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Abstract Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

Abstract Background The quality of patient-reported outcome measures (PROMs) used to assess the outcomes of primary hyperparathyroidism (PHPT), a common endocrine disorder that can negatively affect patients’ health-related quality of life due to chronic symptoms, has not been rigorously examined. This systematic review aimed to summarize and evaluate evidence on the measurement properties of PROMs used in adult patients with PHPT, and to provide recommendations for appropriate measure selection. Methods After PROSPERO registration (CRD42023438287), Medline, EMBASE, CINAHL Complete, Web of Science, PsycINFO, and Cochrane Trials were searched for full-text articles in English investigating PROM development, pilot studies, or evaluation of at least one PROM measurement property in adult patients with any clinical form of PHPT. Two reviewers independently identified studies for inclusion and conducted the review following the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) Methodology to assess risk of bias, evaluate the quality of measurement properties, and grade the certainty of evidence. Results From 4989 records, nine PROM development or validation studies were identified for three PROMs: the SF-36, PAS, and PHPQoL. Though the PAS demonstrated sufficient test-retest reliability and convergent validity, and the PHPQoL sufficient test-retest reliability, convergent validity, and responsiveness, the certainty of evidence was low-to-very low due to risk of bias. All three PROMs lacked sufficient evidence for content validity in patients with PHPT. Conclusions Based upon the available evidence, the SF-36, PAS, and PHPQoL cannot currently be recommended for use in research or clinical care, raising important questions about the conclusions of studies using these PROMs. Further validation studies or the development of more relevant PROMs with strong measurement properties for this patient population are needed.

Abstract Modern coexistence theory (MCT) offers a conceptually straightforward approach for connecting empirical observations with an elegant theoretical framework, gaining popularity rapidly over the past decade. However, beneath this surface‐level simplicity lie various assumptions and subjective choices made during data analysis. These can lead researchers to draw qualitatively different conclusions from the same set of experiments. As the predictions of MCT studies are often treated as outcomes, and many readers and reviewers may not be familiar with the framework's assumptions, there is a particular risk of ‘researcher degrees of freedom’ inflating the confidence in results, thereby affecting reproducibility and predictive power. To tackle these concerns, we introduce a checklist consisting of statistical best practices to promote more robust empirical applications of MCT. Our recommendations are organised into four categories: presentation and sharing of raw data, testing model assumptions and fits, managing uncertainty associated with model coefficients and incorporating this uncertainty into coexistence predictions. We surveyed empirical MCT studies published over the past 15 years and discovered a high degree of variation in the level of statistical rigour and adherence to best practices. We present case studies to illustrate the dependence of results on seemingly innocuous choices among competition model structure and error distributions, which in some cases reversed the predicted coexistence outcomes. These results demonstrate how different analytical approaches can profoundly alter the interpretation of experimental results, underscoring the importance of carefully considering and thoroughly justifying each step taken in the analysis pathway. Our checklist serves as a resource for authors and reviewers alike, providing guidance to strengthen the empirical foundation of empirical coexistence analyses. As the field of empirical MCT shifts from a descriptive, trailblazing phase to a stage of consolidation, we emphasise the need for caution when building upon the findings of earlier studies. To ensure that progress made in the field of ecological coexistence is based on robust and reliable evidence, it is crucial to subject our predictions, conclusions and generalisability to a more rigorous assessment than is currently the trend.

Dynamin-related protein 1 (Drp1) is a mitochondrial fission protein and a viable target for cardioprotection against myocardial ischaemia-reperfusion injury. Here, we reported a novel Drp1 inhibitor (DRP1i1), delivered using a cardiac-targeted nanoparticle drug delivery system, as a more effective approach for achieving acute cardioprotection. DRP1i1 was encapsulated in cubosome nanoparticles with conjugated cardiac-homing peptides (NanoDRP1i1) and the encapsulation efficiency was 99.3 ± 0.1 %. In vivo, following acute myocardial ischaemia-reperfusion injury in mice, NanoDRP1i1 significantly reduced infarct size and serine-616 phosphorylation of Drp1, and restored cardiomyocyte mitochondrial size to that of sham group. Imaging by mass spectrometry revealed higher accumulation of DRP1i1 in the heart tissue when delivered as NanoDRP1i1. In human cardiac organoids subjected to simulated ischaemia-reperfusion injury, treatment with NanoDRP1i1 at reperfusion significantly reduced cardiac cell death, contractile dysfunction, and mitochondrial superoxide levels. Following NanoDRP1i1 treatment, cardiac organoid proteomics further confirmed reprogramming of contractile dysfunction markers and enrichment of the mitochondrial protein network, cytoskeletal and metabolic regulation networks when compared to the simulated injury group. These proteins included known cardioprotective regulators identified in human organoids and in vivo murine studies following ischaemia-reperfusion injury. DRP1i1 is a promising tool compound to study Drp1-mediated mitochondrial fission and exhibits promising therapeutic potential for acute cardioprotection, especially when delivered using the cardiac-targeted cubosome nanoparticles.

Non-point source pollution and water eutrophication from agricultural runoff present global challenges that impact ground and surface waters. The search for a feasible and sustainable mitigation strategy to combat this issue remains ongoing. This scoping review aims to explore one potential solution by examining relevant literature on agricultural practices of the past and recent edge-of-field measures, designed to ameliorate the impacts of agricultural runoff on soil and water quality. The study focuses on integrating findings from diverse research fields into a novel myco-phytoremediation approach, which involves the synergistic relationship of plants, arbuscular mycorrhizal fungi, and plant beneficial bacteria within vegetative buffer strips. The implementation of these augmented buffer strips enhances nutrient retention in the soil, reduces runoff volume, promotes biodiversity, and increases plant biomass. This biomass can be converted into biochar, an effective sorbent that can be used to filter dissolved and particulate nutrients from surface waterways. The resulting nutrient-rich biochar can be repurposed as a form of bio-fertiliser, optimizing fertiliser consumption and subsequently reducing the depletion rate of phosphorus, a limited resource. This paper investigates a circular model of abatement of agricultural runoff via maximal nutrient retention and subsequent recycling of nitrogen and phosphorus back into the agricultural system. The key impact lies in its contribution to addressing the issue of non-point source pollution and eutrophication by encouraging multidisciplinary research aimed at solving these complex environmental issues.

The force developed by actively lengthened muscle depends on different structures across different scales of lengthening. For small perturbations, the active response of muscle is well captured by a linear-time-invariant (LTI) system: a stiff spring in parallel with a light damper. The force response of muscle to longer stretches is better represented by a compliant spring that can fix its end when activated. Experimental work has shown that the stiffness and damping (impedance) of muscle in response to small perturbations is of fundamental importance to motor learning and mechanical stability, while the huge forces developed during long active stretches are critical for simulating and predicting injury. Outside of motor learning and injury, muscle is actively lengthened as a part of nearly all terrestrial locomotion. Despite the functional importance of impedance and active lengthening, no single muscle model has all these mechanical properties. In this work, we present the viscoelastic-crossbridge active-titin (VEXAT) model that can replicate the response of muscle to length changes great and small. To evaluate the VEXAT model, we compare its response to biological muscle by simulating experiments that measure the impedance of muscle, and the forces developed during long active stretches. In addition, we have also compared the responses of the VEXAT model to a popular Hill-type muscle model. The VEXAT model more accurately captures the impedance of biological muscle and its responses to long active stretches than a Hill-type model and can still reproduce the force-velocity and force-length relations of muscle. While the comparison between the VEXAT model and biological muscle is favorable, there are some phenomena that can be improved: the low frequency phase response of the model, and a mechanism to support passive force enhancement.

