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Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is associated with acute brain injury (ABI), including central nervous system (CNS) ischemia (defined as ischemic stroke or hypoxic-ischemic brain injury [HIBI]) and intracranial hemorrhage (ICH). Data on prediction models for neurologic outcomes in VV-ECMO are limited. Methods: We analyzed adult (age ≥18 years) VV-ECMO patients in the Extracorporeal Life Support Organization (ELSO) Registry (2009-2021) from 676 centers. ABI was defined as CNS ischemia, ICH, brain death, and seizures. Data on 67 variables were extracted, including clinical characteristics and pre-ECMO/on-ECMO variables. Random forest, CatBoost, LightGBM, and XGBoost machine learning (ML) algorithms (10-fold leave-one-out cross-validation) were used to predict ABI. Feature importance scores were used to pinpoint the most important variables for predicting ABI. Results: Of 37,473 VV-ECMO patients (median age, 48.1 years; 63% male), 2644 (7.1%) experienced ABI, including 610 (2%) with CNS ischemia and 1591 (4%) with ICH. The areas under the receiver operating characteristic curve for predicting ABI, CNS ischemia, and ICH were 0.70, 0.68, and 0.70, respectively. The accuracy, positive predictive value, and negative predictive value for ABI were 85%, 19%, and 95%, respectively. ML identified higher center volume, pre-ECMO cardiac arrest, higher ECMO pump flow, and elevated on-ECMO serum lactate level as the most important risk factors for ABI and its subtypes. Conclusions: This is the largest study of VV-ECMO patients to use ML to predict ABI reported to date. Performance was suboptimal, likely due to lack of standardization of neuromonitoring/imaging protocols and data granularity in the ELSO Registry. Standardized neurologic monitoring and imaging are needed across ELSO centers to detect the true prevalence of ABI.

Abstract Finalization of eukaryotic nuclear DNA replication relies on DNA ligase 1 (LIG1) to seal DNA nicks generated during Okazaki Fragment Maturation (OFM). Using a mutational reporter in Saccharomyces cerevisiae, we previously showed that mutation of the high-fidelity magnesium binding site of LIG1Cdc9 strongly increases the rate of single-base insertions. Here we show that this rate is increased across the nuclear genome, that it is synergistically increased by concomitant loss of DNA mismatch repair (MMR), and that the additions occur in highly specific sequence contexts. These discoveries are all consistent with incorporation of an extra base into the nascent lagging DNA strand that can be corrected by MMR following mutagenic ligation by the Cdc9-EEAA variant. There is a strong preference for insertion of either dGTP or dTTP into 3–5 base pair mononucleotide sequences with stringent flanking nucleotide requirements. The results reveal unique LIG1Cdc9-dependent mutational motifs where high fidelity DNA ligation of a subset of OFs is critical for preventing mutagenesis across the genome.

Abstract Background Back pain is very common and a leading cause of disability worldwide. Due to health care system inequalities, Indigenous communities have a disproportionately higher prevalence of injury and acute and chronic diseases compared to the general Canadian population. Indigenous communities, particularly in northern Canada, have limited access to evidence-based spine care. Strategies established in collaboration with Indigenous peoples are needed to address unmet healthcare needs, including spine care (chiropractic and movement program) services. This study aimed to understand the views and perspectives of Cross Lake community leaders and clinicians working at Cross Lake Nursing Station (CLNS) in northern Manitoba regarding the implementation of the Global Spine Care Initiative (GSCI) model of spine care (MoC) and related implementation strategies. Method A qualitative exploratory design using an interpretivist paradigm was used. Twenty community partners were invited to participate in semi-structured interviews underpinned by the Theoretical Domains Framework (TDF) adapted to capture pertinent information. Data were analyzed deductively and inductively, and the interpretation of findings were explored in consultation with community members and partners. Results Community leaders (n = 9) and physicians, nurses, and allied health workers (n = 11) emphasized: 1) the importance of contextualizing the MoC (triaging and care pathway) and proposed new services through in-person community engagement; 2) the need and desire for local non-pharmacological spine care approaches; and 3) streamlining patient triage and CLNS workflow. Recommendations for the streamlining included reducing managerial/administrative duties, educating new incoming clinicians, incorporating follow-up appointments for spine pain patients, and establishing an electronic medical record system along with a patient portal. Suggestions regarding how to sustain the new spine care services included providing transportation, protecting allocated clinic space, resolving insurance coverage discrepancies, addressing misconceptions about chiropractic care, instilling the value of physical activity for self-care and pain relief, and a short-term (30-day) incentivised movement program which considers a variety of movement options and offers a social component after each session. Conclusion Community partners were favorable to the inclusion of a refined GSCI MoC. Adapting the TDF to unique Indigenous needs may help understand how best to implement the MoC in communities with similar needs.

Abstract Background Lung cancer is a heterogeneous disease and the primary cause of cancer-related mortality worldwide. Somatic mutations, including large structural variants, are important biomarkers in lung cancer for selecting targeted therapy. Genomic studies in lung cancer have been conducted using short-read sequencing. Emerging long-read sequencing technologies are a promising alternative to study somatic structural variants, however there is no current consensus on how to process data and call somatic events. In this study, we preformed whole genome sequencing of lung cancer and matched non-tumour samples using long and short read sequencing to comprehensively benchmark three sequence aligners and seven structural variant callers comprised of generic callers (SVIM, Sniffles2, DELLY in generic mode and cuteSV) and somatic callers (Severus, SAVANA, nanomonsv and DELLY in somatic modes). Results Different combinations of aligners and variant callers influenced somatic structural variant detection. The choice of caller had a significant influence on somatic structural variant detection in terms of variant type, size, sensitivity, and accuracy. The performance of each variant caller was assessed by comparing to somatic structural variants identified by short-read sequencing. When compared to somatic structural variants detected with short-read sequencing, more events were detected with long-read sequencing. The mean recall of somatic variant events identified by long-read sequencing was higher for the somatic callers (72%) than generic callers (53%). Among the somatic callers when using the minimap2 aligner, SAVANA and Severus achieved the highest recall at 79.5% and 79.25% respectively, followed by nanomonsv with a recall of 72.5%. Conclusion Long-read sequencing can identify somatic structural variants in clincal samples. The longer reads have the potential to improve our understanding of cancer development and inform personalized cancer treatment.

