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Abstract Immune thrombocytopenic purpura (ITP) is an immune disorder characterized by thrombocytopenia. Fostamatinib is an orally administered spleen tyrosine kinase inhibitor intended to treat refractory ITP. To evaluate the efficacy and safety of fostamatinib as a subsequent‐line therapy for ITP in adults. We searched four electronic databases for primary studies of any design. Primary efficacy outcomes included proportions of patients achieving overall (≥30 × 109 cells/L), partial (≥50 × 109 cells/L), and stable (as defined in original studies) platelet response. Safety outcomes included rescue medication use and other adverse events. We used narrative synthesis and Mantel–Haenszel random effect meta‐analysis to summarize results. Our systematic review included 11 studies for analyses (n = 722). Weighted mean proportions of patients achieving overall, partial, and stable responses with fostamatinib treatment were 0.70 [0.62, 0.76], 0.48 [0.36, 0.61], and 0.28 [0.16, 0.44], respectively. Fostamatinib was favored over placebo for partial (relative risk [RR] = 3.04, 95% confidence interval [CI] [1.53, 6.06]) and stable (RR = 6.43, 95% CI [1.58, 26.23]) responses. Patients on fostamatinib required less rescue medication and were more likely to experience hypertension. Fostamatinib is a viable subsequent‐line therapy option for refractory ITP. Given the heterogeneous data and large number of small studies, these results should be interpreted cautiously.

Objective Emerging research suggests that rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This prospective pilot study evaluates changes in intestinal microbial composition in patients with RA initiating treatment with either methotrexate (MTX) or a tumor necrosis factor inhibitor (TNFi). Methods Consecutive patients, fulfilling the 2010 American College of Rheumatology/EULAR classification criteria for RA, who started treatment with either MTX or TNFi delivered a stool sample upon initiation of immunosuppression and 3 months later. A 16S ribosomal RNA gene‐based validated microbiota test (GA‐map Dysbiosis Index Score [DIS], Genetic Analysis, Oslo, Norway) was used to evaluate for the presence and degree of dysbiosis. Fecal levels of Prevotella copri (P. copri) were analyzed by custom‐made quantitative polymerase chain reaction. Changes in microbial composition were analyzed in relation to changes in disease activity, as measured by the disease activity score based on 28‐joint counts, using C‐reactive protein. Results At baseline, dysbiosis was present in 33 of 50 (66%) participants and more common in participants with more than 2 years of disease duration (P = 0.019). At the 3‐month follow‐up, 27 of 50 (54%) were good treatment responders and the DIS had improved in 14 of 50 (28%). Participants initiating TNFi more often exhibited improvement in the DIS compared with those initiating MTX (P = 0.031). P. copri was identified in 32 of 50 (64%) at baseline. An improvement in disease activity score based on 28‐joint counts, using C‐reactive protein was associated with a simultaneous decrease in P. copri abundance (rs = 0.30, P = 0.036). Conclusion This study affirms that dysbiosis is a feature of RA. Although patients were not randomized to MTX or TNFi, the findings suggest that specific therapies may differentially modulate the gastrointestinal microbiota in RA. The association between P. copri and treatment response requires further study.

Abstract Classic galactosemia (CG) arises from loss‐of‐function mutations in the Galt gene, which codes for the enzyme galactose‐1‐phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low‐galactose diet, GALT's substrate galactose‐1‐phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides—galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1—were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

Abstract Background Mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC‐EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro‐regenerative, anti‐apoptotic, and antifibrotic properties. Consequently, MSC‐EVs represent a cell‐free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non‐immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage. Main Topics Covered This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC‐EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC‐EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC‐EV cargoes. We also discuss available preclinical studies demonstrating that MSC‐EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials. Conclusions Finally, we highlight the potential of MSC‐EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice. Highlights The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC‐derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose‐derived MSC‐EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC‐EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR‐let‐7a is associated with inhibition of apoptosis, miR‐100 supports cell survival, miR‐125b helps suppress pro‐inflammatory cytokines and miR‐20 promotes anti‐inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC‐EVs reduce intestinal inflammation by suppressing pro‐inflammatory mediators (e.g., TNF‐α, IL‐1β, IL‐6) and increasing anti‐inflammatory factors (e.g., IL‐4, IL‐10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.

Abstract Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex fluid is rich in extracellular vesicles (EVs). Here, we have applied a microfluidic technology, lipid‐based protein immobilization (LPI) and liquid chromatography with tandem mass spectrometry (LC‐MS/MS) to characterize the proteome of human milk EVs. Mature milk from six mothers was subjected to EV isolation by ultracentrifugation followed by size exclusion chromatography. Three of the samples were carefully characterized; suggesting a subset enriched by small EVs. The EVs were digested by trypsin in an LPI flow cell and in‐solution digestion, giving rise to two fractions of peptides originating from the surface proteome (LPI fraction) or the complete proteome (in‐solution digestion). LC‐MS/MS recovered peptides corresponding to 582 proteins in the LPI fraction and 938 proteins in the in‐solution digested samples; 400 of these proteins were uniquely found in the in‐solution digested samples and were hence denoted “cargo proteome”. GeneOntology overrepresentation analysis gave rise to distinctly different functional predictions of the EV surfaceome and the cargo proteome. The surfaceome tends to be overrepresented in functions and components of relevance for the immune system, while the cargo proteome primarily seems to be associated with EV biogenesis.

ABSTRACT The mesopelagic zone represents one of the few habitats that remains relatively untouched from anthropogenic activities. Among the many species inhabiting the north Atlantic mesopelagic zone, glacier lanternfish (Benthosema glaciale) is the most abundant and widely distributed. This species has been regarded as a potential target for a dedicated fishery despite the scarce knowledge of its population genetic structure. Here, we investigated its genetic structure across the North Atlantic and into the Mediterranean Sea using 121 SNPs, which revealed strong differentiation among three main groups: the Mediterranean Sea, oceanic samples, and Norwegian fjords. The Mediterranean samples displayed less than half the genetic variation of the remaining ones. Very weak or nearly absent genetic structure was detected among geographically distinct oceanic samples across the North Atlantic, which contrasts with the low motility of the species. In contrast, a longitudinal gradient of differentiation was observed in the Mediterranean Sea, where genetic connectivity is known to be strongly shaped by oceanographic processes such as current patterns and oceanographic discontinuities. In addition, 12 of the SNPs, in linkage disequilibrium, drove a three clusters' pattern detectable through Principal Component Analysis biplot matching the genetic signatures generally associated with large chromosomal rearrangements, such as inversions. The arrangement of this putative inversion showed frequency differences between open‐ocean and more confined water bodies such as the fjords and the Mediterranean, as it was fixed in the latter for the second most common arrangement of the fjord's samples. However, whether genetic differentiation was driven by local adaptation, secondary contact, or a combination of both factors remains undetermined. The major finding of this study is that B. glaciale in the North Atlantic‐Mediterranean is divided into three major genetic units, information that should be combined with demographic properties to outline the management of this species prior to any eventual fishery attempt.

