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Abstract Background Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. Methods A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. Results In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. Conclusions MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3–5 years to evaluate the research advancements and update this guidance as needed.

Abstract Introduction Herlyn–Werner–Wunderlich syndrome , a rare Müllerian ducts congenital disease, is characterized by a diphtheritic uterus, blind hemivagina, and ipsilateral renal agenesis. Diagnosis is at young age by ultrasound and magnetic resonance imaging, and the prognosis is good. Usually, complications evolve endometriosis and secondary pelvic inflammation. Case report A 40-year-old female patient, Brazilian, white, primigravida, diagnosed at 30 years with a didelphic uterus on ultrasound, and 4 years later, with a left ovarian endometrioma, multiple ovarian cysts, and left renal agenesis on magnetic resonance imaging. Subsequently, due to dyspareunia and a feeling of swelling, the patient underwent transvaginal ultrasound with bowel preparation, and a hematocolpos was found and Herlyn–Werner–Wunderlich syndrome was suspected; 10 years after the diagnosis she had a planned pregnancy. She presented frequent contractions following the 15th week of pregnancy and fortunately there were no complications or premature labor. Labor was inducted at 40 weeks and 6 days without progress and a cesarean section was indicated and performed without complications. Herlyn–Werner–Wunderlich syndrome often goes unnoticed, leading to inadequate treatment. Individuals with Herlyn–Werner–Wunderlich syndrome commonly face fertility issues, such as high miscarriage rate (21–33%), and obstetric complications, such as spontaneous abortions (40% risk), intrauterine growth restriction, postpartum hemorrhage, increased fetal mortality, preterm delivery (21–29%), and elevated rates of cesarean sections. In addition, there is higher susceptibility of developing endometriosis, especially with hemivaginal obstruction, and pelvic adhesions. Conclusion Early diagnosis enables timely treatment and, consequently, fewer complications. Still, when these factors are absent, vaginal birth may still be possible. The true prevalence and incidence of complications related to Herlyn–Werner–Wunderlich syndrome are still unknown.

Introduction: Medical cannabis (MC) is available upon certification for one of several qualifying conditions in Florida, USA. Previous studies suggested that some people seek cannabis for medical conditions/symptoms beyond those legally permitted. However, data remain limited on patient motives for seeking MC and their experiences around its impact on their health. We aimed to compare reported qualifying conditions for MC certification with the most frequently self-reported reasons for using MC while assessing the alignment between the two and understanding the perceived impacts of MC on self-reported conditions and symptoms. Methods: We conducted a cross-sectional study using survey data from the Medical Marijuana and Me (M3) Data Bank of individuals receiving MC in Florida, USA, in 2022. Participants were recruited via convenience sampling from nine MC clinics/clinic networks across Florida and were asked to fill out an online survey. The study measures included sociodemographic variables, self-reported health conditions, self-reported main reasons for using MC, self-reported qualifying conditions for MC certification, and self-reported perceived impact of MC on health conditions. We cross-tabulated reported qualifying conditions and reasons for MC use and reported the perceived impact per condition. Results: A total of 632 participants completed the survey, of whom 396 (62.66%) were female and 471 (74.53%) were non-Hispanic white. The median (IQR) age was 45 (35, 58). The most frequently reported qualifying conditions were post-traumatic stress disorder (PTSD) (n = 187, 29.59%), a condition not on the qualifying conditions list (n = 175, 27.69%), medical conditions of the same kind/comparable to those listed (n = 140, 22.15%), and chronic nonmalignant pain (n = 62, 25.63%). The top ten most frequently reported reasons for using MC were anxiety (n = 383, 60.60%), chronic pain (n = 278, 43.99%), depression (n = 252, 39.87%), PTSD (n = 220, 34.81%), headaches/migraine (n = 134, 21.20%), fibromyalgia (n = 67, 10.60%), attention-deficit hyperactivity disorder (ADHD) (n = 59, 9.34%), bipolar disorder (n = 53, 8.39%), high blood pressure (n = 41, 6.49%), and cancer (n = 18,2.85%). Of respondents, 70–90% with each qualifying condition reported it as one of the main reasons for using MC. Most respondents reported improvement of anxiety (n = 430/451, 95.34%), depression (n = 381/392, 97.20%), chronic pain (n = 305/310, 98.39%), insomnia/sleeping problems (n = 225/295, 86.44%), PTSD (n = 247/270, 91.48%), headaches/migraine (n = 172/218, 78.90%), ADHD (n = 82/123, 66.67%), bipolar disorder (n = 79/89, 88.76%), and fibromyalgia (n = 77/82, 93.90%). Most respondents were unsure/reported no change in blood pressure (n = 93/162, 57.41%). A small percentage reported perceived worsening impacts on their conditions. Conclusion: Qualifying conditions and self-reported reasons for using MC aligned for most respondents. Yet, a notable proportion of respondents sought MC for broader treatment effects beyond those delineated by the officially recognized qualifying conditions in Florida, USA. Most patients perceived positive effects, including those with limited available evidence on efficacy.

Abstract The first therapeutical goal followed by neurooncological surgeons dealing with prefrontal gliomas is attempting supramarginal tumor resection preserving relevant neurological function. Therefore, advanced knowledge of the frontal aslant tract (FAT) functional neuroanatomy in high-order cognitive domains beyond language and speech processing would help refine neurosurgeries, predicting possible relevant cognitive adverse events and maximizing the surgical efficacy. To this aim we performed the recently developed correlational tractography analyses to evaluate the possible relationship between FAT’s microstructural properties and cognitive functions in 27 healthy subjects having ultra-high-field (7-Tesla) diffusion MRI. We independently assessed FAT segments innervating the dorsolateral prefrontal cortices (dlPFC-FAT) and the supplementary motor area (SMA-FAT). FAT microstructural robustness, measured by the tract’s quantitative anisotropy (QA), was associated with a better performance in episodic memory, visuospatial orientation, cognitive processing speed and fluid intelligence but not sustained selective attention tests. Overall, the percentual tract volume showing an association between QA-index and improved cognitive scores (pQACV) was higher in the SMA-FAT compared to the dlPFC-FAT segment. This effect was right-lateralized for verbal episodic memory and fluid intelligence and bilateralized for visuospatial orientation and cognitive processing speed. Our results provide novel evidence for a functional specialization of the FAT beyond the known in language and speech processing, particularly its involvement in several higher-order cognitive domains. In light of these findings, further research should be encouraged to focus on neurocognitive deficits and their impact on patient outcomes after FAT damage, especially in the context of glioma surgery.