Abstract Background Cardiac fibromas are extremely rare in adults. The preferred treatment is surgical resection, but antiarrhythmic medications or heart transplantation have also been used previously. The cardiac imaging, particularly MRI, can be useful to help delineate between primary cardiac tumors, and surgical factors such as the extent/size of the fibroma, involvement of the coronary arteries or mitral apparatus and amount of residual myocardium influence whether surgical resection is feasible. Case presentation A 42-year-old male presented with a wide-complex tachycardia, unresponsive to amiodarone. An echocardiogram was performed which showed a possible posterior wall mass. A cardiac MRI showed a well circumscribed lateral wall intracardiac fibroma, measuring 5.2 × 5.1 × 3.8 cm with preserved function. Surgical resection was successful, and he was discharged without a defibrillator. Conclusions Cardiac fibromas are encapsulated tumors which do not infiltrate myocardium and should be surgically resected if possible.

Abstract Microplastics (MPs) have been found in a diverse range of organisms across trophic levels. While a majority of the information on organismal exposure to plastics in the environment comes from gastrointestinal (GI) data, the prevalence of MP particles in other tissues is not well understood. Additionally, many studies have not been able to detect the smallest, most prevalent, MPs (1 µm – 5 mm) that are the most likely to distribute to tissues in the body. To address these knowledge gaps, MPs in the GI tract and muscle of Atlantic killifish (Fundulus heteroclitus) collected from two sites (Falmouth and Bourne) on Buzzards Bay, Cape Cod, MA were quantified down to 2 µm in size. Eight fish from Falmouth and 10 fish Bourne site were analyzed. Fourier-transform infrared spectroscopy and Raman spectroscopy were used to identify all particles. The mean concentrations of MPs in the GI tract and muscle from fish collected from Falmouth was 85.5 ± 70.2 and 11 ± 12.5 particles per gram wet weight, respectively. Fish collected from Bourne site had mean particle concentrations of 12.2 ± 18.1 and 1.69 ± 5.36 particles per gram wet weight. Of the 2,008 particles analyzed in various fish tissue samples, only 3.4% (69 particles) were identified as plastic; polymers included nylon, polyethylene, polypropylene, and polyurethane. MPs detected in the GI tract samples also tended to be more diverse in both size and polymer type than those found in the muscle. We found that MPs

Abstract Plant metabolism faces a challenge of investing enough enzymatic capacity to a pathway without overinvestment. As it takes energy and resources to build, operate, and maintain enzymes, there are benefits and drawbacks to accurately matching capacity to the pathway influx. The relationship between functional capacity and physiological load could be explained through symmorphosis, which would quantitatively match enzymatic capacity to pathway influx. Alternatively, plants could maintain excess enzymatic capacity to manage unpredictable pathway influx. In this study, we use photorespiration as a case study to investigate these two hypotheses in Betula papyrifera. This involves altering photorespiratory influx by manipulating the growth environment, via changes in CO2 concentration and temperature, to determine how photorespiratory capacity acclimates to environmental treatments. Surprisingly, the results from these measurements indicate that there is no plasticity in photorespiratory capacity in B. papyrifera, and that a fixed capacity is maintained under each growth condition. The fixed capacity is likely due to the existence of reserve capacity in the pathway that manages unpredictable photorespiratory influx in dynamic environments. Additionally, we found that B. papyrifera had a constant net carbon assimilation under each growth condition due to an adjustment of functional rubisco activity driven by changes in activation state. These results provide insight into the acclimation ability and limitations of B. papyrifera to future climate scenarios currently predicted in the next century.

Abstract Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5’ untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Abstract Low-abundance members of microbial communities are difficult to study in their native habitats, including Escherichia coli, a minor but common inhabitant of the gastrointestinal tract, and key opportunistic pathogen of the urinary tract. While multi-omic analyses have detailed interactions between uropathogenic Escherichia coli (UPEC) and the bladder mediating urinary tract infection (UTI), little is known about UPEC in its pre-infection reservoir, the gastrointestinal tract, partly due to its low relative abundance (

ABSTRACT Aims/Hypothesis In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects. Materials and Methods In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post‐randomization to fenofibrate or placebo. Results The Hp phenotypes 1‐1, 2‐1, and 2‐2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P

Multiple randomized controlled trials (RCTs) have examined first-line pharmacological agents such as anticholinergics and β3 agonists for the management of overactive bladder symptoms (OAB). Although earlier systematic reviews and (network) meta-analyses aimed to summarize the evidence, a substantial number of trials were not included, so a comprehensive and methodologically rigorous evaluation of the comparative effectiveness of all first-line pharmacological treatments is lacking. We aim to conduct a series of systematic reviews and network meta-analyses (NMAs) for a comprehensive assessment of the effectiveness and safety of first-line pharmacological treatments for OAB. Eligible studies will include RCTs comparing anticholinergics and β3 agonists to one another or to placebo in adults with OAB or detrusor overactivity. Pairs of reviewers with methodological training will independently evaluate candidate studies to determine eligibility and extract relevant data. We will incorporate patient-important outcomes, including urinary urgency episodes, urgency incontinence episodes, any type of incontinence episodes, urinary frequency, nocturia, and adverse events. We will conduct the NMAs using a frequentist framework and a graph theory model for each outcome. Analysis will follow rigorous methodologies, including handling of missing data and assessment of the risk of bias. We will conduct sensitivity and subgroup analyses and will apply the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to rate evidence certainty. Our approach aims to address the knowledge gap in the treatment of OAB by synthesizing evidence from RCTs worldwide. We will employ robust statistical methods, including frequentist NMA, to general clinically relevant and patient-important insights. Sensitivity and subgroup analyses will enhance the robustness and generalizability of our findings. Our reviews strive to inform evidence-based decisions in the management of OAB, to ultimate improve patient outcomes. Our study results may guide health policy decisions, such as reimbursement policies, and future studies in functional urology.The protocol for the review series is registered on PROSPERO as CRD42023266915.

