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Fibrinogen is a large molecule synthesized in the liver and released in the blood. Circulating levels of fibrinogen are upregulated after bleeding or clotting events and support wound healing. In the context of an injury, thrombin activation drives conversion of fibrinogen to fibrin. Fibrin deposition contains tissue damage, stops blood loss, and prevents microbial infection. In most circumstances, fibrin needs to be removed to allow the resolution of inflammation and tissue repair, whereas failure of this may lead to the development of various disorders. However, the contribution of fibrinogen to tissue inflammation and repair is likely to be context-dependent. In this study, the concept that fibrin needs to be removed to allow tissue repair and to reduce inflammation is challenged by our observations that, in the intestine, fibrinogen is constitutively produced by a subset of intestinal epithelial cells and deposited at the basement membrane as fibrin where it serves as a substrate for wound healing under physiological conditions such as epithelial shedding at the tip of the small intestinal villus and surface epithelium of the colon as well as under pathological conditions that require rapid epithelial repair. The functional integrity of the intestine is ensured by the constant renewal of its simple epithelium. Superficial denuding of the epithelial cell layer occurs regularly and is rapidly corrected by a process called restitution that can be influenced by various soluble and insoluble factors. Epithelial cell interaction with the extracellular matrix greatly influences the healing process by acting on cell morphology, adhesion, and migration. The functional contribution of a fibrin(ogen) matrix in the intestine was studied under physiological and pathological contexts. Our results (immunofluorescence, immunoelectron microscopy, and quantitative PCR) show that fibrin(ogen) is a novel component of the basement membrane associated with the differentiated epithelial cell population in both the small intestine and colon. Fibrin(ogen) alone is a weak ligand for epithelial cells and behaves as an anti-adhesive molecule in the presence of type I collagen. Furthermore, the presence of fibrin(ogen) significantly shortens the time required to achieve closure of wounded epithelial cell monolayers and co-cultures in a PI3K-dependent manner. In human specimens with Crohn’s disease, we observed a major accumulation of fibrin(ogen) throughout the tissue and at denuded sites. In mice in which fibrin formation was inhibited with dabigatran treatment, dextran sulfate sodium administration provoked a significant increase in the disease activity index and pathological features such as mucosal ulceration and crypt abscess formation. Taken together, these results suggest that fibrin(ogen) contributes to epithelial healing under both normal and pathological conditions.

Primary cilia are sensory antennae located at the cell surface which mediate a variety of extracellular signals involved in development, tissue homeostasis, stem cells and cancer. Primary cilia are found in an extensive array of vertebrae cells but can only be generated when cells become quiescent. The small intestinal epithelium is a rapidly self-renewing tissue organized into a functional unit called the crypt–villus axis, containing progenitor and differentiated cells, respectively. Terminally differentiated villus cells are notoriously devoid of primary cilia. We sought to determine if intestinal crypts contain a quiescent cell population that could be identified by the presence of primary cilia. Here we show that primary cilia are detected in a subset of cells located deep in the crypts slightly above a Paneth cell population. Using a normal epithelial proliferative crypt cell model, we show that primary cilia assembly and activity correlate with a quiescent state. These results provide further evidence for the existence of a quiescent cell population in the human small intestine and suggest the potential for new modes of regulation in stem cell dynamics.

The role of laminin receptors in colorectal cancer (CRC) is the subject of ongoing research. Histopathological studies have suggested that the 67 kDa laminin receptor (67LR) is involved in the carcinogenesis of various malignancies, including CRC. However, the exact composition and nature of 67LR have been a source of confusion for many years. A recent study from our group reported that the 37 kDa form of RPSA participates as a laminin receptor renamed the RPSA-containing laminin receptor (RCLR) but is not the precursor form of the 67LR since the 67 kDa protein associated with 67LR corresponds to the 67 kDa elastin-binding protein (67EBP), which also acts as a laminin receptor. The present study aims to analyze the distinct expression patterns of these two laminin receptor components in CRC. Expressions of RCLR and 67EBP were analyzed in CRC tissues using Western blot and quantitative RT-PCR analyses. The primary colorectal adenocarcinoma tissues and corresponding resection margins showed an overexpression of both RPSA and 67EBP at the protein level in the CRC tissues. An analysis of the publicly available CRC datasets confirmed the overexpression of RPSA and 67EBP in CRC tissues. In conclusion, the elevated expression of these two non-integrin laminin receptors in CRC lesions suggests their critical roles in colorectal carcinogenesis and emphasizes their potential usefulness as tissue biomarkers.

