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This study describes the relationships between different physiological measurements and combinations of critical velocity and performance in elite open-water swimmers. A total of 15 international male open-water swimmers performed a 5 × 200 m front crawl incremental test to estimate maximal aerobic speed (MAS), maximal oxygen consumption (VO2max), the first lactate threshold (VLT1), the second lactate threshold (VLT2), the speed corresponding to 2 mmol/L (V2mmol/L) and to 4 mmol/L (V4mmol/L), and the lactate threshold (VDmax). A 10 km pool trial was also performed to assess swimming performance. Official competition performances in 200, 400, 800, and 1500 m events were collected and were also used to calculate critical velocity (CV) with various combinations of distances. Personal best performances in 1500 m events were 941.76 ± 20.28 s. For the 10 km trial, performance was strongly correlated to VLT1 and moderately to V2mmol/L (r = 0.73 and 0.67, respectively). For the 400, 800, and 1500 m events, strong correlations were observed for V2mmol/L and V4mmol/L. Moderate correlations with these events were also observed for VLT1 and for VDmax (400 and 800 m only). For long-distance swimmers, assessment with a fixed blood lactate value seems to be a good option to estimate swimming performance in distance events. In addition, 10 km performance seems to be more related to the aerobic threshold than the anaerobic threshold.

Abstract Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems.

Background and aims: We aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of statin usage in the UK Biobank, a large prospective population cohort. Methods: Using an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (

The ProteinPaint Hi-C tool (ppHiC) facilitates web-based visualization and collaborative exploration of Hi-C data, a vital resource for understanding three-dimensional genomic structures. ppHiC allows researchers to easily analyze large Hi-C datasets on a web browser without requiring the computational expertise that has heretofore limited access to this complex genomic data. The platform is compatible with multiple Hi-C data versions and boasts a highly customizable interface, including a configuration panel for the precise adjustment of key visualization parameters. The tool’s interactive features offer a broad range of views, from whole-genome landscapes to detailed interactions between pairs of loci, that are accessible within a single, integrated environment. Here, we demonstrate how using ppHiC to visualize an altered chromatin conformational landscape in neuroblastoma can inform understanding of the genomic rearrangements in this cancer.

Abstract Radiopharmaceutical therapy using $$\upalpha$$ α -emitting $$^{225}$$ 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with $$\upalpha$$ α -sensitive detection devices can measure radioactivity distributions at 20–40 $$\upmu {\hbox {m}}$$ μ m resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [225Ac]Ac-Macropa-PEG4-YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [225Ac]Ac-Macropa-PEG4-YS5 were sacrificed at 24 h and 168 h post-injection for quantitative $$\upalpha$$ α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and $$^{213}$$ 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous $$^{225}$$ 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. $$^{225}$$ 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following $$^{225}$$ 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

Abstract Background Ethnicity is known to be an important correlate of health outcomes, particularly during the COVID-19 pandemic, where some ethnic groups were shown to be at higher risk of infection and adverse outcomes. The recording of patients’ ethnic groups in primary care can support research and efforts to achieve equity in service provision and outcomes; however, the coding of ethnicity is known to present complex challenges. We therefore set out to describe ethnicity coding in detail with a view to supporting the use of this data in a wide range of settings, as part of wider efforts to robustly describe and define methods of using administrative data. Methods We describe the completeness and consistency of primary care ethnicity recording in the OpenSAFELY-TPP database, containing linked primary care and hospital records in > 25 million patients in England. We also compared the ethnic breakdown in OpenSAFELY-TPP with that of the 2021 UK census. Results 78.2% of patients registered in OpenSAFELY-TPP on 1 January 2022 had their ethnicity recorded in primary care records, rising to 92.5% when supplemented with hospital data. The completeness of ethnicity recording was higher for women than for men. The rate of primary care ethnicity recording ranged from 77% in the South East of England to 82.2% in the West Midlands. Ethnicity recording rates were higher in patients with chronic or other serious health conditions. For each of the five broad ethnicity groups, primary care recorded ethnicity was within 2.9 percentage points of the population rate as recorded in the 2021 Census for England as a whole. For patients with multiple ethnicity records, 98.7% of the latest recorded ethnicities matched the most frequently coded ethnicity. Patients whose latest recorded ethnicity was categorised as Other were most likely to have a discordant ethnicity recording (32.2%). Conclusions Primary care ethnicity data in OpenSAFELY is present for over three quarters of all patients, and combined with data from other sources can achieve a high level of completeness. The overall distribution of ethnicities across all English OpenSAFELY-TPP practices was similar to the 2021 Census, with some regional variation. This report identifies the best available codelist for use in OpenSAFELY and similar electronic health record data.

Abstract The World Health Organization estimates that air pollution causes approximately seven million premature deaths worldwide each year. Solutions to air pollution are well known, yet this rarely equates to easily actionable. Here we demonstrate how art science collaboration can successfully highlight the issue of air pollution and create wider civic discourse around its amelioration. We document a light painting photographic technique that uses data from calibrated low-cost particulate matter sensors to measure and depict air pollution. We also use a postcard technique to grasp individuals’ sentiments regarding air pollution. The photographs from three countries, Ethiopia, India and United Kingdom, visually highlight the importance of location and occupation upon human exposure. The photographs are used as a proxy to communicate and create dialogues, spaces and places about air pollution. The sentiment analysis shows how this approach can foster awareness and create agency for stakeholders to take actions to tackle air pollution.

Background: Chronic Kidney Disease (CKD), is often detected late due to its asymptomatic nature in the early stage of the disease. Overproduction of reactive oxygen species contributes to various pathological processes through oxidative stress (OS), impacting on cellular structures and functions with previous studies suggesting a link between OS and CKD progression. This study investigated the association between serum peroxiredoxin-4 (Prx4), a biomarker of oxidative stress, and the development of CKD in the general population. Methods: This study featured data from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, involving 5341 participants without CKD at baseline who underwent extensive prospective health evaluations. Serum Prx4 levels were quantified using an immunoluminometric assay. The primary outcome was new-onset CKD as defined by the composite of urinary albumin excretion (UAE) > 30 mg/24-h, an estimated glomerular filtration rate (eGFR)

ABSTRACT Wound infections, exacerbated by the prevalence of antibiotic-resistant bacterial pathogens, necessitate innovative antimicrobial approaches. Polymicrobial infections, often involving Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), present challenges due to biofilm formation and antibiotic resistance. Hypochlorous acid (HOCl), a potent antimicrobial agent, holds promise as an alternative therapy. An electrochemical bandage (e-bandage) that generates HOCl in situ via precise polarization controlled by a miniaturized potentiostat was evaluated for the treatment of murine wound biofilm infections containing both P. aeruginosa with “difficult-to-treat” resistance and MRSA. Previously, HOCl-producing e-bandage was shown to reduce murine wound biofilms containing P. aeruginosa alone. Here, in 5-mm excisional skin wounds containing 48-h biofilms comprising MRSA and P. aeruginosa combined, polarized e-bandage treatment reduced MRSA by 1.1 log10 CFU/g (P = 0.026) vs non-polarized e-bandage treatment (no HOCl production), and 1.4 log10 CFU/g (0.0015) vs Tegaderm only controls; P. aeruginosa was similarly reduced by 1.6 log10 CFU/g (P = 0.0032) and 1.6 log10 CFU/g (P = 0.0015), respectively. For wounds infected with MRSA alone, polarized e-bandage treatment reduced bacterial load by 1.1 log10 CFU/g (P = 0.0048) and 1.3 log10 CFU/g (P = 0.0048) compared with non-polarized e-bandage and Tegaderm only, respectively. The e-bandage treatment did not negatively impact wound healing or cause tissue toxicity. The addition of systemic antibiotics did not enhance the antimicrobial efficacy of e-bandages. This study provides additional evidence for the HOCl-producing e-bandage as a novel antimicrobial strategy for managing wound infections, including in the context of antibiotic resistance and polymicrobial infections.IMPORTANCENew approaches are needed to combat the rise of antimicrobial-resistant infections. The HOCl-producing electrochemical bandage (e-bandage) leverages in situ generation of HOCl, a natural biocide, for broad-spectrum killing of wound pathogens. Unlike traditional therapies that may exhibit limited activity against biofilms and antimicrobial-resistant organisms, the e-bandage offers a potent, standalone solution that does not contribute to further resistance or require adjunctive antibiotic therapy. Here, we show the ability of the e-bandage to address polymicrobial infection by antimicrobial resistant clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa, two commonly isolated, co-infecting wound pathogens. Effectiveness of the HOCl-producing e-bandage in reducing pathogen load while minimizing tissue toxicity and avoiding the need for systemic antibiotics underscores its potential as a tool in managing complex wound infections.