Bourbon virus is a tickborne virus that can cause human disease. Cases have been reported in Kansas, Oklahoma, and Missouri, USA. We identified Bourbon virus–specific neutralizing antibodies in patients from North Carolina. Bourbon virus infections are likely more common than previously thought, highlighting the need for improved diagnostics and surveillance.

We recently expanded the viral genomic surveillance program in Minnesota, USA, to include human respiratory syncytial virus. We performed whole-genome sequencing of 575 specimens collected at Minnesota healthcare facilities during July 2023–February 2024. Subgroups A and B differed in their genomic landscapes, and we identified 23 clusters of genetically identical genomes.

The discovery that contracting skeletal muscle generates reactive oxygen species (ROS) was first reported over 40 years ago. The prevailing view in the 1980s was that exercise-induced ROS production promotes oxidation of proteins and lipids resulting in muscle damage. However, a paradigm shift occurred in the 1990s as growing research revealed that ROS are signaling molecules, capable of activating transcriptional activators/coactivators and promoting exercise-induced muscle adaptation. Growing evidence supports the notion that reduction-oxidation (redox) signaling pathways play an important role in the muscle remodeling that occurs in response to endurance exercise training. This review examines the specific role that redox signaling plays in this endurance exercise-induced skeletal muscle adaptation. We begin with a discussion of the primary sites of ROS production in contracting muscle fibers followed by a summary of the antioxidant enzymes involved in the regulation of ROS levels in the cell. We then discuss which redox-sensitive signaling pathways promote endurance exercise-induced muscle adaptation and debate the strength of the evidence supporting the notion that redox signaling plays an essential role in muscle adaptation to endurance exercise training. In hopes of stimulating future research, we highlight several important unanswered questions in this field.

Purpose: The purpose of this study was to evaluate risk factors associated with positive urine cultures following holmium laser enucleation of the prostate (HoLEP). Materials and Methods: The data from a prospectively maintained database were analyzed to evaluate urine culture results following HoLEP and determine the contribution of predefined variables (age, prostate size, Charlson comorbidity score, surgical time [surrogate for case difficulty], the presence of a catheter preoperatively, postoperative urinary retention, and preoperative positive culture) on urine culture positivity at 60 days postoperatively. Statistical analyses included logistic regression and ANOVA. Results: The data from 136 subjects were included in the database and were evaluated at a median of 13.37 ± 6.72 months after their HoLEP. Postoperative positive cultures were noted in 23 subjects (16.91%). Preoperative positive cultures were found to predict positive postoperative urine cultures (odds ratio: 3.78, confidence interval: 1.18–12.78, P = 0.03). However, the preoperative and postoperative results were discordant in 9 of 14 subjects with both positive preoperative and postoperative cultures. Conclusions: Positive preoperative cultures were predictive of positive postoperative cultures. However, the pre- and postoperative results were often discordant. Host factors increasing susceptibility to bacteriuria may explain these findings.

California is the primary US producer of processing tomatoes. After decades-long excellent protection against the common tropical Meloidogyne spp. M. incognita, M. javanica, and M. arenaria (root-knot nematode: RKN) by Mi-resistant tomato cultivars, resistance-breaking RKN populations are spreading throughout the San Joaquin Valley. For some time, nematicidal crop management tools have diminished under CA State regulatory pressure. In recent years, new non-volatile compounds have been developed with novel modes of action. In this project with susceptible processing tomato grown on an M. incognita-infested site, the efficacy of three fluorinated nematicides was evaluated in 10 field trials from 2011 to 2021. Seven trials included fluensulfone, six included fluazaindolizine, and five included fluopyram. On average, tomato root-galling (0 – 10 scale) at harvest was reduced by 3.2, 2.3, and 2.5 by fluazaindolizine, fluensulfone, and fluopyram, respectively, compared to the untreated control. These reductions in root-galling corresponded with estimated yield gains of approximately 21%, 14%, and 15%, respectively, over the untreated control. The reproduction of RKN during the tomato crop was not affected by the nematicides. The tested compounds have a very low acute mammalian toxicity and are more target-specific than previous generations of nematicides. However, there is considerable concern about the persistence of synthetic per- and polyfluoroalkyl substances (PFAS) in the environment, including pharmaceuticals and pesticides containing fluorine with the C-F3 functional group.

Abstract Background To evaluate procedure times for two cataract planning systems (ZEISS CALLISTO eye and the Wavetec AnalyzOR) in predicting residual astigmatism (prediction error) and other visual outcomes in patients with corneal astigmatism (maximum allowable up to 3.0D) at postoperative month 1. Methods This was a prospective, single center, parallel treatment group, bilateral and unilateral, randomized, 1-month study on patients scheduled to undergo routine, small-incision cataract surgery with a toric intraocular lens implantation. Both groups underwent preop measurements with the IOLMaster 700 (Zeiss, Jena, Germany) and surgery with the LenSx device (Alcon). Lens selection in the CALLISTO eye group was based on Zeiss VERACITY Surgery Planner (a web-based tool) and on the Wavetec AnalyzOR component of the ORA system (a real-time intraoperative aberrometer) for those eyes in the ORA group. All procedure and intraoperative times were measured with a stopwatch. Postoperative visual outcomes were evaluated between 1 and 2 months after surgery. Results There were 23 eyes in the CALLISTO group and 28 eyes in the ORA group. The mean surgical time for the CALLISTO group was 28.09 ± 1.72 min compared to 34.41 ± 1.52 min for the ORA group (P = 0.01). Toric lens placement mean time in the CALLISTO group was 2.47 ± 0.34 min compared to 3.88 ± 0.29 min in the ORA group (P = 0.0034). At month 1 postoperatively, the manifest refractive spherical error (MRSE) in the CALLISTO eye group 0.022 ± 0.388 diopters (D) compared to -0.174 ± 0.322 D in the ORA group; these were not statistically different. There was a higher percentage (75%) of eyes with an MRSE within 0.25D in the ORA group compared to the CALLISTO eye group (56.5%); at all other levels outcomes were numerically higher in the CALLISTO eye group. Conclusions Less surgical time was needed when using the CALLISTO eye than the ORA when performing cataract surgery with toric lens implantation. There were similar visual outcomes between the groups and no statistical differences.