Abstract Pulmonary veno‐occlusive disease (PVOD) is a rare form of pulmonary vascular disease that is difficult to distinguish clinically from pulmonary arterial hypertension (PAH). Multiple genes have been implicated in disease pathogenesis in PAH and PVOD and the diseases are thought to be genetically distinct. In this report we present a case of first‐degree relatives with pathological evidence of PVOD and PAH. The index patient was diagnosed with PAH at age 42, was treated with escalating pulmonary vasodilator therapy, but eventually succumbed to her disease. On autopsy, her pathology was consistent with PAH. Her son was diagnosed with PAH at age 16, did well on pulmonary vasodilator therapy for over 10 years, but ultimately developed refractory right ventricular failure and received a heart and lung transplantation. Pathology of his explanted lung was consistent with PVOD, and genetic testing was negative for recognized variants that cause PAH or PVOD.

Background Prepregnancy diabetes and obesity are associated with hypertensive disorders of pregnancy (HDPs). However, the proportion of cases of HDP in the population explained by diabetes and obesity (population attributable fraction), especially among American Indian and Alaska Native and Native Hawaiian and Other Pacific Islander, is not well characterized. Methods and Results We conducted a cross‐sectional analysis of data on individuals with a live singleton birth from the US National Vital Statistics System between 2016 and 2019. We used adjusted logistic regression to estimate the prevalence odds ratios of HDPs and tested interaction for race and ethnicity. We calculated the population attributable fraction for the effect of obesity and diabetes on HDPs. Among 13 201 338 birthing individuals, (mean age, 29±6 years), 7% had HDP. The prevalence of HDP was highest among American Indian and Alaska Native individuals (9.1%). Prepregnancy diabetes (prevalence odds ratio, 2.63 [95% CI, 2.59–2.67]) and obesity (prevalence odds ratio, 2.95 [95% CI, 2.93–2.97]) were associated with HDPs. Compared with non‐Hispanic White individuals, the association of diabetes with HDPs was strongest among Native Hawaiian and Other Pacific Islander (prevalence odds ratio, 3.05 [95% CI, 2.48–3.77]), and the association of obesity with HDP was strongest among Asian individuals (prevalence odds ratio, 3.44 [95% CI, 3.35–3.54]; all P for interaction

Abstract Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US‐enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer‐mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA‐based MB products, facilitating the potential translation of next‐generation PBCA MB.

Abstract Background Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease‐modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery. Methods We characterised the progression of altered dynamics of whole‐brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting‐state fMRI and identified quasi‐periodic patterns (QPPs) of brain activity constituting the most prominent resting‐state networks. Results The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell‐type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans. Conclusion Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research. Highlights Hyperactivity in the LCN‐linked regions within short QPPs observed before motor impairment onset. DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD‐like phenotype development. Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD‐like stage.

Abstract Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high disease mortality. Personalized in vitro breast cancer models hold great promise for high‐throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient‐specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA‐MB‐468) and patient‐derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA‐MB‐468 tumoroids show higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient‐derived models. These microphysiological systems can thus be personalized by using patient‐derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment.

Abstract The high latitude ionospheric evolution of the May 10‐11, 2024, geomagnetic storm is investigated in terms of Total Electron Content and contextualized with Incoherent Scatter Radar and ionosonde observations. Substantial plasma lifting is observed within the initial Storm Enhanced Density plume with ionospheric peak heights increasing by 150–300 km, reaching levels of up to 630 km. Scintillation is observed within the cusp during the initial expansion phase of the storm, spreading across the auroral oval thereafter. Patch transport into the polar cap produces broad regions of scintillation that are rapidly cleared from the region after a strong Interplanetary Magnetic Field reversal at 2230UT. Strong heating and composition changes result in the complete absence of the F2‐layer on the eleventh, suffocating high latitude convection from dense plasma necessary for Tongue of Ionization and patch formation, ultimately resulting in a suppression of polar cap scintillation on the eleventh.

Abstract Bermudagrass (Cynodon dactylon (L.) Pers.) is one of the primary perennial forages in the southeastern USA. Newer hybrid cultivars have superior production and nutritive value compared to common ecotypes. However, there are many challenges facing bermudagrass production in the region. First, the bermudagrass stem maggot (BSM; Atherigona reversura Villeneuve) has severely damaged bermudagrass throughout the region. Strategically timed pyrethroid applications significantly reduce adult BSM populations, but efforts are needed to develop integrated pest management plans. Second, an increasing number of producers are noting challenges with green‐up following winter dormancy. This may be attributed to disease, unbalanced soil fertility, and weed pressure. Perhaps one of the most limiting factors for continued production is the deficit of sprigs and trained personnel to sprig hybrid bermudagrasses. This research is critically important as the need for cold‐tolerant bermudagrass is increasing as tall fescue (Lolium arundinaceum (Schreb.) S. J. Darbyshire) is declining due to changes in temperature and precipitation throughout the northern parts of the region. Plant breeders are investigating hybrid bermudagrass at latitudes >35° with respect to freeze or cold tolerance. Despite the many challenges facing hybrid bermudagrass in the southeastern USA, researchers are working to ensure its persistence, productivity, and availability for the future.