Insects are a main component of a stable ecosystem and influence crop production. Pollinators, in particular, by regulating pollination between flowers, shape and secure plant communities around crop fields. They are also essential for food provisioning by sustaining the pollination of crops. Studies in recent decades have been covering the mixture of effects various factors have on pollinators. However, there is still a gap in understanding how different taxa in pollinator guilds respond to these pressures and how is network structure affected by it. Therefore, here we tried to further uncover the complex relationship between habitat suitability and pollinator biodiversity in an agro-riparian matrix. Using bipartite network analysis and geographical information systems (GIS) in four sites with different land cover configuration, we assessed faunal and floral diversity, land cover differences and network metrics. Hymenoptera were responsible for most of the visits, while also exhibiting higher levels of richness across sites. Lepidoptera on the other hand, were the order less represented. Overall, tillage intensity and Arundo donax were determinant in differences in the number of visits for both orders, with Diptera and Coleoptera being less affected. However, results regarding visitation rates reported tillage’s higher explanatory power, in comparison with A. donax. Intensive sites showed significantly higher levels of nestedness and lower specialization and diversity across taxa. The results suggest that intensive agriculture and exotic species infestation can impact pollinator taxa differently, thus influencing network structure. By scoping network metrics, we can better determine what species are more affected by agricultural expansion, assess ecosystem resilience and consequently, determine appropriate conservation measures to maintain stable plant-pollinator networks.

Objective This study sought to understand the current experiences and subsequent needs of digital maternal health application users based on an interdisciplinary analysis of features currently available in the digital marketplace (including mobile applications and mobile-friendly websites). Methods Following secondary analysis of previously collected interview and focus group data, we used qualitative thematic analysis to observe recurring themes within current maternal health applications and prospective augmentation of related technology for future development. Results Study findings suggested tailored features would best serve the target population, and eleven unique themes comprising additions and improvements to maternal health applications emerged. These included seven major areas: improved mental health support, need for forums and support groups, lack of lactation and breastfeeding support, lack of quality food and nutrition access and product finders, minimal financial literacy information, tailored culturally competent information, and need for localized information and resources. Findings also suggested four main improvements for digital offerings in the current maternal health space: increased emphasis on resources available for postpartum care, importance of minimizing the number of hubs used, need for making information more digestible by ensuring it is written, edited, and provided at appropriate reading levels by more coordinated interaction of words and graphics, and ensuring the trust and credibility of such applications. Conclusions Maternal health applications are improving; however, more features can be added in a localized manner. Additional improvements could be made to current offerings, maximizing the utility of applications, especially in hard-to-reach areas such as maternity care deserts. With the advent of artificial intelligence, developers are poised with the ability to make platforms more focused and tailored for their users.

Behavior-specific praise is an easy-to-implement, teacher-delivered strategy that supports academic engagement while preventing and reducing disruptive behavior. By letting students know what they did, specifically, to meet academic, behavioral, and/or social expectations, students who find teacher attention reinforcing are more likely to engage in the same behavior more often in the future. While teacher-delivered behavior-specific praise was classified as a potentially evidence-based practice using Council for Exceptional Children standards, less is known about the effects of students who deliver behavior-specific praise to their peers. This systematic literature review and meta-analysis explored the literature base and found 36 articles meeting inclusion criteria. Fifteen articles included positive peer reporting as the independent variable, 20 included tootling as the intervention, two compared those interventions, and three used an “other” form of peer praise (i.e., peer praise notes, peer monitor tokens). Nine tootling articles met all eight quality indicators by absolute coding, and 32 out of all 36 studies met an 80% weighted quality indicator coding criterion for being methodologically sound. From these, we classified positive peer reporting in the mixed evidence category and tootling in the evidence-based practice category. We discuss benefits of various components in each type of peer praise intervention, limitations of the literature review, and make recommendations for future researchers.

Abstract Many studies have used mobile device location data to model SARS-CoV-2 dynamics, yet relationships between mobility behavior and endemic respiratory pathogens are less understood. We studied the effects of population mobility on the transmission of 17 endemic viruses and SARS-CoV-2 in Seattle over a 4-year period, 2018-2022. Before 2020, visits to schools and daycares, within-city mixing, and visitor inflow preceded or coincided with seasonal outbreaks of endemic viruses. Pathogen circulation dropped substantially after the initiation of COVID-19 stay-at-home orders in March 2020. During this period, mobility was a positive, leading indicator of transmission of all endemic viruses and lagging and negatively correlated with SARS-CoV-2 activity. Mobility was briefly predictive of SARS-CoV-2 transmission when restrictions relaxed but associations weakened in subsequent waves. The rebound of endemic viruses was heterogeneously timed but exhibited stronger, longer-lasting relationships with mobility than SARS-CoV-2. Overall, mobility is most predictive of respiratory virus transmission during periods of dramatic behavioral change and at the beginning of epidemic waves.

Abstract Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

This study aims to test the validity and reliability of instruments measuring the variable of innovation capacity in the management system of Islamic boarding school education institutions in Jambi City. This research method employed a cross-sectional survey design with a quantitative approach. The sample size for this study consisted of 162 teachers (Ustad/Ustadzah) in Islamic boarding school education institutions. Quantitative data were analyzed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) using SPSS 23 and AMOS 18. The results of this study indicated that EFA identified five factor structures to construct the dimensions of Innovation Capacity (IC), namely Opportunity Exploration (OE), Idea Sustainability (IS), Idea Introduction (II), Idea Emergence (IE), and Idea Realization (IR). Meanwhile, these findings were verified and confirmed by CFA regarding the factorial validity analysis of the Innovation Capacity dimension from the EFA testing results. This study suggests that future innovation capacity instruments require further adjustment to enhance the level of reliability and the ability to explain differences related to the measured constructs within different contexts, cultures, and conditions.

Background: Modern literature has brought into question if wear of tibial inserts made from conventional or highly crosslinked polyethylene (HXL PE) is still a factor limiting longevity of total knee arthroplasty (TKA) in the mid- to long-term. It is the objective of this study to determine: 1) most common causes of mid- to long-term TKA failure, 2) the prevalence of delamination, and 3) the medial/lateral linear wear rates of conventional and HXL PE tibial inserts retrieved in the mid- to long-term. Methods: A tibial insert retrieval cohort of 107 inserts (79 conventional, 28 HXL PE) with a minimum time in situ of 6.5 years (mean 11.7 ± 4) was studied. Failure causes were determined from chart-review, delamination presence was assessed microscopically, and medial/lateral linear wear was determined by minimal thickness changes measured with a dial-indicator. Results: The most common mid-to long-term etiologies for failure were instability (44.9%), PE wear 15%), aseptic loosening (14%), and infection (13.1%). Delamination occurred in 70% of inserts (72.1% conventional, 64.3% HXLPE). Gross material loss due to delamination appeared to be the underlying reason for at least 33.3% of cases exhibiting instability. Of the cases removed for infection, 75% exhibited no histopathological hallmarks of acute infection. The medial/lateral wear rates were 0.054/0.051 (conventional) and 0.014/0.011 (HXL) mm/y, respectively. Conclusions: Polyethylene wear still appears to be a major primary and secondary cause for TKA revision in the mid- to long-term. Wear may manifest as destabilizing delamination or as continuous release of fine wear particles potentially resulting in inflammatory responses and subsequent failure.

ABSTRACTSeveral cellular factors have been reported to be required for replication of classical swine fever virus (CSFV), a member of the genus Pestivirus within the family Flaviviridae. However, many steps of its replication cycle are still poorly understood. The low-density lipoprotein receptor (LDLR) is involved in cell entry and post-entry processes of different viruses including other members of the Flaviviridae. In this study, the relevance of LDLR in replication of CSFV and another porcine pestivirus, Bungowannah pestivirus (BuPV), was investigated by antibody-mediated blocking of LDLR and genetically engineered porcine cell lines providing altered LDLR expression levels. An LDLR-specific antibody largely blocked infection with CSFV, but had only a minor impact on BuPV. Infections of the genetically modified cells confirmed an LDLR-dependent replication of CSFV. Compared to wild type cells, lower and higher expression of LDLR resulted in a 3.5-fold decrease or increase in viral titers already 20 h post infection. Viral titers were 25-fold increased in LDLR-overexpressing cells compared to cells with reduced LDLR expression at 72 h post infection. The varying LDLR expression levels had no clear effect on permissivity to BuPV. A decoy receptor assay using recombinant soluble LDLR provided no evidence that LDLR may function as a receptor for CSFV or BuPV. Differences in their dependency on LDLR suggest that CSFV and BuPV likely use different mechanisms to interact with their host cells. Moreover, this study reveals similarities in the replication cycles of CSFV and other members of the family Flaviviridae that are dependent on LDLR.

