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Abstract Background Pain, the primary complaint in rheumatoid arthritis (RA), is multifaceted, and may be driven by inflammatory disease activity and central sensitisation. We aimed to ascertain what proportion of RA pain severity is explained by markers of inflammation and quantitative sensory testing (QST) indices of central sensitisation. Methods This was a cross-sectional analysis of data from individuals with clinically active RA. Pain severity was assessed using numerical rating scales and inflammation via 28-joint Disease Activity Score (DAS28) and Ultrasound (Greyscale, Power Doppler). Pain sensitivity was assessed by ‘static’ (tibialis anterior or brachioradialis pressure pain detection threshold-PPT-TA/PPT-BR) and ‘dynamic’ (temporal summation-TS, conditioned pain modulation-CPM) QST. Bivariate associations used Spearman’s correlation coefficients, and multivariable linear regression models determined relative contributions to pain severity. Results In bivariate analyses of N = 96 (age 65 ± 10y, 77% females) people with RA, pain severity was significantly associated with inflammation indices (r = 0.20 to 0.55), and CPM (r=-0.26). In multivariable models that included TS, CPM, age, sex, and body mass index, inflammation indices remained significantly associated with pain severity. Multivariable models explained 22 to 27% of pain variance. Heterogeneity was apparent for associations with pain between subscores for pain now, strongest or average over the past 4-weeks. Conclusions In individuals with clinically active RA, markers of inflammatory disease activity best explain RA pain with only marginal contributions from QST indices of central sensitisation. Although inflammation plays a key role in the experience of RA pain, the greater proportion of pain severity remains unexplained by DAS28 and ultrasound indices of inflammation.

Abstract Coral reef fisheries are a vital source of nutrients for thousands of nutritionally vulnerable coastal communities around the world. Marine protected areas are regions of the ocean designed to preserve or rehabilitate marine ecosystems and thereby increase reef fish biomass. Here, we evaluate the potential effects of expanding a subset of marine protected areas that allow some level of fishing within their borders (sustainable-use MPAs) to improve the nutrition of coastal communities. We estimate that, depending on site characteristics, expanding sustainable-use MPAs could increase catch by up to 20%, which could help prevent 0.3-2.85 million cases of inadequate micronutrient intake in coral reef nations. Our study highlights the potential add-on nutritional benefits of expanding sustainable-use MPAs in coral reef regions and pinpoints locations with the greatest potential to reduce inadequate micronutrient intake level. These findings provide critical knowledge given international momentum to cover 30% of the ocean with MPAs by 2030 and eradicate malnutrition in all its forms.

Abstract The dopamine reward prediction error signal is known to be subjective but has so far only been assessed in aggregate choices. However, personal choices fluctuate across trials and thus reflect the instantaneous subjective reward value. In the well-established Becker-DeGroot-Marschak (BDM) auction-like mechanism, participants are encouraged to place bids that accurately reveal their instantaneous subjective reward value; inaccurate bidding results in suboptimal reward (“incentive compatibility”). In our experiment, male rhesus monkeys became experienced over several years to place accurate BDM bids for juice rewards without specific external constraints. Their bids for physically identical rewards varied trial by trial and increased overall for larger rewards. In these highly experienced animals, responses of midbrain dopamine neurons followed the trial-by-trial variations of bids despite constant, explicitly predicted reward amounts. Inversely, dopamine responses were similar with similar bids for different physical reward amounts. Support Vector Regression demonstrated accurate prediction of the animals’ bids by as few as twenty dopamine neurons. Thus, the phasic dopamine reward signal reflects instantaneous subjective reward value.

Abstract Introduction Uncontrolled non-infectious uveitis affecting the posterior segment (NIU-PS) can lead to vision loss due to repeated bouts of inflammation and consequent tissue damage. Patients with chronic NIU-PS who experience recurrent uveitis after being treated with systemic and short-acting local corticosteroids may benefit from the sustained-release 0.18-mg fluocinolone acetonide implant (FAi). Methods In this case series, 18 eyes with chronic, recurrent NIU-PS and cystoid macular edema (CME) treated with the 0.18-mg FAi were analyzed retrospectively. Data on patient demographics, clinical history, previous and concomitant treatments for uveitis recurrence, time to and number of uveitis recurrences, intraocular pressure (IOP), central subfield thickness (CST), and visual acuity (VA) were collected and summarized. Results A majority of patients (14/15 [93%]) had a history of ocular surgery, largely cataract extraction, and all developed chronic and recurrent NIU-PS and CME. At baseline, patients had a mean age of 72 years (range: 46 to 93), were 53% male, and had a mean duration of NIU-PS of 3 years (range: 1 to 19). Patients were followed for an average of 16.5 months (range: 2 to 42.5 months) post FAi. Eleven of the 18 eyes (61%) had ≥ 5 recurrences of uveitis since diagnosis, with an average time to recurrence of approximately 12 weeks (range: 1 to 27). All eyes treated with the 0.18-mg FAi showed reduced NIU-PS recurrence and visual and anatomical improvement, as measured by VA and CST, respectively. Two eyes had an IOP elevation that was managed with topical therapy, and one eye was treated with topical prednisolone for additional inflammation management. Two eyes required adjunct therapy with short-acting intravitreal corticosteroids at 7 and 16 weeks for NIU-PS recurrence after 0.18-mg FAi insertion. Conclusion After receiving the 0.18-mg FAi, eyes with uncontrolled NIU-PS had sustained resolution of CME and inflammation with limited need for supplementary steroid drops or injections and minimal steroid class-specific adverse effects; none required incisional IOP-lowering surgery.

Abstract Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.

