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Abstract Chronic limb-threatening ischemia (CLTI) significantly increases the risk of major adverse limb events (MALE) and major adverse cardiac events (MACE) after lower extremity revascularization (LER). This study aims to identify novel biomarkers that help to further reduce the risk of postoperative cardiovascular complications. In this prospective, nonrandomized, observational study, baseline serum levels of sirtuin 1 (SIRT1) were assessed in 147 diabetic patients scheduled for LER due to CLTI, and participants were followed for the occurrence of MALE and MACE over 12 months. Fifty-three patients experienced MALE, and 33 experienced MACE within the follow-up period. Lower baseline SIRT1 levels were significantly associated with an increased risk of MALE and MACE, independent of other risk factors. The ROC curve analysis identified a SIRT1 cutoff of 3.79 ng/mL for predicting the risk of MALE. Moreover, incorporating SIRT1 into predictive models significantly enhanced the accuracy of predicting adverse outcomes. Results suggest serum SIRT1 is a potential independent marker for predicting MALE and MACE in diabetic patients with CLTI undergoing LER. Further research is needed to clarify the mechanistic pathways in which SIRT1 may influence cardiovascular outcomes, and the role of this novel biomarker in the management of PAD and CLTI among patients with diabetes.

Abstract Background Aggressive malignancies, such as pancreatic cancer, are increasingly impacting young, female populations. Our investigation centered on whether the observed trends in cancer incidence were unique to pancreatic cancer or indicative of a broader trend across various cancer types. To delve deeper into this phenomenon, we analyzed cancer incidence trends across different age and sex groups. Furthermore, we explored differences in cancer incidence within specific young subgroups aged 18 to 26 and 27 to 34, to better understand the emerging incidence trend among young individuals. Methods This study collected cancer incidence data from one of the Surveillance, Epidemiology, and End Results cancer registry databases (SEER22), with 10,183,928 total cases from 2000 to 2020. Data were analyzed through Joinpoint trend analysis approach to evaluate sex- and age-specific trends in cancer incidence. Exposure rates were reported as Average Annual Percentage Changes (AAPCs). Results The analysis revealed significant age and sex-specific disparities, particularly among individuals aged 18–26 and 27–34. Pancreatic cancer incidence rates increased more in females aged 18–26 (AAPC, 9.37% [95% CI, 7.36–11.41%]; p

Abstract A detailed knowledge of the decay properties of the so called Hoyle state in the $$^{12}$$ 12 C nucleus ( $$E_x=7.654$$ E x = 7.654 MeV, $$0^+$$ 0 + ) is required to calculate the rate at which carbon is forged in typical red-giant stars. This paper reports on a new almost background-free measurement of the radiative decay branching ratio of the Hoyle state using advanced charged particle coincidence techniques. The exploitation, for the first time in a similar experiment, of a bidimensional map of the coincidence efficiency allows to reach an unitary value and, consequently, to strongly reduce sources of systematic uncertainties. The present results suggest a value of the radiative branching ratio of $$\Gamma _{rad}/\Gamma _{tot}=4.2(6)\cdot 10^{-4}$$ Γ rad / Γ tot = 4.2 ( 6 ) · 10 - 4 . This finding helps to resolve the tension between recent data published in the literature.

Abstract Robotic literature widely addresses deformable object manipulation, but few studies analyzed human manipulation accounting for different levels of deformability and task properties. We asked participants to grasp and insert rigid and deformable objects into holes with varying tolerances and depths, and we analyzed the grasping behavior, the reaching velocity profile, and completion times. Results indicated that the more deformable the object is, the nearer the grasping point is to the extremity to be inserted. For insertions in the long hole, the selection of the grasping point is a trade-off between task accuracy and the number of re-grasps required to complete the insertion. The compliance of the deformable object facilitates the alignment between the object and the hole. The reaching velocity profile when increasing deformability recalls the one observed when task accuracy and precision decrease. Identifying human strategy allows the implementation of human-inspired high-level reasoning algorithms for robotic manipulation.