ABSTRACTThere is a need for operational decision-making methodologies applicable at local management scales which are inclusive and enable the integration of plural values, knowledges and perspectives of co-produced ecosystem services. Here we describe a deliberative scenario analysis method using ‘management intervention bundles’ as distinct scenarios to assess the perceived impact of changing management on woodland ecosystem services. We used three hypothetical future management scenarios, Biodiversity Conservation, People Engagement and Austerity, alongside scenarios of the Past, Present and an existing Management Plan. We assessed the perceived impacts of these scenarios on 11 ecosystem services using local expert workshops in six sites across Scotland. The experts were chosen to represent a range of different perspectives, from biodiversity to the local economy, community concerns and recreation. Overall, Management Plan, Biodiversity Conservation and People Engagement scenarios performed significantly better than Past, Present and Austerity scenarios. Further quantitative and in-depth qualitative analysis revealed trade-offs and noteworthy patterns. We explore some of these key trade-offs and patterns and argue that our methodology has potential to be an effective tool for local managers to support local decision-making at management scales for co-produced ecosystem services. Our methodology enabled a diverse group of local experts to express and deliberate a range of values, experiences and viewpoints. This knowledge sharing and collective learning allowed the development of shared values and perspectives, which are thought to be critical in more equitable and inclusive decision-making.

ABSTRACT Over 2.5 million prosthetic joint implantation surgeries occur annually in the United States. Periprosthetic joint infections (PJIs), though occurring in only 1–2% of patients receiving replacement joints, are challenging to diagnose and treat and are associated with significant morbidity. The Gram-positive bacterium Enterococcus faecalis, which can be highly antibiotic-resistant and is a robust biofilm producer on indwelling medical devices, accounts for 2–11% of PJIs. E. faecalis PJIs are understudied compared to those caused by other pathogens, such as Staphylococcus aureus. This motivates the need to generate a comprehensive understanding of E. faecalis PJIs to guide future treatments for these infections. To address this, we describe a panel of E. faecalis strains isolated from the surface of prosthetic joints in a cohort of individuals treated at the Mayo Clinic in Rochester, MN. Here, we present the first complete genome assemblage of E. faecalis PJI isolates. Comparative genomics shows differences in genome size, virulence factors, antimicrobial resistance genes, plasmids, and prophages, underscoring the genetic diversity of these strains. These isolates have strain-specific differences in in vitro biofilm biomass, biofilm burden, and biofilm morphology. We measured robust changes in biofilm architecture and aggregation for all isolates when grown in simulated synovial fluid (SSF). Finally, we evaluated the antibiotic efficacy of these isolates and found strain-specific changes across all strains when grown in SSF. Results of this study highlight the existence of genetic and phenotypic heterogeneity among E. faecalis PJI isolates which will provide valuable insight and resources for future E. faecalis PJI research.IMPORTANCEPeriprosthetic joint infections (PJIs) affect ~1–2% of those who undergo joint replacement surgery. Enterococcus faecalis is a Gram-positive opportunistic pathogen that causes ~10% of PJIs in the United States each year, but our understanding of how and why E. faecalis causes PJIs is limited. E. faecalis infections are typically biofilm-associated and can be difficult to clear with antibiotic therapy. Here, we provide complete genomes for four E. faecalis PJI isolates from the Mayo Clinic. These isolates have strain-specific differences in biofilm formation, aggregation, and antibiotic susceptibility in simulated synovial fluid. These results provide important insight into the genomic and phenotypic features of E. faecalis isolates from PJI.

Phage therapy is a promising antibacterial strategy, especially given that drug-resistant bacterial infections are escalating worldwide. Because phages are not active against all strains of a given species, phages being considered for therapeutic use would ideally be tested against bacterial isolates from individual patients prior to administration. Standardized, clinically validated phage susceptibility testing (PST) methods are needed for assessing in vitro phage activity. This study compared two high-throughput liquid-based PST assays. The first, using the Biolog Omnilog™, assessed changes in microbial respiration leading to color changes based on a tetrazolium dye. The second, Agilent BioTek Cytation 7, assessed changes in optical density. Both used 96-well microtiter plate formats. A total of 55 diverse phages with activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, or Enterococcus faecalis were studied against their respective susceptible bacterial hosts and non-susceptible controls, with susceptibility defined based on plaque assay. PST was performed by both assays in replicates, with results compared in terms of hold times (time through which bacterial growth is inhibited by phage compared to controls). Coefficients of variance and interclass correlation coefficients were used to assess inter- and intra-assay reproducibility. Based on a ≤50% coefficient of variance cutpoint, 87% of Biolog and 84% of Agilent assays were considered valid for susceptible bacteria, with 100% considered valid for non-susceptible bacteria by both systems. Using a 8 h hold time cutpoint, 100% of the results matched between the two assays. The interclass correlation coefficient showed 26% excellent agreement, 35% good agreement, and 17% moderate agreement between the two assays for susceptible isolates and 100% excellent agreement for non-susceptible isolates. Overall, the assays compared provided good/fair statistical reproducibility for the assessment of phage susceptibility.

Abstract INTRODUCTION This study investigates the relationship between cognitive functioning and 59 modifiable and intrinsic factors at the cusp of midlife. METHODS We analyzed data from 1221 participants in the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife; Mage = 33.20, %Female = 52.74). We assessed the impact of 59 factors on cognitive functioning using regularized regression and co‐twin control models, controlling for earlier‐life cognitive functioning and gray matter volume. RESULTS Eight robust factors were identified, including education attainment, cognitive complexity, purpose‐in‐life, and smoking status. Twins reporting higher levels of cognitive complexity and purpose‐in‐life showed better cognitive performance than their cotwin, while smoking was negatively associated. Using meta‐analytically derived effect size threshold, we additionally identified that twins experiencing more financial difficulty tend to perform less well compared with their cotwin. DISCUSSION The findings highlight the early midlife link between cognitive functioning and lifestyle/psychological factors, beyond prior cognitive performance, brain status, genetic and familial confounders. Our results further highlight the potential of established adulthood as a crucial window for dementia prevention interventions targeting lifestyle and psychosocial factors. Highlights Cog complexity(+), purpose‐in‐life(+) were associated with cognition in early midlife. Smoking(−) was also associated with cognition in early midlife. Results were consistent controlling for genetic and environmental confounds. Association between EA and cognition might be mostly genetic and familial confounded.

Abstract INTRODUCTION Commercially available plasma p‐tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS We evaluated associations between ALZPath plasma p‐tau217 and amyloid‐beta positron emission tomography (Aβ‐PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non‐Hispanic/Latino older adults. One‐ and two‐cutoff ranges were derived and evaluated to assess agreement with Aβ‐PET. RESULTS A total of 239 participants underwent blood draw and Aβ‐PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p‐tau217 showed excellent discrimination of Aβ‐PET positive and negative participants (visual read: AUC = 0.91 [0.87–0.95], p

The recent imperative by the National Institutes of Health to share scientific data publicly underscores a significant shift in academic research. Effective as of January 2023, it emphasizes that transparency in data collection and dedicated efforts towards data sharing are prerequisites for translational research, from the lab to the bedside. Given the role of data access in mitigating potential bias in clinical models, we hypothesize that researchers who leverage open-access datasets rather than privately-owned ones are more diverse. In this brief report, we proposed to test this hypothesis in the transdisciplinary and expanding field of artificial intelligence (AI) for critical care. Specifically, we compared the diversity among authors of publications leveraging open datasets, such as the commonly used MIMIC and eICU databases, with that among authors of publications relying exclusively on private datasets, unavailable to other research investigators (e.g., electronic health records from ICU patients accessible only to Mayo Clinic analysts). To measure the extent of author diversity, we characterized gender balance as well as the presence of researchers from low- and middle-income countries (LMIC) and minority-serving institutions (MSI) located in the United States (US). Our comparative analysis revealed a greater contribution of authors from LMICs and MSIs among researchers leveraging open critical care datasets (treatment group) than among those relying exclusively on private data resources (control group). The participation of women was similar between the two groups, albeit slightly larger in the former. Notably, although over 70% of all articles included at least one author inferred to be a woman, less than 25% had a woman as a first or last author. Importantly, we found that the proportion of authors from LMICs was substantially higher in the treatment than in the control group (10.1% vs. 6.2%, p

Objective: There is little research available regarding the instructional practices of librarians who support students completing knowledge synthesis projects. This study addresses this research gap by identifying the topics taught, approaches, and resources that academic health sciences librarians employ when teaching students how to conduct comprehensive searches for knowledge synthesis projects in group settings. Methods: This study applies an exploratory-descriptive design using online survey data collection. The final survey instrument included 31 open, closed, and frequency-style questions. Results: The survey received responses from 114 participants, 74 of whom met the target population. Some key results include shared motivations to teach in groups, including student learning and curriculum requirements, as well as popular types of instruction such as single session seminars, and teaching techniques, such as lectures and live demos. Conclusion: This research demonstrates the scope and coverage of librarian-led training in the knowledge synthesis research landscape. Although searching related topics such as Boolean logic were the most frequent, librarians report teaching throughout the review process like methods and reporting. Live demos and lectures were the most reported approaches to teaching, whereas gamification or student-driven learning were used rarely. Our results suggest that librarian’s application of formal pedagogical approaches while teaching knowledge synthesis may be under-utilized, as most respondents did not report using any formal instructional framework.