Summary: A growing number of studies have applied evolutionary and ecological principles to understanding cancer. However, few such studies have examined whether phenotypic plasticity––the ability of a single individual or genome to respond differently to different environmental circumstances––can impact the origin and spread of cancer. Here, we propose the adaptive horizontal transmission hypothesis to explain how flexible decision-making by selfish genetic elements can cause them to spread from the genome of their original host into the genomes of other hosts through the evolution of transmissible cancers. Specifically, we hypothesize that such cancers appear when the likelihood of successful vertical transmission is sufficiently low relative to the likelihood of successful horizontal transmission. We develop an evolutionary optimization model of this hypothesis, highlight empirical findings that support it, and offer suggestions for future research. Generally, phenotypically plastic selfish genetic elements might play an important role in the evolution of transmissible cancers.

Abstract. Background:. Despite the recent emphasis on promoting international collaborations within orthopaedic surgery, criteria for determining the strengths of such partnerships has not been established. The purpose of this study was to evaluate orthopaedic experts' perceptions of the most valuable characteristics of international academic partnerships. Methods:. This study was conducted using a modified Delphi methodology. Experts were identified through the Consortium of Orthopaedic Academic Traumatologists (COACT). Responses were collected from February to September 2022. Three rounds of surveys listing possible topics on a 5-point Likert scale were used to develop consensus among a group of experts. Consensus criteria for topic inclusion in the final scale was determined as a rating of “strongly agree” or “agree” by ≥70% of the participants in the third survey. Results:. The Round 1 survey was distributed to 96 invited participants within the COACT network, of which 50 experts (52.1%) completed the first survey. Consensus was reached on 54 topics organized into the following 5 categories: Research, Advocacy/Leadership, Training/Surgical Skills, Education/Knowledge Exchange, and Sustainability and Safety (RATES Criteria). Conclusions:. Determining the most valuable characteristics of successful international academic partnerships can lead to more sustainable, mutually beneficial collaborations. The criteria identified in this study can provide the foundation for developing new partnerships and assessing existing ones.

Due to observed impacts of sea level rise, many sediment management strategies in coastal settings are seeking ways to beneficially use locally dredged sediment in restoration, nourishment, and construction projects. The placement of sediment in shallow, near-marsh areas is a promising application of dredged material to both increase accretion and provide protection to marshes and intertidal flats in back bay areas. However, dredged material in these areas often include fine-grained (

Background:. It is increasingly apparent that plastic surgery residency applications with lengthy research publications are the new standard in applicant competitiveness. This study aims to evaluate the research history of plastic surgery program faculty leadership to understand the trends and evolution of research expectations. Methods:. The curriculum vitaes of faculty involved in residency admissions among all US Accreditation Council for Graduate Medical Education-accredited integrated and independent plastic surgery programs were reviewed. Doximity, program websites, and Scopus were used to gather information. H-index and publication count at the time of medical school and residency graduations were collected. Student t test and Pearson product-moment correlation were used for analysis. Results:. Of the 236 plastic surgeons considered, faculty averaged one publication by medical school graduation, two by general surgery residency graduation, and six by plastic surgery residency graduation. Integrated residents held more publications after medical school (1.67 versus 0.56; P = 0.09) and plastic surgery residency (8.48 versus 4.89; P = 0.01) compared with independent residents. Later plastic surgery residency graduation year correlated with more publications (P < 0.001). Chairs had higher h-indices compared with program directors and associate positions (chair: 23.7, program director: 14.7, associate: 12.2; P < 0.001). Conclusions:. The majority of faculty leaders’ research was published after residency. The emerging trend of increased research volume among plastic surgeons-in-training may be a consequence of competitive research requirements to matriculate into residency. Longer-term career follow-up of newer graduates will need to be assessed to determine whether this predicts future postgraduate productivity or if it is just the price of admission to train as a plastic surgeon.

Discovering new deep hydrothermal vent systems is one of the biggest challenges in ocean exploration. They are a unique window to elucidate the physical, geochemical, and biological processes that occur on the seafloor and are involved in the evolution of life on Earth. In this study, we present a molecular analysis of the microbial composition within the newly discovered hydrothermal vent field, JaichMaa ‘ja ‘ag, situated in the Southern Pescadero Basin within the Gulf of California. During the cruise expedition FK181031 in 2018, 33 sediment cores were collected from various sites within the Pescadero vent fields and processed for 16S rRNA amplicon sequence variants (ASVs) and geochemical analysis. Correlative analysis of the chemical composition of hydrothermal pore fluids and microbial abundances identified several sediment-associated phyla, including Thermotogota, that appear to be enriched in sediment horizons impacted by hydrothermal fluid flow. Comparative analysis of Thermotogota with the previously explored Auka hydrothermal vent field situated 2 km away displayed broad similarity between the two locations, although at finer scales (e.g., ASV level), there were notable differences that point to core-to-core and site-level factors revealing distinct patterns of distribution and abundance within these two sediment-hosted hydrothermal vent fields. These patterns are intricately linked to the specific physical and geochemical conditions defining each vent, illuminating the complexity of this unique deep ocean chemosynthetic ecosystem.

IntroductionThe Burkholderia cepacia complex encompasses a group of gram-negative opportunistic pathogens that cause chronic lung infections in people with cystic fibrosis. Distinct from other respiratory pathogens, Burkholderia causes a unique clinical disease in a subset of patients known as ‘cepacia syndrome’, fulminant pneumonia accompanied by bacteraemia and sepsis with a mortality rate of up to 75%. Due to the bacteraemia associated with this disease, the mechanisms that allow Burkholderia to resist the bactericidal effects of serum complement-depending killing are vital. Antibodies usually promote serum killing; however, we have described ‘cloaking antibodies’, specific for lipopolysaccharides that paradoxically protect serum-sensitive bacteria from complement-mediated lysis. Cloaking antibodies that protect Pseudomonas aeruginosa have been found in 24%–41% of patients with chronic lung diseases. The presence of these antibodies is also associated with worse clinical outcomes. Here, we sought to determine the relevance of cloaking antibodies in patients with Burkholderia infection.MethodsTwelve Burkholderia spp. were isolated from nine pwCF and characterised for susceptibility to healthy control serum. Patient serum was analysed for the titre of the cloaking antibody. The ability of the patient serum to prevent healthy control serum (HCS) killing of its cognate isolates was determined.ResultsWe found that several of the Burkholderia strains were shared between patients. Ten of the 12 isolates were highly susceptible to HCS killing. Four of nine (44%) patients had cloaking antibodies that protected their cognate strain from serum killing. Depleting cloaking antibodies from patient serum restored HCS killing of Burkholderia isolates.DiscussionCloaking antibodies are prevalent in patients with Burkholderia pulmonary infection and protect these strains from serum killing. Removal of cloaking antibodies via plasmapheresis, as previously described for individuals with life-threatening Pseudomonas infection, may be a useful new strategy for those with serious and life-threatening Burkholderia infection.