Abstract Background Sepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive. Methods C57BL/6 wild type (WT), Casp8 −/− , Ripk3 −/− , and Zbp1 −/− mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways. Results In the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI. Conclusions These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.

Abstract Aim To compare newly graduated nurse retention and employment experiences across two distinct graduate nurse programs through periods of health care delivery stability and instability. Background A global nursing workforce shortage, coupled with increasing demands on health services, requires a specific focus on building capability and improved retention of nurses. The graduate nurse cohort is a critical supply source that potentially can be harnessed if their needs are better understood. Design A longitudinal (2015–2023) cross-sectional design was used to examine retention and experiences of newly graduated nurses from two (‘traditional, unit-based’ versus ‘mobile’) supported programs. Methods Retention rates were obtained through analysis of employment databases. Descriptive data on impressions and experiences was collected at two time points via a short series of questions contained in a survey, from graduate nurses who remained in employment. Results Retention rates for graduate nurses were high (85%) during periods of stability, but even higher for the ‘mobile’ graduate nurse program. Both programs were adversely affected by instability however, the impact was substantial (around 50%) for the peak period of instability (2020) in the ‘mobile’ program. Survey data indicated that during the period of instability graduate nurses in traditional, unit-based programs had a more positive experience when compared with graduate nurses participating in the ‘mobile’ program; This contrasts with the period of stability, where graduate nurses in the ‘mobile’ program indicated more positive responses. Discussion Findings re-emphasise the importance of supportive structures for newly graduated nurses as effective in retaining these staff. However, for the first time, evidence is provided that ‘mobility’, diversity, and difference can be viewed positively by graduate nurses. Furthermore, it provides improved understanding about mechanisms, support and boundaries, all interrelating factors, in ‘stretching’ capacity of graduate nurses. Conclusion Longitudinal analysis of graduate nurses, participating in two diverse programs, through periods of stability and instability offers insights into their challenges and outcomes. These insights can directly inform targeted strategies for inclusion in supported programs that lead to improved graduate nurse retention and contribute to building an agile nursing workforce.

Abstract This paper presents a novel single-layer, single-sided, dual-wideband linear-to-circular (LTC) polarsation converter. The unit cell of the polarisation converter comprises two identical diagonally oriented C-shaped metallic strips arranged symmetrically and integrated with four outwardly extending diagonal parasitic strips. The LTC polarisation converter is placed on the top side of an ultra-thin substrate layer with a profile size of 0.020 λo at 11.9 GHz and 0.05 λo at 30.7 GHz. The inclusion of parasitic strips in the unit cell design is pivotal, inducing a 90º phase shift between the orthogonal wave components, thus enhancing LTC polarisation conversion. The design achieved near-equal transmission amplitudes and maintained a stable phase difference of nearly 90° across two distinct frequency bands, enabling right-hand circular polarisation in the lower frequency band and left-hand circular polarisation in the higher frequency band. Numerical and experimental results showed that the polariser can realise a wideband LTC polarisation conversion for both x- and y-polarised electromagnetic wave incidences at two distinct frequency bands of 6.78–17.08 GHz (fractional bandwidth of 86.3%) and 25.09–36.40 GHz (36.8%). The converter maintained consistent polarisation conversion performance across a broad range of incidence angles and exhibited high and uniform total transmittance in both operational frequency bands.

Abstract With an interest in monitoring the patency of stents that are used to treat strictures in the bile duct, this paper reports the investigation of a wireless sensing system to interrogate a microsensor integrated into the stent. The microsensor is comprised of a 28-μm-thick magnetoelastic foil with 8.25-mm length and 1-mm width. Magnetic biasing is provided by permanent magnets attached to the foil. These elements are incorporated into a customized 3D polymeric package. The system electromagnetically excites the magnetoelastic resonant sensor and measures the resulting signal. Through shifts in resonant frequency and quality factor, the sensor is intended to provide an early indication of sludge accumulation in the stent. This work focuses on challenges associated with sensor miniaturization and placement, wireless range, drive signal feedthrough, and clinical use. A swine specimen in vivo experiment is described. Following endoscopic implantation of the sensor enabled plastic stent into the bile duct, at a range of approximately 17 cm, the signal-to-noise ratio of ~106 was observed with an interrogation time of 336 s. These are the first reported signals from a passive wireless magnetoelastic sensor implanted in a live animal.

Abstract Background Epigenome‐wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. Results We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p

Abstract Talin regulates crucial cellular functions, including cell adhesion and motility, and affects human diseases. Triggered by mechanical forces, talin plays crucial roles in facilitating the formation of focal adhesions and recruiting essential focal adhesion regulatory elements such as vinculin. The structural flexibility allows talin to fine-tune its signaling responses. This study presents our 2.7 Å cryoEM structures of talin, which surprisingly uncovers several auto-inhibitory states. Contrary to previous suggestions, our structures reveal that (1) the first and last three domains are not involved in maintaining talin in its closed state and are mobile, (2) the talin F-actin and membrane binding domain are loosely attached and thus available for binding, and (3) the main force-sensing domain is oriented with its vinculin binding sites ready for release. These structural snapshots offer insights and advancements in understanding the dynamic talin activation mechanism, which is crucial for mediating cell adhesion.

Abstract We developed and evaluated the Digital Platform for Exercise (DPEx): a decentralized, patient-centric approach designed to enhance all aspects of clinical investigation of exercise therapy. DPEx integrated provision of a treadmill with telemedicine and remote biospecimen collection permitting all study procedures to be conducted in patient’s homes. Linked health biodevices enabled high-resolution monitoring of lifestyle and physiological response. Here we describe the rationale and development of DPEx as well as feasibility evaluation in three different cohorts of patients with cancer: a phase 0a development study among three women with post-treatment primary breast cancer; a phase 0b proof-of-concept trial of neoadjuvant exercise therapy in 13 patients with untreated solid tumors; and a phase 1a level-finding trial of neoadjuvant exercise therapy in 53 men with localized prostate cancer. Collectively, our study demonstrates the utility of a fully digital, decentralized approach to conduct clinical trials of exercise therapy in a clinical population.