Summary: Soft tissue defects of the distal third of the leg are challenging and management with simple split thickness skin graft or conservative measures is often difficult. The peroneus brevis muscle flap is well described in the literature to cover such defects. The aim of our study was to review the different applications and potential complications of the peroneus brevis muscle flap.A comprehensive review of all existing evidence on the use of peroneus brevis muscle flaps for coverage of defects in the distal third of the leg in adult populations was performed.Two hundred forty-eight records were identified in the literature search, among which 15 met the PICOS (Patient, Intervention, Comparison, Outcome and Study design) criteria. All selected studies were retrospective. Overall, 222 patients who received peroneus brevis muscle flaps were analyzed. Indications for reconstruction were post-traumatic defects, infected wounds, and chronic wounds. The overall complication rate was 21% (46/222) with the most commonly reported complication being skin graft loss. We observed 2 cases of partial flap loss, 17 cases of skin graft loss, 2 cases of post-operative hematoma, 2 cases of recurrent infection, 12 cases of partial flap necrosis, 3 cases of skin graft necrosis, and 8 cases of delayed wound healing. Overall, 16 patients (7%) required revision surgery. No cases of donor site morbidity were described.The current review shows that the peroneus brevis muscle flap is a versatile and reliable option for the coverage of small to medium sized defects of the distal leg, ankle, and foot with low complication rates and donor site morbidity.

Abstract Cyberbullying is associated with various mental health concerns in adolescents, including body dissatisfaction and disordered eating behaviours. However, there is a significant research gap concerning the unique effects of appearance-related cyberbullying (ARC) on adolescent mental health. This study examined the prevalence and psychological consequences of ARC among middle to late adolescent females (aged 14–19 years, M age = 15.98, N = 336). Participants completed an online survey regarding their experiences of ARC, body image variables, and eating disorder symptomology. Findings indicate the widespread occurrence of ARC among adolescent females, with body shape and size emerging as predominant targets. Experiences of ARC-victimisation positively correlated with increased concerns about body shape, body shame, and eating disorder symptomology. Conversely, experiences of ARC-victimisation were negatively correlated with body esteem and body appreciation. Finally, appearance-related cybervictimisation was significantly associated with adolescent females’ desire to pursue appearance alterations through methods such as dieting and exercising, altering self-presentation, and undergoing cosmetic procedures due to perceived experiences of ARC. These findings highlight the urgent need for preventative measures, such as age-appropriate social media policies and health promotion programs that encourage positive online behaviour, and strategies to address the impacts of ARC to protect the mental well-being of adolescent females.

Abstract Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson’s Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

Abstract Global warming is a major challenge to the sustainable and humane production of food because of the increased risk of livestock to heat stress. Here, the example of the prolactin receptor (PRLR) gene is used to demonstrate how gene editing can increase the resistance of cattle to heat stress by the introduction of mutations conferring thermotolerance. Several cattle populations in South and Central America possess natural mutations in PRLR that result in affected animals having short hair and being thermotolerant. CRISPR/Cas9 technology was used to introduce variants of PRLR in two thermosensitive breeds of cattle – Angus and Jersey. Gene‐edited animals exhibited superior ability to regulate vaginal temperature (heifers) and rectal temperature (bulls) compared to animals that were not gene‐edited. Moreover, gene‐edited animals exhibited superior growth characteristics and had larger scrotal circumference. There was no evidence for deleterious effects of the mutation on carcass characteristics or male reproductive function. These results indicate the potential for reducing heat stress in relevant environments to enhance cattle productivity.

Abstract Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA‐binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG‐132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF‐α/IL‐12/IL‐23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF‐α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA‐binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host‐directed therapy against tuberculosis (TB).

Abstract We study an asymptotically free theory of N relativistic Dirac fermions and a real scalar field coupled by Yukawa and scalar self-interactions in three dimensions using functional renormalisation. In the limit of many fermion flavours, the cubic scalar coupling becomes exactly marginal due to quantum fluctuations, leading to a line of strongly-coupled infrared fixed points. Fermion mass can be generated through a quantum phase transition even if chiral symmetry is absent. The line of fixed points terminates at a critical endpoint due to the loss of vacuum stability. Exactly at the endpoint, scale symmetry is broken spontaneously, leading to the generation of fermion mass. Intriguingly, the absence of chiral symmetry is a prerequisite for the spontaneous generation of fermion mass, and not a consequence thereof. We also highlight close similarities between Gross-Neveu and Gross-Neveu-Yukawa theories at and away from critical points, and establish the large-N equivalence of their functional RG flows and quantum effective actions. Further implications including for conformal field theories are indicated.

Abstract Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5’-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10−16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10−3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.

Objective Self‐monitored point‐of‐care urate‐measuring devices are an underexplored strategy to improve adherence to urate‐lowering therapy and clinical outcomes in gout. This study observed patient‐led urate self‐monitoring practice and assessed its influence on allopurinol adherence, urate control, and health‐related quality of life. Methods People with gout (n = 31) and prescribed allopurinol self‐monitored their urate concentrations (HumaSens2.0plus) at baseline and thereafter monthly for 12 months (3 months per quarter). Adherence to allopurinol was measured using medication event monitoring technology (Medication Event Monitoring System cap). Time spent below the target urate concentration (

Abstract We demonstrate in a proof-of-concept experiment spectral-domain optical coherence tomography where steering of the optical beam that probes the sample in a transverse scan does not make use of any mechanical element. Steering is done with the help of a phase-only spatial light modulator, that introduces a spatially-dependent phase between the two orthogonal polarization components of an optical beam, and some optical elements that control the polarization of light. We demonstrate that making use of the non-mechanical beam steering system considered here, we can reproduce the main traits of imaging with standard OCT that makes use of mechanical-assisted optical beam steering.