Using the peer-exposure ratio, we explore the factor exposure heterogeneity in green and brown stocks. By looking at peer groups of S&P 500 index firms over 2014-2020 based on their greenhouse gas emission levels, we find that, on average, green stocks exhibit less factor exposure heterogeneity than brown stocks for most of the traditional equity factors but the value factor. Hence, investment managers shifting their investments from brown stocks to green stocks have less room to differentiate themselves regarding their factor exposures. Finally, we find that factor exposure heterogeneity has increased for green stocks compared to earlier periods.

Drowsy driving contributes to roughly 20% of traffic fatalities, yet most detection systems rely on behavioral cues that appear only after impairment has set in. Here we ask whether first and second derivatives of heart rate variability (HRV) can detect pre-crash states earlier than conventional approaches. Twenty-five participants completed 49 driving simulator sessions while we recorded cardiac activity through capacitive ECG electrodes embedded in the seat backrest—a non-contact method that avoids the privacy concerns of camera-based monitoring. To prevent circular evaluation, ground truth labels were based solely on crash proximity rather than HRV-derived scores. The combined HRV feature set (conventional metrics plus derivatives) achieved AUC = 0.863 for pre-crash prediction; derivatives alone reached only AUC = 0.573, indicating their value as complementary rather than standalone features. Driving performance indicators remained the strongest predictors (AUC = 0.999). Temporally, derivative-based detection preceded behavioral manifestations by 5–8 min and crash events by 6.8 ± 2.3 min. Across 1591 crashes and 6.78 million data points, we found that HRV derivatives capture physiological changes that precede overt impairment, though their utility depends on integration with other feature types.

Digital therapeutics (DTx), a class of software-based clinical interventions, are promising new technologies that can potentially prevent, manage, or treat a spectrum of medical disorders and diseases as well as deliver unprecedented portability for patients and scalability for health care providers. Their adoption and implementation were accelerated by the need for remote care during the COVID-19 pandemic, and awareness about their utility has rapidly grown among providers, payers, and regulators. Despite this, relatively little is known about the capacity of DTx to provide economic value in care. This study aimed to systematically review and summarize the published evidence regarding the cost-effectiveness of clinical-grade mobile app-based DTx and explore the factors affecting such evaluations. A systematic review of economic evaluations of clinical-grade mobile app-based DTx was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. Major electronic databases, including PubMed, Cochrane Library, and Web of Science, were searched for eligible studies published from inception to October 28, 2022. Two independent reviewers evaluated the eligibility of all the retrieved articles for inclusion in the review. Methodological quality and risk of bias were assessed for each included study. A total of 18 studies were included in this review. Of the 18 studies, 7 (39%) were nonrandomized study-based economic evaluations, 6 (33%) were model-based evaluations, and 5 (28%) were randomized clinical trial-based evaluations. The DTx intervention subject to assessment was found to be cost-effective in 12 (67%) studies, cost saving in 5 (28%) studies, and cost-effective in 1 (6%) study in only 1 of the 3 countries where it was being deployed in the final study. Qualitative deficiencies in methodology and substantial potential for bias, including risks of performance bias and selection bias in participant recruitment, were identified in several included studies. This systematic review supports the thesis that DTx interventions offer potential economic benefits. However, DTx economic analyses conducted to date exhibit important methodological shortcomings that must be addressed in future evaluations to reduce the uncertainty surrounding the widespread adoption of DTx interventions. PROSPERO International Prospective Register of Systematic Reviews CRD42022358616; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022358616.