Background Engaged teachers experience a positive, fulfilling, and work-related state of mind related to their work tasks able to affect their well-being positively. Nevertheless, teachers are particularly exposed to burnout risk, which is highly probable to occur during teachers’ professional careers. The current study investigates the mediating effect of burnout, through which work engagement influences subjective well-being.Methods Participants were 807 Italian teachers (Female, 91.7%; Mage = 47.54; SD = 9.91). Self-report instruments were administered to evaluate teachers’ burnout (BAT, Burnout Assessment Tool), well-being (WHO-5 Well-being Index), and work engagement (UWES-3, Utrecht Work Engagement Scale).Results Findings show that exhaustion (β = −0.2162, p

Paradoxical deterioration in patients with tuberculous meningitis is a significant diagnostic and treatment challenge. We present the case of a 55-year-old previously healthy male, human immunodeficiency virus (HIV)-negative, presenting with headache, fever, agitation and slurred speech, who was ultimately diagnosed with tuberculous meningoencephalitis confirmed by cerebrospinal fluid polymerase chain reaction positive for Mycobacterium tuberculosis complex. After initiation of a standard antitubercular therapy combined with glucocorticoids, the patient experienced an initial neurological improvement. However, after 3 months of therapy, he had a major stroke with neurological deterioration, clinically and radiologically attributable to a paradoxical deterioration or an immune reconstruction syndrome as described in HIV-positive patients. Due to the persistence of inflammatory symptoms and radiological evidence of worsening tuberculomas despite ongoing antituberculosis therapy, off-label use of the tumour necrosis factor (TNF) inhibitor infliximab was initiated. The patient received three doses of infliximab at 5 mg/kg at monthly intervals, which led to marked clinical and radiological improvement. Follow-up magnetic resonance imaging showed regression of lesions, and the patient was eventually discharged with a significant recovery of motor and speech functions. This case underscores the potential of TNF inhibitors in managing severe cases of paradoxical deterioration in patients with tuberculous meningitis, challenging existing treatment paradigms and suggesting a need for further research into the pathophysiology and treatment of this condition.

Abstract Is Stochastic Gradient Descent (SGD) substantially different from Metropolis Monte Carlo dynamics? This is a fundamental question at the time of understanding the most used training algorithm in the field of Machine Learning, but it received no answer until now. Here we show that in discrete optimization and inference problems, the dynamics of an SGD-like algorithm resemble very closely that of Metropolis Monte Carlo with a properly chosen temperature, which depends on the mini-batch size. This quantitative matching holds both at equilibrium and in the out-of-equilibrium regime, despite the two algorithms having fundamental differences (e.g. SGD does not satisfy detailed balance). Such equivalence allows us to use results about performances and limits of Monte Carlo algorithms to optimize the mini-batch size in the SGD-like algorithm and make it efficient at recovering the signal in hard inference problems.

Non-A non-B aortic dissection is considered a rare nosological entity, included in the Stanford classification, representing a small percentage of the total aortic dissections that occur annually. Regarding this form, the literature reports a more complicated disease course compared to other types of dissection. We describe the case of a 76-year-old patient who accessed the triage section of an emergency department for a polytrauma picture and, after surgical treatment of a leg fracture, received a diagnosis of non-A non-B aortic dissection, "localized" to the arch and incidentally detected. The angio-computed tomography (CT) showed that the only intimal tear was located in the central portion of the aortic arch, with no exit tear. No signs of malperfusion or clinical symptoms related to the aortic finding were evident. The Aortic Team decided on a conservative approach, whereby the patient was started on medical therapy to control blood pressure in a monitored bed of a semi-intensive care unit. The persistent asymptomatic state, a condition of hemodynamic stability, and an unchanged angio-CT picture enabled discharge on day 7 and the assignment to a close follow-up.

Abstract The utilization of kidneys from donors with acute kidney injury (AKI) is often limited by unpredictable post-transplantation outcomes. The aim of our study was to identify protein mediators implicated in either recovery or failure of these organs. Forty kidney biopsies from donors with (20) and without AKI (20) were selected and then subdivided according to the post-transplant outcome defined as a threshold of 45 ml/min for the eGFR at 1 year from transplantation. Tissue homogenates were analysed by western blot to assess how the levels of 17 pre-selected proteins varied across the four groups. Samples from AKI kidneys with a poor outcome showed a fourfold increase in the levels of PPARg and twofold reduction of STAT1 compared to the other groups (p