Different molecular classifications for gastric cancer (GC) have been proposed based on multi‐omics platforms with the long‐term goal of improved precision treatment. However, the GC (phospho)proteome remains incompletely characterized, particularly at the level of tyrosine phosphorylation. In addition, previous multiomics‐based stratification of patient cohorts has lacked identification of corresponding cell line models and comprehensive validation of broad or subgroup‐selective therapeutic targets. To address these knowledge gaps, we applied a reverse approach, undertaking the most comprehensive (phospho)proteomic analysis of GC cell lines to date and cross‐validating this using publicly available data. Mass spectrometry (MS)‐based (phospho)proteomic and tyrosine phosphorylation datasets were subjected to individual or integrated clustering to identify subgroups that were subsequently characterized in terms of enriched molecular processes and pathways. Significant congruence was detected between cell line proteomic and specific patient‐derived transcriptomic subclassifications. Many protein kinases exhibiting ‘outlier’ expression or phosphorylation in the cell line dataset exhibited genomic aberrations in patient samples and association with poor prognosis, with casein kinase I isoform delta/epsilon (CSNK1D/E) being experimentally validated as potential therapeutic targets. Src family kinases were predicted to be commonly hyperactivated in GC cell lines, consistent with broad sensitivity to the next‐generation Src inhibitor eCF506. In addition, phosphoproteomic and integrative clustering segregated the cell lines into two subtypes, with epithelial–mesenchyme transition (EMT) and proliferation‐associated processes enriched in one, designated the EMT subtype, and metabolic pathways, cell–cell junctions, and the immune response dominating the features of the other, designated the metabolism subtype. Application of kinase activity prediction algorithms and interrogation of gene dependency and drug sensitivity databases predicted that the mechanistic target of rapamycin kinase (mTOR) and dual specificity mitogen‐activated protein kinase kinase 2 (MAP2K2) represented potential therapeutic targets for the EMT and metabolism subtypes, respectively, and this was confirmed using selective inhibitors. Overall, our study provides novel, in‐depth insights into GC proteomics, kinomics, and molecular taxonomy and reveals potential therapeutic targets that could provide the basis for precision treatments.

Abstract It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non‐anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and PO2, and renal function were then monitored for up to 8 h post‐treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and PO2 were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post‐treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue PO2 fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide‐induced diuresis.

Abstract Background Mechanical augmentation upon implantation is essential for the long‐term success of tissue‐engineered intervertebral discs (TE‐IVDs). Previous studies utilized stiffer materials to fabricate TE‐IVD support structures. However, these materials undergo various failure modes in the mechanically challenging IVD microenvironment. FlexiFil (FPLA) is an elastomeric 3D printing filament that is amenable to the fabrication of support structures. However, no present study has evaluated the efficacy of a flexible support material to preserve disc height and support the formation of hydrated tissues in a large animal model. Methods We leveraged results from our previously developed FE model of the minipig spine to design and test TE‐IVD support cages comprised of FPLA and PLA. Specifically, we performed indentation to assess implant mechanical response and scanning electron microscopy to visualize microscale damage. We then implanted FPLA and PLA support cages for 6 weeks in the minipig cervical spine and monitored disc height via weekly x‐rays. TE‐IVDs cultured in FPLA were also implanted for 6 weeks with weekly x‐rays and terminal T2 MRIs to quantify tissue hydration at study endpoint. Results Results demonstrated that FPLA cages withstood nearly twice the deformation of PLA without detrimental changes in mechanical performance and minimal damage. In vivo, FPLA cages and stably implanted TE‐IVDs restored native disc height and supported the formation of hydrated tissues in the minipig spine. Displaced TE‐IVDs yielded disc heights that were superior to PLA or discectomy‐treated levels. Conclusions FPLA holds great promise as a flexible and bioresorbable material for enhancing the long‐term success of TE‐IVD implants.

Background Little is known about factors contributing to burnout and intent to leave in cardiologists and other cardiology health care workers. Methods and Results The Coping With COVID survey assessed work conditions, burnout, and intent to leave among physicians, nurses, advanced practice providers, and other clinical staff (OCS) from April 2020 to December 2020. Single‐item measures assessed work conditions, burnout (emotional exhaustion), and intent to leave. Multilevel logistic regression examined work life variables' relationships to burnout among role types and feeling valued as a mediator. Open‐ended comments analyzed via grounded theory contributed to a conceptual model. Coping With COVID was completed by 1199 US cardiology health care workers (354 physician/520 nurses/198 advanced practice providers/127 OCS). Nurses were most likely to report burnout (59% nurses, 57% OCS, 46% advanced practice providers, 40% physicians, P

Abstract Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6‐guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT‐PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6‐impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6‐guided trial recommendations. The primary study outcome is the 3‐month absolute change in the composite pain intensity score assessed using Patient‐Reported Outcomes Measurement Information System (PROMIS) measures. Follow‐up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Abstract Neurodegenerative diseases (NDDs) affect more than 50 million people worldwide, posing a significant global health challenge as well as a high socioeconomic burden. With aging constituting one of the main risk factors for some NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD), this societal toll is expected to rise considering the predicted increase in the aging population as well as the limited progress in the development of effective therapeutics. To address the high failure rates in clinical trials, legislative changes permitting the use of alternatives to traditional pre‐clinical in vivo models are implemented. In this regard, microphysiological systems (MPS) such as organ‐on‐a‐chip (OoC) platforms constitute a promising tool, due to their ability to mimic complex and human‐specific tissue niches in vitro. This review summarizes the current progress in modeling NDDs using OoC technology and discusses five critical aspects still insufficiently addressed in OoC models to date. Taking these aspects into consideration in the future MPS will advance the modeling of NDDs in vitro and increase their translational value in the clinical setting.