Marine coastal habitats are often characterized by strong gradients of anthropogenic disturbance such as pollution, typically most severe at urban waterfronts. These variations create stress for local organisms leading to their distribution along the disturbance as a function of their tolerance. non-indigenous species (NIS) are considered more tolerant to anthropogenic disturbances than their native counterparts, thriving in urban areas, where native species are sparser. It is however not yet entirely clear if these distribution patterns are due to larval behavior and preferential settlement or post-settlement processes. In the present study, we investigated the abundance of adults and settlers of two native (Ostrea edulis, Mytilus galloprovincialis) and two non-indigenous (Magallana gigas, Xenostrobus securis) bivalves along a strong marine urban environmental gradient. Oysters had sparse abundances of both adults and settlers at all sites, with no obvious distributional gradients. The two mussel species showed different settler-adult distributions along the gradient. Both settlers and adults of the native mussel M. galloprovincialis strongly decreased moving from the outermost periurban site to the innermost urban site, consistent with preferential settlement of larvae according to environmental conditions. The non-indigenous adult mussel X. securis showed a distribution pattern opposite to that of M. galloprovincialis, markedly increasing in abundance from the outermost to the innermost site. This was not paralleled by the distribution of X. securis settlers, which established over a larger area, including sites where adults were essentially absent. The mismatch between settler and adult distributions for X. securis suggests that post-settlement factors dictate spatial adult distribution.

Coronary artery disease is caused by the buildup of atherosclerotic plaque in the coronary arteries, affecting the blood supply to the heart, one of the leading causes of death around the world. X-ray coronary angiography is the most common procedure for diagnosing coronary artery disease, which uses contrast material and x-rays to observe vascular lesions. With this type of procedure, blood flow in coronary arteries is viewed in real-time, making it possible to detect stenoses precisely and control percutaneous coronary interventions and stent insertions. Angiograms of coronary arteries are used to plan the necessary revascularisation procedures based on the calculation of occlusions and the affected segments. However, their interpretation in cardiac catheterisation laboratories presently relies on sequentially evaluating multiple 2D image projections, which limits measuring lesion severity, identifying the true shape of vessels, and analysing quantitative data. In silico modelling, which involves computational simulations of patient-specific data, can revolutionise interventional cardiology by providing valuable insights and optimising treatment methods. This paper explores the challenges and future directions associated with applying patient-specific in silico models in catheterisation laboratories. We discuss the implications of the lack of patient-specific in silico models and how their absence hinders the ability to accurately predict and assess the behaviour of individual patients during interventional procedures. Then, we introduce the different components of a typical patient-specific in silico model and explore the potential future directions to bridge this gap and promote the development and utilisation of patient-specific in silico models in the catheterisation laboratories.

Summary: Background: Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe the incidence and differences in demographic and clinical characteristics in recorded long COVID in primary care records in England. Methods: With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. Using OpenSAFELY, we calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and adjusted (for age, sex, 9 NHS regions of England, and the dominant variant circulating) rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models. Findings: We identified a total of 55,465 people recorded to have long COVID over the study period, which included 20,025 diagnoses codes and 35,440 codes for further assessment. The incidence of new long COVID records increased steadily over 2021, and declined over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5–179) and 100.5 in men (99.5–102). The majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 or more weeks before the long COVID record. Interpretation: In this descriptive study, EHR recorded long COVID was very low between 2020 and 2023, and incident records of long COVID declined over 2022. Using EHR diagnostic or referral codes unfortunately has major limitations in identifying and ascertaining true cases and timing of long COVID. Funding: This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073).

Staphylococcus epidermidis is part of the commensal microbiota of the skin and mucous membranes, though it can also act as a pathogen in certain scenarios, causing a range of infections, including periprosthetic joint infection (PJI). Transcriptomic profiling may provide insights into mechanisms by which S. epidermidis adapts while in a pathogenic compared to a commensal state. Here, a total RNA-sequencing approach was used to profile and compare the transcriptomes of 19 paired PJI-associated S. epidermidis samples from an in vivo clinical source and grown in in vitro laboratory culture. Genomic comparison of PJI-associated and publicly available commensal-state isolates were also compared. Of the 1919 total transcripts found, 145 were from differentially expressed genes (DEGs) when comparing in vivo or in vitro samples. Forty-two transcripts were upregulated and 103 downregulated in in vivo samples. Of note, metal sequestration-associated genes, specifically those related to staphylopine activity (cntA, cntK, cntL, and cntM), were upregulated in a subset of clinical in vivo compared to laboratory grown in vitro samples. About 70% of the total transcripts and almost 50% of the DEGs identified have not yet been annotated. There were no significant genomic differences between known commensal and PJI-associated S. epidermidis isolates, suggesting that differential genomics may not play a role in S. epidermidis pathogenicity. In conclusion, this study provides insights into phenotypic alterations employed by S epidermidis to adapt to infective and non-infected microenvironments, potentially informing future therapeutic targets for related infections.

Background: Late effects of cancer treatment, such as neurocognitive deficits and fatigue, can be debilitating. Other than head and neck–specific functional deficits such as impairments in swallowing and speech, little is known about survivorship after oropharyngeal cancer. This study examines the lived experience of fatigue and neurocognitive deficits in survivors of oropharyngeal squamous cell cancer and impact on their daily lives. Methods: This work is part of the multicentre mixed method ROC-oN study (Radiotherapy for Oropharyngeal Cancer and impact on Neurocognition), evaluating fatigue and neurocognitive function in patients following radiotherapy +/- chemotherapy for oropharyngeal cancer and impact on quality of life. Semi-structured interviews were conducted in adults treated with radiotherapy (+/-chemotherapy) for oropharyngeal squamous cell carcinoma >/=24 months from completing treatment. Reflexive thematic analysis performed. Results: 21 interviews (11 men and 10 women; median age 58 years and median time post-treatment 5 years) were conducted and analysed, yielding six themes: (1) unexpected burden of fatigue, (2) noticing changes in neurocognitive function, (3) the new normal, (4) navigating changes, (5)insufficient awareness and (6)required support. Participants described fatigue that persisted beyond the acute post-treatment period and changes in neurocognitive abilities across several domains. Paid and unpaid work, emotions and mood were impacted. Participants described navigating the new normal by adopting self-management strategies and accepting external support. They reported lack of recognition of these late effects, being poorly informed and being unprepared. Follow-up services were thought to be inadequate. Conclusions: Fatigue and neurocognitive impairment were frequently experienced by survivors of oropharyngeal cancer, at least two years after treatment. Patients felt ill-prepared for these late sequelae, highlighting opportunities for improvement of patient information and support services.

Abstract Spontaneous pneumomediastinum (SPM) is a rare condition in children and young adults that raises concern for esophageal perforation or extension of an air leak, resulting in admissions with multiple interventions performed. To assess our outcomes, and to evaluate our resource utilization, we reviewed our experience with SPM. We conducted a retrospective review of SPM cases in patients aged 5–25 years old occurring between 2011 and 2021 at a single academic tertiary care center. Clinical, demographic, and outcome variables were collected and analyzed, and cohorts were compared using Fischer’s Exact Test and Welch’s T Test. 166 SPM cases were identified—all of which were Emergency Department (ED) presentations. 84% of the cases were admitted. 70% had Computerized Tomography (CT) scans, with no defined criteria for imaging. Comparison of floor admissions with discharges from the ED showed no significant difference in presenting symptoms, demographics, or outcomes between the two groups. Recurrence was noted in 4 patients with a range of 5.9 months–4.9 years from the initial episode. In the largest SPM study in the pediatric and young adult population, we noted no significant difference in management or outcomes in admitted or ED discharge patients nor those with CT imaging. Our results suggest that a large number of SPM can be managed safely with discharge from the ED.