Abstract Background Osteoarthritis (OA) is a multifactorial, hypertrophic, and degenerative condition involving the whole joint and affecting a high percentage of middle-aged people. It is due to a combination of factors, although the pivotal mechanisms underlying the disease are still obscure. Moreover, current treatments are still poorly effective, and patients experience a painful and degenerative disease course. Methods We used an integrative approach that led us to extract a consensus signature from a meta-analysis of three different OA cohorts. We performed a network-based drug prioritization to detect the most relevant drugs targeting these genes and validated in vitro the most promising candidates. We also proposed a risk score based on a minimal set of genes to predict the OA clinical stage from RNA-Seq data. Results We derived a consensus signature of 44 genes that we validated on an independent dataset. Using network analysis, we identified Resveratrol, Tenoxicam, Benzbromarone, Pirinixic Acid, and Mesalazine as putative drugs of interest for therapeutics in OA for anti-inflammatory properties. We also derived a list of seven gene-targets validated with functional RT-qPCR assays, confirming the in silico predictions. Finally, we identified a predictive subset of genes composed of DNER, TNFSF11, THBS3, LOXL3, TSPAN2, DYSF, ASPN and HTRA1 to compute the patient’s risk score. We validated this risk score on an independent dataset with a high AUC (0.875) and compared it with the same approach computed using the entire consensus signature (AUC 0.922). Conclusions The consensus signature highlights crucial mechanisms for disease progression. Moreover, these genes were associated with several candidate drugs that could represent potential innovative therapeutics. Furthermore, the patient’s risk scores can be used in clinical settings.

Abstract The diffuse presence of small copper ore deposits in the Alpine area, mostly exploited since Late Medieval times, led most scholars to assume that these deposits may actually be active much earlier and that many of the circulating prehistoric metal objects found in the area were produced with local copper sources. This assumption was recently validated for the Recent Bronze Age through the use of lead isotope tracers, and well supported by the archaeometallurgical evidences found in the South-Eastern Alps. However, the scarcity of available lead isotope data for pre-Bronze Age metals precluded to date the reconstruction of the metal flow through the Late Neolithic and Eneolithic (or Copper Age). Based on 49 new analyses of important archaeological objects from the Alpine region, the Po River Valley and Central Italy, mostly axes dated from the Late Neolithic to the Late Eneolithic, here we show that the diffusion of copper in Northern Italy (approximately 4500–2200 BC) includes three major periods of metal use and/or production, each related to specific ore sources. The South Alpine copper was massively used only starting from the middle of the 3rd millennium BC, in connection or slightly earlier than the Beaker event.

Abstract The study aimed to assess the metabolomic profile of the synovial fluid (SF) of dogs affected by spontaneous osteoarthritis (OA) and compare any differences based on disease progression. Sixty client-owned dogs affected by spontaneous OA underwent clinical, radiographic, and cytologic evaluations to confirm the diagnosis. The affected joints were divided into four study groups based on the Kallgreen–Lawrence classification: OA1 (mild), OA2 (moderate), OA3 (severe), and OA4 (extremely severe/deforming). The osteoarthritic joint’s SF was subjected to cytologic examination and 1H-NMR analysis. The metabolomic profiles of the study groups’ SF samples were statistically compared using one-way ANOVA. Sixty osteoarthritic joints (45 stifles, 10 shoulders and 5 elbows) were included in the study. Fourteen, 28, and 18 joints were included in the OA1, OA2, and OA3 groups, respectively (0 joints in the OA4 group). Metabolomic analysis identified 48 metabolites, five of which were significantly different between study groups: Mannose and betaine were elevated in the OA1 group compared with the OA2 group, and the 2-hydroxyisobutyrate concentration decreased with OA progression; in contrast, isoleucine was less concentrated in mild vs. moderate OA, and lactate increased in severe OA. This study identified different 1H-NMR metabolomic profiles of canine SF in patients with progressive degrees of spontaneous OA, suggesting 1H-NMR metabolomic analysis as a potential alternative method for monitoring OA progression. In addition, the results suggest the therapeutic potentials of the metabolomic pathways that involve mannose, betaine, 2-hydroxyisobutyrate, isoleucine, and lactate.