ABSTRACT The Southampton pneumococcal carriage study of children under 5 years old continued during the coronavirus disease 2019 (COVID-19) pandemic. Here, we present data from October 2018 to March 2023 describing prevalence of pneumococci and other pathobionts during the winter seasons before, during, and after the introduction of non-pharmaceutical interventions (NPIs) to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Nasopharyngeal swabs were collected from children attending outpatient clinics at a secondary care hospital and community healthcare sites. Pre-NPIs, in 2019/2020, the carriage prevalence of pneumococci at the hospital site was 32% (n = 161 positive/499 participants). During NPIs, this fell to 19% (n = 12/64), although based on fewer participants compared to previous years due to COVID-19 restrictions on health-care attendance. In 2021/2022, after NPIs had eased, prevalence rebounded to 33% (n = 15/46) [compared to NPIs period, χ2 (1, N = 110) =2.78, P = 0.09]. Carriage prevalence at community healthcare sites fell significantly from 27% (n = 127/470) in 2019/2020 to 19% during the NPI period (n = 44/228) in 2020/2021 [χ2 (1, N = 698) =4.95, P = 0.026]. No rebound was observed in 2021/2022 [19% (n = 56/288)]. However, in a multivariate logistic regression model, neither site had a significantly lower carriage prevalence during the NPI period compared to the post NPI period. A reduction in serotype diversity was observed in 2020/2021. Carriage of Haemophilus influenzae was particularly affected by NPIs with a significant reduction observed. In conclusion, among children under 5 years of age, transient, modest, and statistically non-significant alterations in carriage of both Streptococcus pneumoniae and H. influenzae were associated with SARS-CoV-2 NPIs.IMPORTANCEStreptococcus pneumoniae (the pneumococcus) continues to be a major contributor to global morbidity and mortality. Using our long-running pediatric study, we examined changes in pneumococcal carriage prevalence in nearly 3,000 children under the age of 5 years between the winters of 2018/2019 and 2022/2023. This period coincided with the severe acute respiratory syndrome coronavirus 2 pandemic and, in particular, the implementation of national strategies to limit disease transmission in the UK. We observed a transient reduction of both Streptococcus pneumoniae and Haemophilus influenzae in these populations during this period of non-pharmaceutical interventions. This aligned with the reduction in invasive pneumococcal disease seen in the UK and is therefore a likely contributor to this phenomenon.

BackgroundA coordinated care system helps provide timely access to treatment for suspected acute stroke. In Northwestern Ontario (NWO), Canada, communities are widespread with several hospitals offering various diagnostic equipment and services. Thus, resources are limited, and health care providers must often transfer patients with stroke to different hospital locations to ensure the most appropriate care access within recommended time frames. However, health care providers frequently situated temporarily (locum) in NWO or providing care remotely from other areas of Ontario may lack sufficient information and experience in the region to access care for a patient with a time-sensitive condition. Suboptimal decision-making may lead to multiple transfers before definitive stroke care is obtained, resulting in poor outcomes and additional health care system costs. ObjectiveWe aimed to develop a tool to inform and assist NWO health care providers in determining the best transfer options for patients with stroke to provide the most efficient care access. We aimed to develop an app using a comprehensive geomapping navigation and estimation system based on machine learning algorithms. This app uses key stroke-related timelines including the last time the patient was known to be well, patient location, treatment options, and imaging availability at different health care facilities. MethodsUsing historical data (2008-2020), an accurate prediction model using machine learning methods was developed and incorporated into a mobile app. These data contained parameters regarding air (Ornge) and land medical transport (3 services), which were preprocessed and cleaned. For cases in which Ornge air services and land ambulance medical transport were both involved in a patient transport process, data were merged and time intervals of the transport journey were determined. The data were distributed for training (35%), testing (35%), and validation (30%) of the prediction model. ResultsIn total, 70,623 records were collected in the data set from Ornge and land medical transport services to develop a prediction model. Various learning models were analyzed; all learning models perform better than the simple average of all points in predicting output variables. The decision tree model provided more accurate results than the other models. The decision tree model performed remarkably well, with the values from testing, validation, and the model within a close range. This model was used to develop the “NWO Navigate Stroke” system. The system provides accurate results and demonstrates that a mobile app can be a significant tool for health care providers navigating stroke care in NWO, potentially impacting patient care and outcomes. ConclusionsThe NWO Navigate Stroke system uses a data-driven, reliable, accurate prediction model while considering all variations and is simultaneously linked to all required acute stroke management pathways and tools. It was tested using historical data, and the next step will to involve usability testing with end users.

Summary: Background: Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. Methods: 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. Findings: Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment. Interpretation: Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC. Funding: The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the “European Union Next Generation EU/PRTR,” the Regional Government of Castile and León (CSI144P20), European Union.

Pulmonary hypertension (PH) is a common and prognostically important complication of mitral regurgitation (MR). Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) are traditionally used to diagnose PH, however these indices measure static rather than pulsatile load, leading to an incomplete representation of pulmonary vascular load on the right ventricle (RV). Pulmonary arterial compliance (PAC) is one method for quantifying pulsatile load, and is both a stronger predictor of prognosis in left heart failure, as well as a more sensitive measure of early pulmonary vascular dysfunction than PVR. With the expansion of transcatheter mitral and tricuspid valve therapies, there is renewed interest to more accurately define the load imposed by the pulmonary vasculature on the RV, especially in the early phase, prior to the onset of chronic PH. This review discusses the pathophysiology of pH in left heart failure and MR, the utility of PAC as a measure of RV afterload, and its calculation for clinical use and interpretation, underlining the utility of PAC as an adjunct for assessing pulmonary vascular haemodynamics.

Background & Aims: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited, due to inadequate risk stratification and suboptimal performance of current screening modalities. Methods: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance with MRI and applied global untargeted metabolomics to 612 longitudinal serum samples from 203 patients. Among them, 37 developed HCC during follow-up. Results: We identified 150 metabolites with significant abundance changes in samples collected prior to HCC (Cases) compared to samples from patients who did not develop HCC (Controls). Tauro-conjugated bile acids and gamma-glutamyl amino acids were increased, while acyl-cholines and deoxycholate derivatives were decreased. Seven amino acids including serine and alanine had strong associations with HCC risk, while strong protective effects were observed for N-acetylglycine and glycerophosphorylcholine. Machine learning using the 150 metabolites, age, gender, and PNPLA3 and TMS6SF2 single nucleotide polymorphisms, identified 15 variables giving optimal performance. Among them, N-acetylglycine had the highest AUC in discriminating Cases and Controls. When restricting Cases to samples collected within 1 year prior to HCC (Cases-12M), additional metabolites including microbiota-derived metabolites were identified. The combination of the top six variables identified by machine learning (alpha-fetoprotein, 6-bromotryptophan, N-acetylglycine, salicyluric glucuronide, testosterone sulfate and age) had good performance in discriminating Cases-12M from Controls (AUC 0.88, 95% CI 0.83-0.93). Finally, 23 metabolites distinguished Cases with LI-RADS-3 lesions from Controls with LI-RADS-3 lesions, with reduced abundance of acyl-cholines and glycerophosphorylcholine-related lysophospholipids in Cases. Conclusions: This study identified N-acetylglycine, amino acids, bile acids and choline-derived metabolites as biomarkers of HCC risk, and microbiota-derived metabolites as contributors to HCC development. Impact and implications:: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited. There is an urgent need for improvement in risk stratification and new screening modalities, particularly blood biomarkers. Longitudinal collection of paired blood samples and MRI images from patients with cirrhosis is particularly valuable in assessing how early blood and imaging markers become positive during the period when lesions are observed to obtain a diagnosis of HCC. We generated a multicenter prospective cohort of patients with cirrhosis under surveillance with contrast MRI, applied untargeted metabolomics on 612 serum samples from 203 patients and identified metabolites associated with risk of HCC development. Such biomarkers may significantly improve early-stage HCC detection for patients with cirrhosis undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality.

