equations of eGFR in African American and non-African American participants in association with incident stroke and dementia, differences were minimal. Limitations: Incident dementia was ascertained through International Classification of Diseases (Ninth and Tenth Revisions) codes. Conclusions: Our findings illustrate participants with 2021 eGFR 90 mL/min/1.73 m2 have higher risk of dementia in both African American and non-African American participants, but not of stroke. Plain Language Summary: Existing research has established that declined kidney function is associated with stroke and dementia. Kidney function is commonly estimated using inputs of blood proteins alongside demographic inputs of age, sex at birth, and race. Inclusion of race to estimate kidney function has gained increased scrutiny given its problematic nature of being a societal construct rather than an inherent biological trait that affects function of the kidneys. Recommendations were recently made to remove race from this estimation, and data were lacking on the relationship between new estimates of kidney function with outcomes such as stroke and dementia. Our research provides updated risk estimates for stroke and dementia using the new estimation for kidney function in a large multiethnic cohort.

Aquaculture has traditionally focused on supporting human food production, but there is a growing need for aquaculture associated with environmental restoration. For example, the in situ and ex situ rearing of corals for coral reef restoration is now implemented worldwide, but its success is limited by the lack of reef herbivores to combat the phase shift from coral-to-macroalgae-dominance on reefs, especially in the Caribbean. Laboratory-based aquaculture of some reef herbivores is possible but labor-intensive and insufficient to supply the numbers needed for large-scale restoration. We examined whether this bottleneck could be alleviated by the semi-wild mariculture of the Caribbean King Crab (MaguiMithrax spinosissimus)in saltwater quarries for subsequent use in coral reef restoration in the Florida Keys, Florida (USA).We surveyed the physico-chemical characteristics of 16 saltwater quarries in the Florida Keys relative to conditions in the wild and, in four quarries where crabs occurred, we examined crab population dynamics in comparison to that in the wild. Water chemistry and the availability of food (macroalgae) and crevice shelters were suitable for crab mariculture down to depths of at least 6 m. Herbivore competitors and predators were few in quarries, and there was no difference in the population size structure, fecundity, predatory mortality, or health of crabs in quarries compared to that in the wild. Therefore, the low-cost semi-wild mariculture of large numbers M. spinosissimus is feasible in saltwater quarries and could alleviate a logistical bottleneck to herbivore restoration on Caribbean coral reefs.

The ability to cope with stress is imperative for performance in competitive gaming, yet there is a lack of research examining the impact of gaming and esports participation on physiological stress. One way to measure physiological stress is via heart rate variability (HRV). The current literature examining HRV during competitive gaming is limited, with most studies focusing on multiplayer online battle arena games. To better understand the physiological demands of gaming, investigation into the stress imposed on players during gameplay of various game genres is required. In this study, we compared the physiological stress incurred on players who played either a competitive (sports) or a non-competitive (action-adventure) video game. Forty participants played either a sports or action-adventure game, whilst having their heart rate and heart rate variability monitored. Results showed that, compared to a pre-gaming baseline, playing either game increased heart rate, lowered RR intervals, and reduced both vagally mediated time and frequency domain vmHRV. Playing the sport game for 10 min induced higher heart rate and lower RR intervals compared to playing the action-adventure game. However, 10 min of game play was not enough to identify meaningful differences in vmHRV based on game genre played. These findings advance our understanding of the impact of video gaming on heart rate and heart rate variability, providing a useful method for coaches and players to index player stress and recovery.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response.CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts.Our GWAS identified two genome-wide significant (P

Background: Unhealthy alcohol use is a leading cause of preventable mortality and a risk factor for an array of social and health problems. The Intervention in Small primary care Practices to Implement Reduction in unhealthy alcohol use (INSPIRE) study is part of a nationwide campaign to improve the identification and treatment of patients engaging in unhealthy alcohol use. Methods: We conducted a single arm, pragmatic study consisting of seventeen primary care practices in the Chicago metropolitan area, Wisconsin, and California across two waves with a 6-month latent period, a 12-month intervention period, followed by a 6-month sustainability period. Enrolled practices were independent, Federally Qualified Health Centers, network-based, and academic health centers. INSPIRE utilized the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework to examine implementation feasibility, fidelity, and performance of clinicians on practice adoption of screening, brief intervention, referral to treatment (SBIRT) and medication for unhealthy alcohol use (MAUD) activities in primary care clinics. Results: Seventeen eligible primary care practices were enrolled over the course of 21 months beginning in March of 2020 through December of 2021. There was a pause in recruitment from March of 2020 through July of 2020 due to the Covid-19 pandemic. The majority of enrolled practices were small (

Objective: To explore outcomes of anterior cruciate ligament (ACL) reconstructive surgery (ACLR) between individuals using private and public healthcare. Methods: We conducted a cross-sectional study of participants, 9–36 months post-ACLR using public or private healthcare services. Multivariable linear regression assessed the association between healthcare service used (private versus public) with self-reported outcomes (Knee injury and Osteoarthritis Outcome Score (KOOS) subscales of pain, symptoms, sport/recreation, knee-related quality of life (QoL); 0–100 scale), adjusting for potential confounders. Results: A total of 314 participants were included (median age 29 years, 35 ​% female). One hundred and thirty-nine (44 ​%) underwent ACLR using private healthcare. Individuals using private healthcare for ACLR reported better post-ACLR knee-related QoL (mean difference 5.1; 95%CI 0.6 to 9.7) than individuals using public healthcare, when adjusted for available confounders. No other KOOS subscale scores (pain, symptoms, sport/recreation) differed between healthcare groups in our adjusted analysis. Conclusions: Australian young adults who underwent ACLR using private healthcare (compared to public healthcare) services reported better knee-related QoL post-operatively in this cross-sectional cohort. Sociodemographic and socioeconomic factors contributed little to the differences observed. Future research should consider potential disparities in outcomes between participants using differing healthcare services both clinically and when recruiting participants into research studies evaluating outcomes post-ACLR.