Abstract BackgroundThe Society of Thoracic Surgeons and European System for Cardiac Operative Risk Evaluation (EuroSCORE) II risk scores are the most commonly used risk prediction models for in-hospital mortality after adult cardiac surgery. However, they are prone to miscalibration over time and poor generalization across data sets; thus, their use remains controversial. Despite increased interest, a gap in understanding the effect of data set drift on the performance of machine learning (ML) over time remains a barrier to its wider use in clinical practice. Data set drift occurs when an ML system underperforms because of a mismatch between the data it was developed from and the data on which it is deployed. ObjectiveIn this study, we analyzed the extent of performance drift using models built on a large UK cardiac surgery database. The objectives were to (1) rank and assess the extent of performance drift in cardiac surgery risk ML models over time and (2) investigate any potential influence of data set drift and variable importance drift on performance drift. MethodsWe conducted a retrospective analysis of prospectively, routinely gathered data on adult patients undergoing cardiac surgery in the United Kingdom between 2012 and 2019. We temporally split the data 70:30 into a training and validation set and a holdout set. Five novel ML mortality prediction models were developed and assessed, along with EuroSCORE II, for relationships between and within variable importance drift, performance drift, and actual data set drift. Performance was assessed using a consensus metric. ResultsA total of 227,087 adults underwent cardiac surgery during the study period, with a mortality rate of 2.76% (n=6258). There was strong evidence of a decrease in overall performance across all models (P ConclusionsAll models show a decrease in at least 3 of the 5 individual metrics. CEM and variable importance drift detection demonstrate the limitation of logistic regression methods used for cardiac surgery risk prediction and the effects of data set drift. Future work will be required to determine the interplay between ML models and whether ensemble models could improve on their respective performance advantages.

This study investigates the biochemical composition and biological properties of different parts (leaves, roots, and twigs) of two Cistus species (Cistus monspeliasis and Cistus parviflorus). The extracts were analysed using UHPLC-MS/MS to determine their chemical profiling. A range of antioxidant assays were performed to evaluate the extract’s antioxidant capabilities. The enzyme inhibition studies focused on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase, and α-glucosidase and tyrosinase. In addition, the study examined the antimicrobial effects on different bacteria and yeasts and evaluated the toxicity using the MTT assay. Quinic acid, citric acid, gallic acid, catechin, quercetin derivatives, kaempferol, myricetin, ellagic acid, prodelphinidins, procyanidins, scopoletin, and flavogallonic acid dilactone are the main bioactive compounds found in both species. In enzyme inhibition assays, C. monspeliasis roots exhibited significant activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with the values of 2.58 ± 0.02 mg GALAE/g and 11.37 ± 1.93 mg GALAE/g, respectively. Cytotoxicity studies showed mostly weak toxicity, with some samples moderately reducing viability in RAW and HepG2 cells. These findings underscore the diverse biochemical profiles and bioactive potential of Cistus species, suggesting their utility as natural sources of antioxidants and enzyme inhibitors for pharmaceutical and nutraceutical development.

In Italy, free vaccinations for Herpes Zoster (HZ), pneumococcal (PCV), and influenza (FLU) are recommended each year for individuals turning 65. Despite this, achieving optimal vaccination coverage remains challenging. This study assesses coverage rates for HZ, PCV, and FLU in Forlì, Northern Italy, and examines how altitude, urban planning, and health organization variables (such as the presence of a vaccination center) impact vaccine uptake. Vaccination coverages were calculated for birth cohorts between 1952 and 1958 for each municipality in the Forlì area as of 1 March 2024. The geographical factors influencing the vaccination uptake were extracted from the Italian National Institute of Statistics (ISTAT) records and evaluated through a multivariate analysis. The sample analyzed included 15,272 vaccine campaign targets from Forlì’s province (185,525 citizens); the vaccine uptake rates for HZ, PCV, and FLU were 26.9%, 36.7%, and 43.5%, respectively. Gender did not appear to influence vaccine uptake. Living in a flat area appeared to increase vaccine uptake in a statistically significant way for all the vaccinations when compared to a mountainous area (HZ: OR: 1.50, PCV: OR: 1.33, FLU: OR: 1.67). The presence of a vaccine service in low-urbanized areas was shown to increase vaccine uptake for all vaccinations (HZ: OR: 1.65, PCV: OR: 1.93, FLU: OR: 1.53) compared with low-urbanized areas without a vaccination center or more urbanized areas with a vaccination center. This study emphasizes the significance of the territorial context, along with the ease of access to vaccinations and geographic barriers, as key determinants in achieving vaccination targets. Local health authorities should consider these factors when implementing vaccination campaigns.