Abstract Background Nine in every thousand children born in the United Kingdom have congenital heart disease, and 250,000 adults are living with the condition. This study aims to investigate the associations between congenital heart disease and educational outcomes among school-aged children in Scotland. Methods Routine health and education databases were linked to produce a cohort of all singleton children born in Scotland and attending a local authority run primary, secondary, or special school in Scotland at some point between 2009 and 2013. Children with congenital heart disease within this cohort were compared with children unaffected by congenital conditions. Outcomes investigated were special educational need (SEN), absenteeism, exclusion, academic attainment, and unemployment. All analyses were adjusted for sociodemographic and maternity confounders. Absenteeism was investigated as a mediating factor in the associations with attainment and unemployment. Results Of the 715,850 children, 6,295 (0.9%) had congenital heart disease and 4,412 (6.1%) had isolated congenital heart disease. Congenital heart disease and isolated congenital heart disease were both significantly associated with subsequent special educational need (OR 3.45, 95% CI 3.26–3.65, p

Abstract Objective Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2‐item scale polygenic score with anxiety in MS. Methods Using a case–control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview‐diagnosed, and lifetime self‐report physician‐diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome‐wide association study and was tested using regression. Results A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta‐analyses identified that in MS, each 1‐SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09–1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. Interpretation Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Abstract Background Causal mediation analysis plays a crucial role in examining causal effects and causal mechanisms. Yet, limited work has taken into consideration the use of sampling weights in causal mediation analysis. In this study, we compared different strategies of incorporating sampling weights into causal mediation analysis. Methods We conducted a simulation study to assess 4 different sampling weighting strategies-1) not using sampling weights, 2) incorporating sampling weights into mediation “cross-world” weights, 3) using sampling weights when estimating the outcome model, and 4) using sampling weights in both stages. We generated 8 simulated population scenarios comprising an exposure (A), an outcome (Y), a mediator (M), and six covariates (C), all of which were binary. The data were generated so that the true model of A given C and the true model of A given M and C were both logit models. We crossed these 8 population scenarios with 4 different sampling methods to obtain 32 total simulation conditions. For each simulation condition, we assessed the performance of 4 sampling weighting strategies when calculating sample-based estimates of the total, direct, and indirect effects. We also applied the four sampling weighting strategies to a case study using data from the National Survey on Drug Use and Health (NSDUH). Results Using sampling weights in both stages (mediation weight estimation and outcome models) had the lowest bias under most simulation conditions examined. Using sampling weights in only one stage led to greater bias for multiple simulation conditions. Discussion Using sampling weights in both stages is an effective approach to reduce bias in causal mediation analyses under a variety of conditions regarding the structure of the population data and sampling methods.

Objective Sutter Health launched system‐wide general population standardized suicide screening with the Columbia‐Suicide Severity Rating Scale (C‐SSRS) screen (triage) version in 23 hospitals in 2019, replacing a one‐question “danger to self” (DTS) assessment. This study analyzed the impact of C‐SSRS implementation on screening rates, positive screenings, and documented psychiatric care within 90 days for all patients and a subgroup diagnosed with Major Depressive Disorder (MDD). Methods Adults seen at hospitals in the pre‐period (July 1, 2017−June 30, 2019) and post‐period (July 1, 2019−December 31, 2020) were identified using electronic health records. Outcomes were compared using chi‐square statistics and interrupted time series (ITS) models. Results Pre‐period, 92.8% (740,984/798,653) of patients were screened by DTS versus 84.6% (504,015/595,915) by C‐SSRS in the post‐period. Positive screening rates were 1.5% pre‐period and 2.2% post‐period, and 9.2% pre‐period versus 10.8% post‐period for those with MDD. Among individuals with positive screenings, 64.0% (pre‐period) had documented follow‐up psychiatric care versus 52.5% post‐period and 66.4% of those with moderate or high‐risk. Among all patients seen there was an overall increase in documentation of psychiatric care within 90 days (0.87% pre‐ to 0.96% post‐period). ITS models revealed a 9.6% decline in screening, 1.3% increase in positive screenings, and 12.9% decline in documented psychiatric care following C‐SSRS implementation (all p

Objectives: To report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. Methods: Reference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. β-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. Results: Carbapenem-resistant Enterobacterales (CRE) detection increased (P < 0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. Conclusion: CRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

Objective The rising prevalence of mental health symptoms brought on by the COVID19 pandemic led to the inception and development of EMERging Anxiety, Loneliness, Depression (EMERALD) well-being programme. EMERALD was designed to improve psychological well-being of the general population who had not previously sought mental health support. The programme incorporated a focus on lifestyle medicine and was underpinned by solution focused health coaching. The aim of the paper is to describe the programme according to the Template for Intervention Description and Replication (TIDieR) checklist to provide detailed reporting of the intervention's elements. Methods The TIDieR checklist was utilised to comprehensively describe the programme, including theoretical underpinnings, materials, procedures, providers, mode of delivery and tailoring of the programme. The Behaviour Change Technique Taxonomy v2 was used to identify the specific behaviour change techniques used within the solution focused health coaching framework. Results The programme was developed to align with the latest evidence-based literature in lifestyle medicine and solution focused coaching. The programme also offered allied health expertise, online educational modules and was tailored to the participants. The programme was delivered online through a telehealth platform. Conclusion The TIDieR checklist has enabled the provision of a detailed structure of the EMERALD program intervention. The behaviour change taxonomy has facilitated the outlining of specific techniques used in health coaching sessions. Both structures have operationalised the detail of the intervention for the purposes of replication and informing the literature.

Objective Most patients who have an implantable cardioverter-defibrillator (ICD) implant do not receive life-prolonging therapy from it. Little research has been undertaken to determine which patients benefit the least from ICD therapy. As patients age and accumulate comorbidities, the risk of death increases and the benefit of ICDs diminishes. We sought to evaluate the impact of comorbidity, frailty, functional status on death with no prior appropriate ICD therapy.Methods A prospective, multicentre, observational study involving 12 English hospitals was undertaken. Patients were eligible for inclusion for the study if they were scheduled to have a de novo, upgrade to or replacement of a transvenous or subcutaneous ICD or cardiac resynchronisation therapy device and defibrillator (CRT-D). Baseline characteristics were collected. Participants were asked to complete a frailty assessment (Fried score) and a functional status questionnaire (EuroQol 5-Dimension 5-Level (EQ-5D-5L)). The Charlson Comorbidity Index was calculated. Patients were prospectively followed up for 2.5 years. The primary outcome was death with no prior appropriate therapy.Results In total, 675 patients were enrolled, mean age 65.7 (IQR 65–75) years. A total of 63 patients (9.5%) died during follow-up, 58 without receiving appropriate ICD therapy. Frailty was present in 86/675 (12.7%) and severe comorbidity in 69/675 (10.2%). Multivariate predictors of death with no appropriate therapy were identified and a risk score comprising frailty, comorbidity, increasing age, estimated glomerular filtration rate and EQ-5D-5L was developed.Conclusion Comorbidities, frailty and the EQ-5D-5L score are powerful, independent predictors of death with no prior appropriate therapy in ICD/CRT-D recipients.