Objective: Describe the injury characteristics, game circumstances, and immediate action and management of injuries sustained by boys and girls participating in junior community Australian football. Design: Cohort Study. Methods: All community junior Australian football players from one Victorian-based league were eligible to participate if they were injured during a game and presented to the gameday first aid medics. Injured players were subsequently followed up with a phone call to undertake an injury surveillance survey. The injury surveillance survey gathered information relating to the injury characteristics, game circumstances and management undertaken. Additionally, all players who sustained a head impact were asked about the presence or absence of concussion-related symptoms. Results: 439 players sustained an injury in the 2022 season, with 354 (80.6 ​%) participating in the survey. The head was the most frequently reported injured body region (n ​= ​194, 54.8 ​%), with approximately half (n ​= ​101) being a diagnosed or suspected sports-related concussion. The next three most frequently reported body regions were the ankle (n ​= ​29, 8.2 ​%), knee (n ​= ​24, 6.8 ​%), and shoulder (n ​= ​20, 5.6 ​%). Almost all injuries were acute onset (n ​= ​340, 96.0 ​%) and resulted from a contact-based mechanism (94.9 ​%, n ​= ​222 direct contact, n ​= ​114 indirect contact). Tackling was the most frequently reported game circumstance resulting in an injury (n ​= ​160, 45.2 ​%). Conclusion: The head was the most frequently reported injured body region, with approximately one in every two reported head impacts resulting in a diagnosed/suspected sports-related concussion. Injury prevention strategies that promote safety when tackling and being tackled may reduce the frequency of injury, warranting further investigation.

Background: The association between cardiovascular disease and advanced liver disease is incompletely understood. To explore this interaction, we compared management, clinical outcomes, readmission rates, and resource utilization in ST-elevation myocardial infarction (STEMI) patients with and without liver disease. Methods: The Nationwide Readmissions Database (2016–2020) was queried to identify hospitalizations for STEMI. Cohorts were stratified by presence of liver disease. Liver disease was defined as documented diagnosis of liver cirrhosis or liver failure. Multivariable regression model and propensity score matching was used to compare the risk of outcomes. Results: Among 1,029,608 hospitalizations for STEMI; 45,478 (4.4 %) patients had a history of significant liver disease. Patient with liver disease had higher baseline prevalence of diabetes, chronic kidney disease, anemia, and heart failure. After propensity matching (N = 24,067 in each group), patients with liver disease had higher in-hospital mortality (48.8 % vs 17.3 %, aOR: 6.80 [CI: 6.55–7.06], p

Background: Acute blood loss and transfusion are recognized risks factors of total hip (THA) and total knee arthroplasty (TKA). This study aimed to investigate the clinical value of immediate postoperative hemoglobin and hematocrit (H&H) tests following primary elective THA and TKA. Methods: This retrospective observational study was undertaken at a single academic hospital. Medical records were reviewed for a consecutive series of patients undergoing primary elective THA and TKA over a 12-month period. Patient demographic data; the use of preoperative anticoagulants; preoperative and postoperative blood test results; and the incidence of postoperative allogenic blood transfusion (ABT) were collected. The primary outcome measure was the incidence of postoperative ABT prescribed in response to the immediate postoperative H&H result. Results: Overall, 367 eligible patients were included, with 167 THA (46%) and 200 TKA (54%) cases. Only 3 patients (0.8%) received a postoperative ABT; none on the day of surgery or on postoperative day 1. Immediate postoperative H&H tests were drawn in 246 patients (67%), but it did not influence clinical decision-making with regards to transfusion. No significant differences in ABT were observed in relation to patient age, sex, body mass index, operation (THA or TKA), or the use of preoperative anticoagulation medication. The incidence of ABT was significantly higher in patients with a combined preoperative hemoglobin

Fusion In-vessel components, assembled and maintained using laser welding, one of the most promising techniques, exhibit complex distributions of residual stress, microstructures, and material properties. These residual stresses can compromise structural integrity and lifespan of critical components. Although using advanced experimental measurements can evaluate the residual stress for individual case, extending the measurements to massive number of components are costly and time-consuming. Traditional machine learning (ML) models struggle to account for the heterogeneity and anisotropy of these stress distributions. Here, we develop a novel ML framework based on the Eurofer97 steel, the structural material for in-vessel components. The ML framework is trained on high-resolution residual stress data derived from recently-developed evaluation techniques. Combining with microstructures, the model enables prediction of heterogenous and anisotropic residual stress distribution. It successfully predicts the compressive residual stress in fusion zone (∼−200 MPa) balanced by tensile residual stress in heat affected zone (∼300 MPa), aligning closely with experimental results with the R-squared value of 0.989 and the mean square error of 10−4. Unlike experiments that take hours, the ML model provides predictions within seconds. It offers valuable insights into residual stress prediction for various joints, enhancing the reliability and lifetime prediction of in-vessel components.