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent ''one-two punch'' against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

Pangolins are the most trafficked mammals in the world and are severely threatened by poaching the loss, degradation, and fragmentation of habitat. In Malaysian Borneo, conservation initiatives for the Sunda pangolin (Manis javanica) are hindered by a paucity of data on their distribution and population size. Using MaxEnt niche modelling and consolidated species location data, we projected the distribution of Sunda pangolins in Sabah. Additionally, we assessed the accessibility of their forest habitats to humans to understand potential threats. Our model indicated that, as of 2015, approximately half of Sabah’s land area (39,530 km²) is suitable for pangolins, with 43% in protected forests, 38% in production forests, and 19% outside of these areas. Alarmingly, our data suggest that nearly all (91%) of these suitable habitats are relatively easily accessible to poachers. Our findings provide a state-level baseline understanding of Sunda pangolin distribution and assess potential threats in Sabah. These can inform short- and long-term conservation management plans for pangolin to safeguard this critically endangered species.

Abstract Among extant species, the ability to sample the extremes of body size—one of the most useful predictors of an individual's ecology—is highly unlikely. This improbability is further exaggerated when sampling the already incomplete fossil record. We quantify the likelihood of sampling the uppermost limits of body size in the fossil record using Tyrannosaurus rex Osborn, 1905 as a model, selected for its comparatively well‐understood life history parameters. We computationally generate a population of 140 million T. rex (based on prior estimates), modelling variation about the growth curve both with and without sexual dimorphism (the former modelled after Alligator mississippiensis), and building in sampling limitations related to species survivorship and taphonomic bias, derived from fossil data. The 99th percentile of body mass in T. rex has likely already been sampled, but it will probably be millennia before much larger giants (99.99th percentile) are sampled at present collecting rates. Biomechanical and ecological limitations notwithstanding, we estimate that the absolute largest T. rex may have been 70% more massive than the currently largest known specimen (~15,000 vs. ~8800 kg). Body size comparisons of fossil species should be based on ontogenetically controlled statistical parameters, rather than simply comparing the largest known individuals whose recovery is highly subject to sampling intensity.

Abstract In regions characterized by a high concentration of small reservoirs, there is often public debate about the effectiveness of these structures in locally adapting to and mitigating drought impacts, bearing in mind their potential to modify or induce drought events in downstream areas. In this study, we investigated the influence of a Dense Network of Small Reservoirs (DNR) on the emergence and intensification of drought impacts at catchment scale, as well as their local social benefits. This analysis was based on the Socio‐Hydrological‐Agricultural‐Reservoir (SHARE) model, specially developed for this purpose, with a medium‐sized catchment in the semi‐arid region of Brazil as a case study. We identified that, while a DNR can prolong the effects of a hydrological drought on storage in a large strategic reservoir at the catchment outlet by obstructing surface‐runoff connectivity, it plays a crucial role in mitigating drought impacts at a local level. Specifically, the presence of small reservoirs has the potential to boost local agricultural production by up to 5 times compared to scenarios without these structures. In addition, our simulation results suggest there is a notable reduction in the need for emergency water distribution by water trucks in the presence of a DNR. This study highlights the need for a balanced approach to implementing public policies, weighing the local benefits of small reservoirs against the possible downstream impacts on large reservoirs.

Background Coproduction is defined as patients and clinicians collaborating equally and reciprocally in healthcare and is a crucial concept for quality improvement (QI) of health services. Learning Health Networks (LHNs) provide insights to integrate coproduction with QI efforts from programmes from various health systems.Objective We describe interventions to develop and maintain patient and family partner (PFP) coproduction, measured by PFP-reported and programme-reported scales. We aim to increase percentage of programmes with PFPs reporting active QI work within their programme, while maintaining satisfaction in PFP-clinician relationships.Methods Conducted in the Cystic Fibrosis Learning Network (CFLN), an LHN comprising over 30 cystic fibrosis (CF) programmes, people with CF, caregivers and clinicians cocreated interventions in readiness awareness, inclusive PFP recruitment, onboarding process, partnership development and leadership opportunities. Interventions were adapted by CFLN programmes and summarised in a change package for existing programmes and the orientation of new ones. We collected monthly assessments for PFP and programme perceptions of coproduction and PFP self-rated competency of QI skills and satisfaction with programme QI efforts. We used control charts to analyse coproduction scales and run charts for PFP self-ratings.Results Between 2018 and 2022, the CFLN expanded to 34 programmes with 52% having ≥1 PFP reporting active QI participation. Clinicians from 76% of programmes reported PFPs were actively participating or leading QI efforts. PFPs reported increased QI skills competency (17%–32%) and consistently high satisfaction and feeling valued in their work.Conclusions Implementing system-level programmatic strategies to engage and sustain partnerships between clinicians and patients and families with CF improved perceptions of coproduction to conduct QI work. Key adaptable strategies for programmes included onboarding and QI training, supporting multiple PFPs simultaneously and developing financial recognition processes. Interventions may be applicable in other health conditions beyond CF seeking to foster the practice of coproduction.

The fitness effects of new mutations determine key properties of evolutionary processes. Beneficial mutations drive evolution, yet selection is also shaped by the frequency of small-effect deleterious mutations, whose combined effect can burden otherwise adaptive lineages and alter evolutionary trajectories and outcomes in clonally evolving organisms such as viruses, microbes, and tumors. The small effect sizes of these important mutations have made accurate measurements of their rates difficult. In microbes, assessing the effect of mutations on growth can be especially instructive, as this complex phenotype is closely linked to fitness in clonally evolving organisms. Here, we perform high-throughput time-lapse microscopy on cells from mutation-accumulation strains to precisely infer the distribution of mutational effects on growth rate in the budding yeast, Saccharomyces cerevisiae. We show that mutational effects on growth rate are overwhelmingly negative, highly skewed towards very small effect sizes, and frequent enough to suggest that deleterious hitchhikers may impose a significant burden on evolving lineages. By using lines that accumulated mutations in either wild-type or slippage repair-defective backgrounds, we further disentangle the effects of 2 common types of mutations, single-nucleotide substitutions and simple sequence repeat indels, and show that they have distinct effects on yeast growth rate. Although the average effect of a simple sequence repeat mutation is very small (approximately 0.3%), many do alter growth rate, implying that this class of frequent mutations has an important evolutionary impact.