Background The essential hypertension phenotype results from an interplay between genetic and environmental factors. The influence of lifestyle exposures such as excess adiposity, alcohol consumption, tobacco use, diet, and activity patterns on blood pressure (BP) is well established. Additionally, polygenic risk scores for BP traits are associated with clinically significant phenotypic variation. However, interactions between genetic and environmental risk factors in hypertension morbidity and mortality are poorly characterized. Methods and Results We used genotype and phenotype data from up to 49 234 participants from the HUNT (Trøndelag Health Study) to model gene–environment interactions between genome‐wide polygenic risk scores for systolic BP and diastolic BP and 125 environmental exposures. Among the 125 environmental exposures assessed, 108 and 100 were independently associated with SBP and DBP, respectively. Of these, 12 interactions were identified for genome‐wide PRSs for systolic BP and 4 for genome‐wide polygenic risk scores for diastolic BP, 2 of which were overlapping (P

BACKGROUND:. Patients with acute hypoxemic respiratory failure are at high risk of death and prolonged time on the ventilator. Interventions often aim to reduce both mortality and time on the ventilator. Many methods have been proposed for analyzing these endpoints as a single composite outcome (days alive and free of ventilation), but it is unclear which analytical method provides the best performance. Thus, we aimed to determine the analysis method with the highest statistical power for use in clinical trials. METHODS:. Using statistical simulation, we compared multiple methods for analyzing days alive and free of ventilation: the t, Wilcoxon rank-sum, and Kryger Jensen and Lange tests, as well as the proportional odds, hurdle-Poisson, and competing risk models. We compared 14 scenarios relating to: 1) varying baseline distributions of mortality and duration of ventilation, which were based on data from a registry of patients with acute hypoxemic respiratory failure and 2) the varying effects of treatment on mortality and duration of ventilation. RESULTS AND CONCLUSIONS:. All methods have good control of type 1 error rates (i.e., avoid false positive findings). When data are simulated using a proportional odds model, the t test and ordinal models have the highest relative power (92% and 90%, respectively), followed by competing risk models. When the data are simulated using survival models, the competing risk models have the highest power (100% and 92%), followed by the t test and a ten-category ordinal model. All models struggled to detect the effect of the intervention when the treatment only affected one of mortality and duration of ventilation. Overall, the best performing analytical strategy depends on the respective effects of treatment on survival and duration of ventilation and the underlying distribution of the outcomes. The evaluated models each provide a different interpretation for the treatment effect, which must be considered alongside the statistical power when selecting analysis models.

Abstract In engineered photonic lattices, topological photonic (TP) modes present a promising avenue for designing waveguides with suppressed backscattering. However, the integration of the TP modes in electromagnetic systems has faced longstanding challenges. The primary obstacle is the insufficient development of high‐efficiency coupling technologies between the TP modes and the conventional transmission modes. This dilemma leads to significant scattering at waveguide terminals when attempting to connect the TP waveguides with other waveguides. In this study, a topological photonic substrate‐integrated waveguide (TPSIW) is proposed that can seamlessly integrate into traditional microstrip line systems. It successfully addresses the matching problem and demonstrates efficient coupling of both even and odd TP modes with the quasi‐transverse electromagnetic modes of microstrip lines, resulting in minimal energy losses. In addition, topological leaky states are introduced through designed slots on the TPSIW top surface. These slots enable the creation of TP leaky‐wave antennas with beam steering capabilities. A wireless link based on TPSIWs are further established that enables the transmission of distinct signals toward different directions. This work is an important step toward the integration of TP modes in microwave systems, unlocking the possibilities for the development of high‐performance wireless devices.

Abstract The gradual accumulation of phosphorus from historical fertilization can contribute to the eutrophication of surface waters by increasing the potential for subsurface leaching losses. Grazing lands areas are a priority for concern, and phytoremediation efforts in grazing lands have prioritized grasses that may be used as forage for cattle. This study investigated the influence of three different forage species—Paspalum notatum, Hemarthria altissima, and Cynodon nlemfuensis—on the loss of phosphorus in leachate from surface soils. The experiment used a nested pot mesocosm design that allowed us to monitor leachate volume and concentration biweekly over the course of 3 months. Pots containing P. notatum plants leached significantly more phosphorus than pots containing C. nlemfuensis or empty pots with no plants growing in them, despite losing an equivalent amount of water. H. altissima lost equivalent amounts of phosphorus in leachate water, but each H. altissima plant removed approximately 33.6 mg of phosphorus, approximately 2.5× that removed by P. notatum (13.4 mg). C. nlemfuensis had lower average leachate phosphorus concentrations at each biweekly sampling than either plant species (C. nlemfuensis‐P. notatum, padj = 0.001; C. nlemfuensis‐H. altissima, padj = 0.02), averaging only 0.110 ppm in leachate relative to 0.175 ppm and 0.200 ppm in pots beneath H. altissima and P. notatum, respectively. This, combined with C. nlemfuensis' slightly higher‐than‐average aboveground P content and overall aboveground biomass expression suggest it is the best possible phytoremediation candidate. As even minor leachate P loads can be critically threatening to neighboring oligotrophic water bodies, if the conservation of downstream environments is the priority, the short‐term threat of increased leachate must be considered. Further research is needed to explore the underlying mechanisms and field‐scale implications of these findings.