Oligo-deoxythymidine (oligo-dT) ligand-based affinity chromatography is a robust method for purifying mRNA drug substances within the manufacturing process of mRNA-based products, including vaccines and therapeutics. However, the conventional batch mode of operation for oligo-dT chromatography has certain drawbacks that reduce the productivity of this process. Here, we report a new continuous oligo-dT chromatography process for the purification of in vitro transcribed mRNA, which reduces losses, improves the efficiency of oligo-dT resin use, and intensifies the chromatography process. Furthermore, the quality by design (QbD) framework was used to establish a design space for the newly developed method. The optimization of process parameters (PPs), including salt type, salt concentration, load flow rate and mRNA load concentration both in batch and the continuous mode, achieved a greater than 90% yield (mRNA recovery) along with greater than 95% mRNA integrity and greater than 99% purity. The productivity of continuous chromatography was estimated to be 5.75-fold higher, and the operating cost was estimated 15% lower, when compared with batch chromatography. Moreover, the QbD framework was further used to map the relationship between critical quality attributes and key performance indicators as a function of critical process parameters and critical material attributes.

Many apps (e.g., social media, online streaming) include a social component where individual privacy decisions go beyond individual contexts and affect other people. We investigated people's willingness to adopt four apps and assessed the attentional processes underlying how people make tradeoffs when their own privacy and/or others' privacy is violated in a within-subjects design (NStudy1 = 304; NStudy2 = 355). We also assessed individual differences in the willingness to adopt apps in terms of other-oriented traits (e.g., empathic concern, justice sensitivity etc.). The main findings show that (1) when own privacy was protected and others' privacy was not protected, people were more willing to adopt apps (compared to when others' privacy was protected and own privacy not protected). (2) Individual differences in information acquisition predicted the decision to adopt apps. More attention to others' privacy information was associated with lower willingness to adopt apps when others' privacy was not protected. (3) Higher sensitivity to justice and self-transcendence values were associated with lower adoption of the apps when self or other-privacy violations were present. Our results suggest that people differ in how much they care about whether their privacy decisions might affect others negatively. Accordingly, they differ in their attention to privacy information especially in situations where own and others' privacy is in conflict. People's justice concerns extend to concern for both self and other-privacy violations. These findings imply that although people may care about privacy, individual differences are important to understand why people care about own and others' privacy differently.

Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor and immune stimulatory effects of an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L and IFNβ. We demonstrated this virus successfully infects HGSOC cell lines and primary human ascites samples in vitro. We evaluated the anti-tumor and immunostimulatory activity in vivo in immune competent mouse models. Intraperitoneal delivery of MEM-288 decreased ascites and solid tumor burden compared to controls, and treatment generated a systemic anti-tumor immune response. The tumor microenvironment had a higher proportion of anti-tumor macrophages and decreased markers of angiogenesis. MEM-288 is a promising immunotherapy agent in HGSOC, with further pre-clinical studies required to understand the mechanism of action in the peritoneal microenvironment and clinical activity in combination with other therapies.

Summary: Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Background: Drug-coated balloons (DCBs) may be a viable alternative to drug-eluting stents (DES) for de novo small caliber coronary artery lesions. However, there remains a lack of data regarding the long-term efficacy of this approach. Objectives: The purpose of this study was to compare the rates of major adverse cardiovascular events (MACE) after 3-year follow-up among patients randomized to DCB versus DES for the treatment of small caliber coronary arteries with reference vessel diameter between 2 and 3 mm. Methods: We systematically searched MEDLINE, EMBASE, and CENTRAL databases from their inception to July 2023 for randomized controlled trials comparing DCB versus DES for small caliber coronary artery disease. The primary end point was MACE at 3-year follow-up. Risk of bias was assessed using the Cochrane Risk of Bias Tool (RoB 2). Pooled risk ratios (RRs) and 95% CIs were estimated using random effects meta-analytic models. Results: Four randomized controlled trials (n = 1,402) were included. In total, 706 patients were randomized to DCB and 696 to DES. Participants were mostly male (74%), with a mean/median age ranging from 60 to 68 years. Pooled data across trials for MACE showed wide CIs, with little indication of DES superiority over DCB (RR: 0.71; 95% CI: 0.36-1.41). Most individual components of MACE were inconclusive. There was a potential signal for a reduction of target vessel thrombosis with DCB compared to DES (RR: 0.25; 95% CI: 0.06-1.08). Conclusions: Although sample sizes are small, 3-year outcomes suggest that DCB may be a reasonable alternative to DES for the treatment of small coronary arteries.

Summary: Sensing is a critical function of artificial cells; however, this is challenging to realize using bottom-up approaches. Here, we present a protocol for building protocell membranes that sense cues important for redox biochemistry and signaling by combining synthetic phospholipids and natural lipids. We detail procedures for building giant unilamellar vesicles as protocell models that fluoresce in response to the biologically significant redox agents peroxynitrite, hydrogen peroxide, and hydrogen sulfide.For complete details on the use and execution of this protocol, please refer to (i) Gutierrez and Aggarwal et al.1 as well as (ii) Erguven and Wang et al.2 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Despite the availability of a wide range of antihypertensive agents, a significant proportion of individuals with resistant hypertension (RHTN) struggle to achieve blood pressure (BP) control. Obesity ranks among the most significant modifiable risk factors for RHTN, with 56–91% of patients with RHTN classified as overweight or obese. Glucagon-like peptide-1 receptor agonist (GLP-1 RAs) are a class of anti-obesity medications that have recently demonstrated efficacy in reducing BP and improving cardiovascular (CV) outcomes in individuals with overweight or obesity. Among the available GLP-1-based therapies, liraglutide, semaglutide, and tirzepatide have been approved for chronic weight management in this population. Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, has the greatest effect on weight loss and BP reduction compared to GLP-1 RAs alone. To our knowledge, no trials have directly evaluated the effect of GLP-1 RAs or dual GLP-1/GIP receptor agonists on RHTN management. In this review article, we propose that targeting weight loss through GLP-1-based therapies should be explored as a treatment option for individuals with RHTN who are overweight or obese.