ABSTRACT The injectisome encoded by Salmonella pathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterize the secretome of a clinical strain of invasive non-typhoidal Salmonella enterica serovar Enteritidis that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein. sseM is widely distributed among the five subspecies of Salmonella enterica, is found in many clinically relevant serovars, and is co-transcribed with pipB2, a SPI-2 effector gene. The translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely, β-2-syntrophin, utrophin/dystrophin, α-catulin, α-dystrobrevin, and β-dystrobrevin. The interaction between SseM and β-2-syntrophin and α-dystrobrevin was verified in Salmonella Typhimurium-infected cells and relied on the postsynaptic density-95/discs large/zonula occludens-1 (PDZ) domain of β-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A ΔsseM mutant strain had a small competitive advantage over the wild-type strain in the S. Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild-type SseM from S. Typhimurium or S. Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within a Salmonella effector mediates interactions with the DAPC and modulates the systemic growth of bacteria in mice. Furthermore, the ΔsseM mutant strain displayed enhanced replication in bone marrow-derived macrophages, demonstrating that SseM restrains intracellular bacterial growth to modulate Salmonella virulence.IMPORTANCEIn Salmonella enterica, the injectisome machinery encoded by Salmonella pathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells, which are required for Salmonella virulence. The identification and functional characterization of SPI-2 injectisome effectors advance our understanding of the interplay between Salmonella and its host(s). Using an optimized method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal Salmonella enterica serovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector—SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a postsynaptic density-95/discs large/zonula occludens-1 (PDZ)-binding motif that is essential for interaction with the PDZ-containing host protein β-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique among Salmonella effectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.

We report discovery and spectroscopic follow-up of 21 astrometric binaries containing solar-type stars and dark companions with masses near 1.4 $M_{\odot}$. The simplest interpretation is that the companions are dormant neutron stars (NSs), though ultramassive white dwarfs (WDs) and tight WD+WD binaries cannot be fully excluded. We selected targets from Gaia DR3 astrometric binary solutions in which the luminous star is on the main sequence and the dynamically-implied mass of the unseen companion is (a) more than $1.25\,M_{\odot}$ and (b) too high to be any non-degenerate star or close binary. We obtained multi-epoch radial velocities (RVs) over a period of 670 days, spanning a majority of the orbits' dynamic range in RV. The RVs broadly validate the astrometric solutions and significantly tighten constraints on companion masses. Several systems have companion masses that are unambiguously above the Chandrasekhar limit, while the rest have masses between 1.25 and 1.4 $M_{\odot}$. The orbits are significantly more eccentric at fixed period than those of typical WD + MS binaries, perhaps due to natal kicks. Metal-poor stars are overrepresented in the sample: 3 out of 21 objects (14%) have [Fe/H]$\sim-1.5$ and are on halo orbits, compared to $\sim 0.5\%$ of the parent Gaia binary sample. The metal-poor stars are all strongly enhanced in lithium. The formation history of these objects is puzzling: it is unclear both how the binaries escaped a merger or dramatic orbital shrinkage when the NS progenitors were red supergiants, and how they remained bound when the NSs formed. Gaia has now discovered 3 black holes (BHs) in astrometric binaries with masses above 9 $M_{\odot}$, and 21 NSs with masses near $1.4\,M_{\odot}$. The lack of intermediate-mass objects in this sample is striking, supporting the existence of a BH/NS mass bimodality over 4 orders of magnitude in orbital period.

Abstract Circulating tumor cells (CTCs) have garnered special attention as promising cancer biomarkers. Phenotypic changes of CTCs reveal invaluable information for oncologists in disease prognosis and adjusting their treatment options. Microfluidic technology has emerged as a promising tool for CTC isolation; however, two major hurdles remain to be solved in employing them in CTC analysis. First, a rapid CTC isolation scheme is needed to allow immediate use of patient samples for point‐of‐care treatment monitoring. Second, multiplexed and streamlined CTC imaging is needed to facilitate CTC detection. Here, a microfluidic CTC sequential trapping array (STA) is proposed which addresses these hurdles enabling pipette‐based CTC isolation and simultaneous profiling of multiple CTC protein expressions. The STA device isolates CTCs based on their size difference from blood cells and increases sample processing throughput through its parallel design configuration. It successfully isolates CTC from a depleted peripheral blood mononuclear cells sample of breast cancer patients with a high recovery rate of 80% and discriminates the number and types of CTCs in breast cancer based on their disease stage. These findings will open a new avenue in clinical translation of CTC profiling technologies. It will be an example for future translational developments in CTC‐based cancer management.

PurposeRepeated mild traumatic brain injuries (mTBI) are a continuing healthcare concern worldwide, given its potential for enduring adverse neurodegenerative conditions. Past research suggests a potential protective effect of n-3 polyunsaturated fatty acids (PUFA) in experimental models of mTBI. The aim of this study was to investigate whether the neuroprotective benefits of n-3 PUFA persist following repetitive weight drop injury (WDI).MethodsMale fat-1 mice (n = 12), able to endogenously convert n-6 PUFA to n-3 PUFA, and their wild type (WT) counterparts (n = 12) were maintained on a 10% w/w safflower diet. At 9–10 weeks of age, both groups received one mild low-impact WDI on the closed cranium daily, for three consecutive days. Following each WDI, time to righting reflex and seeking behaviour were measured. Neurological recovery, cognitive, motor, and neurobehavioural outcomes were assessed using the Neurological Severity Score (NSS) over 7 days (168 h) post-last WDI. Brains were assessed for cerebral microhemorrhages by Prussian blue and cellular damage by glial fibrillary acidic protein (GFAP) staining.ResultsFat-1 mice exhibited significantly faster righting reflex and seeking behaviour time, and lower mean NSS scores and at all post-WDI time points (p ≤ 0.05) compared to WT mice. Immunohistochemistry showed no significant difference in presence of cerebral microhemorrhage however, fat-1 mice had significantly lower GFAP staining in comparison to WT mice (p ≤ 0.05).Conclusionn-3 PUFA is effective in restoring cognitive, motor, and behavioural function after repetitive WDI, which may be mediated through reduced cellular damage of the brain.

Rheumatoid arthritis is a chronic inflammatory disease that shows characteristic diurnal variation in symptom severity, where joint resident fibroblast-like synoviocytes (FLS) act as important mediators of arthritis pathology. We investigate the role of FLS circadian clock function in directing rhythmic joint inflammation in a murine model of inflammatory arthritis. We demonstrate FLS time-of-day-dependent gene expression is attenuated in arthritic joints, except for a subset of disease-modifying genes. The deletion of essential clock gene Bmal1 in FLS reduced susceptibility to collagen-induced arthritis but did not impact symptomatic severity in affected mice. Notably, FLS Bmal1 deletion resulted in loss of diurnal expression of disease-modulating genes across the joint, and elevated production of MMP3, a prognostic marker of joint damage in inflammatory arthritis. This work identifies the FLS circadian clock as an influential driver of daily oscillations in joint inflammation, and a potential regulator of destructive pathology in chronic inflammatory arthritis.

The terms “offshore” and “open ocean” have been used to describe aquaculture sites that are further from the coast or in higher energy environments. Neither term has been clearly defined in the scientific literature nor in a legal context, and the terms are often used interchangeably. These and other related terms (for example “exposed”, “high-energy”) variously refer to aspects of a site such as the geographic distance from shore or infrastructure, the level of exposure to large waves and strong currents, the geographic fetch, the water depth, or some combination of these parameters. The ICES Working Group (ICES, 2024) on Open Ocean Aquaculture (WGOOA) therefore identified a need to define the terminology to reduce ambiguity for these types of aquaculture sites or more precisely, to: (1) promote a common understanding and avoid misuse for different classifications; (2) enable regulators to identify the characteristics of a marine site; (3) allow farmers to be able to assess or quantitatively compare sites for development; (4) equip developers and producers to identify operational parameters in which the equipment and vessels will need to operate; (5) provide insurers and investors with the terminology to consistently assess risk and premiums; and (6) circumvent the emergence of narratives that root in different cognitive interpretations of the terminology in public discourse. This paper describes the evolution of the use of the term “offshore aquaculture” and define the most relevant parameters to shift to a more definitive and robust term “exposed aquaculture” that can inherently relay clearer information. Adoption of this more definitive definition of “exposed” will allow the user to define a site with more than just distance from shore. Key differences and the importance of these terms are discussed that affect various interest groups. Follow-up articles in this compilation from scientific members of the WGOOA as well as other scientists outside ICES are incorporated that develop a set of definitions and a rigorous exposure index.