Abstract The excessive accumulation and malfunctioning of visceral adipose tissue (VAT) is a major determinant of increased risk of obesity-related comorbidities. Thus, risk stratification of people living with obesity according to their amount of VAT is of clinical interest. Currently, the most common VAT measurement methods include mathematical formulae based on anthropometric dimensions, often biased by human measurement errors, bio-impedance, and image techniques such as X-ray absorptiometry (DXA) analysis, which requires specialized equipment. However, previous studies showed the possibility of classifying people living with obesity according to their VAT through blood chemical concentrations by applying machine learning techniques. In addition, most of the efforts were spent on men living with obesity while little was done for women. Therefore, this study aims to compare the performance of the multilinear regression model (MLR) in estimating VAT and six different supervised machine learning classifiers, including logistic regression (LR), support vector machine and decision tree-based models, to categorize 149 women living with obesity. For clustering, the study population was categorized into classes 0, 1, and 2 according to their VAT and the accuracy of each MLR and classification model was evaluated using DXA-data (DXAdata), blood chemical concentrations (BLDdata), and both DXAdata and BLDdata together (ALLdata). Estimation error and $$\hbox {R}^{2}$$ R 2 were computed for MLR, while receiver operating characteristic (ROC) and precision-recall curves (PR) area under the curve (AUC) were used to assess the performance of every classification model. MLR models showed a poor ability to estimate VAT with mean absolute error $$\ge 401.40$$ ≥ 401.40 and $$\hbox {R}^{2} \le 0.62$$ R 2 ≤ 0.62 in all the datasets. The highest accuracy was found for LR with values of 0.57, 0.63, and 0.53 for ALLdata, DXAdata, and BLDdata, respectively. The ROC AUC showed a poor ability of both ALLdata and DXAdata to distinguish class 1 from classes 0 and 2 (AUC = 0.31, 0.71, and 0.85, respectively) as also confirmed by PR (AUC = 0.24, 0.57, and 0.73, respectively). However, improved performances were obtained when applying LR model to BLDdata (ROC AUC $$\ge $$ ≥ 0.61 and PR AUC $$\ge $$ ≥ 0.42), especially for class 1. These results seem to suggest that, while a direct and reliable estimation of VAT was not possible in our cohort, blood sample-derived information can robustly classify women living with obesity by machine learning-based classifiers, a fact that could benefit the clinical practice, especially in those health centres where medical imaging devices are not available. Nonetheless, these promising findings should be further validated over a larger population.

Abstract Background Unintentional injuries are a leading cause of death among children aged 1–19 years worldwide. Systematic reviews assessing various risk factors for different childhood injuries have been published previously. However, most of the related literature does not distinguish minor from severe or fatal injuries. This study aims to describe and summarize the current knowledge on the determinants of severe and fatal childhood unintentional injuries and to discuss the differences between risk factors for all injuries (including minor injuries) and severe and fatal injuries. The study also aims to quantify the reduction in childhood injuries associated with a reduction in exposure to some of the identified risk factors in the Canadian population. Methods A systematic review and meta-analysis will be conducted by searching MEDLINE, Embase, CINAHL, and Web of Science. Observational and experimental cohort studies assessing children and adolescents aged ≤ 19 years old and determinants of severe and fatal unintentional injury, such as personal behaviors, family and environmental characteristics, and socioeconomic and geographic context, will be eligible. The main outcome will be a composite of any severe or fatal unintentional injuries (including burns, drowning, transport-related injuries, and falls). Any severity measurement scale will be accepted as long as severe cases require at least one hospital admission. Two authors will independently screen for inclusion, extract data, and assess the quality of the data using the Cochrane ROBINS-E tool. Meta-analysis will be performed using random effects models. Subgroup analyses will examine age subgroups and high- vs low-income countries. Sensitivity analysis will be conducted after restricting analyses to studies with a low risk of bias. Attributable fractions will be computed to assess the burden of identified risk factors in the Canadian population. Discussion Given the numerous determinants of childhood injuries and the challenges that may be involved in identifying which individuals should be prioritized for injury prevention efforts, this evidence may help to inform the identification of high-risk children and prevention interventions, considering the disproportionate consequences of severe and fatal injuries. This evidence may also help pediatric healthcare providers prioritize counseling messaging. Systematic review registration PROSPERO CRD42023493322.

Abstract Monometallic and bimetallic Cu:Ni catalysts with different Cu:Ni molar ratios (3:1, 2:1, 1:1, 1:2, 1:3) were synthesized by wetness impregnation on activated carbon and characterized by TPR (temperature programmed reduction), XRD (X-ray diffraction) and XPS (X-ray photoelectron spectroscopy). The synthesized catalysts were evaluated in the gas phase production of diethyl carbonate from ethanol and carbon dioxide. The largest catalytic activity was obtained over the bimetallic catalyst with a Cu:Ni molar ratio of 3:1. Its improved activity was attributed to the formation of a Cu–Ni alloy on the surface of the catalyst, evidenced by XPS and in agreement with a previous assignment based on Vegard law and TPR analysis. During the reaction rate experiments, it observed the presence of a maximum of the reaction rate as a function of temperature, a tendency also reported for other carbon dioxide–alcohol reactions. It showed that the reaction rate-temperature data can be adjusted with a reversible rate equation. The initial rate as a function of reactant partial pressure data was satisfactorily adjusted using the forward power law rate equation and it was found that the reaction rate is first order in CO2 and second order in ethanol.

Abstract Although asexuality became a growing research subject over the last decade, data on the mental health of individuals identifying as asexual is still rare. The key objective of the present study was to examine depressive symptoms among individuals identifying as asexual. Data of LGBTQIA+ (Lesbian, Gay, Bi-sexual, Trans*, Queer, Inter*, Asexual and/or + indicating others within the community) and cisgender heterosexual individuals was collected through an online survey during the COVID-19 lockdowns in Germany. The survey included questions about sexual and gender identity, depressive symptoms, and asexual identity. An analysis of N = 6601 participants was conducted. A total of n = 445 individuals identified as asexual. Regression results indicated identifying as asexual being significantly associated with higher depressive symptoms. Results suggest that individuals identifying as asexual represent a vulnerable group within the group of sexual minorities, one that fundamentally requires special psychosocial support, especially in times of pandemics.

Abstract Age-related changes in emotional processing are complex, with a bias toward positive information. However, the impact of aging on emotional responses in positive everyday situations remains unclear. Virtual Reality (VR) has emerged as a promising tool for investigating emotional processing, offering a unique balance between ecological validity and experimental control. Yet, limited evidence exists regarding its efficacy to elicit positive emotions in older adults. Our study aimed to explore age-related differences in positive emotional responses to immersion in both social and nonsocial virtual emotional environments. We exposed 34 younger adults and 24 older adults to natural and social 360-degree video content through a low immersive computer screen and a highly immersive Head-Mounted Display, while recording participants' physiological reactions. Participants also provided self-report of their emotions and sense of presence. The findings support VR’s efficacy in eliciting positive emotions in both younger and older adults, with age-related differences in emotional responses influenced by the specific video content rather than immersion level. These findings underscore the potential of VR as a valuable tool for examining age-related differences in emotional responses and developing VR applications to enhance emotional wellbeing across diverse user populations.