ABSTRACT Introduction We present a relationship‐centred shared‐decision‐making (RCSDM) process model to explicate factors that shape decision‐making processes during physical medicine and rehabilitation (PMR) encounters among patients, their care partners and practitioners. Existing shared decision‐making (SDM) models fall short in addressing the everyday decisions routinely made regarding persons with chronic disabilities who require high levels of support, their care partners and rehabilitation practitioners. In PMR, these everyday decisions are small scale, immediate and in service to a larger therapeutic goal. They can be thought of as micro‐decisions and involve multiple practitioners, care partners and patients. How micro‐decisions are made in this context is contingent on multiple roles and relationships among these relevant parties. Our model centres on micro‐decisions among patients, their care partners and practitioners based on our disorders of consciousness (DoC) research. Methods To develop our model, we examined peer‐reviewed literature in SDM in PMR, chronic disability and person‐centeredness; formed collaborations and co‐created our constructs with rehabilitation practitioners and with care partners who have lived experience of caring for persons with DoC; analysed emerging empirical data and vetted early versions with expert scientific and clinical audiences. Our model builds from the core tenets of relational autonomy, and scholarship and activism of disability advocates. Findings Our model conceptualizes four non‐hierarchical levels of analysis to understand the process of micro‐decision‐making in chronic disability and medical rehabilitation: social forces (historical and sociological); roles and relationships (multiple and intersecting); relational dimensions (interactional and contextual) and micro‐decision moments (initiation, response and closure). Discussion Relationships among patients, their care partners and practitioners are the intersubjective milieu within which decisions are made. Our conceptual model explicates the process of micro‐decision‐making in PMR. Patient or Public Contribution Care partners (or caregivers) and rehabilitation practitioners are active members of our team. We work together to develop research projects, collect, analyse and disseminate data. The conceptual model we present in this manuscript was co‐created—input from care partners and practitioners on previously collected data became the impetus to develop the RCSDM process model and share co‐authorship in this manuscript.

Abstract Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world‐wide. Gram‐negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early‐onset sepsis. However, therapy failure may result due to various factors. The purpose of this study was to identify predictors of gentamicin therapy failure in neonates with sepsis. This was a prospective cross‐sectional study at the Neonatal Intensive Care Unit at Windhoek Central Hospital over a period of 5 months in 2019. Neonates received intravenous gentamicin 5 mg/kg/24 h in combination with either benzylpenicillin 100 000 IU/kg/12 h or ampicillin 50 mg/kg/8 h. Logistic regression modeling was performed to determine the predictors of treatment outcomes. 36% of the 50 neonates were classified as having gentamicin treatment failure. Increasing treatment duration by 1 day resulted in odds of treatment failure increasing from 1.0 to 2.41. Similarly, one unit increase in CRP increases odds of gentamicin treatment failure by 49%. The 1 kg increase in birthweight reduces the log odds of treatment failure by 6.848, resulting in 99.9% decrease in the odds of treatment failure. One unit increase in WBC reduces odds of gentamicin treatment failure by 27%. Estimates of significant predictors of treatment failure were precise, yielding odds ratios that were within 95% confidence interval. This study identified the following as predictors of gentamicin therapy failure in neonates: prolonged duration of treatment, elevated C‐reactive protein, low birthweight, and low white blood cell count.

Abstract Introduction A subset of people with Parkinson's disease (PD) develop dementia faster than others. We aimed to profile PD cognitive subtypes at risk of dementia based on their rate of cognitive decline. Method Latent class mixed models stratified subtypes in Parkinson's Progression Markers Initiative (PPMI) (N = 770) and ICICLE‐PD (N = 212) datasets based on their decline in the Montreal Cognitive Assessment over at least 4 years. Baseline demographic and cognitive data at diagnosis were compared between subtypes to determine their clinical profile. Results Four subtypes were identified: two with stable cognition, one with steady decline, and one with rapid decline. Performance on Judgement of Line Orientation, but not category fluency, was associated with a steady decline in the PPMI dataset, and deficits in category fluency, but not visuospatial function, were associated with a steady decline in the ICICLE‐PD dataset. Discussion People with PD susceptible to cognitive decline demonstrate unique clinical profiles at diagnosis, although this differed between cohorts. Highlights Four cognitive subtypes were revealed in two Parkinson's disease samples. Unique profiles of cognitive impairment were related to cognitive decline. Judgement of Line Orientation/category fluency predictive of steady decline. Global deficits related to rapid cognitive decline and increased dementia risk.

Abstract Paleomagnetic data is collected from bulk samples, containing a mixture of stable and unstable magnetic particles. Recently, magnetic microscopy techniques have allowed the examination of individual magnetic grains. However, accurately determining the magnetic moments of these grains is difficult and time‐consuming due to the inherent ambiguity of the data and the large number of grains in each image. Here we introduce a fast and semi‐automated algorithm that estimates the position and magnetization of dipolar sources solely based on the magnetic microscopy data. The algorithm follows a three‐step process: (a) employ image processing techniques to identify and isolate data windows for each magnetic source; (b) use Euler Deconvolution to estimate the position of each source; (c) solve a linear inverse problem to estimate the dipole moment of each source. To validate the algorithm, we conducted synthetic data tests, including varying particle concentrations and non‐dipolarity. The tests show that our method is able to accurately recover the position and dipole moment of particles that are at least 15 μm apart for a source‐sensor separation of 5 μm. For grain concentrations of 6,250 grains/mm3, our method is able to detect over 60% of the particles present in the data. We applied the method to real data of a speleothem sample, where it accurately retrieved the expected directions induced in the sample. The semi‐automated nature of our algorithm, combined with its low processing cost and ability to determine the magnetic moments of numerous particles, represents a significant advancement in facilitating paleomagnetic applications of magnetic microscopy.

Abstract Endothelial programmed death‐ligand 1 (PD‐L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans‐endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD‐L1 expression. Here, a new microfluidic device is developed to investigate the relationship between transmural flow and PD‐L1 expression in microvascular networks (MVNs). After treating the MVNs with transmural flow for 24 h, the expression of PD‐L1 in endothelial cells is upregulated. Additionally, CD8 T cell activation by phytohemagglutinin (PHA) is suppressed when cultured in the MVNs pre‐conditioned with transmural flow. Moreover, transmural flow is able to further increase PD‐L1 expression in the vessels formed in the tumor microenvironment. Finally, by utilizing blocking antibodies and knock‐out assays, it is found that transmural flow‐driven PD‐L1 upregulation is controlled by integrin αVβ3. Overall, this study provides a new biophysical explanation for high PD‐L1 expression in tumoral vasculatures.

BACKGROUND Atherosclerosis is triggered by the retention of apolipoprotein B‐containing lipoproteins by proteoglycans. In addition to low‐density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans. METHODS AND RESULTS Solid‐phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody‐arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA‐cp rats. This competitive reduction was dose dependent (25–250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5‐week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot‐blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA‐cp rats. CONCLUSIONS Both acute (passive) and long‐term administration (idiotypic cascade) of chP3R99 antibody reduced low‐density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin‐resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.