Few studies have considered household interventions for reducing endocrine disrupting chemical (EDC) exposures. We conducted a secondary analysis of a randomized controlled trial, originally designed to reduce lead exposure, to evaluate if the intervention lowered EDC exposures in young children. Study participants were children from the Cincinnati, Ohio area (n = 250, HOME Study). Prenatally, families received a housing intervention that included paint stabilization and dust mitigation, or as a control, injury prevention measures. At 24-months, we measured organophosphate esters (OPEs) and phthalates or their metabolites in dust and urine. We measured perfluoroalkyl substances (PFAS) in dust and serum at 24- and 36-months, respectively. We assessed associations between dust and biomarker EDCs using Spearman correlations, characterized EDC mixtures via principal components analysis, and investigated treatment effects using linear regression. To mitigate selection bias, we fit statistical models using inverse probability of retention weights. Correlations between dust EDCs and analogous biomarkers were weak-to-moderate (ρ’s ≤ 0.3). The intervention was associated with 23 % (95 % CI: −38, −3) lower urinary DEHP metabolites and, in a per-protocol analysis, 34 % lower (95 % CI: −55, −2) urinary MBZP. Additionally, among Black or African American children, the intervention was associated with lower serum concentrations of several PFAS (e.g., −42 %; 95 % CI: −63, −8 for PFNA). Household interventions that include paint stabilization and dust mitigation may reduce childhood exposures to some phthalates and PFAS in Blacks/African Americans. These findings highlight the need for larger studies with tailored and sustained housing interventions.

Background: Transcatheter aortic valve replacement (TAVR) is an important treatment option for patients with severe symptomatic aortic stenosis. It is important to identify predictors of excellent outcomes (good clinical outcomes, more time spent at home) after TAVR that are potentially amenable to improvement. Objectives: The purpose of the study was to use machine learning to identify potentially modifiable predictors of clinically relevant patient-centered outcomes after TAVR. Methods: We used data from 8,332 TAVR cases (January 2016-December 2021) from 21 hospitals to train random forest models with 57 patient characteristics (demographics, comorbidities, surgical risk score, lab values, health status scores) and care process parameters to predict the end point, a composite of parameters that designated an excellent outcome and included no major complications (in-hospital or at 30 days), post-TAVR length of stay of 1 day or less, discharge to home, no readmission, and alive at 30 days. We used recursive feature elimination with cross-validation and Shapley Additive Explanation feature importance to identify parameters with the highest predictive values. Results: The final random forest model retained 29 predictors (15 patient characteristics and 14 care process components); the area under the curve, sensitivity, and specificity were 0.77, 0.67, and 0.73, respectively. Four potentially modifiable predictors with relatively high Shapley Additive Explanation values were identified: type of anesthesia, direct movement to stepdown unit post-TAVR, time between catheterization and TAVR, and preprocedural length of stay. Conclusions: This study identified four potentially modifiable predictors of excellent outcome after TAVR, suggesting that machine learning combined with hospital-level data can inform modifiable components of care, which could support better delivery of care for patients undergoing TAVR.

Background: Patella baja is a known complication of total knee arthroplasty (TKA). There is a limited understanding of the association between patellar resurfacing and the incidence of patella baja. We aimed to compare rates of patella baja between unresurfaced and resurfaced patellas in patients undergoing TKA. Methods: A retrospective review of patients who underwent TKA between October 2009 and January 2020 was performed. Patients were included if they had at least one preoperative radiograph and a 1-year follow-up radiograph. Blackburne-Peel index (BPI) and Insall-Salvati ratios (ISRs) were measured on preoperative and 1-year postoperative radiographs and were used to define patella baja vs pseudopatella baja. Statistical analysis was performed using a linear model analysis of variance and the Fisher’s exact test. Results: Three hundred eighteen TKAs were included, with 176 being resurfaced and 142 unresurfaced patellas. Of the resurfaced group, 4% (7/176) had true patella baja, compared to 5.6% (8/142) of the unresurfaced patellas. Of the resurfaced patellas, 8% (14/176) had pseudopatella baja, compared to 7% (10/142) in the unresurfaced group. Patellar resurfacing was not associated with a higher incidence of patella baja (P = .60) or pseudopatella baja (P = .83). Lower preoperative ISRs (P = .04) and BPIs (0.03) were highly predictive of a higher incidence of patella baja post-TKA. Conclusions: Patellar resurfacing in TKA is not associated with a higher incidence of patella baja in TKA when compared to unresurfaced patellas. Lower preoperative ISRs and BPIs are highly predictive of a higher incidence of postoperative patella baja.