Abstract Diabetes mellitus (DM) is a risk factor for the development of ulnar nerve entrapment (UNE). Differences in surgical outcomes for UNE between patients with and without DM have been reported, but studies on presurgical management are scarce. This study aimed to evaluate the presurgical management of UNE in patients with (DM diagnosis

Abstract Background DNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss. Results The search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss. Conclusions Evidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.

Abstract Background Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. Main body By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. Conclusion The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Abstract No-take marine protected areas (MPAs) can mitigate the effects of overfishing, climate change and habitat degradation, which are leading causes of an unprecedented global biodiversity crisis. However, assessing the effectiveness of MPAs, especially in remote oceanic islands, can be logistically challenging and often restricted to relatively shallow and accessible environments. Here, we used a long-term dataset (2010–2019) collected by the DeepSee submersible of the Undersea Hunter Group that operates in Isla del Coco National Park, Costa Rica, to (1) determine the frequency of occurrence of elasmobranch species at two depth intervals (50–100 m; 300–400 m), and (2) investigate temporal trends in the occurrence of common elasmobranch species between 2010 and 2019, as well as potential drivers of the observed changes. Overall, we observed 17 elasmobranch species, 15 of which were recorded on shallow dives (50–100 m) and 11 on deep dives (300–400 m). We found a decreasing trend in the probability of occurrence of Carcharhinus falciformis over time (2010–2019), while other species (e.g. Taeniurops meyeni, Sphyrna lewini, Carcharhinus galapagensis, Triaenodon obesus, and Galeocerdo cuvier) showed an increasing trend. Our study suggests that some species like S. lewini may be shifting their distributions towards deeper waters in response to ocean warming but may also be sensitive to low oxygen levels at greater depths. These findings highlight the need for regional 3D environmental information and long-term deepwater surveys to understand the extent of shark and ray population declines in the ETP and other regions, as most fishery-independent surveys from data-poor countries have been limited to relatively shallow waters.

Objective(s): Preeclampsia (PE) is a complication of pregnancy that might increase progeny risk of cardiovascular and metabolic problems, mainly in males. Renin angiotensin aldosterone system is known to be involved. (Pro) renin/renin receptor ((P)RR) has been shown to participate in cardiovascular pathology. The aim of this work was to evaluate (P)RR expression and function upon cardiovascular and renal tissues from PE dams’ offspring.Materials and Methods: We used offspring from normal pregnant and preeclamptic rats, evaluating body, heart, aorta and kidney weight, length, and blood pressure along 3 months after birth. Subsets of animals received handle region peptide (HRP) (0.2 mg/Kg, sc). Another group received vehicle. Animals were sacrificed at first, second, and third months of age, tissues were extracted and processed for immunoblot to detect (P)RR, PLZF, β-catenin, DVL-1, and PKCα. (P)RR and PLZF were also measured by RT-PCR. Results: We found that offspring developed hypertension. Male descendants remained hypertensive throughout the whole experiment. Female animals tended to recover at second month and returned to normal blood pressure at third month. HRP treatment diminished hypertension in both male and female animals. Morphological evaluations showed changes in heart, aorta, and kidney weight, and HRP reverted this effect. Finally, we found that (P)RR, PLZF, and canonical WNT transduction pathway molecules were stimulated by PE, and HRP treatment abolished this increase. Conclusion: These findings suggest that PE can induce hypertension in offspring, and (P)RR seems to play an important role through the canonical WNT pathway and that gender seems to influence this response.

Abstract Background Definitive local therapy with stereotactic ablative radiation therapy (SABR) for ultracentral lung lesions is associated with a high risk of toxicity, including treatment related death. Stereotactic MR-guided adaptive radiation therapy (SMART) can overcome many of the challenges associated with SABR treatment of ultracentral lesions. Methods We retrospectively identified 14 consecutive patients who received SMART to ultracentral lung lesions from 10/2019 to 01/2021. Patients had a median distance from the proximal bronchial tree (PBT) of 0.38 cm. Tumors were most often lung primary (64.3%) and HILUS group A (85.7%). A structure-specific rigid registration approach was used for cumulative dose analysis. Kaplan-Meier log-rank analysis was used for clinical outcome data and the Wilcoxon Signed Rank test was used for dosimetric data. Results Here we show that SMART dosimetric improvements in favor of delivered plans over predicted non-adapted plans for PBT, with improvements in proximal bronchial tree DMax of 5.7 Gy (p = 0.002) and gross tumor 100% prescription coverage of 7.3% (p = 0.002). The mean estimated follow-up is 17.2 months and 2-year local control and local failure free survival rates are 92.9% and 85.7%, respectively. There are no grade ≥ 3 toxicities. Conclusions SMART has dosimetric advantages and excellent clinical outcomes for ultracentral lung tumors. Daily plan adaptation reliably improves target coverage while simultaneously reducing doses to the proximal airways. These results further characterize the therapeutic window improvements for SMART. Structure-specific rigid dose accumulation dosimetric analysis provides insights that elucidate the dosimetric advantages of SMART more so than per fractional analysis alone.

Abstract Plant biostimulants are widely applied in agriculture for their ability to improve plant fitness. In the present work, the impact of Graminaceae-derived protein hydrolysate (P) and its lighter molecular fraction F3 (

Abstract Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1 −/− mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD.

Abstract Background Bioinstrumentation is essential to biomedical engineering (BME) undergraduate education and professional practice. Several strategies have been suggested to provide BME students with hands-on experiences throughout the curriculum, promoting their preparedness to pursue careers in industry and academia while increasing their learning and engagement. This paper describes the implementation of challenge-based learning (CBL) in an undergraduate bioinstrumentation blended course over the COVID-19 pandemic. Methods The CBL experience was implemented in a third-year bioinstrumentation course from the BME program at Tecnologico de Monterrey. Thirty-nine students enrolled in two sections formed fourteen teams that tackled blended learning activities, including online communication, lab experiments, and in-person CBL activities. Regarding the latter, students were challenged to design, prototype, and test a respiratory or cardiac gating device for radiotherapy. An institutional student opinion survey was used to assess the success of our CBL implementation. Results Student responses to the end-of-term survey showed that they strongly agreed that this course challenged them to learn new concepts and develop new skills. Furthermore, they rated the student-lecturer interaction very positively despite the blended format. Overall, students assessed their learning experience positively. However, implementing this CBL experience required a substantial time increase in planning, student tutoring, and constant communication between lecturers and the industry partner. Conclusion This work provides an effective instance of CBL for BME education to improve students’ learning experience despite decreased resource efficiency. Our claim is supported by the student’s performance and the positive feedback from our industrial partner.