Abstract Climate change and metals independently stress soil microbiomes, but their combined effects remain unresolved. Here we show that future climate affects soil cadmium through altered soil microbiome and nutrient cycles, with soil pH as critical factor. In soils with pH7 soil show no climate impacts on cadmium mobilization, though imprints on microbiome structure were apparent. Subsequent nutrient cycling increased under future climate, stimulating soil respiration and nitrous oxide release. These findings underscore complex interactions between climate change and soil contaminants affecting the soil microbiome and its activity and highlights potential impacts on crop production, groundwater quality, and climate feedback.

Abstract The end-of-life tyres (ELTs) are currently critical environmental and societal problems due to their large quantity and chemical structure. The thermochemical process has been acknowledged as a viable option for extracting material and energy from ELTs. This review outlines the cutting-edge thermochemical techniques for recycling tyres, encompassing gasification, pyrolysis, and incineration. Additionally, it delves into the primary by-products, including oil, gas, and char. The advantages and disadvantages of each process are discussed in terms of energy efficiency, product yield, and environmental impact. The optimal reaction conditions for each product yield and quality are identified and described. The correlation between process parameters and product composition, yield and quality is clarified. Products after further processing are illustrated with specific examples. Future research directions such as upgrade of char product using low-temperature partial-oxidation process are given. This review is novel in its comprehensive synthesis of the latest advancements in thermochemical techniques for recycling ELTs, highlighting recent innovations in gasification, pyrolysis, and incineration methods. It is also a timely review due to the urgent need for sustainable waste management solutions amidst growing environmental concerns and stringent regulations on tyre disposal. Graphical Abstract

Abstract Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Abstract Background The current understanding of climate anxiety among adolescents is sparse. This study identifies the characteristics of adolescents living in Quebec (Canada) who experience impairments induced by climate anxiety, who have feelings of self-efficacy and who adopt pro-environment behaviors. It also characterizes the association between climate anxiety, feelings of self-efficacy, and environmental actions. Methods We used a cross-sectional design to analyze data from the COMPASS study on adolescent health. Participants (n = 45 362) from 113 schools in Quebec (Canada) answered questions about climate anxiety, self-efficacy, behavioral engagement, and several indicators of well-being. Data were analyzed using ordered logistic regressions adjusted for potential confounders (age, gender, school type, material deprivation, etc.). Results 9% of adolescents reported that thinking about climate change made it difficult to sleep at least sometimes. 6% of adolescents reported that thinking about climate change interfered with their ability to get work or assignments done at least sometimes. Only 34% believed they could do something to address the problem, and 43% tried to reduce their behaviors that contribute to climate change at least sometimes. Adolescents who were boys or who were less anxious experienced less impairment and were less involved in the fight against climate change. Adolescents from less affluent families experienced more difficulty sleeping and interference with work but were not more engaged. Those with stronger school connectedness experienced less impairment and were more often involved in the fight against climate change. Adolescents who felt they could do something about climate change were more likely to try to reduce behaviors that contribute to climate change. Conclusion The findings are useful to identify and support vulnerable groups that are more likely to experience impairment due to climate anxiety. The feeling of climate self-efficacy was not well developed among some groups of adolescents. Improving adolescents’ beliefs in their capacity to help address climate change may be a key strategy to promote pro-environmental actions. As the threat of climate change increases, it will be important to follow the evolution of climate anxiety and engagement among adolescents.

Objective: To determine factors significantly associated with alternative discharge destination (ADCD) following lobectomy, including the modified 5-item Frailty Index (mFI-5). Methods: Patients in the 2017-2020 NSQIP who underwent elective lobectomy and were admitted from home were included, with ADCD defined as a patient who was discharged to any nonhome location. Four multivariable logistic regression models for ADCD were evaluated for predictive power. Model A was created from backward selection of variables significantly associated with ADCD in bivariate analyses, model B was the mFI-5, model C was mFI-5 and a minimally invasive approach, and model D was mFI-5 and age group. Results: Among the 15,868 patients, 687 (4.3%) experienced ADCD. Model A identified older age, hypertension, dyspnea, history of chronic obstructive pulmonary disease, and increased length of stay as significantly associated with ADCD. A minimally invasive approach was significantly protective of ADCD. Model A had the best predictive power of the models tested (C-statistic = 0.785). Model B, which assessed mFI-5 alone, had fair predictive power (C-statistic = 0.637). Adding surgical approach (C-statistic = 0.673; model C) or age group (C-statistic = 0.682; model D) as independent variables with mFI-5 improved model fit. Conclusions: Patients who were frail or age >75 years were more likely to have postlobectomy ADCD. Although the variables identified in model A better predict ADCD, consideration of surgical approach or age with mFI-5 can help surgeons anticipate discharge destination following lobectomy.

Abstract Background Focal entrapment of the common fibular (peroneal) nerve (CFN) is the most common nerve entrapment in the lower extremity. Accurate diagnosis can be difficult due to co-existent pathology such as low back pathology. A 1% lidocaine block of CFN is often used to confirm the local entrapment pathology and demonstrate possibility of pain relief. A surprising, unexpected and temporary strengthening of CFN supplied ankle and foot muscles is occasionally produced, termed the Phoenix sign. Aetiology of this phenomenon has been puzzling, but restoration of neural circulation and nutrition via improved local blood flow has been postulated to be responsible. Methods This is a double-blinded, randomized, prospective controlled trial of 20 patients, comparing 2 vasodilating agents and their ability to produce the Phoenix effect. Ultrasound guided infiltration of 0.3 mL 1% lidocaine or papaverine HCl 10 mg/mL was executed adjacent to CFN. Motor strength pre- infiltration and 4 min post-infiltration were measured for anterior compartment muscles utilizing MRC manual motor testing reported on a 0–5 scale. The extensor hallucis longus (EHL) muscle proved to be the most significant. Results Average motor strength of the EHL improved from 2.2 (+/-0.40) to 4.9 (+/-0.32).) in the lidocaine group. In the papaverine group, pre-infiltration EHL motor strength averaging 2.1 (+/-0.93) improved to 4.4 (+/- 1.01) post-infiltration. Papaverine and lidocaine produced similar statistically significant increases in muscle strength (p =