Digital therapeutics (DTx), software as a medical device, present a promising avenue for addressing the increasing burden of a range of conditions, yet their widespread implementation remains contingent upon demonstrating economic value—an understudied domain in current literature. Using a Group Concept Mapping approach, this study synthesized perspectives from healthcare professionals, researchers, industry, and public sector representatives to understand factors perceived to influence DTx economic value throughout its lifecycle. Analysis revealed 59 factors organized into eight clusters. Stakeholders consistently identified DTx Impact on Patient Outcomes and DTx Implementation as the most influential clusters affecting economic value. However, DTx Associated Costs and DTx Monetization Models clusters were reported as not receiving sufficient consideration throughout the DTx development lifecycle, particularly among researchers. Consequently, a conceptual framework of priority clusters and factors driving DTx economic value is proposed.

An increasing number of studies have shown the prowess of long short-term memory (LSTM) networks for hydrological modelling and forecasting. One drawback of these methods is the requirement for large amounts of training data to properly reproduce streamflow events. For maximum annual streamflow, this can be problematic since they are by definition less common than middle or low flows, leading to under-representation in the model's training set. This study investigates six methods to improve the peak-streamflow simulation skill of LSTM models used for flood frequency analysis (FFA) in ungauged catchments. These include adding meteorological data variables, providing streamflow simulations from a distributed hydrological model, oversampling peak-streamflow events, adding multi-head attention mechanisms, adding data from a large set of “donor” catchments, and combining some of these elements in a single model. Furthermore, results are compared to those obtained by the distributed hydrological model HYDROTEL. The study is performed on 88 catchments in the province of Quebec using a leave-one-out cross-validation implementation, and an FFA is applied using observations, as well as model simulations. Results show that LSTM-based models are able to simulate peak streamflow as well as (for a simple LSTM model implementation) or better than (with hybrid LSTM–hydrological model implementations) the distributed hydrological model. Multiple pathways forward to further improve the LSTM-based model's ability to predict peak streamflow are provided and discussed.

Background and Objective VIR-2218 is an investigational N -acetylgalactosamine–conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology. This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers. Methods Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50–900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods. Results In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3’VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration ( t max ) of 4–7 h, and had a short median plasma half-life of 2–5 h. Plasma exposures for area under the plasma concentration–time curve up to 12 h (AUC 0–12 ) and mean maximum concentrations ( C max ) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for C max . A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3’VIR-2218, with a median t max of 6–10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3’VIR-2218 was similar to that of VIR-2218, with plasma AUC 0–12 and C max values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, with approximately 17–48% of the administered dose recovered in urine as unchanged VIR-2218 over 0–24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data). Conclusions VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection. Clinical Trial Registration No NCT03672188, September 14, 2018.

Preterm birth increases risk of cardiovascular disease and early death. A body of evidence suggests left ventricle (LV) echocardiographic alterations in children and adults born preterm. We aimed to determine if neonatal characteristics were associated with alterations in LV structure and function in preterm adults. We evaluated a cohort of 86 young adults born preterm below 30 weeks of gestation, and 85 full-term controls. We determined LV dimensions and function using tissue Doppler imaging, conventional and speckle tracking echocardiography (STE). Adults born preterm had smaller LV dimensions, but these differences did not remain after adjustment for body surface area (BSA), which was smaller in the preterm group. Stroke volume and cardiac output were reduced even after adjustment for BSA. We found a smaller e’ wave in the preterm group, but other markers of systolic and diastolic function did not differ. Use of antenatal steroids may be associated with a further reduced cardiac output in those born preterm. Adults born preterm show alterations in markers of LV dimensions and function. Identification of these markers may represent opportunities for early prevention of cardiovascular events in this at-risk population.