Abstract The cladoceran crustacean Daphnia exhibits phenotypic plasticity, a phenomenon that leads to diverse phenotypes from one genome. Alternative usage of gene isoforms has been considered a key gene regulation mechanism for controlling different phenotypes. However, to understand the phenotypic plasticity of Daphnia, gene isoforms have not been comprehensively analyzed. Here we identified 25,654 transcripts derived from the 9710 genes expressed during environmental sex determination of Daphnia magna using the long-read RNA-Seq with PacBio Iso-Seq. We found that 14,924 transcripts were previously unidentified and 5713 genes produced two or more isoforms. By a combination of Illumina short-read RNA-Seq, we detected 824 genes that implemented switching of the highest expressed isoform between females and males. Among the 824 genes, we found isoform switching of an ortholog of CREB-regulated transcription coactivator, a major regulator of carbohydrate metabolism in animals, and a correlation of this switching event with the sexually dimorphic expression of carbohydrate metabolic genes. These results suggest that a comprehensive catalog of isoforms may lead to understanding the molecular basis for environmental sex determination of Daphnia. We also infer the applicability of the full-length isoform analyses to the elucidation of phenotypic plasticity in Daphnia.

Abstract Direct human-caused mortality accounts for about half of all large mammal mortality in North America. For social species like gray wolves (Canis lupus), the death of pack members can disrupt pack structure and cause pack dissolution, and mortality of breeding adults or wolves during reproduction and pup-rearing can decrease pup recruitment. We estimated minimum and maximum probability of wolf pack persistence in Wisconsin, USA, during biological years (15 April–14 April) 2011–2019 and evaluated the influence of pack size and legal harvest mortality on pack persistence during 2012–2014. Harvests comprised 75–161 mortalities within 194 monitored packs during 2012–2014, with 56–74% of packs having no wolves harvested each year. As an index of reproduction during 2013–2019, we also estimated the proportion of packs where pups responded to howl surveys. We evaluated the influence of pack size, legal harvest, and agency removal on reproduction during 2013–2015. Annual maximum pack persistence probability was uniformly high (0.95–1.00), and annual minimum pack persistence probability ranged from 0.86–0.98 with a possible decline during years of harvest. Reproduction was similar in years following harvest and agency removal (2013–2015, pup response = 0.27–0.40), and years without harvest or agency removal the year prior (2016–2019, pup response = 0.28–0.66). Pack size had a positive effect on pack persistence and reproduction. Total number of wolf mortalities and number of adult male and females removed did not influence pack persistence or reproduction. We suggest that low per-pack mortality, timing of harvest and agency removal, and harvest characteristics during 2012–2014 supported stable pack persistence and reproduction.

Abstract Deep learning models (DLMs) have gained importance in predicting, detecting, translating, and classifying a diversity of inputs. In bioinformatics, DLMs have been used to predict protein structures, transcription factor-binding sites, and promoters. In this work, we propose a hybrid model to identify transcription factors (TFs) among prokaryotic and eukaryotic protein sequences, named Deep Regulation (DeepReg) model. Two architectures were used in the DL model: a convolutional neural network (CNN), and a bidirectional long-short-term memory (BiLSTM). DeepReg reached a precision of 0.99, a recall of 0.97, and an F1-score of 0.98. The quality of our predictions, the bias-variance trade-off approach, and the characterization of new TF predictions were evaluated and compared against those produced by DeepTFactor, as well as against experimental data from three model organisms. Predictions based on our DLM tended to exhibit less variance and bias than those from DeepTFactor, thus increasing reliability and decreasing overfitting.

Abstract Fluorinated graphene, a two-dimensional nanomaterial composed of three atomic layers, a central carbon layer sandwiched between two layers of fluorine atoms, has attracted considerable attention across various fields, particularly for its potential use in biomedical applications. Nonetheless, scant effort has been devoted to assessing the potential toxicological implications of this nanomaterial. In this study, we scrutinize the potential impact of fluorinated graphene on a protein model, HP35 by utilizing extensive molecular dynamics (MD) simulation methods. Our MD results elucidate that upon adsorption to the nanomaterial, HP35 undergoes a denaturation process initiated by the unraveling of the second helix of the protein and the loss of the proteins hydrophobic core. In detail, substantial alterations in various structural features of HP35 ensue, including alterations in hydrogen bonding, Q value, and RMSD. Subsequent analyses underscore that hydrophobic and van der Waals interactions (predominant), alongside electrostatic energy (subordinate), exert influence over the adsorption of HP35 on the fluorinated graphene surface. Mechanistic scrutiny attests that the unrestrained lateral mobility of HP35 on the fluorinated graphene nanomaterial primarily causes the exposure of HP35's hydrophobic core, resulting in the eventual structural denaturation of HP35. A trend in the features of 2D nanostructures is proposed that may facilitate the denaturation process. Our findings not only substantiate the potential toxicity of fluorinated graphene but also unveil the underlying molecular mechanism, which thereby holds significance for the prospective utilization of such nanomaterials in the field of biomedicine.

Abstract This research aimed to determine whether accomplished surfers could accurately perceive how changes to surfboard fin design affected their surfing performance. Four different surfboard fins, including conventional, single-grooved, and double-grooved fins, were developed using computer-aided design combined with additive manufacturing (3D printing). We systematically installed these 3D-printed fins into instrumented surfboards, which six accomplished surfers rode on waves in the ocean in a random order while blinded to the fin condition. We quantified the surfers’ wave-riding performance during each surfing bout using a sport-specific tracking device embedded in each instrumented surfboard. After each fin condition, the surfers rated their perceptions of the Drive, Feel, Hold, Speed, Stiffness, and Turnability they experienced while performing turns using a visual analogue scale. Relationships between the surfer’s perceptions of the fins and their surfing performance data collected from the tracking devices were then examined. The results revealed that participants preferred the single-grooved fins for Speed and Feel, followed by double-grooved fins, commercially available fins, and conventional fins without grooves. Crucially, the surfers’ perceptions of their performance matched the objective data from the embedded sensors. Our findings demonstrate that accomplished surfers can perceive how changes to surfboard fins influence their surfing performance.