The major histocompatibility (MHC) locus, also known as the Human Leukocyte Antigen (HLA) genes, is located on the short arm of chromosome 6, and contains three regions (Class I, Class II and Class III). This 5 Mbp locus is one of the most variable regions of the human genome, yet it also encodes a set of highly conserved and important proteins related to immunological response. Genetic variations in this region are responsible for more diseases than in the entire rest of the human genome. However, information on local structural features of the DNA is largely ignored. With recent advances in long-read sequencing technology, it is now becoming possible to sequence the entire 5 Mbp MHC locus, producing complete diploid haplotypes of the whole region. Here, we describe structural maps based on the complete sequences from six different homozygous HLA cell lines. We find long-range structural variability in the different sequences for DNA stacking energy, position preference and curvature, variation in repeats, as well as more local changes in regions forming open chromatin structures, likely to influence gene expression levels. These structural maps can be useful in visualizing large scale structural variation across HLA types, in particular when this can be complemented with epigenetic signals.

Summary: Background: This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC. Methods: All adult (≥18 years) PDAC patients who underwent pancreatectomy between January 2011 and December 2022 in Ontario, Canada, were identified for this population-based cohort study (ICD-O-3 codes: C250, C251, C252, C253, C257, C258). Patient demographics, comorbidities, PDAC stage, medical and surgical management, and survival data were sourced from multiple linked provincial administrative databases at ICES. All-cause mortality was compared between patients with and without a pre-operative abdominal MRI after controlling for multiple covariates. Findings: A cohort of 4579 patients consisted of 2432 men (53.1%) and 2147 women (46.9%) with a mean age of 65.2 years (standard deviation: 11.2 years); 2998 (65.5%) died while 1581 (34.5%) survived. Median follow-up duration post-resection was 22.4 months (interquartile range: 10.8–48.8 months), and median survival post-pancreatectomy was 25.9 months (95% confidence interval [95% CI]: 24.8, 27.5). Patients who underwent a pre-operative abdominal MRI had a median survival of 33.1 months (95% CI: 30.7, 37.2) compared to 21.1 months (95% CI: 19.8, 22.6) for all others. A total of 2354/4579 (51.4%) patients underwent a pre-operative abdominal MRI, which was associated with a 17.2% (95% CI: 11.0, 23.1) decrease in the rate of all-cause mortality, with an adjusted hazard ratio (aHR) of 0.828 (95% CI: 0.769, 0.890). Interpretation: Pre-operative abdominal MRI was associated with improved overall survival for PDAC patients who underwent pancreatectomy, possibly due to better detection of liver metastases than CT. Funding: Northern Ontario Academic Medicine Association (NOAMA) Clinical Innovation Fund.

Abstract Artificial intelligence (AI) has the potential to transform care delivery by improving health outcomes, patient safety, and the affordability and accessibility of high-quality care. AI will be critical to building an infrastructure capable of caring for an increasingly aging population, utilizing an ever-increasing knowledge of disease and options for precision treatments, and combatting workforce shortages and burnout of medical professionals. However, we are not currently on track to create this future. This is in part because the health data needed to train, test, use, and surveil these tools are generally neither standardized nor accessible. There is also universal concern about the ability to monitor health AI tools for changes in performance as they are implemented in new places, used with diverse populations, and over time as health data may change. The Future of Health (FOH), an international community of senior health care leaders, collaborated with the Duke-Margolis Institute for Health Policy to conduct a literature review, expert convening, and consensus-building exercise around this topic. This commentary summarizes the four priority action areas and recommendations for health care organizations and policymakers across the globe that FOH members identified as important for fully realizing AI’s potential in health care: improving data quality to power AI, building infrastructure to encourage efficient and trustworthy development and evaluations, sharing data for better AI, and providing incentives to accelerate the progress and impact of AI.

Abstract Introduction Interventional treatment options for the lumbar degenerative spine have undergone a significant amount of innovation over the last decade. As new technologies emerge, along with the surgical specialty expansion, there is no manuscript that utilizes a review of surgical treatments with evidence rankings from multiple specialties, namely, the interventional pain and spine communities. Through the Pacific Spine and Pain Society (PSPS), the purpose of this manuscript is to provide a balanced evidence review of available surgical treatments. Methods The PSPS Research Committee created a working group that performed a comprehensive literature search on available surgical technologies for the treatment of the degenerative spine, utilizing the ranking assessment based on USPSTF (United States Preventative Services Taskforce) and NASS (North American Spine Society) criteria. Results The surgical treatments were separated based on disease process, including treatments for degenerative disc disease, spondylolisthesis, and spinal stenosis. Conclusions There is emerging and significant evidence to support multiple approaches to treat the symptomatic lumbar degenerative spine. As new technologies become available, training, education, credentialing, and peer review are essential for optimizing patient safety and successful outcomes.

Abstract Background Sinusitis is a common diagnosis that can be erroneously associated with routine weather‐related barometric pressure changes. In actuality, these pressure changes likely exacerbate migraine headaches, which can cause facial pain and pressure rather than true sinus inflammation. Objective The present study sought to characterize the representation of both sinusitis and migraine in association with barometric pressure changes across websites on the Internet. Methods An Internet search for relevant terms was conducted, and content of the resulting pages was assessed for associations between weather‐related pressure changes and either sinusitis or migraine. Variations in reported results across different subtypes of Internet sources were analyzed. The primary outcomes measured were (1) whether a given media source associated barometric weather changes with sinusitis, (2) whether that source associated barometric weather changes with migraine, and (3) treatment options offered by that source. Results Of the 116 included webpages, 36 (31.03%) associated sinusitis and routine barometric pressure changes. Of these, 10 (27.77%) were otolaryngology practice sites. Sixty‐seven webpages (57.76%) associated migraine and routine barometric pressure changes. Of these, nonotolaryngology webpages were more likely to report this link. Conclusions Otolaryngology practice sites were observed to be the most frequent professional medical resource reporting the unsubstantiated claim that routine barometric pressure changes are associated with sinusitis. Nonotolaryngology sources were more likely to link weather‐related pressure changes to migraine. These results suggest that opportunities exist for otolaryngology practice sites to educate patients about nonrhinogenic headache etiologies.