Abstract Background Patients with Ehlers-Danlos syndromes (EDS) often experience high rates of joint subluxations and dislocations, and associated pain that may require surgical interventions. Orthopaedic surgical management is challenging in this population, and patients will often undergo multiple unsuccessful surgeries. Outcomes data specific to patients with EDS are sparse in the orthopaedic surgery literature. We conducted a scoping review to evaluate the evidence and outcomes for orthopaedic surgery specifically for the EDS population. Methods PubMed MEDLINE, Embase, The Cochrane Library, Cochrane Controlled Register of Trials (CENTRAL), CINHL, and Scopus from their inception to February 28, 2024 for all studies that reported outcomes for orthopaedic surgery in patients with EDS. Two reviewers independently determined study eligibility, rated study quality, and extracted data. Methodology followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The studies in this scoping review include Level III (retrospective cohort and case control) and Level IV (case series) evidence. Results The literature search yielded a total of 71 citations published between 1990 and 2023. All were primary studies. 38 were single case studies, 14 were case series, and 19 were retrospective cohort studies. No randomized clinical studies or systematic reviews were identified. Overall, the reported findings for the various anatomical sites and procedures indicated that surgery outcomes were inconsistent. Our review highlights the need for future research to determine whether currently established surgical approaches for various orthopaedic conditions offer long-term clinical benefit in patients with EDS. This is clearly a challenging diagnosis, and more rigorous clinical studies are required to identify optimal treatment approaches. Conclusions Our review found little evidence-based research to guide optimal surgical treatment in EDS. Established surgical techniques that have been shown to be successful in the wider orthopaedic population should be studied to determine their efficacy in the EDS population.

Abstract Objective To obtain physicians’ “real-world” perspectives on early experiences with triamcinolone acetonide suprachoroidal injection (SCS-TA) for treatment of patients with uveitic macular edema (UME). Results Twelve retina/uveitis specialists in the United States were surveyed about SCS-TA injection procedure and patient outcomes. Survey participants administered ≥ 291 SCS-TA injections to 243 patients with UME with various disease characteristics (etiologies, chronicity, and anatomical subtypes). Commonly reported reasons for SCS-TA adoption included potential for lowering the risk of steroid-associated intraocular pressure elevations versus intravitreal injections or implants (100%), potential for longer duration of action versus intravitreal steroid injections or implants (92%), and desire to use a new delivery modality (83%). Nearly all participants (92%) found injection procedure relatively easy post-training, with most (75%) procedurally comfortable after completing 2–5 injections. 58% of participants indicated that their patients gained 2–3 lines of vision by first follow-up visit, and 92% reported having patients who experienced 100–150 μm or greater reduction in central subfield thickness. Overall, 92% of participants were satisfied with SCS-TA treatment outcomes. Findings from this survey of early adopters of SCS-TA indicate that the suprachoroidal injection technique was easy to learn and resulted in favorable patient outcomes consistent with clinical trial data.

Abstract Background The 4 serotypes of dengue virus (DENV1-4) can each cause potentially deadly dengue disease, and are spreading globally from tropical and subtropical areas to more temperate ones. Nepal provides a microcosm of this global phenomenon, having met each of these grim benchmarks. To better understand DENV transmission dynamics and spread into new areas, we chose to study dengue in Nepal and, in so doing, to build the onsite infrastructure needed to manage future, larger studies. Methods and results During the 2022 dengue season, we enrolled 384 patients presenting at a hospital in Kathmandu with dengue-like symptoms; 79% of the study participants had active or recent DENV infection (NS1 antigen and IgM). To identify circulating serotypes, we screened serum from 50 of the NS1+ participants by RT-PCR and identified DENV1, 2, and 3 – with DENV1 and 3 codominant. We also performed whole-genome sequencing of DENV, for the first time in Nepal, using our new on-site capacity. Sequencing analysis demonstrated the DENV1 and 3 genomes clustered with sequences reported from India in 2019, and the DENV2 genome clustered with a sequence reported from China in 2018. Conclusion These findings highlight DENV’s geographic expansion from neighboring countries, identify China and India as the likely origin of the 2022 DENV cases in Nepal, and demonstrate the feasibility of building onsite capacity for more rapid genomic surveillance of circulating DENV. These ongoing efforts promise to protect populations in Nepal and beyond by informing the development and deployment of DENV drugs and vaccines in real time.

Abstract We examined the effect of annual exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), on the rate of first hospitalization with a PD-related diagnosis (hospitalization with PD) among Medicare Fee-for-Service beneficiaries (2001-2016). Machine learning-derived annual air pollution concentrations were linked to residential ZIP codes. For each exposure, we fitted four models: 1) traditional outcome stratification, 2) marginal structural, 3) doubly robust, and 4) generalized propensity score matching Poisson regression models, adjusted for sociodemographic and meteorological confounders and long-term trends. Among 49,121,026 beneficiaries, incidence rate ratios of 1.08 (95% CI: 1.07, 1.10), 1.07 (95% CI: 1.05, 1.08), and 1.03 (95% CI: 1.02, 1.05) for an interquartile range increase in PM2.5 (3.72 µg/m3), NO2 (13.84 ppb), and O3 (10.09 ppb), respectively, were estimated from doubly robust models. Results were similar across modeling approaches. In this nationwide study, higher air pollution exposure increased the rate of hospitalizations with PD.