Abstract Rib fractures are highly predictive of non-accidental trauma in children under 3 years old. Rib fracture detection in pediatric radiographs is challenging because fractures can be obliquely oriented to the imaging detector, obfuscated by other structures, incomplete, and non-displaced. Prior studies have shown up to two-thirds of rib fractures may be missed during initial interpretation. In this paper, we implemented methods for improving the sensitivity (i.e. recall) performance for detecting and localizing rib fractures in pediatric chest radiographs to help augment performance of radiology interpretation. These methods adapted two convolutional neural network (CNN) architectures, RetinaNet and YOLOv5, and our previously proposed decision scheme, “avalanche decision”, that dynamically reduces the acceptance threshold for proposed regions in each image. Additionally, we present contributions of using multiple image pre-processing and model ensembling techniques. Using a custom dataset of 1109 pediatric chest radiographs manually labeled by seven pediatric radiologists, we performed 10-fold cross-validation and reported detection performance using several metrics, including F2 score which summarizes precision and recall for high-sensitivity tasks. Our best performing model used three ensembled YOLOv5 models with varied input processing and an avalanche decision scheme, achieving an F2 score of 0.725 ± 0.012. Expert inter-reader performance yielded an F2 score of 0.732. Results demonstrate that our combination of sensitivity-driving methods provides object detector performance approaching the capabilities of expert human readers, suggesting that these methods may provide a viable approach to identify all rib fractures.

Abstract The United States government makes a substantial investment in biomedical training programs each year. However, for most trainees, these opportunities do not translate into career progression in academic research pathways. Only about one-fifth of postdoctoral fellows eventually secure a tenure-track faculty position, and even among these candidates, attrition is high. Although a number of factors govern career choices and career longevity, the transition from trainee to faculty is a challenging process and requires knowledge and skills that are not necessarily developed during a traditional university experience. Many postdoctoral fellows receive adequate training in research skills and scientific communication, but new faculty report not being sufficiently prepared for the job search process and for starting their labs. To address this critical training gap, the ITERT core (Interdisciplinary Translational Education and Research Training) and the Office of Postdoctoral Fellows at the University of Texas MD Anderson Cancer Center implemented a structured course for both postdoctoral fellows and senior PhD students to provide formalized training for successfully navigating academic positions in biomedical research. Here we report on the pilot Navigating Academic Careers course conducted in 2021–2022 for 30 PhD students and postdocs. The nine-module course was conducted over 13 weeks in 25.5 h instructional sessions. The key educational objectives included 1) navigating the job application and the interview/negotiation process, 2) hiring, leading, and mentoring lab personnel and program support staff, 3) project administration and financial stewardship, 4) managing time and work-life balance and 5) developing collaborations, branding, personalized niche, and networking. Survey-based analysis at the time of the course was used to capture the participants’ assessment of the course content, organization, and delivery, with a follow-up survey conducted approximately 2 years post-course (2024) to evaluate longer-term impacts of the training. Initial in-course assessment revealed that 89.9% of respondents found the scope and instructional content appropriate, and 91.1% found the course relevant and applicable to their career needs. Longer-term post-course evaluation indicated that 80% of respondents applied the learnings of the course, that 80% reported feeling more confident in navigating an academic job search, and that 66.6% continued to report agreement with the course preparing them for their current role/ongoing job search, with 46.7% already securing jobs in academic research, including as independent faculty. The outcomes of this pilot course suggest that integrating this into the broader postdoctoral training curriculum can enhance both the transition and early-career success of talented scientists-in-training into working professionals in biomedical careers, as faculty and science-trained staff.

Abstract Background Pneumonia is a major public health problem with an impact on morbidity and mortality. Its management still represents a challenge. The aim was to determine whether a new diagnostic algorithm combining lung ultrasound (LUS) and procalcitonin (PCT) improved pneumonia management regarding antibiotic use, radiation exposure, and associated costs, in critically ill pediatric patients with suspected bacterial pneumonia (BP). Methods Randomized, blinded, comparative effectiveness clinical trial. Children 1 ng/mL, antibiotics were recommended. Results 194 children were enrolled, 113 (58.2%) females, median age of 134 (IQR 39–554) days. 96 randomized into EG and 98 into CG. 1. In 75/194 patients the image test was not suggestive of BP with PCT 1 ng/ml, all of them received antibiotics. A total of 0.035 mSv radiation/patient was eluded. A reduction of 77% CXR/patient was observed. LUS did not significantly increase costs. Conclusions Combination of LUS and PCT showed no risk of mistreating BP, avoided radiation and did not increase costs. The algorithm could be a reliable tool for improving pneumonia management. Clinical Trial Registration: NCT04217980.

Abstract In the human genome, heterozygous sites refer to genomic positions with a different allele or nucleotide variant on the maternal and paternal chromosomes. Resolving these allelic differences by chromosomal copy, also known as phasing, is achievable on a short-read sequencer when using a library preparation method that captures long-range genomic information. TELL-Seq is a library preparation that captures long-range genomic information with the aid of molecular identifiers (barcodes). The same barcode is used to tag the reads derived from the same long DNA fragment within a range of up to 200 kilobases (kb), generating linked-reads. This strategy can be used to phase an entire genome. Here, we introduce a TELL-Seq protocol developed for targeted applications, enabling the phasing of enriched loci of varying sizes, purity levels, and heterozygosity. To validate this protocol, we phased 2–200 kb loci enriched with different methods: CRISPR/Cas9-mediated excision coupled with pulse-field electrophoresis for the longest fragments, CRISPR/Cas9-mediated protection from exonuclease digestion for mid-size fragments, and long PCR for the shortest fragments. All selected loci have known clinical relevance: BRCA1, BRCA2, MLH1, MSH2, MSH6, APC, PMS2, SCN5A-SCN10A, and PKI3CA. Collectively, the analyses show that TELL-Seq can accurately phase 2–200 kb targets using a short-read sequencer.

Abstract During the preparation of fixed prosthesis (including individual bridges and crowns) it is important to select the materials that have the best features and properties to predict a successful clinical treatment. The objective of this study was to determine if the chemical and structural characteristics could cause to increase the fracture resistance, we used four bis-acryl resins Luxatemp, Protemp, Structur and Telio. Three-points bending by Flexural test were performed in ten bars and they were carried out to compare with Anova test. In addition, the bis-acryl resins were analyzed by scanning electron microscopy, to analyze microstructure and morphology and the molecular structure were performed by Infrared Spectroscopy through Attenuated Total Reflectance. A higher flexural strength was found in Luxatemp and Structur with, no significant differences between this study groups. Regarding Protemp and Telio, these study groups showed a lower flexural strength when were compared with Luxatemp and Structur. These results corroborate SEM and ATR analysis because Luxatemp sample showed a regular size particle on the surface and chemically presents a long cross-linkage polymer chain. The presence of CO3, SiO2 and N–H groups as a fillers particle interacting with OH groups cause a higher flexural strength compared with another groups.