Abstract CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Abstract The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal’s adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

The present study was undertaken to evaluate the prevalence, underlying resistance mechanism, and virulence involved in Pseudomonas aeruginosa (n = 35) isolated from freshwater fishes in Andhra Pradesh, India. Antibiogram studies revealed that 68.5, 62.8, 37.1, 11.4, 8.5, 57.1, 54.2, and 48.5% of isolates had resistance to oxytetracycline, co-trimoxazole, doxycycline, enrofloxacin, ciprofloxacin, cefotaxime, ceftazidime, and ampicillin, respectively. The resistant isolates harboured the tetA (85.7%), tetD (71.4%), tetM (91.4%), sul1 (80%), blaCTX-M (57.1%), blaTEM (42.8%), and blaSHV (48.5%) genes. In total, 50% of the isolates were altered as multi-drug resistant, and the multiple antibiotic resistance index was calculated as 0.4. Furthermore, 37.3, 48.5, and 14.2% of isolates were categorized as strong, moderate, and weak biofilm formers, possessing pslA (91.5%) and pslD (88.6%) biofilm encoding genes. In total, 82.8% of the isolates exhibited efflux pump activity and harboured the mexA (74.2%), mexB (77.1%), and oprM (37.1%) genes. Virulent genes oprL, toxA, exoS, and phzM were detected in 68.5, 68.5, 100, and 17.1% of isolates, respectively. The data suggested that P. aeruginosa harbours multiple resistance mechanisms and virulence factors that may contribute to antibiotic resistance and pathogenicity, and their distribution in fish culture facilities highlights the public health hazards of the food chain. HIGHLIGHTS Multi-drug-resistant P. aeruginosa strains were identified and characterized from freshwater fishes in Andhra Pradesh, India.; Improper farm management and disease outbreaks are the major risk factors associated with antimicrobial use.; Different antibiotic resistance mechanisms and virulence gene determinants were identified using the polymerase chain reaction.;

Background: Low computed tomography (CT)-determined muscle mass, commonly determined with height-adjusted muscle indexes (MIs), predicts worse survival in several cancers and has been suggested as a prognostic assessment tool. Although several MIs measured at the level of the 3rd lumbar vertebra (L3) are commonly used, it remains unestablished how different L3-determined MIs perform in survival prognostication compared to each other. The objective of this study was to investigate the performance of different MIs for survival prognostication in renal cell carcinoma (RCC). Methods: We retrospectively enrolled 214 consecutive patients with RCC. We determined three L3-MIs (psoas muscle index (PMI), psoas muscle index and erector spinae index (PMI+ESI), and whole skeletal muscle index (SMI)) from preoperative CT scans. Categorization of those with low and normal muscle mass was based on the Youden Index sex-specific MI cut-offs. We determined sensitivity, specificity, and accuracy metrics for predicting 1-year, 5-year, and overall survival (OS) using Cox regression models. Results: Low PMI, PMI+ESI, and SMI significantly predicted decreased 1-year, 5-year, and OS in uni- and multivariate models. PMI+ESI and SMI were more accurate than PMI in males, and PMI and PMI+ESI were more accurate than SMI in females in the prediction of 1-year survival. However, there were no differences in accuracies between MIs in 5-year and OS prediction. Interpretation: PMI+ESI performed well overall in short-term prognostication, but there were no differences between the MIs in long-term prognostication. We recommend the use of PMI+ESI for muscle evaluation, particularly when SMI cannot be evaluated.

Summary: Background: Long COVID is a major problem affecting patient health, the health service, and the workforce. To optimise the design of future interventions against COVID-19, and to better plan and allocate health resources, it is critical to quantify the health and economic burden of this novel condition. We aimed to evaluate and estimate the differences in health impacts of long COVID across sociodemographic categories and quantify this in Quality-Adjusted Life-Years (QALYs), widely used measures across health systems. Methods: With the approval of NHS England, we utilised OpenPROMPT, a UK cohort study measuring the impact of long COVID on health-related quality-of-life (HRQoL). OpenPROMPT invited responses to Patient Reported Outcome Measures (PROMs) using a smartphone application and recruited between November 2022 and October 2023. We used the validated EuroQol EQ-5D questionnaire with the UK Value Set to develop disutility scores (1-utility) for respondents with and without Long COVID using linear mixed models, and we calculated subsequent Quality-Adjusted Life-Months (QALMs) for long COVID. Findings: The total OpenPROMPT cohort consisted of 7575 individuals who consented to data collection, with which we used data from 6070 participants who completed a baseline research questionnaire where 24.6% self-reported long COVID. In multivariable regressions, long COVID had a consistent impact on HRQoL, showing a higher likelihood or odds of reporting loss in quality-of-life (Odds Ratio (OR): 4.7, 95% CI: 3.72–5.93) compared with people who did not report long COVID. Reporting a disability was the largest predictor of losses of HRQoL (OR: 17.7, 95% CI: 10.37–30.33) across survey responses. Self-reported long COVID was associated with an 0.37 QALM loss. Interpretation: We found substantial impacts on quality-of-life due to long COVID, representing a major burden on patients and the health service. We highlight the need for continued support and research for long COVID, as HRQoL scores compared unfavourably to patients with conditions such as multiple sclerosis, heart failure, and renal disease. Funding: This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073).