Abstract Identification of high carotenoid germplasm is crucial to assist breeders in provitamin-A biofortification of sorghum (Sorghum bicolor [L.] Moench). High-performance liquid chromatography is the gold standard for carotenoid quantification, however, it is not feasible for large scale phenotyping due to its high cost and low throughput. In this study, we tested the feasibility of using grain color as a high-throughput method of carotenoid biofortification breeding. We hypothesized that visual, color-based selection can be an effective strategy to identify high-carotenoid accessions. Yellow grain had significantly higher carotenoid content than red, brown, and white grain. The degree of yellowness could distinguish the presence or absence of carotenoids, but could not distinguish carotenoid concentrations within yellow-only accessions. The degree of luminosity of the grain, however, was able to better predict carotenoid concentrations within yellow-only accessions. Genome-wide association studies identified significant marker-trait associations for qualitative and quantitative grain color traits and carotenoid concentrations near carotenoid pathway genes—ZEP, PDS, CYP97A, NCED, CCD, and LycE—three of which were common between grain color and carotenoid traits. These findings suggest that using grain color as a method for screening germplasm may be an effective high-throughput selection tool for prebreeding and early-stage breeding in carotenoid biofortification.

Abstract Natural systems exhibit high spatial variability across multiple scales. Models that can capture ecosystem dynamics across space and time by explicitly incorporating major biological mechanisms are crucial, both for management and for ecological insight. In the case of coral reef systems, much focus has been on modelling variability between reefs, despite substantial variability also existing within reefs. We developed C~scape, a coral metacommunity modelling framework that integrates the demography of corals with population-level responses to physical and environmental spatial layers, to facilitate spatiotemporal predictions of coral dynamics across reefs at fine (100s of metres to kilometres) scales. We used satellite-derived habitat maps to modulate community growth spatially, as a proxy for the many interacting physical and environmental factors—e.g., depth, light, wave exposure, temperature, and substrate type—that drive within-reef variability in coral demography. With a case study from the Great Barrier Reef, we demonstrate the model’s capability for producing hindcasts of coral cover dynamics and show that overlooking within-reef variability may lead to misleading conclusions about metacommunity dynamics. C~scape provides a valuable framework for exploring a range of management and restoration scenarios at relevant spatial scales.

Abstract Chest X-rays are the most commonly performed medical imaging exam, yet they are often misinterpreted by physicians. Here, we present an FDA-cleared, artificial intelligence (AI) system which uses a deep learning algorithm to assist physicians in the comprehensive detection and localization of abnormalities on chest X-rays. We trained and tested the AI system on a large dataset, assessed generalizability on publicly available data, and evaluated radiologist and non-radiologist physician accuracy when unaided and aided by the AI system. The AI system accurately detected chest X-ray abnormalities (AUC: 0.976, 95% bootstrap CI: 0.975, 0.976) and generalized to a publicly available dataset (AUC: 0.975, 95% bootstrap CI: 0.971, 0.978). Physicians showed significant improvements in detecting abnormalities on chest X-rays when aided by the AI system compared to when unaided (difference in AUC: 0.101, p

Abstract Since dietary intake is challenging to directly measure in large-scale cohort studies, we often rely on self-reported instruments (e.g., food frequency questionnaires, 24-hour recalls, and diet records) developed in nutritional epidemiology. Those self-reported instruments are prone to measurement errors, which can lead to inaccuracies in the calculation of nutrient profiles. Currently, few computational methods exist to address this problem. In the present study, we introduce a deep-learning approach—Microbiome-based nutrient profile corrector (METRIC), which leverages gut microbial compositions to correct random errors in self-reported dietary assessments using 24-hour recalls or diet records. We demonstrate the excellent performance of METRIC in minimizing the simulated random errors, particularly for nutrients metabolized by gut bacteria in both synthetic and three real-world datasets. Additionally, we find that METRIC can still correct the random errors well even without including gut microbial compositions. Further research is warranted to examine the utility of METRIC to correct actual measurement errors in self-reported dietary assessment instruments.

Abstract Background Delirium affects 50–85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes. Methods Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4–9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes. Results Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p

Abstract Background Alcohol use disorder (AUD) and major depressive disorder (MDD) drive HIV transmission in many sub-Saharan African settings. The impact of screening and treating AUD and MDD on HIV outcomes is unknown. We aimed to identify the cost-effectiveness of AUD and MDD interventions in Zimbabwe, and their potential contribution to reaching Zimbabwe’s Ending the HIV Epidemic 2030 goal. Methods Using a validated HIV compartmental transmission model in Zimbabwe, we compared four policy scenarios: prevention as usual (baseline); implement AUD screening (using AUDIT) and treatment (motivational interviewing and cognitive-behavioral therapy); implement MDD screening (using PHQ-9) and treatment (cognitive-behavioral therapy); and implement screening and treatment for both. Outcomes were HIV incidence projections, infections averted through 2030, quality-adjusted life-years gained, cost per infection averted, and cost per QALY gained. Analyses considered “spillover,” when treatment for AUD also results in an improvement in MDD and the converse. Sensitivity analyses identified cost reductions necessary for AUD and MDD interventions to be as cost-effective as other HIV interventions, particularly the scale-up of long-acting PrEP. Results AUD and MDD combined will be responsible for 21.1% of new HIV infections in Zimbabwe by 2030. Without considering spillover, compared to the baseline, MDD intervention can reduce new infections by 5.4% at $2039/infection averted and $3186/QALY. AUD intervention can reduce new infections by 5.8%, but at $2,968/infection averted and $4753/QALY, compared to baseline. Both MDD and AUD interventions can reduce new infections by 11.1% at $2810/infection averted and $4229/QALY, compared to baseline. Considering spillover, compared to the baseline, MDD intervention can reduce new infections by 6.4% at $1714/infection averted and $2630/QALY. AUD intervention can reduce new infections by 7.4%, but at $2299/infection averted and $3560/QALY compared to baseline. Both MDD and AUD interventions can reduce new infections by 11.9% at $2247/infection averted and $3382/QALY compared to baseline. For MDD intervention to match the cost-effectiveness of scaling long-acting PrEP, the cost of MDD intervention would need to be reduced from $16.64 to $12.88 per person. Conclusions Implementing AUD and MDD interventions can play an important role in HIV reduction in Zimbabwe, particularly if intervention cost can be decreased while preserving effectiveness.