Abstract The aim of this study was to assess the effects of substituting traditional forage fiber sources with cottonseed cake in the diet on both the quantitative and qualitative characteristics of carcass and meat in Nelore young bulls. Twenty-four Nelore steers starting with an average weight of 377.8 ± 43.5 kg, were individually housed in stalls and provided with individualized feeding over a 112-day confinement period. The study followed a completely randomized design with two treatments and 12 replications. The diets incorporated either whole plant corn silage (WPCS) and, cottonseed cake (CSC) as fiber sources, at a rate of 300 g/kg of dry matter. The CSC diet promoted higher carcass weight. Aging animal meat for seven days significantly decreased the shear force from 83.4 to 71.6 N. Although diets did not influence meat composition, WPCS diet provided higher concentrations of C16:1, C18:1n9c, C18:3n3, and C22:2 acid, and CSC diet higher concentrations of C15:0, C18:1n9t, C18:2n6c, and 20:3n3. The WPCS diet provided higher concentrations of monounsaturated fatty acids and ω9, and the CSC diet had higher concentrations of ω6 and ω6:ω3 ratio in meat. Cottonseed cake used as a fiber source increases the concentration of polyunsaturated fatty acids and ω6 fatty acids in the meat of young bulls finished in feedlot.

Abstract Blooming and pruning is one of the most important developmental mechanisms of the biological brain in the first years of life, enabling it to adapt its network structure to the demands of the environment. The mechanism is thought to be fundamental for the development of cognitive skills. Inspired by this, Chialvo and Bak proposed in 1999 a learning scheme that learns from mistakes by eliminating from the initial surplus of synaptic connections those that lead to an undesirable outcome. Here, this idea is implemented in a neuromorphic circuit scheme using CMOS integrated HfO2-based memristive devices. The implemented two-layer neural network learns in a self-organized manner without positive reinforcement and exploits the inherent variability of the memristive devices. This approach provides hardware, local, and energy-efficient learning. A combined experimental and simulation-based parameter study is presented to find the relevant system and device parameters leading to a compact and robust memristive neuromorphic circuit that can handle association tasks.

Abstract Background Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies. Methods We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment. Results Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation. Conclusions Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops.

Several coronaviruses infect humans, with three, including the SARS-CoV2, causing diseases. While coronaviruses are especially prone to induce pandemics, we know little about their evolutionary history, host-to-host transmissions, and biogeography. One of the difficulties lies in dating the origination of the family, a particularly challenging task for RNA viruses in general. Previous cophylogenetic tests of virus-host associations, including in the Coronaviridae family, have suggested a virus-host codiversification history stretching many millions of years. Here, we establish a framework for robustly testing scenarios of ancient origination and codiversification versus recent origination and diversification by host switches. Applied to coronaviruses and their mammalian hosts, our results support a scenario of recent origination of coronaviruses in bats and diversification by host switches, with preferential host switches within mammalian orders. Hotspots of coronavirus diversity, concentrated in East Asia and Europe, are consistent with this scenario of relatively recent origination and localized host switches. Spillovers from bats to other species are rare, but have the highest probability to be towards humans than to any other mammal species, implicating humans as the evolutionary intermediate host. The high host-switching rates within orders, as well as between humans, domesticated mammals, and non-flying wild mammals, indicates the potential for rapid additional spreading of coronaviruses across the world. Our results suggest that the evolutionary history of extant mammalian coronaviruses is recent, and that cases of long-term virus–host codiversification have been largely over-estimated.

Introduction Reduced thrombin generation is an important component of post cardiopulmonary bypass (CPB) coagulopathy. To replenish coagulation factors and enhance thrombin generation in bleeding surgical patients, frozen plasma (FP) and four-factor prothrombin complex concentrate (4F-PCC) are used. However, the efficacy–safety balance of 4F-PCC relative to FP in cardiac surgery is unconfirmed.Methods and analysis LEX-211 (FARES-II) is an active-control, randomised, phase 3 study comparing two coagulation factor replacement therapies in bleeding adult cardiac surgical patients at 12 hospitals in Canada and the USA. The primary objective is to determine whether 4F-PCC (Octaplex/Balfaxar, Octapharma) is clinically non-inferior to FP for haemostatic effectiveness. Inclusion criteria are any index (elective or non-elective) cardiac surgery employing CPB and coagulation factor replacement with 4F-PCC or FP ordered in the operating room for bleeding management. Patients will be randomised to receive 1500 or 2000 international units of 4F-PCC or 3 or 4 units of FP, depending on body weight. The primary endpoint of haemostatic treatment response is ‘effective’ if no additional haemostatic intervention is required from 60 min to 24 hours after the first initiation of 4F-PCC or FP; or ‘ineffective’ if any other haemostatic intervention (including a second dose of study drug) is required. An estimated 410 evaluable patients will be required to demonstrate non-inferiority (one-sided α of 0.025, power ≥90%, non-inferiority margin 0.10). Secondary outcomes include transfusions, bleeding-related clinical endpoints, coagulation parameters and safety.Ethics and dissemination The trial has been approved by the institutional review boards of all participating centres. Trial completion is anticipated at the end of 2024, and results will be disseminated via publications in peer-reviewed journals and conference presentations in 2025. The results will advance our understanding of coagulation management in bleeding surgical patients, potentially reducing the need for allogeneic blood products and improving outcomes in surgical patients.Trial registration number NCT05523297.

La especialidad de Anatomía Patológica (AP) se basa en el estudio histológico de muestras de tejidos biológicos para obtener diagnósticos clínicos. La revisión de las láminas de microscopía generadas en la actividad asistencial puede ser una herramienta de interés docente. Estas “colecciones de casos”, que podemos definir como “conjuntos cerrados de casos seleccionados por su interés docente”, permiten al residente o estudiante de AP familiarizarse con las características histológicas de los tejidos normales, de las distintas entidades patológicas y otros hallazgos histológicos. En esta revisión narrativa describimos las características de estas colecciones de casos, su tipología, formas de uso, ventajas e inconvenientes; además, describimos el impacto de la digitalización de los servicios de Anatomía Patológica en la elaboración de colecciones de casos.