Large-scale survey assessments (LSAs) are important tools for measuring educational outcomes and shaping policy decisions. We present a framework for comparing LSAs to facilitate studying the impact of design choice on the precision of results, contrasting India’s National Achievement Survey (NAS), the United States’ National Assessment of Educational Progress (NAEP), and the OECD’s Programme for International Student Assessment (PISA). Our framework focuses on four key elements: sampling design, assessment design, analysis methodology, and reporting. The notion of total survey error, which is the accumulation of errors across the four key elements, can be used for both designing and evaluating LSAs. As example, we compare statistics that are commonly (but not always) reported from NAS, NAEP, and PISA to summarize outcomes related to sampling, measurement, and reporting. Our examination reveals several key similarities and differences among the three assessments, thereby highlighting the nuanced ways in which each LSA is tailored to meet the specific needs of their purpose and the challenges they face.

IntroductionNutrition, sleep and physical activity are termed the “big three” health enhancing behaviors (HEB) associated with psychological distress and wellbeing. This study sought to understand differential associations between an expanded group of HEB (nutrition, sleep, physical activity, mindfulness, social connectedness) and psychological distress/wellbeing in early adolescents.MethodsCorrelational and regression analyses were conducted in N=103 (51% females) adolescents (12.6 ± 0.3 years of age) recruited from the Longitudinal Adolescent Brain Study.ResultsHigher scores on sleep, social connectedness and mindfulness scales were significantly associated with lower psychological distress scores. While higher scores on social connectedness and mindfulness scales were significantly associated with higher wellbeing scores. When adjusting for sex, nutrition, sleep, social connectedness and mindfulness accounted for a significant proportion of variance in the psychological distress model whereas physical activity and social connectedness accounted for a significant proportion of the variance in the wellbeing model.DiscussionsOverall findings make a strong case for expansion of the “big three” HEB to include mindfulness and social connectedness, especially given social connectedness emerged as the strongest predictor of both psychological distress and wellbeing. In addition, this research suggests that early adolescent nutrition, sleep quality, and mindfulness should be prioritized in efforts to reduce risk of difficulties, and physical activity prioritized as a protective factor for wellbeing in this population. Findings have implications for interventions, emphasizing the importance of addressing HEB factors comprehensively and tailoring strategies to the unique needs of early adolescents to foster positive mental health outcomes.

Abstract Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Abstract Repetitive bouts of coughing expose the large airways to significant cycles of shear stress. This leads to the release of alarmins and the tussive agent adenosine triphosphate (ATP) which may be modulated by the activity of ion channels present in the human airway. This study aimed to investigate the role of the transient receptor potential subfamily vanilloid member 2 (TRPV2) channel in mechanically induced ATP release from primary bronchial epithelial cells (PBECs). PBECs were obtained from individuals undergoing bronchoscopy. They were cultured in vitro and exposed to mechanical stress in the form of compressive and fluid shear stress (CFSS) or fluid shear stress (FSS) alone at various intensities. ATP release was measured using a luciferin–luciferase assay. Functional TRPV2 protein expression in human PBECs was investigated by confocal calcium imaging. The role of TRPV2 inhibition on FSS-induced ATP release was investigated using the TRPV2 inhibitor tranilast or siRNA knockdown of TRPV2. TRPV2 protein expression in human lung tissue was also determined by immunohistochemistry. ATP release was significantly increased in PBECs subjected to CFSS compared with control (unstimulated) PBECs (N = 3, ***P

Abstract Background Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations. Methods The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits. Discussion The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF. Trial registration ClinicalTrials.gov identifier: NCT03286556.

Abstract Background The presence of coronary plaques with high-risk characteristics is strongly associated with adverse cardiac events beyond the identification of coronary stenosis. Testing by coronary computed tomography angiography (CCTA) enables the identification of high-risk plaques (HRP). Referral for CCTA is presently based on pre-test probability estimates including clinical risk factors (CRFs); however, proteomics and/or genetic information could potentially improve patient selection for CCTA and, hence, identification of HRP. We aimed to (1) identify proteomic and genetic features associated with HRP presence and (2) investigate the effect of combining CRFs, proteomics, and genetics to predict HRP presence. Methods Consecutive chest pain patients (n = 1462) undergoing CCTA to diagnose obstructive coronary artery disease (CAD) were included. Coronary plaques were assessed using a semi-automatic plaque analysis tool. Measurements of 368 circulating proteins were obtained with targeted Olink panels, and DNA genotyping was performed in all patients. Imputed genetic variants were used to compute a multi-trait multi-ancestry genome-wide polygenic score (GPSMult). HRP presence was defined as plaques with two or more high-risk characteristics (low attenuation, spotty calcification, positive remodeling, and napkin ring sign). Prediction of HRP presence was performed using the glmnet algorithm with repeated fivefold cross-validation, using CRFs, proteomics, and GPSMult as input features. Results HRPs were detected in 165 (11%) patients, and 15 input features were associated with HRP presence. Prediction of HRP presence based on CRFs yielded a mean area under the receiver operating curve (AUC) ± standard error of 73.2 ± 0.1, versus 69.0 ± 0.1 for proteomics and 60.1 ± 0.1 for GPSMult. Combining CRFs with GPSMult increased prediction accuracy (AUC 74.8 ± 0.1 (P = 0.004)), while the inclusion of proteomics provided no significant improvement to either the CRF (AUC 73.2 ± 0.1, P = 1.00) or the CRF + GPSMult (AUC 74.6 ± 0.1, P = 1.00) models, respectively. Conclusions In patients with suspected CAD, incorporating genetic data with either clinical or proteomic data improves the prediction of high-risk plaque presence. Trial registration https://clinicaltrials.gov/ct2/show/NCT02264717 (September 2014).