Background: The primary purpose of this study was to evaluate how utilization, physician reimbursement, and patient populations have changed for primary total knee arthroplasty (TKA) from 2013 to 2021 at both a regional and national level within the Medicare population. Methods: The Medicare Physician and Other Practitioners database was queried for all episodes of primary TKA between years 2013 and 2021. TKA utilization per 10,000 beneficiaries, inflation-adjusted physician reimbursement per TKA, and patient demographics of each TKA surgeon were extracted each year. Data were stratified geographically, and Kruskal-Wallis tests were utilized. Results: Between 2013 and 2021, TKA utilization per 10,000 beneficiaries increased at the greatest rate in the Northeast (+15.1%). In 2021, TKA utilization was highest in the Midwest (97.6/10,000; P < .001). The Midwest had the greatest decline in average physician reimbursement per TKA between 2013 and 2021 (−26.3%) and the lowest average reimbursement ($988.70, P < .001) in 2021. Alternatively, the Northeast had the smallest decline in average TKA reimbursement (−22.6%). Nationally, the average number of beneficiaries per TKA surgeon declined (−6.8%), while the average number of TKAs per surgeon (+5.7%) and average services per beneficiary (+24.3%) both increased. The average number of patient comorbidities and proportion of patients with dual Medicare-Medicaid eligibility decreased over time across all regions. Conclusions: This study demonstrates that TKA utilization is increasing and average physician reimbursement per TKA is declining at varying rates across the country, with the Northeast and Midwest most affected. These findings should be addressed in policy discussions to ensure equitable arthroplasty care.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student’s t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression. Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference −4.4 mL/kg/min [95% CI: −3.7 to −5.1 mL/kg/min]) secondary to a reduced O2 delivery (−0.5 L/min [95% CI: −0.4 to −0.6 L/min]) and less oxygen extraction (−2.9 mL/dL [95% CI: −2.5 to −3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (−1.2 g/dL [95% CI: −0.9 to −1.5 g/dL]) and smaller stroke volume (−15 mL [95% CI: −14 to −17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (−9 mL/m2 [95% CI: −8 to −11 mL/m2]) and mass (−12 g/m2 [95% CI: −9 to −14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001). Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Asynchronous distributed multielectrode stimulation (ADMES) is a novel approach to deep brain stimulation for medication resistant temporal lobe epilepsy that has shown promise in rodent and in vitro seizure models. To further evaluate its effects on a pre-clinical model, we characterized the effect of unilateral ADMES in an NHP model of temporal lobe seizures induced by intra-hippocampal injection of penicillin (PCN). Four non-human primates were used for this study in two contemporaneous cohorts. One cohort (n = 3 hemispheres) was implanted with the Medtronic RC + S stimulation (GIN cohort) and recording system connected to two 4-contact ring electrodes to evaluate three unilateral stimulation patterns: 7 Hz Ring ADMES, 20 Hz Dual Ring, and 125 Hz Dual Ring (analog of clinical stimulation). In an additional cohort (EPC cohort, n = 2), two 12-contact segmented electrodes were implanted in the right hippocampus and connected to an externalized recording and stimulation system to allow more flexibility in the stimulation pattern. In this second cohort, 4 variations of stimulation were evaluated (7 Hz Full ADMES, 7 Hz Ring ADMES, 31 Hz Wide Ring, and 31 Hz Dual Ring). In the GIN cohort, we found an increase in seizure frequency and time spent in seizure during the 7 Hz Ring ADMES stimulation compared to the respective post-stimulation. A similar post-stimulation effect was found in the EPC cohort. We also found an increase in seizure frequency during the 7Hz full ADMES compared to the respective post-stimulation. However, we did not find a difference between pre-stimulation and stimulation conditions suggesting a possible post stimulation effect of the 7Hz hippocampal stimulation. In conclusion, in the NHP PCN model of temporal lobe seizures, acute asynchronous hippocampal stimulation was not therapeutic, however, our findings related to the post-stimulation effect can support future studies using hippocampal stimulation for the treatment of temporal lobe epilepsy.

Background: Mechanisms sustaining persistent atrial fibrillation (AF) remain unclear. Objectives: The study sought to evaluate both the clinical outcomes and response to ablation of potential drivers in patients with recurrent persistent AF recurrence following pulmonary vein isolation (PVI). Methods: A total of 100 patients with persistent AF of 1.5 revolutions or focal activations. Cycle lengths were measured pre- and postablation. The primary outcome was freedom from atrial arrhythmia off antiarrhythmic drugs at 1 year as per guidelines. Results: Of 37 patients recruited, 26 had recurrent AF and underwent ECGI-guided ablation of PDs. An average of 6.4 ± 2.7 PDs were targeted per patient. The mean ablation time targeting PDs was 15.5 ± 6.9 minutes. An ablation response occurred in 20 patients (AF termination in 6, cycle length prolongation ≥10% in 14). At 1 year, 14 (54%) of 26 patients were free from arrhythmia, and 12 (46%) of 26 were off antiarrhythmic drugs. Considering the 96 patients who completed follow-up out of the original cohort of 100 patients undergoing cryoablation in this staged strategy, freedom from arrhythmia at 1 year following the last procedure was 72 (75%) of 96, or 70 (73%) of 96 off antiarrhythmic drugs. Conclusions: In patients with recurrent AF despite PVI, ECGI-guided ablation caused an acute response in a majority with reasonable long-term outcomes.

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]). Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1. Outcome: Incident CKD or end-stage kidney disease. Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts. Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31). Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts. Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria. Plain-Language Summary: This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

Background: Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D1 receptor–expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D2 receptor–expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for. Methods: We used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs). Results: In females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle–dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies. Conclusions: Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.