Abstract Introduction Bladder cancer is one of the most common cancers worldwide and can be managed with a range of approaches, including conservative, medical and surgical therapies. Treatment may be associated with considerable morbidity, but despite this, little data exist to reflect patients' subsequent experience. This study aims to evaluate patients' experiences of bladder cancer care by linking data from a national cancer experience survey with data routinely collected from National Health Service (NHS) sources. This study considers patient perspectives and makes recommendations to improve the patient experience of bladder cancer care. Methods Anonymised data from the National Cancer Patient Experience Survey (NCPES) for patients who had received care for bladder cancer were collated and linked with demographic and treatment data. Questions from the NCPES were then categorised into different themes based on their content. This study focused on themes relating to lifestyle, activities of daily living (ADL), symptoms, psychological impact and body perception. Statistical analyses were used to investigate the relationship between patient reported experience, demographics and type of care received. Results NCPES data from 673 patients (487 male, 29 undisclosed) with at least T1 bladder cancer were analysed. Statistically significant differences were identified across the five investigated patient experience themes. No significant difference was seen in patient reported experience between bladder cancer drug treatments (such as intravesical BCG vs. intravesical chemotherapy vs. systemic chemotherapy) and radiotherapy types (curative vs. palliative). Patients treated with cystectomy had significantly worse experiences relating to body image and ADL but not when compared with patients treated with radical radiotherapy. Patients with long‐term health conditions reported worse experiences for all five themes compared with those without. Conclusion The literature surrounding the experience of patients with bladder cancer is limited. This data linkage study demonstrates the impact of bladder cancer care on five patient experience themes, including the effect of different treatment types and the presence of long‐term health conditions. While limited by sample size and data comprehensiveness, this study aims to inform clinicians and service providers of factors affecting patient experience of bladder cancer care, to stimulate service review and development.

The median age of patients with pancreatic ductal adenocarcinoma (PDAC) at diagnosis is 71 years; however, around 10% present with early‐onset pancreatic cancer (EOPC), i.e., before age 50. The molecular mechanisms underlying such an early onset are unknown. We assessed the role of common PDAC drivers (KRAS, TP53, CDKN2A and SMAD4) and determined their mutational status and protein expression in 90 formalin‐fixed, paraffin‐embedded tissues, including multiple primary and matched metastases, from 37 EOPC patients. KRAS was mutated in 88% of patients; p53 was altered in 94%, and p16 and SMAD4 were lost in 86% and 71% of patients, respectively. Meta‐synthesis showed a higher rate of p53 alterations in EOPC than in late‐onset PDAC (94% vs. 69%, P = 0.0009) and significantly higher loss of SMAD4 (71% vs. 44%, P = 0.0025). The majority of EOPC patients accumulated aberrations in all four drivers; in addition, high tumour heterogeneity was observed across all tissues. The cumulative effect of an exceptionally high rate of alterations in all common PDAC driver genes combined with high tumour heterogeneity suggests an important mechanism underlying the early onset of PDAC.

Abstract Aims Outcomes reported for patients with hospitalization for acute heart failure (AHF) treatment vary worldwide. Ethnicity‐associated characteristics may explain this observation. This observational study compares characteristics and 1‐year outcomes of Kyrgyz and Swiss AHF patients against the background of European Society of Cardiology guidelines‐based cardiovascular care established in both countries. Methods and results The primary endpoint was 1 year all‐cause mortality (ACM); the secondary endpoint was 1 year ACM or HF‐related rehospitalization. A total of 538 Kyrgyz and 537 Swiss AHF patients were included. Kyrgyz patients were younger (64.0 vs. 83.0 years, P mild aortic stenosis was more prevalent (P

Key Clinical Message This case report provides a peculiar case of tuberculous constrictive pericarditis (TCP) who presented with right ventricular dysfunction after pericardiectomy. Right ventricular dysfunction is one of the main postoperative complications after pericardiectomy. Rapid and accurate identification of right ventricular dysfunction confirmed by transthoracic echocardiography (TTE), associated with the rapid initiation of diuretics and inotropic therapy is necessary for the patient's complete recovery. Abstract TCP is a condition characterized by chronic inflammation and fibrosis of the pericardium. Pericardiectomy is the standard treatment for patients with constrictive pericarditis and persistent symptoms. One possible surgical complication is right ventricle (RV) failure. We report a case of a 44‐year‐old man who developed RV failure after pericardiectomy for TCP. A 41‐year‐old man with no medical history was referred to our hospital due to progressive dyspnea associated with edema of the lower limbs and significant weight loss (30 kg) over the past 5 months. TTE revealed significant pericardial thickening and mild pericardial effusion with normal RV function. Chest X‐ray showed moderate bilateral pleural effusion. The patient underwent pericardiectomy and bilateral pleural drainage. Histopathological examination showed tuberculosis granulomas with caseous necrosis, and antituberculosis medication was initiated. Postoperative TTEs showed normal RV function and mild pericardial thickening. The patient was discharged home after successful postoperative recovery. Three weeks later, the patient was admitted to the emergency department with dyspnea and hypoxemia. TTE revealed RV systolic dysfunction. Chest CT showed a recurrence of moderate pleural effusion, this time loculated, with restrictive atelectasis of the adjacent lung parenchyma. Diuretics and inotropic therapy were initiated, and the patient underwent lung decortication after confirmation of tuberculous empyema. The patient experienced significant clinical improvement. TTE before discharge showed a decreased RV chamber size with improved RV systolic function. The patient was discharged in a stable condition 30 days after admission with a low dose of oral furosemide. Four months after discharge, he remained asymptomatic with good functional status. Pericardiectomy for TCP may carry the risk of developing RV dysfunction. Furthermore, TCP itself may be associated with other complications, such as empyema. We emphasize the importance of conducting a thorough clinical evaluation for patients with TCP, particularly those undergoing pericardiectomy, to mitigate potential adverse outcomes.

Abstract Introduction Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks. Methods MDD participants (n = 58, mean age = 40.7 years, female = 28) received four ketamine infusions (0.5 mg/kg) 2−3 times weekly. Resting‐state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24 h post‐SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre‐to‐post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n = 55, mean age = 32.6, female = 31), and between HC assessed twice (n = 16) were conducted as follow‐up analyses. Results Following SKI, significant increases in left Hb‐bilateral visual cortex FC, decreases in left Hb‐left inferior parietal cortex FC, and decreases in left NAc‐right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time. Conclusion Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.