Abstract Background Long-read sequencing can enable the detection of base modifications, such as CpG methylation, in single molecules of DNA. The most commonly used methods for long-read sequencing are nanopore developed by Oxford Nanopore Technologies (ONT) and single molecule real-time (SMRT) sequencing developed by Pacific Bioscience (PacBio). In this study, we systematically compare the performance of CpG methylation detection from long-read sequencing. Results We demonstrate that CpG methylation detection from 7179 nanopore-sequenced DNA samples is highly accurate and consistent with 132 oxidative bisulfite-sequenced (oxBS) samples, isolated from the same blood draws. We introduce quality filters for CpGs that further enhance the accuracy of CpG methylation detection from nanopore-sequenced DNA, while removing at most 30% of CpGs. We evaluate the per-site performance of CpG methylation detection across different genomic features and CpG methylation rates and demonstrate how the latest R10.4 flowcell chemistry and base-calling algorithms improve methylation detection from nanopore sequencing. Additionally, we show how the methylation detection of 50 SMRT-sequenced genomes compares to nanopore sequencing and oxBS. Conclusions This study provides the first systematic comparison of CpG methylation detection tools for long-read sequencing methods. We compare two commonly used computational methods for the detection of CpG methylation in a large number of nanopore genomes, including samples sequenced using the latest R10.4 nanopore flowcell chemistry and 50 SMRT sequenced samples. We provide insights into the strengths and limitations of each sequencing method as well as recommendations for standardization and evaluation of tools designed for genome-scale modified base detection using long-read sequencing.

A rare subseasonal-to-seasonal phenomenon – two consecutive flash drought events interrupted by a period of recovery – occurred across eastern Oklahoma, Arkansas, and southern Missouri, spanning the summer and early fall of 2022. These flash drought events (the first in June–July, the second in August–September) led to severe (D2) and extreme (D3) drought conditions via the United States Drought Monitor across much of the region following the first period of rapid drought intensification, and extreme (D3) and exceptional (D4) drought conditions by the end of the second event. A notable driver of both flash drought events included a persistent upper-level ridge either centered over or shifted west and upstream of the flash drought region, leading to broad-scale subsidence and reduced mid-level moisture which acted to limit precipitation development and increase evaporative demand. In addition, several heatwave events developed during the warm season in 2022 and either (1) acted to drive flash drought development via increased evaporative demand or (2) were enhanced by land surface desiccation and land-atmosphere feedbacks following rapid drought intensification. Furthermore, S2S composite forecasts predicted drought development for both events. However, only 20% of the ensembles predicted rapid drought development associated with flash drought for the first event and 16% of the ensembles predicted rapid drought development during the second event. This result highlights a key challenge in S2S prediction of rapidly developing drought conditions versus that of more conventional and slower drought development. The ensembles that did predict rapid drought intensification were associated with the forecasting of positive 500 hPa geopotential height anomalies over the south-central United States (first event) or an amplified wave pattern centered over the west-central United States (second event). Lastly, the compounding effects of two flash droughts in a single warm season led to substantial impacts on agricultural, environmental, and hydrologic sectors across the region.

Abstract The UK contribution to the Detection and Attribution Model Intercomparison Project (DAMIP), part of the sixth phase of the Climate Model Intercomparison Project (CMIP6), is described. The lower atmosphere and ocean resolution configuration of the latest Hadley Centre global environmental model, HadGEM3‐GC3.1, is used to create simulations driven either with historical changes in anthropogenic well‐mixed greenhouse gases, anthropogenic aerosols, or natural climate factors. Global mean near‐surface air temperatures from the HadGEM3‐GC31‐LL simulations are consistent with CMIP6 model ensembles for the equivalent experiments. While the HadGEM3‐GC31‐LL simulations with anthropogenic and natural forcing factors capture the overall observed warming, the lack of marked simulated warming until the 1990s is diagnosed as due to aerosol cooling mostly offsetting the well‐mixed greenhouse gas warming until then. The model has unusual temperature variability over the Southern Ocean related to occasional deep convection bringing heat to the surface. This is most prominent in the model's aerosol only simulations, which have the curious feature of warming in the high southern latitudes, while the rest of the globe cools, a behavior not seen in other CMIP6 models. This has implications for studies that assume model responses, from different climate drivers, can be linearly combined. While DAMIP was predominantly designed for detection and attribution studies, the experiments are also very valuable for understanding how different climate drivers influence a model, and thus for interpretating the responses of combined anthropogenic and natural driven simulations. We recommend institutions provide model simulations for the high priority DAMIP experiments.

Introduction Gout is one of the most common forms of arthritis worldwide. Gout is particularly prevalent in Aotearoa/New Zealand and is estimated to affect 13.1% of Māori men, 22.9% of Pacific men and 7.4% of New Zealand European men. Effective long-term treatment requires lowering serum urate to

Introduction: Sclerosing adenosis is a benign, proliferative breast disease. Few reports of imaging findings exist in the world literature, and none exists in Mexican literature. This study describes the mammography, ultrasound (US), and magnetic resonance imaging (MRI) findings of histopathologically confirmed sclerosing adenosis in Mexican women. Materials and Methods: This retrospective cross-sectional study was conducted in two private medical centers from January 2006 to July 2022. Adult women with a histopathologic diagnosis of sclerosing adenosis and an imaging examination, mammography, breast (US), and/or MRI were included. Results: A total of 169 women with a median age of 47.0 ± 8.4 years were included. Screening was the main indication for the imaging examination (n = 130, 76.9%). Of the 169 patients, 25 (14.8%) had a relative with a history of breast cancer, whereas 23 (13.6%) had a personal history of breast cancer. Mammography was performed on 155 (91.7%) patients. The most common finding was the grouping of amorphous and pleomorphic calcifications (n = 55, 44.7%). Breast US was performed in 147 (86.9%) patients, with an oval, circumscribed, hypoechoic, avascular mass being the most common findings (n = 61,41.5%), followed by architectural distortions (n = 32, 21.8%). Breast MRI was performed in 17 women; non-mass enhancement was the most common finding (n = 8, 47.0%). Conclusion: Our study comprehensively describes sclerosing adenosis multimodality imaging findings with mammography, US, and MRI. We found no specific imaging feature.