Summary: The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Despite the emerging and rapid progress of esports, approaches for ensuring high-quality analytics and training among professional and amateur esports teams are lacking. In this paper, we demonstrate how the application of data science techniques and Machine Learning (ML) approaches in esports, particularly in sim racing science, can illuminate the most important in-game metrics that dictate performance. Thus, using a professional racing simulator and MoTec i2 Pro (v1.1.5, Australia), we gathered extensive telemetry data from 174 participants, who completed 1327 laps on the Brands-Hatch circuit in the Assetto Corsa Competizione (v1.9, KUNOS Simulazioni). We clustered the obtained laps based on performance (lap-time), and then identified driving behaviors within performance groups. We also analyzed the feature subset obtained from a hybrid feature selection approach using two correlation analyses and three ML models.The best model achieved a prediction accuracy of 97.19%, demonstrating that the model effectively captured the critical factors that influenced driving performance during a lap. The results confirm that average speed is the most important metric, followed by lateral acceleration, steering angle, and lane deviation. Our analyses offer key metrics for refining training tools and techniques in sim racing performance improvement.

Background: Cardiac allograft vasculopathy (CAV) accounts for significant long-term morbidity and mortality in heart transplant recipients; limited data exist for donation after circulatory death (DCD). Intravascular ultrasound (IVUS) assessment is a gold standard for early diagnosis of CAV and has strong prognostic power. Methods: We evaluated all consecutive circulatory and brain death heart transplant recipients from January 2020 to March 2022. Patients were followed for need for percutaneous coronary intervention (PCI), development of severe allograft vasculopathy, or death. Among 143 heart transplant recipients, 39 received circulatory death and 104 received brain death hearts. Results: Baseline characteristics were similar between groups: median age (56.3 vs 53.7 years, p = 0.290), female sex (15% vs 26%, p = 0.265), and sirolimus use (69% vs 53%, p = 0.116). At 1 year, there were no significant differences in maximal intimal thickness (0.49 vs 0.46 mm, p = 0.861) or Stanford classification. During a median follow-up of 793 days [interquartile ranges 618, 1003], there was no difference in the unadjusted or adjusted primary composite outcome of death, PCI, or International Society of Heart and Lung Transplantation cardiac allograft vasculopathy maximal intimal thickness ≥0.6 mm (unadjusted hazard ratio (HR) 0.42, 95% confidence interval (CI): 0.05, 3.48, p = 0.42), event rate 9.6% vs 2.6%, p = 0.29, nor was there a difference in death, PCI or severe IVUS disease (HR 1.44, 95% CI 0.81, 2.56, p = 0.21). Conclusion: In DCD heart transplant recipients, circulatory death donors did not have a significantly higher risk for coronary allograft vasculopathy by IVUS or related complications at 1 year following transplantation.

Background: Postoperative urinary retention is a common complication after total hip and knee arthroplasty. Postvoid residual (PVR) scanning is a noninvasive method commonly used to evaluate this complication. Preoperatively increased PVR (PrePVR) has been suggested as a risk factor for postoperative catheterization. The aim of this study was to prospectively assess the importance of PrePVR and its relationship with urinary catheter placement, urology consult, and length of stay postoperatively. Methods: Data was prospectively and consecutively collected at a single institution. All patients were bladder scanned preoperatively to collect PrePVR and subsequently scanned on postoperative days zero and one to collect Postoperative PVR. Chart review was performed to determine the number of straight catheterizations, Foley placement, urology consult and length of stay as well as patient demographics. Results: Ninety-four consecutive patients were included in this study. There was a significantly increased postoperative PVR as compared to PrePVR (48.0 mL vs 21.0 mL; P < .0001). A PrePVR >50 mL was not associated with a significant difference in PVR between before and after surgery (P = .13); length of stay (P = .08); need for straight catheterization (P = .11); postoperative Foley placement (P = 1.0); or urology consult (P = 1.0). The only significant risk factor identified for postoperative Foley catheter placement was age (77.7 vs 64.2; P = .02). Conclusions: PrePVR >50 mL was not an accurate predictor of postoperative urinary retention after total joint arthroplasty. PVR significantly increased in all patients. Male sex and increasing age were associated with large increases in PVR postoperatively and an increased risk of catheterization.

Panniculus morbidus is a complication of morbid obesity characterized by massive abdominal folds that hang below the beltline. Ulceration, dermatitis, and sinus tract formation of the pannus can cause significant morbidity to the patient and impair activities of daily living. If patients fail medical management, the next step is surgical excision. Challenging aspects of the procedure include adequate suspension of the pannus, cost, and prevention of intra-abdominal injuries. We present a case of a 70-year-old female with panniculus morbidus with endometrial carcinoma. We successfully performed a panniculectomy using a novel combination of towel hooks and the Hoyer lift to suspend the abdomen. In the same anesthesia event, she underwent robotic-assisted hysterectomy. No intra-operative or post-operative complications were encountered, and the patient was satisfied with her results. In this case, we demonstrated an effective and cost-efficient approach to panniculectomy in the severely obese patient.