Background Pharmacological prophylaxis during hospital admission can reduce the risk of acquired blood clots (venous thromboembolism) but may cause complications, such as bleeding. Using a risk assessment model to predict the risk of blood clots could facilitate selection of patients for prophylaxis and optimise the balance of benefits, risks and costs. Objectives We aimed to identify validated risk assessment models and estimate their prognostic accuracy, evaluate the cost-effectiveness of different strategies for selecting hospitalised patients for prophylaxis, assess the feasibility of using efficient research methods and estimate key parameters for future research. Design We undertook a systematic review, decision-analytic modelling and observational cohort study conducted in accordance with Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines. Setting NHS hospitals, with primary data collection at four sites. Participants Medical and surgical hospital inpatients, excluding paediatric, critical care and pregnancy-related admissions. Interventions Prophylaxis for all patients, none and according to selected risk assessment models. Main outcome measures Model accuracy for predicting blood clots, lifetime costs and quality-adjusted life-years associated with alternative strategies, accuracy of efficient methods for identifying key outcomes and proportion of inpatients recommended prophylaxis using different models. Results We identified 24 validated risk assessment models, but low-quality heterogeneous data suggested weak accuracy for prediction of blood clots and generally high risk of bias in all studies. Decision-analytic modelling showed that pharmacological prophylaxis for all eligible is generally more cost-effective than model-based strategies for both medical and surgical inpatients, when valuing a quality-adjusted life-year at £20,000. The findings were more sensitive to uncertainties in the surgical population; strategies using risk assessment models were more cost-effective if the model was assumed to have a very high sensitivity, or the long-term risks of post-thrombotic complications were lower. Efficient methods using routine data did not accurately identify blood clots or bleeding events and several pre-specified feasibility criteria were not met. Theoretical prophylaxis rates across an inpatient cohort based on existing risk assessment models ranged from 13% to 91%. Limitations Existing studies may underestimate the accuracy of risk assessment models, leading to underestimation of their cost-effectiveness. The cost-effectiveness findings do not apply to patients with an increased risk of bleeding. Mechanical thromboprophylaxis options were excluded from the modelling. Primary data collection was predominately retrospective, risking case ascertainment bias. Conclusions Thromboprophylaxis for all patients appears to be generally more cost-effective than using a risk assessment model, in hospitalised patients at low risk of bleeding. To be cost-effective, any risk assessment model would need to be highly sensitive. Current evidence on risk assessment models is at high risk of bias and our findings should be interpreted in this context. We were unable to demonstrate the feasibility of using efficient methods to accurately detect relevant outcomes for future research. Future work Further research should evaluate routine prophylaxis strategies for all eligible hospitalised patients. Models that could accurately identify individuals at very low risk of blood clots (who could discontinue prophylaxis) warrant further evaluation. Study registration This study is registered as PROSPERO CRD42020165778 and Researchregistry5216. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and will be published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information. Plain language summary People who are admitted to hospital are at risk of blood clots that can cause serious illness or death. Patients are often given low doses of blood-thinning drugs to reduce this risk. However, these drugs can cause side effects, such as bleeding. Hospitals currently use complex risk assessment models (risk scores, which usually include patient, disease, mobility and intervention factors) to determine the individual risk of blood clots and identify people most likely to benefit from blood-thinning drugs. There are a lot of different risk scores and we do not know which one is best. We also do not know how these scores compare to each other or whether using scores to decide who should get blood-thinning drugs provides good value for money to the NHS. We reviewed all previous studies of risk scores. We found that they did not predict blood clots very well and we could not recommend one score over another. We then created a mathematical model to simulate the use of blood-thinning drugs in people admitted to hospital. The model suggested that giving blood-thinning drugs to everyone who could have them would probably provide the best value for money, in medical patients. Our findings were the same, but less certain, for surgical patients. We also collected information from four NHS hospitals to explore possibilities for future research. Our work showed that routinely collected electronic data on blood clots and bleeding events is not very accurate and that using different scores could result in variable use of blood-thinning medications. Our findings suggest that it may be better value to the NHS and better for patients if we were to offer blood-thinning medications to everyone on admission to hospital, without using any risk score. However, this approach needs further research to ensure it is safe and effective. Such research would not be able to rely on routine electronic data to identify blood clots or bleeding events, in isolation. Scientific summary Background Venous thromboembolism (VTE) is a composite diagnosis including deep-vein thrombosis (DVT) and pulmonary embolism (PE). The condition is a global health burden, affecting over 1:1000 adults worldwide, every year. Previous epidemiological studies have shown more than half of all VTE events to be hospital-associated (or acquired) thrombosis (HAT), occurring during admission or within 90 days of discharge. Current evidence suggests that many HAT events are potentially preventable. Pharmacological prophylaxis in medical and surgical inpatients has been shown to be clinically effective in several large studies and meta-analyses. However, although prophylaxis reduces the risk of VTE for hospital inpatients, it also incurs costs and potentially increases the risk of bleeding. As such, international guidelines recommend a process of individualised VTE risk assessment at the point of hospital admission. Several risk assessment models (RAMs) have been developed to aid this process. The accuracy and cost-effectiveness of these models are uncertain. Further prospective studies in this area are challenging due to national guidance, contract standards and high rates of routine prescribing (> 70%). We sought to assess the clinical and cost-effectiveness of VTE RAMs through secondary research methods, by conducting a systematic review of RAM accuracy and subsequent decision-analytic modelling. In addition, we sought to evaluate the accuracy of routine data sources to identify core VTE and bleeding outcomes and estimate key clinical parameters for any future implementation study. Objectives The prespecified and combined project objectives were as follows: Update existing systematic reviews to identify VTE RAMs for hospital inpatients and determine their comparative accuracy for predicting the risk of VTE. Undertake decision-analytic modelling to determine the cost-effectiveness of pharmacological prophylaxis guided by a RAM, compared to prophylaxis for all and prophylaxis for none. Use the decision-analytic model to identify key areas of uncertainty and determine the value of gathering additional information to reduce uncertainty. Pilot the use and evaluate the accuracy of efficient methods to measure core clinical VTE and bleeding outcomes. Estimate key parameters for planning a future implementation study. Methods Workstream 1 used a systematic review and economic analysis to address objectives 1, 2 and 3. We extended and updated overlapping systematic reviews of available RAMs, performed quality assessment of relevant studies and synthesised performance measures (e.g. sensitivity, specificity and concordance (C) statistics) to evaluate the prognostic accuracy of individual RAMs. We subsequently used this information to inform decision-analytic modelling. The target population for the conceptual model was hospital inpatients, including medical, surgical and trauma patients but excluding critical care patients, children and women admitted to hospital for pregnancy-related reasons. Patients at increased risk of bleeding were assumed not to receive pharmacological prophylaxis under any strategy and were excluded from the model. We compared strategies of using no pharmacological prophylaxis, pharmacological prophylaxis for all and pharmacological prophylaxis given in accordance with validated RAMs. The use of mechanical prophylaxis was considered out of scope for the modelling. We used a lifetime horizon and reported primary outcomes of costs and quality-adjusted life-years (QALYs). Multiple scenario and sensitivity analyses were conducted by subgroup. Workstream two used primary research to address objectives four and five. We conducted a multicentre observational cohort study across four hospitals to compare prespecified methods of efficient data collection to formal case note review. We identified a target population hospitalised during 2019 and extracted data from prospectively completed VTE risk assessments, when available. Research assistants undertook further retrospective case note review for each patient episode. We used electronic health records to evaluate additional risk characteristics and record all relevant clinical outcomes, including the subsequent diagnosis of HAT, major bleeding and clinically relevant non-major bleeding events. We then collated multiple routine data sources for each patient episode to determine the accuracy of these methods in identifying relevant clinical outcomes, compared to a gold standard of case note review. The primary outcome measures for workstream two were contingency tables with sensitivity, specificity and predictive values. Feasibility criteria for any future study using efficient data methods were set a priori. We also estimated the potential variation in prescribing recommendations using multiple validated RAMs and estimated key parameters for any future implementation study. The Venous ThromboEmbolism Assessment Methods study received a favourable opinion from the Proportionate Review Sub-committee of the London – West London & Gene Therapy Advisory Committee (GTAC) Research Ethics Committee and approval from the Health Research Authority (HRA) and Care Research Wales (HCRW) on 18 September 2019 (reference 19/LO/1303, IRAS project ID 262220). Results Workstream 1 Our updated systematic review included 51 studies, comprising 24 unique validated RAMs. The vast majority of studies evaluated VTE RAMs in medical (n = 21), surgical (n = 15) or mixed (n = 4) cohorts of hospital inpatients. The most widely evaluated models were the Caprini RAM (22 studies), the Padua prediction score (16 studies), the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) models (8 studies), the Geneva Risk Score (4 studies) and the Kucher Score (4 studies). All studies had a high or unclear risk of bias, with the main issues related to patient selection, outcome and analysis factors. C-statistics varied markedly between these studies and between models, with no RAM performing obviously better than other models. Similarly, estimates for sensitivity and specificity were highly variable. In the decision analytic modelling, we estimate that in medical inpatients, prophylaxis reduces serious adverse outcomes [fatal PEs, fatal bleeding and non-fatal intracranial haemorrhage (ICH)] from 53 per 10,000 to 42 per 10,000, with a reduction in symptomatic DVTs and non-fatal PEs that is higher than the increase in other bleeds. In the long-term outcomes at 5 years, there is a large reduction in the number of patients experiencing post-thrombotic syndrome (PTS) following prophylaxis from 787 per 10,000 to 385 per 10,000, but minimal difference in overall survival. Modelling showed that thromboprophylaxis for all has a high probability (> 99%) of being the most cost-effective strategy (£20,000 per QALY threshold) based on the performance of existing RAMs in cohorts of medical inpatients. This finding was generally robust under the scenario and sensitivity analyses with one exception; targeting thromboprophylaxis using a Padua score ≥ 3 (84% of cohort) had a 76.6% probability of being the most cost-effective strategy when assuming higher RAM performance (sensitivity 99.9%; specificity 23.7%). The overall expected value of perfect information (EVPI) associated with all parameters included in the probabilistic sensitivity analysis (PSA) when valuing a QALY at £20,000 was £0.06 per patient per year due to the high probability that prophylaxis for all is the optimal strategy. However, the EVPI would be £2.42 per person per year if a more accurate RAM could be developed for medical inpatients. In surgical inpatients, the risk of a serious adverse outcome (as above) is low at 7 per 10,000 but it is increased slightly by prophylaxis to 11 per 10,000 due to the additional risk of fatal bleeding or non-fatal ICH. Although the risk of any symptomatic VTE is reduced form 140 per 10,000 to 41 per 10,000, the risk of any major bleeding is increased from 125 per 10,000 to 370 per 10,000. Prophylaxis still reduces the risk of PTS in surgical inpatients, from 367 per 10,000 to 107 per 10,000, but PTS is less common in the surgical cohort than in the medical cohort. Modelling showed that giving prophylaxis to all surgical inpatients has the highest probability of being cost-effective at £20,000 per QALY, with a 70% likelihood of being optimal, but there is also a 17% likelihood that using a Pannucci score of ≥ 3 would be optimal and a 9% likelihood that using a Pannucci score of ≥ 1 would be optimal. These findings were sensitive to some uncertainties explored in the scenario and sensitivity analyses. In particular, prophylaxis for all may no longer be the optimal strategy for surgical inpatients when the risk of PTS is lower, when using an extended duration of prophylaxis or where a RAM is assumed to have a very high sensitivity. The overall EVPI associated with all parameters included in the PSA when valuing a QALY at £20,000 was £16.35 per person. This does not include the uncertainty of considering which RAM to use as the EVPI and does not include any uncertainty not captured in the PSA, such as uncertainty around the model assumptions or the choice of data sources, or uncertainty around the estimates of sensitivity and specificity. In the analysis of parameter EVPI [expected value of partial perfect information (EVPPI)], the relative risk of VTE for patients having thromboprophylaxis compared to patients not having thromboprophylaxis was the parameter with the largest EVPPI. In specific surgical populations requiring longer durations of prophylaxis, we found that pharmacological prophylaxis for all eligible patients remained optimal in those having elective knee replacement. Offering prophylaxis at a Pannucci score of ≥ 3 (sensitivity of 84% and specificity of 49%) was optimal when prescribing 28 days of low-molecular-weight heparin (LMWH) to patients having elective hip replacement. These conclusions were sensitive to prophylaxis strategy; using direct oral anticoagulants (DOACs) rather than LMWH resulted in prophylaxis for all as the optimal strategy for both hip and knee patients. Workstream 2 The observational cohort study was conducted across all four sites, enrolling 2115 patient hospitalisation episodes, with 2008 eligible for analysis. Medical and surgical cases were evenly balanced, but with more emergency (73.7%) than elective (25.8%) admissions. The sensitivity of routine coding data for detection of HAT and major bleeding events was 62% [95% confidence interval (CI) 54 to 69] and 38% (95% CI 27 to 50), respectively. Local VTE data sets performed better, with sensitivity of 81% (95% CI 75 to 87). The specificity of routine coding data for VTE and bleeding was 98% (95% CI 97 to 99) and 95% (95% CI 94 to 96), respectively, and the specificity of local VTE data sets was 100% (95% CI 99 to 100). We were unable to demonstrate overall feasibility of using efficient outcome measures and did not meet several prespecified criteria. In a smaller subgroup of patients with prospectively collected data, we evaluated potential variation in pharmacological prophylaxis using different RAMs. We identified 543 hospital episodes with VTE risk assessment performed during 2019, with 254 episodes suitable for inclusion, data extraction and comparative analysis. Overall recommendations for pharmacological prophylaxis varied substantially between seven RAMs, ranging from 13% of admitted patients for the IMPROVE associative score (95% CI 9.4 to 17.7) to 91% (95% CI 86.3 to 93.6) for the Department of Health (now Department of Health and Social Care) VTE risk assessment tool. The latter tool resulted in an absolute increase of 28% for prophylaxis recommendation, compared to other RAMs. Within this multicentre cohort of hospitalised inpatients, the HAT event rate was 1.6% (95% CI 1.0 to 2.2) and the major bleeding event rate was 2.5% (95% CI 1.8 to 3.2). Conclusions We updated prior systematic reviews to conclude that that the available evidence has significant methodological limitations and demonstrates current RAMs to have weak predictive accuracy. Decision-analytic modelling showed that the balance of VTE or major bleeding risks, combined with the RAM performance in medical cohorts, means that thromboprophylaxis for all is the optimal strategy within our model for medical inpatients. These findings were robust to multiple scenarios and sensitivity analyses. The optimal strategy for surgical inpatients is to offer thromboprophylaxis to all. However, the scenario analyses for surgical inpatients found that the optimal strategy was sensitive to many of the individual model inputs and assumptions tested. In addition, the optimal strategy for surgical patients receiving extended duration thromboprophylaxis appeared dependent on duration of therapy and prophylaxis strategy. The findings from our cohort study suggest that efficient methods for identifying VTE or major bleeding events during hospital admission or within 90 days of discharge, are not sufficiently sensitive for use in a large data-enabled study. We did not reach several predefined feasibility metrics. We also found limitations in the ability of efficient methods to identify individual risk variables and facilitate RAM comparison in future work. The majority of our sites did not collect contemporaneous data on risk assessment in a digital, or easily accessible format. Implications for policy-makers If, despite drug costs and potential harms, pharmacological prophylaxis for all is the most cost-effective strategy, use of unvalidated RAMs may be suboptimal. Based on our findings, it may be preferable for policy-makers to consider evaluating a new paradigm of ‘opt-out’ VTE prevention, in which all eligible patients are routinely offered pharmacological prophylaxis on hospital admission without complex risk assessment. In this circumstance, patients who are ineligible for pharmacological prophylaxis due to high bleeding risk, specific contraindications or personal choice could opt out, but still utilise evidence-based mechanical thromboprophylaxis strategies. The findings from our cohort study have implications for funders looking to support further work in this area. These data suggest large studies entirely reliant on routine data collection methods for complex time-dependent outcome measures (such as HAT or major bleeding) are likely to be inaccurate. Recommendations for future research Further research should evaluate the following themes in this area of clinical care: Evaluation of routine pharmacological prophylaxis for all eligible medical and surgical patients on hospital admission, compared to current practice of risk assessment using a RAM. Such work would need to be conducted at scale and could not rely on efficient methods for outcome measurement in isolation. Development and validation of RAMs to identify individuals receiving prophylaxis at very low risk of blood clots, who could therefore potentially discontinue pharmacological prophylaxis early during hospital stay. Our analysis was inevitably limited in scope and did not examine the use of RAMs to identify accurate prediction of bleeding risk, the use of mechanical prophylaxis in medical patients with increased bleeding risk (or contraindications to pharmacological prophylaxis) or patients at risk of thromboprophylaxis failure. These issues could be priorities for future research. Study registration This study is registered as Research Registry 5216, PROSPERO CRD42020165778. Funding This award was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127454) and is published in full in Health Technology Assessment; Vol. 28, No. 20. See the NIHR Funding and Awards website for further award information.