La enfermedad de Rosai-Dorfman se define como una histiocitosis de curso generalmente benigno, caracterizada por la acumulación ganglionar de histiocitos que presentan emperipolesis y positividad inmunohistoquímica para S-100 y CD68, y negatividad para CD1a y langerina. Su etiología exacta se desconoce, asociándose a factores autoinmunes, infecciosos y genéticos. El compromiso renal es infrecuente, identificándose en menos del 5% de los pacientes. Se presenta el caso de un hombre de 54 años, con descubrimiento incidental de lesión tumoral que comprometía el polo inferior de riñón izquierdo, quien fue sometido a nefrectomía radical y cuyos hallazgos histopatológicos confirmaron enfermedad de Rosai-Dorfman.

Background Stereotactic thrombolysis for evacuation of large spontaneous intracerebral (ICH) and intraventricular hemorrhage (IVH) typically requires stabilizing the hemorrhage preoperatively. We investigated intracranial hemorrhage expansion (HE) in the pre‐ and postrandomization phase of 2 clinical trials of surgical candidates with protocolized computed tomography (CT) imaging up to 10 days after presentation. Methods Prospective assessment of sequential pre‐ and post‐randomization CT scans of 141 patients enrolled in MISTIE (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation) II/ICES (Intraoperative CT‐guided Endoscopic Surgery for ICH) and 499 patients enrolled in MISTIE III. Primary outcomes were prerandomization HE of ICH >6 mL and IVH >5 mL. Secondary outcome was postrandomization HE. Stability was defined as CT time after which no further HE was observed. We evaluated risk factors for ICH/IVH expansion using multivariable logistic regression analyses after adjustment for demographics, ICH characteristics and treatment. Results Median (interquartile range) diagnostic ICH volume was 40.4 (29.5–54.1) mL. Prerandomization HE >6 mL was detected in 216 (33.8%) subjects. Median time to hematoma stability from diagnostic CT was 7 (4.7–13.6) hours. Median diagnostic IVH volume was 0 (0–1.9) mL. IVH expansion >5 mL occurred in 40 (6.3%) with stability at 6.9 (4.7–11.2) hours. Of subjects with HE, final expansion events were not yet detected at 12 hours from diagnostic CT in 36% (ICH expansion) and 33% (IVH expansion), respectively, with 91% detected by 24 hours. Independent associations with ICH expansion included age, male sex, White race, anticoagulation, ICH volume, deep ICH location, IVH, and time from symptom onset to diagnostic CT. Postsurgical ICH expansion occurred in 24 patients (6.9%) and was associated with delay in achieving stability, number of alteplase doses, and fewer CT hypodensities on diagnostic CT but not with functional outcome. Conclusion In patients with a large ICH eligible for surgical evacuation, about two thirds of HE events stabilize within 12 hours and most within 24 hours. An earlier time window for stereotactic thrombolysis may be feasible.

Background Physician transfer is an alternate option to patient transfer for expedient performance of mechanical thrombectomy in patients with acute ischemic stroke. Methods and Results We conducted a systematic review to identify studies that evaluate the effect of physician transfer in patients with acute ischemic stroke who undergo mechanical thrombectomy. A search of PubMed, Scopus, and Web of Science was undertaken, and data were extracted. A statistical pooling with random‐effects meta‐analysis was performed to examine the odds of reduced time interval between stroke onset and recanalization, functional independence, death, and angiographic recanalization. A total of 12 studies (11 nonrandomized observational studies and 1 nonrandomized controlled trial) were included, with a total of 1894 patients. Physician transfer was associated with a significantly shorter time interval between stroke onset and recanalization with a pooled mean difference estimate of −62.08 (95% CI, −112.56 to −11.61]; P=0.016; 8 studies involving 1419 patients) with high between‐study heterogeneity in the estimates (I2=90.6%). The odds for functional independence at 90 days were significantly higher (odds ratio, 1.29 [95% CI, 1.00–1.66]; P=0.046; 7 studies with 1222 patients) with physician transfer with low between‐study heterogeneity (I2=0%). Physician transfer was not associated with higher odds of near‐complete or complete angiographic recanalization (odds ratio, 1.18 [95% CI, 0.89–1.57; P=0.25; I2=2.8%; 11 studies with 1856 subjects). Conclusions Physician transfer was associated with a significant reduction in the mean of time interval between symptom onset and recanalization and increased odds for functional independence at 90 days with physician transfer compared with patient transfer among patients who undergo mechanical thrombectomy.

Summary: When Aedes albopictus mosquitoes invade regions predominated by Aedes aegypti, either the latter can be displaced or the species can coexist, with potential consequences on disease transmission. Males from both species identify females by listening for her flight sounds. Comparing male hearing systems may provide insight into how hearing could prevent interspecific mating. Here, we show that species-specific differences in female wing beat frequencies are reflected in differences in male ear mechanical tuning frequencies and sound response profiles. Though Aedes albopictus males are attracted to sound, they do not readily display abdominal bending, unlike Aedes aegypti. We observed interspecific differences in male ear mechanical, but not electrical, tuning, suggesting a conserved primary auditory processing pathway. Our work suggests a potential role for hearing in the premating isolation of Aedes aegypti and Aedes albopictus, with implications for predicting future dynamics in their sympatric relationships and our understanding of mosquito acoustic communication.

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1–391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5–142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00–0.69) and the right lacrimal gland (median 0.59, range 0.42–0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021

Platinum silicide (PtSi) presents a promising superconductor for achieving silicon-based Josephson field-effect transistors (JoFETs). In a viable process flow to realize self-aligned PtSi formation, thermal oxidation at 600 °C is required to form a protective oxide layer on the surface of the as-formed PtSi selectively against Pt to facilitate subsequent selective etch in aqua regia. However, sub-10 nm PtSi films tend to agglomerate and even break into discrete PtSi islands upon thermal treatments above 500 °C. To achieve nanoscale JoFETs, we have developed a simple alternative with chemical oxidation at room temperature leading to the formation of homogeneous sub-5 nm PtSi films. The critical temperature of the resultant superconducting PtSi films is found to increase from 0.66 to 0.90 K when the PtSi thickness is raised from 3.1 to 12.7 nm, while, concurrently, the PtSi grains grow larger in thicker films. The critical temperature also increases from 0.53 to 0.66 K for the 3.1 nm PtSi film when the formation temperature is raised from 400 to 500 °C.