Abstract Mitapivat is an investigational, oral, small‐molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3‐DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3‐DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator‐initiated, open‐label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019‐003438‐18), untargeted metabolomics was used to explore the overall metabolic effects of 8‐week treatment with mitapivat in the dose‐finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate‐adjusted p

Actuators based on soft elastomers offer significant advantages to the field of robotics, providing greater adaptability, improving collision resilience, and enabling shape‐morphing. Thus, soft fluidic actuators have seen an expansion in their fields of application. Closed‐cycle hydraulic systems are pressure agnostic, enabling their deployment in extremely high‐pressure conditions, such as deep‐sea environments. However, soft actuators have not been widely adopted on unmanned underwater vehicle control surfaces for deep‐sea exploration due to their unpredictable hydrodynamic behavior when camber‐morphing is applied. This study presents the design and characterization of a soft wing and investigates its feasibility for integration into an underwater glider. It is found that the morphing wing enables the glider to adjust the lift‐to‐drag ratio to adapt to different flow conditions. At the operational angle of attack of 12.5°, the lift‐to‐drag ratio ranges from −70% to +10% compared to a rigid version. Furthermore, it reduces the need for internal moving parts and increases maneuverability. The findings lay the groundwork for the real‐world deployment of soft robotic principles capable of outperforming existing rigid systems. With the herein‐described methods, soft morphing capabilities can be enabled on other vehicles.

Abstract Shallow creep events provide opportunities to understand the mechanical properties and behavior of faults. However, due to physical limitations observing creep events, the precise spatio‐temporal evolution of slip during creep events is not well understood. In 2023, the Superstition Hills and Imperial faults in California each experienced centimeter‐scale slip events that were captured in unprecedented detail by satellite radar, sub‐daily Global Navigation Satellite Systems, and creepmeters. In both cases, the slip propagated along the fault over 2–3 weeks. The Superstition Hills event propagated bilaterally away from its initiation point at average velocities of ∼9 km/day, but propagation velocities were locally much higher. The ruptures were consistent with slip from tens of meters to ∼2 km depths. These slowly propagating events reveal that the shallow crust of the Imperial Valley does not obey purely velocity‐strengthening or velocity‐weakening rate‐and‐state friction, but instead requires the consideration of fault heterogeneity or fault‐frictional behaviors such as dilatant strengthening.

Abstract The Superstition Hills Fault (SHF) exhibits a rich spectrum of slip modes, including M 6+ earthquakes, afterslip, quasi‐steady creep, and both triggered and spontaneous slow slip events (SSEs). Following 13 years of quiescence, creepmeters recorded 25 mm of slip during 16–19 May 2023. Additional sub‐events brought the total slip to 41 mm. The event nucleated on the northern SHF in early‐May and propagated bi‐laterally at rates on the order of kilometers per day. Surface offsets reveal a bi‐modal slip distribution, with slip on the northern section of the fault being less localized and lower amplitude compared to the southern section. Kinematic slip models confirm systematic variations in the slip distribution along‐strike and with depth and suggest that slip is largely confined to the shallow sedimentary layer. Observations and models of the 2023 SSE bear a strong similarity to previous slip episodes in 1999, 2006, and 2010, suggesting a characteristic behavior.

Abstract We construct a high‐resolution shear‐wave velocity (VS) model for the uppermost 100 m using ambient noise tomography near the West Antarctic Ice Sheet Divide camp. This is achieved via joint inversion of Rayleigh wave phase velocity and H/V ratio, whose signal‐to‐noise ratios are boosted by three‐station interferometry and phase‐matched filtering, respectively. The VS shows a steep increase (0.04–0.9 km/s) in the top 5 m, with sharp interfaces at ∼8–12 m, followed by a gradual increase (1.2–1.8 km/s) between 10 and 45 m depth, and to 2 km/s at ∼65 m. The compressional‐wave velocity and empirically‐obtained density profile compares well with the results from Herglotz–Wiechert inversion of diving waves in active‐source shot experiments and ice core analysis. Our approach offers a tool to characterize high‐resolution properties of the firn and shallow ice column, which helps to infer the physical properties of deeper ice sheets, thereby contributes to improved understanding of Earth's cryosphere.

Following the publication of results from multiple landmark cardiovascular outcome trials of antihyperglycemic medications over the past 8 years, there has been a major shift in the focus of care for people with type 2 diabetes, from control of hyperglycemia to managing cardiovascular risk. Multiple international cardiology and diabetes society guidelines and recommendations now endorse sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like protein‐1 receptor agonists as first‐line therapies to mitigate cardiovascular risk. The most recent publication is the 2023 European Society of Cardiology guideline on the management of cardiovascular disease in those with type 2 diabetes that, for the first time, recommends use of both classes of medications for the mitigation of cardiovascular risk for those with or at high risk for atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. Here, we review the evidence behind contemporary society guidelines and recommendations for the management of type 2 diabetes and cardiovascular risk.

Abstract Ten state wildlife management agencies in the United States, including six within the Southeast, have delayed their spring wild turkey (Meleagris gallopavo) hunting seasons since 2017 by five or more days to address concerns related to the potential effects of hunting on wild turkey seasonal productivity. One hypothesis posits that if the spring hunting season is too early, there may be insufficient time for males to breed hens before being harvested, thus leading to reduced seasonal productivity. We conducted an experiment to determine whether delaying the wild turkey hunting season by 2 weeks in south‐middle Tennessee would affect various reproductive rates. In 2021 and 2022, the Tennessee Fish and Wildlife Commission experimentally delayed the spring hunting season to open 14 days later than the traditional date (the Saturday closest to 1 April) in Giles, Lawrence, and Wayne counties. We monitored reproductive rates from 2017 to 2022 in these three counties as well as two adjacent counties, Bedford and Maury, that were not delayed. We used a Before‐After‐Control‐Impact design to analyze the proportion of hens nesting, clutch size, hatchability, nest success, poult survival and hen survival with linear mixed‐effect models and AIC model selection to detect relationships between the 14‐day delay and reproductive parameters. We detected no relationship (p > .05) between the 14‐day delay and any individual reproductive parameter. In addition, recruitment (hen poults per hen that survived until the next breeding season) was very low (

Abstract Marine protected areas (MPAs) can be a useful tool to manage coastal ecosystems, delivering both social and ecological outcomes. However, in many instances, relevant data is missing to conduct proper impact assessments, which is key to identifying ecological and social synergies and potential trade‐offs, and to adapting management according to local objectives. The ecological effects of an MPA established in Palawan, Philippines, in 2016, were assessed. The most common species targeted by fisheries were identified by local fishers. Species size and number were collected through underwater visual census with n = 288 belt transects assigned in different sites and locations to ensure to provide both protected and control (fished) sites for the MPA assessment, and baseline data for three new MPAs that were created in 2022. 91 coral‐reef fish species belonging to 12 families were recorded. Mixed effect linear regression was used to compare target fish populations in protected and control sites. Compared to control locations, 5 years after its implementation, the MPA showed significantly higher species richness, abundance, mean size, and biomass while no significant difference was found on the average trophic level between MPA and control sites. Monitoring the early effects of an MPA and collecting baseline data prior the implementation of an MPA network is key for adaptive management.