Introduction Chronic pain increases the risk of prescription opioid misuse or opioid use disorder (OUD). Non-pharmacological treatments are needed to dually address pain and opioid risks. The purpose of the Mobile and Online-Based Interventions to Lessen Pain (MOBILE Relief) study is to compare a one-session, video-based, on-demand digital pain relief skills intervention for chronic pain (‘Empowered Relief’ (ER); tailored to people at risk for opioid misuse or with opioid misuse/OUD) to a one-session digital health education intervention (‘Living Better’; no pain management skills).Methods and analysis MOBILE Relief is an international online randomised controlled clinical trial. Study participants are adults with chronic, non-cancer pain (≥6 months) with daily pain intensity ≥3/10, taking ≥10 morphine equivalent daily dose and score ≥6 on the Current Opioid Misuse Measure. Participants are recruited through clinician referrals and clinic advertisements. Study procedures include electronic eligibility screening, informed consent, automated 1:1 randomisation to the treatment group, baseline measures, receipt of assigned digital treatment and six post-treatment surveys spanning 3 months. Study staff will call participants at baseline and 1-month and 3 months post-treatment to verify the opioid prescription. The main statistical analyses will include analysis of covariance and mixed effects model for repeated measurements regression.Main outcomes Primary outcomes are self-reported pain catastrophising, pain intensity, pain interference, opioid craving and opioid misuse at 1-month and 3 months post-treatment. We will determine the feasibility of ER (≥50% participant engagement, ≥70% treatment appraisal ratings). We hypothesise the ER group will be superior to the Living Better group in the reduction of multiprimary pain outcomes at 1-month post-treatment and opioid outcomes at 1-month and 3 months post-treatment.Ethics and dissemination The study protocol was approved by the Stanford University School of Medicine Institutional Review Board (IRB 61643). We will publish results in peer-reviewed journals; National Institute of Drug Abuse (funder) and MOBILE Relief participants will receive result summaries.Trial registration number NCT05152134.

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

Summary: The human transcriptome predominantly consists of noncoding RNAs (ncRNAs), transcripts that do not encode proteins. The noncoding transcriptome governs a multitude of pathophysiological processes, offering a rich source of next-generation biomarkers. Toward achieving a holistic view of disease, the integration of these transcripts with clinical records and additional data from omic technologies (“multiomic” strategies) has motivated the adoption of artificial intelligence (AI) approaches. Given their intricate biological complexity, machine learning (ML) techniques are becoming a key component of ncRNA-based research. This article presents an overview of the potential and challenges associated with employing AI/ML-driven approaches to identify clinically relevant ncRNA biomarkers and to decipher ncRNA-associated pathogenetic mechanisms. Methodological and conceptual constraints are discussed, along with an exploration of ethical considerations inherent to AI applications for healthcare and research. The ultimate goal is to provide a comprehensive examination of the multifaceted landscape of this innovative field and its clinical implications.

Introduction Oxygen is frequently prescribed in neurocritical care units. Avoiding hypoxaemia is a key objective in patients with acute brain injury (ABI). However, several studies suggest that hyperoxaemia may also be related to higher mortality and poor neurological outcomes in these patients. The evidence in this direction is still controversial due to the limited number of prospective studies, the lack of a common definition for hyperoxaemia, the heterogeneity in experimental designs and the different causes of ABI. To explore the correlation between hyperoxaemia and poor neurological outcomes and mortality in hospitalised adult patients with ABI, we will conduct a systematic review and meta-analysis of observational studies and RCTs.Methods and analysis The systematic review methods have been defined according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and follow the PRISMA-Protocols structure. Studies published until June 2024 will be identified in the electronic databases MEDLINE, Embase, Scopus, Web of Science, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov. Retrieved records will be independently screened by four authors working in pairs, and the selected variables will be extracted from studies reporting data on the effect of ‘hyperoxaemia’ versus ‘no hyperoxaemia on neurological outcomes and mortality in hospitalised patients with ABI. We will use covariate-adjusted ORs as outcome measures when reported since they account for potential cofounders and provide a more accurate estimate of the association between hyperoxaemia and outcomes; when not available, we will use univariate ORs. If the study presents the results as relative risks, it will be considered equivalent to the OR as long as the prevalence of the condition is close to 10%. Pooled estimates of both outcomes will be calculated applying random-effects meta-analysis. Interstudy heterogeneity will be assessed using the I2 statistic; risk of bias will be assessed through Risk Of Bias In Non-Randomised Studies of Interventions, Newcastle-Ottawa or RoB2 tools. Depending on data availability, we plan to conduct subgroup analyses by ABI type (traumatic brain injury, postcardiac arrest, subarachnoid haemorrhage, intracerebral haemorrhage and ischaemic stroke), arterial partial pressure of oxygen values, study quality, study time, neurological scores and other selected clinical variables of interest.Ethics and dissemination Specific ethics approval consent is not required as this is a review of previously published anonymised data. Results of the study will be shared with the scientific community via publication in a peer-reviewed journal and presentation at relevant conferences and workshops. It will also be shared key stakeholders, such as national or international health authorities, healthcare professionals and the general population, via scientific outreach journals and research institutes’ newsletters.

Antimicrobial resistance (AMR) poses a significant threat to human health. Although vaccines have been developed to combat AMR, it has proven challenging to associate specific vaccine antigens with AMR. Bacterial plasmids play a crucial role in the transmission of AMR. Our recent research has identified a group of bacterial plasmids (specifically, IncHI plasmids) that encode large molecular mass proteins containing bacterial immunoglobulin-like domains. These proteins are found on the external surface of the bacterial cells, such as in the flagella or conjugative pili. In this study, we show that these proteins are antigenic and can protect mice from infection caused by an AMR Salmonella strain harboring one of these plasmids. Furthermore, we successfully generated nanobodies targeting these proteins, that were shown to interfere with the conjugative transfer of IncHI plasmids. Considering that these proteins are also encoded in other groups of plasmids, such as IncA/C and IncP2, targeting them could be a valuable strategy in combating AMR infections caused by bacteria harboring different groups of AMR plasmids. Since the selected antigens are directly linked to AMR itself, the protective effect extends beyond specific microorganisms to include all those carrying the corresponding resistance plasmids.