Orientation: The outbreak of the coronavirus diease 2019 (COVID-19) pandemic directly and indirectly disrupted global production, consumption, and trade patterns. Regional blocs were not an exception. Research purpose: The article aims to investigate the effects of COVID-19 pandemic on regional trade, with a specific focus on the Common Market for Eastern and Southern Africa (COMESA) regional trading bloc. Motivation for the study: The outbreak of the COVID-19 pandemic generated remarkable economic adjustments with severe penalties affecting diverse communities and people globally. As such, regional communities such as COMESA were not an exception. However, relatively little is known about the effects of this pandemic on international trade within particular regional economic communities, and more specifically in the COMESA region. Research design, approach and method: By employing a cross-sectional type gravity model and utilising the Poisson pseudo-maximum likelihood (PPML) method, the article explored trade data for 14 COMESA member states and explicitly regressed intra-COMESA trade values on various measures of the severity of COVID-19 in 2020. The article further assessed the impact of COVID-19 in the COMESA region within the framework of the traditional gravity model variables. Main findings: The findings of this article confirm significant negative effects of COVID-19 cases and lockdown measures on intra-COMESA trade in the exporting country. In the importing country, the effect of COVID-19 on intra-COMESA trade was found to be insignificant regardless of the quantifying measure. Practical/managerial implications: It is recommended in this article that the COMESA regional bloc and the African continent, in general, should expand their respective pharmaceutical production and research and development capacity to be able to respond and advance their future inoculation drives intended to restrain the trade-related impacts of communicable diseases of the COVID-19 nature. Contribution/value-add: This article contributes to the COVID-19 epidemic knowledge base and the existing international trade COVID-19 nexus by enhancing the understanding of the impact of global health shocks on economic outcomes from developing countries perspective. It further presents new empirical evidence that can be utilised as a springboard for policymakers in COMESA to formulate future regional response mechanisms to health crisis of the COVID-19 form.

At high latitudes, lake-atmosphere interactions are disrupted for several months of the year by the presence of an ice cover. By isolating the water column from the atmosphere, ice, typically topped by snow, drastically alters albedo, surface roughness, and heat exchanges relative to the open water period, with major climatic, ecological, and hydrological implications. Lake models used to simulate the appearance and disappearance of the ice cover have rarely been validated with detailed in situ observations of snow and ice. In this study, we investigate the ability of the physically-based 1D Canadian Small Lake Model (CSLM) to simulate the freeze-up, ice-cover growth, and breakup of a small boreal lake. The model, driven offline by local weather observations, is run on Lake Piché, 0.15 km2 and 4 m deep (47.32°N; 71.15°W) from 25 October 2019 to 20 July 2021, and compared to observations of the temperature profile and ice and snow cover properties. Our results show that the CSLM is able to reproduce the total ice thickness (average error of 15 cm) but not the ice type-specific thickness, underestimating clear ice and overestimating snow ice. CSLM manages to reproduce snow depth (errors less than 10 cm). However, it has an average cold bias of 2°C and an underestimation of average snow density of 34 kg m−3. Observed and model freeze-up and break-up dates are very similar, as the model is able to predict the longevity of the ice cover to within 2 weeks. CSLM successfully reproduces seasonal stratification, the mixed layer depth, and surface water temperatures, while it shows discrepancies in simulating bottom waters especially during the open water period.

This case study on the Children, Youth, and Families At-Risk (CYFAR) Professional Development and Technical Assistance (PDTA) Center highlights a government-funded entity’s efforts to provide technical assistance to federal grantees of the CYFAR Sustainable Community Projects (SCP) grant program. The PDTA Center aligns with and supports components of an evidence-based system for innovation support. Through these components, the system provides targeted tools, training for CYFAR SCP grantees, dedicated technical assistance in the form of coaching, and quality improvement support through the evaluation of available program data.

Enhancing grain yield is a primary goal in the cultivation of major staple crops, including wheat. Recent research has focused on identifying the physiological and molecular factors that influence grain weight, a critical determinant of crop yield. However, a bottleneck has arisen due to the trade-off between grain weight and grain number, whose underlying causes remain elusive. In a novel approach, a wheat expansin gene, TaExpA6, known for its expression in root tissues, was engineered to express in the grains of the spring wheat cultivar Fielder. This modification led to increases in both grain weight and yield without adversely affecting grain number. Conversely, a triple mutant line targeting the gene TaGW2, a known negative regulator of grain weight, resulted in increased grain weight but decreased grain number, potentially offsetting yield gains. This study aimed to evaluate the two aforementioned modified wheat genotypes (TaExpA6 and TaGW2) alongside their respective wild-type counterparts. Conducted in southern Chile, the study employed a Complete Randomized Block Design with four replications, under well-managed field conditions. The primary metrics assessed were grain yield, grain number, and average grain weight per spike, along with detailed measurements of grain weight and dimensions across the spike, ovary weight at pollination (Waddington’s scale 10), and post-anthesis expression levels of TaExpA6 and TaGW2. Results indicated that both the TaExpA6 and the triple mutant lines achieved significantly higher average grain weights compared to their respective wild types. Notably, the TaExpA6 line did not exhibit a reduction in grain number, thereby enhancing grain yield per spike. By contrast, the triple mutant line showed a reduced grain number per spike, with no significant change in overall yield. TaExpA6 expression peaked at 10 days after anthesis (DAA), and its effect on grain weight over the WT became apparent after 15 DAA. In contrast, TaGW2 gene disruption in the triple mutant line increased ovary size at anthesis, leading to improved grain weight above the WT from the onset of grain filling. These findings suggest that the trade-off between grain weight and number could be attributed to the overlapping of the critical periods for the determination of these traits.