Abstract Practice questions are highly sought out for use as a study tool among medical students in undergraduate medical education. At the same time, it remains unknown how medical students use and incorporate practice questions and their rationales into their studies. To explore this heavily relied upon study strategy, semi-structured interviews were conducted with second-year medical students to assess how they approach using practice questions. Qualitative thematic analysis revealed several recurrent themes: (1) Medical students use practice questions for primary learning, (2) Medical students place more importance on the rationale of a practice question versus selecting the right answer, and (3) Medical students view practice questions as being designed to be used once or having a single-use. Together, these themes provide insight into how medical students use practice questions to study, which may guide medical educators in their creation of practice questions with appropriate rationales and provide foundational data for future mixed methods analyses seeking to generalize these findings.

Abstract Determining the genetic contributions to Parkinson’s disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study is part of the Global Parkinson’s Genetics Program, supported by the Aligning Science Across Parkinson’s initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population.

Abstract Evanescent Bloch waves are eigensolutions of spatially periodic problems for complex-valued wavenumbers at finite frequencies, corresponding to solutions that oscillate in time and space and that exponentially decay in space. Such evanescent waves are ubiquitous in optics, plasmonics, elasticity, and acoustics. In the limit of zero frequency, the wave “freezes” in time. We introduce frozen evanescent waves as the eigensolutions of the Bloch periodic problem at zero eigenfrequency. Elastic waves, i.e., phonons, in metamaterials serve as an example. We show that, in the complex plane, the Cauchy-Riemann equations for analytical functions connect the minima of the phonon band structure to frozen evanescent phonons. Their exponential decay length becomes unusually large if a minimum in the band structure tends to zero and thereby approaches a soft mode. This connection between unusual static and dynamic behaviors allows to engineer large characteristic decay lengths in static elasticity. For finite-size samples, the static solutions for given boundary conditions are linear combinations of frozen evanescent phonons, leading to interference effects. Theory and experiment are in excellent agreement. Anomalous behavior includes the violation of Saint Venant’s principle, which means that large decay-length frozen evanescent phonons can potentially be applied in terms of remote mechanical sensing.

Abstract Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilize a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigate the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We find that inflammation significantly enhances AR levels and activity in bPSC. More importantly, we identify interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA is one of the top molecules upregulated by inflammation, and inhibiting IL-1RA reverses the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appears to activate AR by counteracting IL-1α's inhibitory effect. Furthermore, using a lineage tracing model, we observe that inflammation induces bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovers mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia.

Abstract Background Brain metastasis (BM) is a rare but severe complication of head and neck squamous cell carcinoma (HNSCC), with limited knowledge of molecular characteristics and immunogenicity. Methods We analyzed 61 cases of HNSCC-BM from three academic institutions (n = 24) and Foundation Medicine Inc (FMI, n = 37). A subset of cases underwent next-generation sequencing, multiple immunofluorescence, and proximity ligation sequencing. Gene enrichment analysis compared alterations in FMI BM samples (n = 37) with local samples (n = 4082). Results Demographics included: median age of 59 years, 75% male, 55% current/former smokers, 75% oropharyngeal primary, and 67% human papillomavirus (HPV) +. ATM (54%), KMT2A (54%), PTEN (46%), RB1 (46%), and TP53 (46%) were frequently altered in BM samples from academic centers (62% HPV/p16+). Structural rearrangements ranged from 9 to 90 variants by proximity ligation sequencing. BMs had low densities of CD8+, PD-1+, PD-L1+, and FOXP3 + cells, and 92% had PD-L1 combined positive scores

Abstract Background Between 25 and 75% of people with persistent post-acute sequelae of SARS-CoV-2 infection (PASC) experience cognitive difficulties, compromising functional ability, quality of life, and activities of daily living, including work. Despite this significant morbidity, there is a paucity of interventions for this disorder that have undergone evaluation within a formal trial setting. Therefore, we have developed a cognitive rehabilitation programme, specifically designed to address the cognitive symptoms of PASC, notably impaired attention and processing speed, while also accounting for other PASC symptoms (fatigue, post-exertional malaise) that may aggravate the cognitive impairment. This study protocol outlines a randomised controlled trial (RCT) designed to evaluate the effectiveness of this programme compared to standard clinical care. Methods This is a multi-centre, parallel-group, individually randomised controlled trial, comparing standard clinical care with and without cognitive rehabilitation. We will recruit 120 non-hospitalised adults (aged 30–60 years) from three NHS sites in England with a history of COVID-19 infection and cognitive impairment persisting more than 3 months after the acute infection. Participants will be randomised (1:1) to the intervention or control groups, with the latter represented as a provision of standard clinical care without cognitive rehabilitation. The cognitive rehabilitation programme consists of ten 1-hour sessions, delivered weekly. Outcomes will be collected at baseline, 3, and 6 months, with participant-defined goal-attainment scores, relating to functional goals, at 3 months as the primary outcome measure. Secondary outcomes will be cognitive function, measures of quality of life, social functioning, mental health, fatigue, sleep, post-exertional malaise, and social and health care service use. We will also evaluate the health-economic benefits of cognitive rehabilitation in this population. Discussion Cognitive impairment in PASC is a major cause of functional disability with no effective treatment. Accordingly, we will undertake an RCT of cognitive rehabilitation, the protocol of which is published here. If this trial is successful in delivering improvements in trial outcomes, it will address a major unmet need relating to this emergent disorder, with a significant impact on affected individuals and the wider health economy. Trial registration ClinicalTrials.gov NCT05731570. Registered on February 16, 2023

Abstract Emergency admissions (EA), where a patient requires urgent in-hospital care, are a major challenge for healthcare systems. The development of risk prediction models can partly alleviate this problem by supporting primary care interventions and public health planning. Here, we introduce SPARRAv4, a predictive score for EA risk that will be deployed nationwide in Scotland. SPARRAv4 was derived using supervised and unsupervised machine-learning methods applied to routinely collected electronic health records from approximately 4.8M Scottish residents (2013-18). We demonstrate improvements in discrimination and calibration with respect to previous scores deployed in Scotland, as well as stability over a 3-year timeframe. Our analysis also provides insights about the epidemiology of EA risk in Scotland, by studying predictive performance across different population sub-groups and reasons for admission, as well as by quantifying the effect of individual input features. Finally, we discuss broader challenges including reproducibility and how to safely update risk prediction models that are already deployed at population level.