Abstract INTRODUCTION The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World‐Wide FINGERS (WW‐FINGERS). As part of WW‐FINGERS, the Australian AU‐ARROW study mirrors aspects of FINGER, as well as US‐POINTER. METHOD AU‐ARROW is a randomized, single‐blind, multisite, 2‐year clinical trial (n = 600; aged 55–79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION The finalized AU‐ARROW protocol is expected to allow development of an evidence‐based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights Study protocol for a single‐blind, randomized controlled trial, the AU‐ARROW Study. The AU‐ARROW Study is a member of the World‐Wide FINGERS (WW‐FINGERS) initiative. AU‐ARROW's primary outcome measure is change in a global composite cognitive score. Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests. Leading to development of an innovative treatment plan to reduce cognitive decline.

Background Coronary artery disease (CAD) is a leading cause of death among the 38.4 million people with HIV globally. The extent to which cardiovascular polygenic risk scores (PRSs) derived in non‐HIV populations generalize to people with HIV is not well understood. Methods and Results PRSs for CAD (GPSMult) and lipid traits were calculated in a global cohort of people with HIV treated with antiretroviral therapy with low‐to‐moderate atherosclerotic cardiovascular disease risk enrolled in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The PRSs were associated with baseline lipid traits in 4495 genotyped participants, and with subclinical CAD in a subset of 662 who underwent coronary computed tomography angiography. Among participants who underwent coronary computed tomography angiography (mean age, 50.9 [SD, 5.8] years; 16.1% women; 41.8% African, 57.3% European, 1.1% Asian), GPSMult was associated with plaque presence with odds ratio (OR) per SD in GPSMult of 1.42 (95% CI, 1.20–1.68; P=3.8×10−5), stenosis >50% (OR, 2.39 [95% CI, 1.48–3.85]; P=3.4×10−4), and noncalcified/vulnerable plaque (OR, 1.45 [95% CI, 1.23–1.72]; P=9.6×10−6). Effects were consistent in subgroups of age, sex, 10‐year atherosclerotic cardiovascular disease risk, ancestry, and CD4 count. Adding GPSMult to established risk factors increased the C‐statistic for predicting plaque presence from 0.718 to 0.734 (P=0.02). Furthermore, a PRS for low‐density lipoprotein cholesterol was associated with plaque presence with OR of 1.21 (95% CI, 1.01–1.44; P=0.04), and partially calcified plaque with OR of 1.21 (95% CI, 1.01–1.45; P=0.04) per SD. Conclusions Among people with HIV treated with antiretroviral therapy without documented atherosclerotic cardiovascular disease and at low‐to‐moderate calculated risk in REPRIEVE, an externally developed CAD PRS was predictive of subclinical atherosclerosis. PRS for low‐density lipoprotein cholesterol was also associated with subclinical atherosclerosis, supporting a role for low‐density lipoprotein cholesterol in HIV‐associated CAD. Registration URL: https://www.reprievetrial.org; Unique identifier: NCT02344290.

Abstract Background Existing financial hardship screening does not capture the multifaceted and dynamic nature of the problem. The use of existing health system data is a promising way to enable scalable and sustainable financial hardship screening. Methods We used existing data from 303 adult patients with cancer at the University of Virginia Comprehensive Cancer Center (2016–2018). All received distress screening and had a valid financial assistance screening based solely on household size‐adjusted income. We constructed a composite index that integrates multiple existing health system data (Epic, distress screening, and cancer registry) to assess comprehensive financial hardship (e.g., material conditions, psychological responses, and coping behaviors). We examined differences of at‐risk patients identified by our composite index and by existing single‐dimension criterion. Dynamics of financial hardship over time, by age, and cancer type, were examined by fractional probit models. Results At‐risk patients identified by the composite index were generally younger, better educated, and had a higher annual household income, though they had lower health insurance coverage. Identified periods to intervene for most patients are before formal diagnosis, 2 years, and 6 years after diagnosis. Within 2 years of diagnosis and more than 4 years after diagnosis appear critical for subgroups of patients who may suffer from financial hardship disparities. Conclusion Existing health system data provides opportunities to systematically measure and track financial hardship in a systematic, scalable and sustainable way. We find that the dimensions of financial hardship can exhibit different patterns over time and across patient subgroups, which can guide targeted interventions. The scalability of the algorithm is limited by existing data availability.

Abstract Aims This study compared those living with and without an intestinal stoma in relation to physical and psychological health, stress and coping, quality of life and resilience. Also, identifying factors that could be used to promote better self‐care in stoma patients in the future. Design A cross‐sectional and comparative study design was employed. Methods Participants were recruited via email and social media (Facebook and Twitter) between August 2018 and March 2019, to complete an online survey. The data were analysed using analysis of variance to examine group difference and a series of hierarchical linear regression analyses determining predictors of psychological well‐being. Results Of 278 participants aged 18–68 years who completed the survey, 129 (46%) had a stoma and reported significantly poorer physical health. Approximately one‐fifth experienced problems with stoma management. Psychological well‐being was mediated by the duration of living with a stoma (under 3 years) and frequency of leaks (weekly and monthly).