Abstract Gas fermentation of CO2 and H2 is an attractive means to sustainably produce fuels and chemicals. Clostridium autoethanogenum is a model organism for industrial CO to ethanol and presents an opportunity for CO2‐to‐ethanol processes. As we have previously characterized its CO2/H2 chemostat growth, here we use adaptive laboratory evolution (ALE) with the aim of improving growth with CO2/H2. Seven ALE lineages were generated, all with improved specific growth rates. ALE conducted in the presence of 2% CO along with CO2/H2 generated Evolved lineage D, which showed the highest ethanol titres amongst all the ALE lineages during the fermentation of CO2/H2. Chemostat comparison against the parental strain shows no change in acetate or ethanol production, while Evolved D could achieve a higher maximum dilution rate. Multi‐omics analyses at steady state revealed that Evolved D has widespread proteome and intracellular metabolome changes. However, the uptake and production rates and titres remain unaltered until investigating their maximum dilution rate. Yet, we provide numerous insights into CO2/H2 metabolism via these multi‐omics data and link these results to mutations, suggesting novel targets for metabolic engineering in this bacterium.

Summary: About 500,000 patients with rare adult solid cancers (RASC) are diagnosed yearly in Europe. Delays and unequal quality of management impact negatively their survival. Since 2017, European reference networks (ERN) aim to improve the quality of care of patients with rare disease. The steering committee of EURACAN, including physicians, researchers and patients review here the previous actions, present objectives of the ERN EURACAN dedicated to RASC. EURACAN promoted management in reference centres, and equal implementation of excellence and innovation in Europe and developed 22 clinical practice guidelines (CPGs). Additionally, fourteen information brochures translated in 24 EU languages were developed in collaboration with patient advocacy groups (ePAGs) and seventeen training session were organized. Nevertheless, connections to national networks in the 26 participating countries (106 centres), simplification of cross-border healthcare, international multidisciplinary tumour boards, registries and monitoring of the quality of care are still required. In this Health Policy, evaluation criteria of the performances of the network and of health care providers are proposed.

Background Dengue is an emerging global viral disease with an increase 30-fold in incidence in the past fifty years. In the past decade it was restricted to only few a states of South and Northern India but in the recent past it has affected almost all the states in India. The objective of this study was to assess the clinical profile, trends and outcome of dengue cases. Methods This retrospective record based cross-sectional study was conducted in tertiary hospital, Mangaluru in Southern India. The study population included all dengue positive cases diagnosed either by IgM Capture ELISA or Dengue Non-structural Protein NS1 antigen over a period of five years. Information from pre-recorded case sheets were used for data collection. The data was analyzed using SPSS Version 20. Results from the analysis have been expressed in percentages, means and graphs. Results The study included 401 dengue cases. Most cases were in the age range of 20-40 years with a male to female ratio of 3:2. Overall seropositivity rate was 23.94% with High IgM prevalence. Monthly distribution showed a maximum cases were in the months of June and July and minimum were in January and February. Among the study participants, 91.5% of patients recovered completely and 1.7% of patients had died. 6.8% of patients were discharged against medical advice. Conclusions Dengue continues to be major public health problem in this part of the globe affecting mainly the working age group. Low seropositivity with High IgM prevelance makes dengue an important differential for febrile illness of vague nature and invokes the need for robust public health response to curb the hyper-endemicity.

Objective: to evaluate the evidence of validity of the internal structure and reliability of the Brazilian version of the Smoking Cessation Counseling instrument Method: psychometric study of confirmatory factor analysis and reliability carried out on 250 nurses in clinical practice. For the analysis of the convergent validity of the factor model, Average Variance Extracted values were calculated, and discriminant analysis was carried out using the Fornell-Larcker criterion. Reliability was examined using Cronbach’s alpha coefficient and composite reliability Results: it was necessary to exclude seven items from the Advanced Counseling domain and one item from the Basic Counseling domain in order to properly obtain the Average Variance Extracted values and the Fornell-Larcker criterion. The composite reliability ranged from 0.76 to 0.86 and the overall Cronbach`s alpha coefficient was 0.86, ranging from 0.53 to 0.84 depending on the domain assessed. The final version of the instrument was made up of 16 items divided into 4 domains Conclusion: the Brazilian version of Smoking Cessation Counseling obtained adequate psychometric evidence of validity and reliability. Further studies are needed to refine the instrument.