Introdução: A prevalência da hepatite C (HCV) é elevada entre os prisioneiros. Se não tratada, proporção substancial das infecções progride para cirrose, hepatocarcinoma ou insuficiência hepática. Organização Mundial de Saúde tem a meta de reduzir a incidência da infecção em 90% até 2030. Objetivo: Descrever a prevalência do anti-HCV e os aspectos sociodemográficos e clínicos, relacionados à presença do anticorpo, na população privada de liberdade. Métodos: Estudo transversal por inquérito epidemiológico, com componente exploratório, observacional, quantitativo-analítico. Foi calculada amostra aleatória simples de 233 pessoas, Intervalo de Confiança (IC) 95%, margem de erro 4% para população de 1564 prisioneiros. Foi avaliada a relação entre os aspectos sociodemográficos e clínicos com o desfecho obtido pelo teste rápido para anti-HCV por meio da medida associativa Razão de Prevalência (RP) e IC de 95% para essa estimativa. Resultados: Participaram 240 pessoas. A prevalência do anti-HCV foi de 2%, sendo que o uso de drogas injetáveis (RP 14,75; RPIC95% 2,09-104,28), ter nascido nas décadas de 1951 a 1980 (RP 9,28; RPIC95% 1,06-81,57) e ser coinfectado com o vírus da hepatite B (RP 10,75; RPIC95% 1,66-69,65) foram os aspectos que apresentaram razão de prevalência para a presença do vírus, passível de generalização para a população. Conclusão: Trata-se de população de difícil acesso, o estudo é relevante por contribuir para medidas preventivas de saúde pública no sistema prisional. Outrossim, mostra a necessidade de se implementar medidas para evitar e conter a disseminação de HCV, visando a microeliminação da hepatite C na população carcerária.

BACKGROUND AND OBJECTIVES: Neonatal pain management is considered one of the eight principles of neonatal care. This study aims to investigate the construct reflecting neonatal non-pharmacological pain management, in a Brazilian rooming-in unit, and identify the preferred intervention. METHODS: This survey study included 47 health professionals assessed through an in-person questionnaire. Factor analysis was conducted with a rotation using the Varimax method. Cronbach’s alpha was 0.78. RESULTS: The construct comprised three factors in the following order: 1) knowledge and impact of neonatal pain on parents, 2) the benefits of pain treatment, and 3) non-pharmacological interventions. Breastfeeding is part of the first factor, revealing its particular importance. The reduction of luminosity is part of the second factor. Non-nutritive sucking with sweet solution, kangaroo position, and music therapy are part of the third factor. CONCLUSION: The construct observed in this rooming-in identified three factors and suggests that breastfeeding is the preferred intervention to implement for non-pharmacological pain management in the neonate.

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Pressure injuries, or pressure ulcers, are a common problem that may lead to infections and major complications, besides being a social and economic burden due to the costs of treatment and hospitalization. While surgery is sometimes necessary, this also has complications such as recurrence or wound dehiscence. Among the newer methods of pressure injury treatment, advanced therapies are an interesting option. This study examines the healing properties of bone marrow mononuclear cells (BM-MNCs) embedded in a plasma-based scaffold in a mouse model. Pressure ulcers were created on the backs of mice (2 per mouse) using magnets and assigned to a group of ulcers that were left untreated (Control, n = 15), treated with plasma scaffold (Plasma, n = 15), or treated with plasma scaffold containing BM-MNC (Plasma + BM-MNC, n = 15). Each group was examined at three time points (3, 7, and 14 days) after the onset of treatment. At each time point, animals were subjected to biometric assessment, bioluminescence imaging, and tomography. Once treatment had finished, skin biopsies were processed for histological and wound healing reverse transcription polymerase chain reaction (RT-PCR) array studies. While wound closure percentages were higher in the Plasma and Plasma + BM-MNC groups, differences were not significant, and thus descriptive data are provided. In all individuals, the presence of donor cells was revealed by immunohistochemistry on posttreatment onset Days 3, 7, and 14. In the Plasma + BM-MNC group, less inflammation was observed by positron emission tomography–computed tomography (PET/CT) imaging of the mice at 7 days, and a complete morphometabolic response was produced at 14 days, in accordance with histological results. A much more pronounced inflammatory process was observed in controls than in the other two groups, and this persisted until Day 14 after treatment onset. RT-PCR array gene expression patterns were also found to vary significantly, with the greatest difference noted between both treatments at 14 days when 11 genes were differentially expressed.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Abstract Peripheral nerve injuries in the upper limb can lead to substantial disability and pain. We aimed to assess how socioeconomic factors affect outcomes after repaired or reconstructed digital or major nerve trunk injuries in the upper limb. We identified 670 individuals, who underwent surgical nerve repair or reconstruction using sensory nerve autografts, in the Swedish National Quality Registry for Hand Surgery 2010–2018. Socioeconomic factors, including education, cohabitation, type of work, sick leave, immigrant status and income, were gathered from the Swedish statistical agency ( www.scb.se ) and National Diabetes Register (NDR). We calculated prevalence ratios (PR) to assess the relationship between socioeconomic factors and surgical outcomes for the nerve injuries. Individuals with a major nerve trunk injury had higher QuickDASH scores and lower income compared to those with digital nerve injury. Individuals with immigration background (adjusted PR = 2.0, 95% CI 1.2–3.2), history of > 4 weeks of sick leave the year before surgery (adjusted PR = 1.8, 95% CI 1.1–3.1), or education level below tertiary (adjusted PR = 2.8, 95% CI 1.7–4.7) had significantly higher QuickDASH scores. Recognizing impact of non-biological factors, including immigration, prior sick leave, and education level, on outcome after nerve surgery is crucial for improving prognosis in socioeconomically deprived individuals.

Abstract When someone violates a social norm, others may think that some sanction would be appropriate. We examine how the experience of emotions like anger and disgust relate to the judged appropriateness of sanctions, in a pre-registered analysis of data from a large-scale study in 56 societies. Across the world, we find that individuals who experience anger and disgust over a norm violation are more likely to endorse confrontation, ostracism and, to a smaller extent, gossip. Moreover, we find that the experience of anger is consistently the strongest predictor of judgments of confrontation, compared to other emotions. Although the link between state-based emotions and judgments may seem universal, its strength varies across countries. Aligned with theoretical predictions, this link is stronger in societies, and among individuals, that place higher value on individual autonomy. Thus, autonomy values may increase the role that emotions play in guiding judgments of social sanctions.

Objectives. The study aimed to assess the relationship of tinnitus with hyperacusis with cognitive impairment as indicated by the Montreal Cognitive Assessment (MoCA) tool. Methods. This multicenter cross-sectional study included individuals with chronic tinnitus from the “Unification of Treatments and Interventions for Tinnitus Patients” (UNITI) database. Participants were recruited from four different tertiary clinical centers located in Athens and Granada (Mediterranean group), as well as Berlin and Regensburg (German group). In total, 380 individuals with a diagnosis of non-pulsatile chronic tinnitus (permanent and constant tinnitus lasting more than 6 months) and no evidence of severe cognitive impairment (MoCA score >22) were enrolled. The evaluation utilized the following tools: MoCA, Tinnitus Handicap Inventory (THI), Hyperacusis Questionnaire (GÜF), Patient Health Questionnaire (PHQ-9), and the European School for Interdisciplinary Tinnitus Research Screening Questionnaire. Results. MoCA scores differed between German and Mediterranean individuals (P