Objective: To investigate the effect of minimally invasive cardiac surgery (MICS) on resource utilization, cost, and postoperative outcomes in patients undergoing left-heart valve operations. Methods: Data were retrospectively reviewed for patients undergoing single-valve surgery (eg, aortic valve replacement, mitral valve replacement, or mitral valve repair) at a single center from 2018 to 2021, stratified by surgical approach: MICS vs full sternotomy (FS). Baseline characteristics and postoperative outcomes were compared. Primary outcome was high resource utilization, defined as direct procedure cost higher than the third quartile or either postoperative LOS ≥7 days or 30-day readmission. Secondary outcomes were direct cost, length of stay, 30-day readmission, in-hospital and 30-day mortality, and major morbidity. Multiple regression analysis was conducted, controlling for baseline characteristics, operative approach, valve operation, and lead surgeon to assess high resource utilization. Results: MICS was correlated with a significantly lower rate of high resource utilization (MICS, 31.25% [n = 115] vs FS 61.29% [n = 76]; P

Summary: Background: The World Health Organization seeks to eliminate viral hepatitis as a public health threat by 2030. This review and meta-analysis aims to evaluate the effectiveness of programs for hepatitis B and C testing and treatment in community pharmacies. Methods: Medline, Embase, Cochrane CENTRAL, and Global Health were searched from database inception until 12 November 2023. Comparative and single arm intervention studies were eligible for inclusion if they assessed delivery of any of the following interventions for hepatitis B or C in pharmacies: (1) pre-testing risk assessment, (2) testing, (3) pre-treatment assessment or (4) treatment. Primary outcomes were proportions testing positive and reaching each stage in the cascade. Random effects meta-analysis was used to estimate pooled proportions stratified by recruitment strategy and setting where possible; other results were synthesised narratively. This study was pre-registered (PROSPERO: CRD42022324218). Findings: Twenty-seven studies (4 comparative, 23 single arm) were included, of which 26 reported hepatitis C outcomes and four reported hepatitis B outcomes. History of injecting drug use was the most identified risk factor from pre-testing risk assessments. The pooled proportion hepatitis C antibody positive from of 19 studies testing 5096 participants was 16.6% (95% CI 11.0%–23.0%; heterogeneity I2 = 96.6%). The pooled proportion antibody positive was significantly higher when testing targeted people with specified risk factors (32.5%, 95% CI 24.8%–40.6%; heterogeneity I2 = 82.4%) compared with non-targeted or other recruitment methods 4.0% (95% CI 2.1%–6.5%; heterogeneity I2 = 83.5%). Meta-analysis of 14 studies with 813 participants eligible for pre-treatment assessment showed pooled attendance rates were significantly higher in pharmacies (92.7%, 95% CI 79.1%–99.9%; heterogeneity I2 = 72.4%) compared with referral to non-pharmacy settings (53.5%, 95% CI 36.5%–70.1%; heterogeneity I2 = 92.3%). The pooled proportion initiating treatment was 85.6% (95% CI 74.8%–94.3%; heterogeneity I2 = 75.1%). This did not differ significantly between pharmacy and non-pharmacy settings. Interpretation: These findings add pharmacies to the growing evidence supporting community-based testing and treatment for hepatitis C. Few comparative studies and high degrees of statistical heterogeneity were important limitations. Hepatitis B care in pharmacies presents an opportunity for future research. Funding: None.

The European DEMOnstration power plant (EU DEMO) project is currently leading the research endeavours within the fusion field with the goal of developing a next generation fusion reactor. Given the challenging nature of the application, it is essential to establish methodologies that can provide convenient and reliable characterisation of the chosen materials within DEMO. In this paper, the recently developed Time-of-Flight Neutron Bragg Edge Imaging (TOF-NBEI) was used on Tungsten (W)/ Copper (Cu) dissimilar joints sample mock-ups of the cooling system design used in the critical divertor component with the goal of mapping the residual stresses across the sample. Residual strain mapping was performed on the W phase with considerable tensile residual strains identified close to the W-Cu interface. The large-grain microstructure of the Cu phase was analysed using the energy-resolved neutron radiographs. The results will be used as a basis for future TOF-NBEI experiments of tungsten monoblocks related to DEMO.

People may be more likely to exercise if they have self-efficacy for exercise (SEE). We conducted an exploratory analysis of SEE using data from a clinical trial designed to increase physical activity (N = 340). We evaluated correlates of baseline SEE and the relationship between baseline SEE and physical activity. Low SEE at baseline was correlated with lower well-being, physical activity, and higher depression at baseline. Participants with high (vs. low) baseline SEE had higher physical activity (but no differential change in activity) over time. These data highlight the potential role of SEE in psychological health and physical activity.

The study measured the levels of azoxystrobin (AZ) and thiabendazole (TBZ) in wallboards and metabolite levels of these fungicides in children. The paper covering of wallboard samples contained a higher concentration of AZ and TBZ than the gypsum core, and similar amounts (w/w) of these two fungicides were present in the samples. These data suggest that commercial products containing a 1:1 (w/w) amount of AZ and TBZ, such as Sporgard® WB or Azo Tech™, were applied to the wallboard paper. This is the first detection of TBZ in mold-and-mildew resistant wallboards. The TBZ metabolite, 5OH-TBZ, was detected in 48% of urine samples collected from children aged 40–84 months, and was co-detected with AZ-acid, a common AZ metabolite, in 37.5% of the urine samples. The detection frequency of 5OH-TBZ was positively associated with the detection frequency of AZ-acid. These findings suggest that certain types of wallboards used in homes and commercial buildings may be a potential source of co-exposure to AZ and TBZ in humans.

Purpose: In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders. Methods: We developed a copy-number variations analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies. Results: Autosomal recessive (AR) modeling detected 34 distinct rare deletions that were homozygous in the proband and heterozygous in both parents. These inherited biallelic deletions were only detected in 52 trios. These “knockout” regions included 37 genes, having among them 8 with an Online Mendelian Inheritance in Man AR annotation. Deletions of NPHP1, followed by OTOA, both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous NPHP1 deletions were detected in 0.3%-0.5% of controls. We reviewed “knockout” patients for the remaining 29 genes without disease associations and identified SLC66A1 as a likely novel cause for AR rod-cone dystrophy in 4 families. Conclusion: A tailored copy-number variations analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with NPHP1 biallelic deletions causing nephronophthisis the leading finding. We propose SLC66A1 as a novel cause for AR retinopathy.