Purpose: This prospective multicenter study investigated the implant fixation of a cementless cup in primary total hip arthroplasty (THA) for osteoarthritis (OA) secondary to developmental dysplasia of the hip (DDH) in Japanese patients. Methods: Ten hospitals in Japan were enrolled in this study. The cohort comprised 267 hips in 228 Japanese patients who underwent primary THA for OA secondary to DDH. An acetabular cup with advanced in-growth, GRIPTION™ coating, was used in all patients. Mean age at surgery was 66.9 (range 45–89) years, and 201 patients (239 hips) were female. Of these patients, 89.1 ​% (238/267) was Crowe group I. Radiolucent lines around the cup, osteolysis, cup migration, grafted bone status, and clinical scores were evaluated preoperatively and at 6 months, 1 year, and 2 years postoperatively. Adverse events were evaluated throughout the study. Implant survivorship was assessed using the Kaplan–Meier method. Results: Nine hips had radiolucent lines ≥2 ​mm that resolved by 6 months. All cups showed bone in-growth and no cups loosened. At 2 years, the bone grafts had remodeled and incorporated in 68 ​% (43/63) of hips. There were four systemic and five surgical site events, and one procedure-related dislocation. The survivorship with cup revision as the endpoint was 99.6 ​% (95 ​% confidence interval, 97.3–99.9). All clinical scores were improved at 2 years compared with preoperatively (p ​

Abstract PELICAN is a novel permutation equivariant and Lorentz invariant or covariant aggregator network designed to overcome common limitations found in architectures applied to particle physics problems. Compared to many approaches that use non-specialized architectures that neglect underlying physics principles and require very large numbers of parameters, PELICAN employs a fundamentally symmetry group-based architecture that demonstrates benefits in terms of reduced complexity, increased interpretability, and raw performance. We present a comprehensive study of the PELICAN algorithm architecture in the context of both tagging (classification) and reconstructing (regression) Lorentz-boosted top quarks, including the difficult task of specifically identifying and measuring the W-boson inside the dense environment of the Lorentz-boosted top-quark hadronic final state. We also extend the application of PELICAN to the tasks of identifying quark-initiated vs. gluon-initiated jets, and a multi-class identification across five separate target categories of jets. When tested on the standard task of Lorentz-boosted top-quark tagging, PELICAN outperforms existing competitors with much lower model complexity and high sample efficiency. On the less common and more complex task of 4-momentum regression, PELICAN also outperforms hand-crafted, non-machine learning algorithms. We discuss the implications of symmetry-restricted architectures for the wider field of machine learning for physics.

Abstract Analysis of DNA methylation in cell-free DNA reveals clinically relevant biomarkers but requires specialized protocols such as whole-genome bisulfite sequencing. Meanwhile, millions of cell-free DNA samples are being profiled by whole-genome sequencing. Here, we develop FinaleMe, a non-homogeneous Hidden Markov Model, to predict DNA methylation of cell-free DNA and, therefore, tissues-of-origin, directly from plasma whole-genome sequencing. We validate the performance with 80 pairs of deep and shallow-coverage whole-genome sequencing and whole-genome bisulfite sequencing data.

Abstract Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p

Abstract Background People who inject drugs (PWID) remain a high priority population under the federal Ending the HIV Epidemic initiative with 11% of new HIV infections attributable to injection drug use. There is a critical need for innovative, efficacious, scalable, and community-driven models of healthcare in non-stigmatizing settings for PWID. We seek to test a Comprehensive-TeleHarm Reduction (C-THR) intervention for HIV prevention services delivered via a syringe services program (SSP). Methods The CHARIOT trial is a hybrid type I effectiveness-implementation study using a parallel two-arm randomized controlled trial design. Participants (i.e., PWID; n = 350) will be recruited from a syringe services program (SSP) in Miami, Florida. Participants will be randomized to receive either C-THR or non-SSP clinic referral and patient navigation. The objectives are: (1) to determine if the C-THR intervention increases engagement in HIV prevention (i.e., HIV pre-exposure prophylaxis; PrEP or medications for opioid use disorder; MOUD) compared to non-SSP clinic referral and patient navigation, (2) to examine the long-term effectiveness and cost-effectiveness of the C-THR intervention, and (3) to assess the barriers and facilitators to implementation and sustainment of the C-THR intervention. The co-primary outcomes are PrEP or MOUD engagement across follow-up at 3, 6, 9 and 12 months. For PrEP, engagement is confirmed by tenofovir on dried blood spot or cabotegravir injection within the previous 8 weeks. For MOUD, engagement is defined as screening positive for norbuprenorphine or methadone on urine drug screen; or naltrexone or buprenorphine injection within the previous 4 weeks. Secondary outcomes include PrEP adherence, engagement in HCV treatment and sustained virologic response, and treatment of sexually transmitted infections. The short and long term cost-effectiveness analyses and mixed-methods implementation evaluation will provide compelling data on the sustainability and possible impact of C-THR on comprehensive HIV prevention delivered via SSPs. Discussion The CHARIOT trial will be the first to our knowledge to test the efficacy of an innovative, peer-led telehealth intervention with PWID at risk for HIV delivered via an SSP. This innovative healthcare model seeks to transform the way PWID access care by bypassing the traditional healthcare system, reducing multi-level barriers to care, and meeting PWID where they are. Trial Registration: ClinicalTrials.gov NCT05897099. Trial registry name: Comprehensive HIV and Harm Prevention Via Telehealth (CHARIOT). Registration date: 06/12/2023.

Abstract Background Optimal management of voluntary energy expenditure is crucial to the survival and reproductive success of wild animals. Nevertheless, a growing appreciation of inter-individual variation in the internal state driving movement suggests that individuals may follow different, yet equally optimal tactics under the same environmental conditions. However, few studies in wild populations have investigated the occurrence and demographic context of different contemporaneous energetic expenditure tactics. Here, we explore this neglected aspect of energy budgeting in order to determine the effect of life-history traits such as age and reproductive status on the co-occurrence of different energy-budgeting tactics in wild populations. Methods We investigated inter-individual heterogeneity in energy expenditure within a wild population of European badgers (Meles meles) by quantifying individual overall dynamic body acceleration (ODBA, from tri-axial accelerometry collars) and total daily energy expenditure (DEE, from doubly-labelled water) during 6–9 day deployments and dosing periods over six different seasons (spring, summer, and autumn) in 2018–2019. We obtained ODBA values for 41 deployments (24 unique badgers) and DEE measurements for 41 dosings (22 unique badgers). We then evaluated correlations between these energetic metrics and computed individual ratios of ODBA/DEE as a proxy for the proportion of total energy spent on activity. We measured the impact of alternative ODBA/DEE ratios on body condition, and use survival models constructed using 29 years of demographic data from the same population to situate body-condition changes in the context of age and reproductive status. Results Both ODBA and DEE were highly variable between individuals and exhibited season-specific relationships with individual body condition and life-history factors. DEE scaled allometrically with body weight, but only in summer and autumn; post-reproductive female badgers were lighter than other badgers during the spring but expended on average 350 kJ/day more than predicted from allometric scaling. Older badgers expended significantly less energy on movement during the summer than did younger adults. The ratio of ODBA to DEE (OD) provides a measure of proportional investment into movement. This ratio correlated more significantly with next-season body condition than either energetic metric did independently. However, the majority of individuals with high OD ratios were either younger badgers or reproductive females, for which lower body condition typically presented less of a mortality risk in previous analyses of this population. Conclusions Within a single population under the same environmental conditions, we found wide inter-individual variation in both mechanical and total energy expenditure. The adoption of different tactics aligns with relationships between life-history parameters and mortality risk previously studied within the population. Crucially, younger badgers and reproductive females appeared able to tolerate energy expenditure tactics that depleted their body condition more than other badgers. These findings provide a mechanism by which differences in individual energetic context set by life history can maintain heterogeneity in wild populations, providing a wide range of potential energetic tactics under changing environmental conditions.