Abstract Given the high prevalence of pain in older adults and current trends in opioid prescribing, inclusion of genetic information in risk prediction tools may improve opioid risk assessment. Our objectives were to (1) determine the feasibility of recruiting socioeconomically disadvantaged and racially diverse middle aged and older adult populations for a study seeking to identify risk factors for opioid‐related falls and other serious adverse effects and (2) explore potential associations between the Risk Index for Overdose or Serious Opioid‐induced Respiratory Depression (CIP‐RIOSORD) risk class and other patient factors with falls and serious opioid adverse effects. This was an observational study of 44 participants discharged home from the emergency department with an opioid prescription for acute pain and followed for 30 days. We found pain interference may predict opioid‐related falls or serious adverse effects within older, opioid‐treated patients. If validated, pain interference may prove to be a beneficial marker for risk stratification of older adults initiated on opioids for acute pain.

Abstract Biomedical sciences PhDs pursue a wide range of careers inside and outside academia. However, there is little data regarding how career interests of PhD students relate to the decision to pursue postdoctoral training or to their eventual career outcomes. Here, we present the career goals and career outcomes of 1452 biomedical sciences PhDs who graduated from Vanderbilt University between 1997 and 2021. We categorized careers using an expanded three‐tiered taxonomy and flags that delineate key career milestones. We also analyzed career goal changes between matriculation and doctoral defense, and the reasons why students became more‐ or less‐interested in research‐intensive faculty careers. We linked students' career goal at doctoral defense to whether they did a postdoc, the duration of time between doctoral defense and the first non‐training position, the career area of the first non‐training position, and the career area of the job at 10 years after graduation. Finally, we followed individual careers for 10 years after graduation to characterize movement between different career areas over time. We found that most students changed their career goal during graduate school, declining numbers of alumni pursued postdoctoral training, many alumni entered first non‐training positions in a different career area than their goal at doctoral defense, and the career area of the first non‐training position was a good indicator of the job that alumni held 10 years after graduation. Our findings emphasize that students need a wide range of career development opportunities and career mentoring during graduate school to prepare them for futures in research and research‐related professions.

Abstract Objectives To assess the impact of early tracheostomy (ET) versus late tracheostomy (LT) placement on mortality and decannulation rates of COVID patients. Methods A retrospective chart review was performed of all patients infected with COVID‐19 who underwent tracheostomy tube placement in an Ochsner‐affiliated hospital from March 2020 to May 2022. Patients were identified using the electronic medical record and data was collated using the “Epic SlicerDicer” tool. Descriptive statistics were gathered and compared between patients who underwent ET placement and those who underwent LT placement. Patient demographics, previous medical history, tracheostomy procedural details, arterial blood gases, complications, and outcomes including time to wean from the ventilator, and time to decannulation were recorded. Results Two‐hundred nineteen patients were included in the study. There were no statistically significant differences in liberation from mechanical ventilation rates between early and LT (62% vs. 55%, p = .19), or in decannulation rates (40% vs. 32%, p = .14). The mean duration of time to liberation from mechanical ventilation for early trach was 13.88 versus 18.17 days for late trach, however, no statistically significant difference was found (p = .12). Similarly, mean duration of time to decannulation was 41.17 days for early versus 47.72 for late trach (p = .15). Conclusion Contrary to some studies in the literature, the results presented here suggest ETs are not associated with hastened liberation from mechanical ventilation or increased decannulation rates. Further prospective studies may be warranted in assessing the impact of early versus LT in the COVID patient population. Level of Evidence III.

Abstract The present study aimed to investigate the factors associated with the level of rumination about the war among people living in Poland and Ukraine. This cross‐sectional study recruited internet users from advertisements on social media. Levels of rumination, Depression, Anxiety and Stress Scale (DASS), Impact of Event Scale‐Revised (IES‐R), time spent on news of the war, and related demographic variables were collected. The reliability and construct validity of rumination were estimated. Potential factors associated with the level of rumination were identified using univariate linear regression analysis, and further entered into a stepwise multivariate linear regression model to identify independent factors. Due to the non‐normality of distribution, multivariate linear regression with 5000 bootstrap samples was used to verify the results. A total of 1438 participants were included in the analysis, of whom 1053 lived in Poland and 385 lived in Ukraine. The questionnaires on rumination were verified to have satisfactory reliability and validity. After analysis with stepwise and bootstrap regression, older age, female gender, higher DASS and IES‐R scores, and longer time spent on news of the war were significantly associated with higher levels of rumination for both people living in Poland and Ukraine. Lower self‐rated health status, history of chronic medical illness and coronavirus disease 2019 infection were also positively associated with rumination for people living in Poland. We identified several factors associated with the level of rumination about the Russo‐Ukrainian War. Further investigations are warranted to understand how rumination affects individuals’ lives during crises such as war.

Abstract Next‐generation sequencing of pooled samples (Pool‐seq) is an important tool in population genomics and molecular ecology. In Pool‐seq, the relative number of reads with an allele reflects the allele frequencies in the sample. However, unequal individual contributions to the pool and sequencing errors can lead to inaccurate allele frequency estimates, influencing downstream analysis. When designing Pool‐seq studies, researchers need to decide the pool size (number of individuals) and average depth of coverage (sequencing effort). An efficient sampling design should maximise the accuracy of allele frequency estimates while minimising the sequencing effort. We describe a novel tool to simulate single nucleotide polymorphism (SNP) data using coalescent theory and account for sources of uncertainty in Pool‐seq. We introduce an R package, poolHelper, enabling users to simulate Pool‐seq data under different combinations of average depth of coverage and pool size, accounting for unequal individual contributions and sequencing errors, modelled by adjustable parameters. The mean absolute error is computed by comparing the sample allele frequencies obtained based on individual genotypes with the frequency estimates obtained with Pool‐seq. poolHelper enables users to simulate multiple combinations of pooling errors, average depth of coverage, pool sizes and number of pools to assess how they influence the error of sample allele frequencies and expected heterozygosity. Using simulations under a single population model, we illustrate that increasing the depth of coverage does not necessarily lead to more accurate estimates, reinforcing that finding the best Pool‐seq study design is not straightforward. Moreover, we show that simulations can be used to identify different combinations of parameters with similarly low mean absolute errors. This can help users to define an effective sampling design by using those combinations of parameters that minimise the sequencing effort. The poolHelper package provides tools for performing simulations with different combinations of parameters (e.g. pool size, depth of coverage, unequal individual contribution) before sampling and generating data, allowing users to define sampling schemes based on simulations. This allows researchers to focus on the best sampling scheme to answer their research questions. poolHelper is comprehensively documented with examples to guide effective use.