Summary: Background: With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need. Methods: Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.gov NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021. Findings: The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm. Interpretation: In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia. Funding: The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Summary: Background: Autochthonous transmission of Zika virus (ZIKV) has been reported in 87 countries since 2015. Although most infections are mild, there is risk of Guillain-Barré syndrome and adverse pregnancy outcomes. Vaccines are urgently needed to prevent Zika, but sufficient understanding of humoral responses and tools to assess ZIKV-specific immunity are lacking. Methods: We developed a blockade-of-binding (BOB) ELISA using A9E and G9E, two strongly neutralising ZIKV-specific monoclonal antibodies, which do not react with dengue virus. Receiver operating characteristic curve analysis assessed A9E and G9E BOB serodiagnostic performance. BOB was then applied to samples from a surveillance cohort in Risaralda, Colombia, and phase 1 ZIKV vaccine trial samples, comparing results against traditional serologic tests. Findings: In the validation sample set (n = 120), A9E BOB has a sensitivity of 93.5% (95% CI: 79.3, 98.9) and specificity 97.8 (95% CI: 92.2, 99.6). G9E BOB had a sensitivity of 100% (95% CI: 89.0, 100.0) and specificity 100% (95% CI: 95.9, 100). Serum from natural infections consistently tested positive in these assays for up to one year, and reactivity tracks well with ZIKV infection status among sera from endemic areas with complicated flavivirus exposures. Interestingly, a leading ZIKV vaccine candidate elicited minimal BOB reactivity despite generating neutralising antibody responses. Interpretation: In conclusion, A9E and G9E BOB assays are sensitive and specific assays for detecting antibodies elicited by recent or remote ZIKV infections. Given the additional ability of these BOB assays to detect immune responses that target different epitopes, further development of these assays is well justified for applications including flavivirus surveillance, translational vaccinology research and as potential serologic correlates of protective immunity against Zika. Funding: R21 AI129532 (PI: S. Becker-Dreps), CDC BAA 2017-N-18041 (PI: A. M. de Silva), Thrasher Fund (PI: M. H. Collins), K22 AI137306 (PI: M. H. Collins).

Similar to streptavidin, the binding of biotin by avidin does not appear to be cooperative in the traditional sense of altered binding strength, though it appears to be cooperative in terms of ligand induced structural communication across subunits in the protein as previously shown for streptavidin. In this work we provide data from intrinsic tryptophan fluorescence as evidence of a cooperative structural change. The technique involves examination of the changes in fluorescence emission corresponding to the various tryptophan populations accompanying avidin-biotin binding. We note that the 335 nm emission population (i.e. more hydrophobic local environment) saturates prior to full ligation and the saturation of the 350 nm emission population commonly used in standard binding activity assays. We also note that total integrated fluorescence emission and peak height during the titration of ligand into streptavidin also reach saturation prior to the 4:1 stoichiometric end point. Unique to avidin and distinct from the behavior of streptavidin described in our prior work, the wavelength of maximum emission and full width at half maximum (FWHM) data do not saturate prior to the 4:1 stoichiometric end point. Avidin also exhibited larger FWHM for both apo and holo forms suggesting greater heterogeneity in local tryptophan environments, as compared to streptavidin. Taken together, the data suggests that the binding of the first 3 biotins effect greater structural changes in the protein than the final ligand in a similar way for avidin and streptavidin.

Summary: SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.

Sex steroid hormones (SSH) such as oestrogen, progesterone and testosterone are cholesterol derived molecules that regulate various physiological processes. They are present in both blood and saliva, where they come in contact with oral tissues and oral microorganisms. Several studies have confirmed the effect of these hormones on different periodontal-disease-associated bacteria, using single-species models. Bacteria can metabolize SSH, use them as alternative for vitamin K and also use them to induce the expression of virulence factors. However, it is still unclear what the effects of SSH are on the oral microbiome. In this study, we investigated the effects of four SSH on commensal in vitro oral biofilms. Saliva-derived oral biofilms were grown in Mc Bain medium without serum or menadione using the Amsterdam Active-Attachment model. After initial attachment in absence of SSH, the biofilms were grown in medium containing either oestradiol, oestriol, progesterone or testosterone at a 100-fold physiological concentration. Menadione or ethanol were included as positive control and negative control, respectively. After 12 days with daily medium refreshments, biofilm formation, biofilm red fluorescence and microbial composition were determined. The supernatants were tested for proteolytic activity using the Fluorescence Resonance Energy Transfer Analysis (FRET). No significant differences were found in biofilm formation, red fluorescence or microbial composition in any of the tested groups. Samples grown in presence of progesterone and oestradiol showed proteolytic activity comparable to biofilms supplemented with menadione. In contrast, testosterone and oestriol showed a decreased proteolytic activity compared to biofilms grown in presence of menadione.None of the tested SSH had large effects on the ecology of in vitro oral biofilms, therefore a direct translation of our results into in vivo effects is not possible. Future experiments should include other host factors such as oral tissues, immune cells and combinations of SSH as present in saliva, in order to have a more accurate picture of the phenomena taking place in both males and females.

Rationale & Objective: Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Study Design: Prospective observational cohort. Setting & Participants: In the Atherosclerosis Risk in Communities) study, 948 participants were studied. Exposures: The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Outcome: Incident CKD after 15 years of follow-up defined as ≥40% estimated glomerular filtration rate decline to