Abstract We present high-quality angle-resolved photoemission (ARPES) and density functional theory calculations (DFT+U) of SmCoIn5. We find broad agreement with previously published studies of LaCoIn5 and CeCoIn5 1,2, confirming that the Sm 4f electrons are mostly localized. Nevertheless, our model is consistent with an additional delocalized Sm component, stemming from hybridization between the 4f electrons and the metallic bands at “hot spot” positions in the Brillouin zone. The dominant hot spot, called γ Z , is similar to a source of delocalized f states found in previous experimental and theoretical studies of CeCoIn5 1,3. In this work, we identify and focus on the role of the Co d states in exploring the relationship between heavy quasiparticles and the magnetic interactions in SmCoIn5, which lead to a magnetically ordered ground state from within an intermediate valence scenario4–6. Specifically, we find a globally flat band consisting of Co d states near E = − 0.7 eV, indicating the possibility of enhanced electronic and magnetic interactions in the “115” family of materials through localization in the Co layer, and we discuss a possible origin in geometric frustration. We also show that the delocalized Sm 4f states can hybridize directly with the Co 3d x z /3d y z orbitals, which occurs in our model at the Brillouin zone boundary point R in a band that is locally flat and touches the Fermi level from above. Our work identifies microscopic ingredients for additional magnetic interactions in the “115” materials beyond the RKKY mechanism, and strongly suggests that the Co d bands are an important ingredient in the formation of both magnetic and superconducting ground states.

Abstract Despite the large public health toll of smoking, genetic studies of smoking cessation have been limited with few discoveries of risk or protective loci. We investigated common and rare variant associations with success in quitting smoking using a cohort from 8 randomized controlled trials involving 2231 participants and a total of 10,020 common and 24,147 rare variants. We identified 14 novel markers including 6 mapping to genes previously related to psychiatric and substance use disorders, 4 of which were protective (CYP2B6 (rs1175607105), HTR3B (rs1413172952; rs1204720503), rs80210037 on chr15), and 2 of which were associated with reduced cessation (PARP15 (rs2173763), SCL18A2 (rs363222)). The others mapped to areas associated with cancer including FOXP1 (rs1288980) and ZEB1 (rs7349). Network analysis identified significant canonical pathways for the serotonin receptor signaling pathway, nicotine and bupropion metabolism, and several related to tumor suppression. Two novel markers (rs6749438; rs6718083) on chr2 are flanked by genes associated with regulation of bodyweight. The identification of novel loci in this study can provide new targets of pharmacotherapy and inform efforts to develop personalized treatments based on genetic profiles.

Abstract CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

Abstract Background Understanding how health trajectories are related to the likelihood of adverse outcomes and healthcare utilization is key to planning effective strategies for improving health span and the delivery of care to older adults. Frailty measures are useful tools for risk stratification in community-based and primary care settings, although their effectiveness in adults younger than 60 is not well described. Methods We performed a 10-year retrospective analysis of secondary data from the Ontario Health Study, which included 161,149 adults aged ≥ 18. Outcomes including all-cause mortality and hospital admissions were obtained through linkage to ICES administrative databases with a median follow-up of 7.1-years. Frailty was characterized using a 30-item frailty index. Results Frailty increased linearly with age and was higher for women at all ages. A 0.1-increase in frailty was significantly associated with mortality (HR = 1.47), the total number of outpatient (IRR = 1.35) and inpatient (IRR = 1.60) admissions over time, and length of stay (IRR = 1.12). However, with exception to length of stay, these estimates differed depending on age and sex. The hazard of death associated with frailty was greater at younger ages, particularly in women. Associations with admissions also decreased with age, similarly between sexes for outpatient visits and more so in men for inpatient. Conclusions These findings suggest that frailty is an important health construct for both younger and older adults. Hence targeted interventions to reduce the impact of frailty before the age of 60 would likely have important economic and social implications in both the short- and long-term.

Background: Glenoid retroversion and humeral head subluxation is a progressive disorder due to abnormal force coupling and increased contact force. In situ placement of anatomic total shoulder arthroplasty (TSA) components in this scenario results in edge loading, progressive subluxation, and early failure. Wedged glenoid components have been demonstrated to improve glenohumeral alignment, but have not been correlated with mid-term clinical outcomes. Methods: Patients undergoing TSA using a wedged all-polyethylene glenoid component for retroverted glenoid deformity were identified from a prospectively maintained database. Preoperative planning computed tomography was routinely performed and compared to postoperative correction on radiographic evaluation. Evidence of loosening was correlated to prospectively collect clinical outcome using patient-reported outcome measures. A matched group of neutrally aligned glenohumeral joints undergoing anatomic TSA was used to compare improvement in clinical outcomes. Results: Over a 5-year period, 17 patients with mean age 60 (range 43-81, standard deviation 10.5) were identified with a mean preoperative neoglenoid retroversion of 16.7° (standard deviation 4.5). At a mean follow-up of 43.8 months (range 27-60), no revision surgeries were undertaken. Improvement in the Oxford Shoulder Score was 18 points (P

Abstract Background Tele-harm reduction (THR) is a telehealth-enhanced, peer-led, harm reduction intervention delivered within a trusted syringe services program (SSP) venue. The primary goal of THR is to facilitate linkage to care and rapid, enduring virologic suppression among people who inject drugs (PWID) with HIV. An SSP in Miami, Florida, developed THR to circumvent pervasive stigma within the traditional healthcare system. Methods During intervention development, we conducted in-depth interviews with PWID with HIV (n = 25) to identify barriers and facilitators to care via THR. We employed a general inductive approach to transcripts guided by iterative readings of the raw data to derive the concepts, themes, and interpretations of the THR intervention. Results Of the 25 PWID interviewed, 15 were in HIV care and adherent to medication; 4 were in HIV care but non-adherent; and 6 were not in care. Themes that emerged from the qualitative analysis included the trust and confidence PWID have with SSP clinicians as opposed to professionals within the traditional healthcare system. Several barriers to treatment were reported among PWID, including perceived and actual discrimination by friends and family, negative internalized behaviors, denial of HIV status, and fear of engaging in care. Facilitators to HIV care included empathy and respect by SSP staff, flexibility of telehealth location, and an overall destigmatizing approach. Conclusion PWID identified barriers and facilitators to receipt of HIV care through the THR intervention. Interviews helped inform THR intervention development, centered on PWID in the destigmatizing environment of an SSP.

Abstract Background A carotid-cavernous fistula is an abnormal communication between the arteries and veins within the cavernous sinus. While conservative management may be prudent in low risk cases, many patients require intervention and endovascular embolization has evolved as the preferred method of treatment. Embolization can be performed via either the transarterial or transvenous approach. One major challenge of the transvenous approach is the complex and variable compartmentation of the cavernous sinus, which often requires the use of low profile microcatheters to navigate and reach the fistulous point. Fibered coils are also preferred when performing transvenous embolization of carotid-cavernous fistula, as they are of higher thrombogenicity and allow for faster occlusion of the fistula. However, most low profile (0.017-inch) microcatheters are not able to deploy fibered coils based on the manufacturer’s instructions. Case presentation We present two successful cases of off-label use of Medtronic Concerto fibered coils via a 0.017-inch microcatheter during transvenous embolization of carotid-cavernous fistula in a 60-year-old and an 80-year-old Chinese female, respectively. Conclusion Our case series highlight the possibility of deploying large diameter (up to 10 mm) Concerto fibered coils through a low profile (0.017-inch) microcatheter in an off-label manner for transvenous embolization of indirect carotid-cavernous fistula.