Abstract The diamond potential of kimberlites is difficult to assess due to several mantle and magmatic processes affecting diamond content. Traditionally, initial evaluations are based on the compositions of mantle-derived minerals (garnet, chromite, clinopyroxene), which allow an assessment of pressure-temperature conditions and lithologies suitable for diamond formation. Here we explore a complementary approach that considers the conditions of diamonds destruction by interaction with melts/fluids (metasomatism). We test the hypothesis that carbonate-rich metasomatism related to kimberlite melt infiltration into the deep lithosphere is detrimental to diamond preservation. Our results show that high diamond grades in kimberlites worldwide are exclusively associated with high-Mg/Fe olivine, which corresponds to mantle lithosphere minimally affected by kimberlite-related metasomatism. Diamond dissolution in strongly metasomatised lithosphere containing low-Mg/Fe olivine provides a causal link to the empirical associations between low diamond grades, abundant Ti-Zr-rich garnets and kimberlites with high Ti and low Mg contents. This finding show-cases olivine geochemistry as a viable tool in diamond exploration.

Abstract Background Inflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia. Methods Between 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-β40 (Aβ-40), amyloid-β42 (Aβ-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex. Results Of 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5–72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7–60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aβ-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029−-0.002], p = 2.8 × 10–2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046−-0.008], p = 6.0 × 10–3) and more white matter hyperintensities (0.047 [0.016 – 0.077], p = 3.0 × 10–3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aβ-40, and Aβ-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women. Conclusions While associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.

Background: Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage accumulating with time is a main cause of aging, driving many age-related diseases. Previous studies in normal and premature aging mice, due to defective DNA repair, indicated reduced hepatic thyroid hormone signaling accompanied by decreased type 1 deiodinase (DIO1) and increased DIO3 activities. We investigated whether aging-related changes in deiodinase activity are driven by systemic signals or represent cell- or organ-autonomous changes. Methods: We quantified liver and plasma thyroid hormone concentrations, deiodinase activities and expression of T3-responsive genes in mice with a global, liver-specific and for comparison brain-specific inactivation of Xpg, one of the endonucleases critically involved in multiple DNA repair pathways. Results: Both in global and liver-specific Xpg knockout mice, hepatic DIO1 activity was decreased. Interestingly, hepatic DIO3 activity was increased in global, but not in liver-specific Xpg mutants. Selective Xpg deficiency and premature aging in the brain did not affect liver or systemic thyroid signaling. Concomitant with DIO 1 inhibition, Xpg−/− and Alb-Xpg mice displayed reduced thyroid hormone-related gene expression changes, correlating with markers of liver damage and cellular senescence. Conclusions: Our findings suggest that DIO1 activity during aging is predominantly modified in a tissue-autonomous manner driven by organ/cell-intrinsic accumulating DNA damage. The increase in hepatic DIO3 activity during aging largely depends on systemic signals, possibly reflecting the presence of circulating cells rather than activity in hepatocytes.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a common liver disease increasing cardiovascular disease (CVD) morbidity and mortality. Autoantibodies against apolipoprotein A-1 (AAA-1) are a possible novel CVD risk factor promoting inflammation and disrupting cellular lipid homeostasis, two prominent pathogenic features of NAFLD. We explored the role of AAA-1 in NAFLD and their association with CVD risk. Methods HepaRG cells and liver sections from ApoE−/− mice exposed to AAA-1 were used for lipid quantification and conditional protein expression. Randomly selected sera from 312 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND) general population cohort were used to measure AAA-1. A Fatty Liver Index (FLI) ≥ 60 and a 10-year Framingham Risk Score (FRS) ≥ 20% were used as proxy of NAFLD and high CVD risk, respectively. Results In-vitro and mouse models showed that AAA-1 increased triglyceride synthesis leading to steatosis, and promoted inflammation and hepatocyte injury. In the 112 PREVEND participants with FLI ≥ 60, AAA-1 were associated with higher FRS, alkaline phosphatase levels, lower HDL cholesterol and tended to display higher FLI values. Univariate linear and logistic regression analyses (LRA) confirmed significant associations between AAA-1, FLI and FRS ≥ 20%, while in adjusted LRA, FLI was the sole independent predictor of FRS ≥ 20% (OR: 1.05, 95%CI 1.01–1.09, P = 0.003). AAA-1 was not an independent FLI predictor. Conclusions AAA-1 induce a NAFLD-compatible phenotype in vitro and in mice. Intricate associations exist between AAA-1, CVD risk and FLI in the general population. Further work is required to refine the role of AAA-1 in NAFLD and to determine if the AAA-1 association with CVD is affected by hepatic steatosis.

Objective: Evidence-based treatment guidelines for the management of postthyroidectomy hypocalcemia are absent. The aim of this study was to evaluate a newly developed symptom-based treatment algorithm including a protocolized attempt to phase out supplementation. Methods: In a prospective multicenter study, patients were treated according to the new algorithm and compared to a historical cohort of patients treated with a biochemically based approach. The primary outcome was the proportion of patients receiving calcium and/or alfacalcidol supplementation. Secondary outcomes were calcium-related complications and predictors for supplementation. Results: One hundred thirty-four patients were included prospectively, and compared to 392 historical patients. The new algorithm significantly reduced the proportion of patients treated with calcium and/or alfacalcidol during the first postoperative year (odds ratio (OR): 0.36 (95% CI: 0.23–0.54), P < 0.001), and persistently at 12 months follow-up (OR: 0.51 (95% CI: 0.28–0.90), P < 0.05). No severe calcium-related complications occurred, even though calcium-related visits to the emergency department and readmissions increased (OR: 11.5 (95% CI: 4.51–29.3), P

Objective: To better understand the microbial profile of complicated parapneumonic effusions and empyema, and to evaluate whether antimicrobial selection would differ if guided by targeted metagenomic sequencing (tMGS) vs conventional cultures (CCs) alone. Patients and Methods: We analyzed the pleural fluid of a cohort of 47 patients undergoing thoracentesis from January 1, 2017 to August 31, 2019, to characterize their microbial profile. All samples underwent 16S ribosomal ribonucleic acid gene polymerase chain reaction, followed by tMGS. Results: Pleural space infection was deemed clinically present in 20 of the 47 (43%) participants. Of those, n=7 (35%) had positive pleural fluid cultures and n=14 (70%) had positive tMGS results. The organisms identified by tMGS were concordant with CCs; however, tMGS detected additional bacterial species over CCs alone. Streptococcus and Staphylococcus species were the most common organisms identified, with Streptococcus intermedius/constellatus identified in 5 patients. Polymicrobial infections were found in 6 of the 20 patients, with anaerobes being the most common organisms identified in these cases. Conclusion: Streptococci and staphylococci were the most common organisms identified in infected pleural fluid. Anaerobes were common in polymicrobial infections. When compared with CCs, tMGS had higher sensitivity than CCs. Targeted metagenomic sequencing identified additional organisms, not identified by CCs, with associated potential management implications.

Abstract Background Intake-balance assessments measure energy intake (EI) by summing energy expenditure (EE) with concurrent change in energy storage (ΔES). Prior work has not examined the validity of such calculations when EE is estimated via open-source techniques for research-grade accelerometry devices. The purpose of this study was to test the criterion validity of accelerometry-based intake-balance methods for a wrist-worn ActiGraph device. Methods Healthy adults (n = 24) completed two 14-day measurement periods while wearing an ActiGraph accelerometer on the non-dominant wrist. During each period, criterion values of EI were determined based on ΔES measured by dual X-ray absorptiometry and EE measured by doubly labeled water. A total of 11 prediction methods were tested, 8 derived from the accelerometer and 3 from non-accelerometry methods (e.g., diet recall; included for comparison). Group-level validity was assessed through mean bias, while individual-level validity was assessed through mean absolute error, mean absolute percentage error, and Bland–Altman analysis. Results Mean bias for the three best accelerometry-based methods ranged from -167 to 124 kcal/day, versus -104 to 134 kcal/day for the non-accelerometry-based methods. The same three accelerometry-based methods had mean absolute error of 323–362 kcal/day and mean absolute percentage error of 18.1-19.3%, versus 353–464 kcal/day and 19.5-24.4% for the non-accelerometry-based methods. All 11 methods demonstrated systematic bias in the Bland–Altman analysis. Conclusions Accelerometry-based intake-balance methods have promise for advancing EI assessment, but ongoing refinement is necessary. We provide an R package to facilitate implementation and refinement of accelerometry-based methods in future research (see paulhibbing.com/IntakeBalance).