Abstract Background Apixaban is a non-vitamin K antagonist oral anticoagulant (NOACs) recently emerged as an effective alternative to conventional vitamin K antagonists (VKAs) in the treatment of several thromboembolic disorders. However, in case of overdose or in patients requiring emergency surgery there is a high bleeding rate and severe adverse side effects due to the absence of an antidote. There is promising data from in vitro and clinical studies, that certain antithrombotic agents (that is Rivaroxaban and Ticagrelor) have been successfully removed by the extracorporeal hemoadsorption therapy CytoSorb. Here, we present the case of a patient successfully treated with CytoSorb as a kind of antidote to enable emergency surgery for bilateral nephrostomy. Case presentation A 82-year-old Caucasian man was admitted to the Emergency Room with acute kidney injury (AKI) in the context of severe bilateral hydroureteronephrosis. The patient’s medical history included chronic obstructive pulmonary disease, arterial hypertension, atrial fibrillation (anticoagulated with Apixaban) and a locally advanced prostate adenocarcinoma treated with trans-ureteral resection of the bladder and radiotherapy in the previous months. The indication for a bilateral nephrostomy could not be considered immediately given the major bleeding risk due to Apixaban, which was discontinued and replaced with calciparin. After 36 hours of continuous renal replacement therapy (CRRT), the Apixaban blood level was still elevated and it was decided to install CytoSorb into the running CRRT to accelerate the drug clearance. After 2 hours 30 minutes, there was good reduction of Apixaban from 139 to 72 ng/ml (reduction rate of 48.2%) registered, and this allowed for an easy placement of bilateral nephrostomies without complications. Four days after surgery renal function parameters further normalized, the patient did not require additional dialysis treatments and Apixaban therapy was prescribed again once the patient returned home. Conclusions In this case we report the findings of a patient with post-renal AKI requiring emergency nephrostomy placement while on chronic anticoagulation with Apixaban therapy. Combined treatment with CRRT and CytoSorb was associated with the rapid and effective removal of Apixaban allowing for prompt and urgent surgery while simultaneously ensuring the low risk of bleeding as well as an uneventful post-operative course.

Abstract Familial Hypercholesterolemia (FH) is characterized by an increase in Low-Density Lipoprotein Cholesterol (LDL-C) and by premature Cardiovascular Disease (CVD). However, it remains to be fully elucidated if FH impairs cholesterol efflux capacity (CEC), and whether CEC is related to lipoprotein subfraction distribution. This study aimed at comparing FH patients and age, sex and BMI matched controls in terms of LDL and HDL subfraction distribution as well as CEC. Forty FH patients and 80 controls, matched for age, sex and BMI, were enrolled in this case–control study. LDL and HDL subfractions were analyzed using the Quantimetrix Lipoprint System. CEC was evaluated as aq-CEC and ABCA1-CEC. FH subjects showed a significantly higher concentration of all LDL subfractions, and a shift from large to small HDL subfraction pattern relative to controls. FH subjects with previous CVD event had smaller LDL lipoproteins than controls and FH subjects without previous CVD event. Both aq-CEC and ABCA1-CEC were increased in FH patients with respect to controls. To conclude, FH subjects had a metabolic profile characterized not only by higher LDL-C but also by shift from large to small HDL subfraction phenotype. However, FH subjects showed an increase CEC than controls.

Abstract Tumour DNA sequencing is essential for precision medicine since it guides therapeutic decisions but also fosters the identification of patients who may benefit from germline testing. Notwithstanding, the tumour-to-germline testing workflow presents a few caveats. The low sensitivity for indels at loci with sequences of identical bases (homopolymers) of ion semiconductor-based sequencing techniques represents a well-known limitation, but the prevalence of indels overlooked by these techniques in high-risk populations has not been investigated. In our study, we addressed this issue at the homopolymeric regions of BRCA1/2 in a retrospectively selected cohort of 157 patients affected with high-grade ovarian cancer and negative at tumour testing by ION Torrent sequencing. Variant allele frequency (VAF) of indels at each of the 29 investigated homopolymers was systematically revised with the IGV software. Thresholds to discriminate putative germline variants were defined by scaling the VAF to a normal distribution and calculating the outliers that exceeded the mean + 3 median-adjusted deviations of a control population. Sanger sequencing of the outliers confirmed the occurrence of only one of the five putative indels in both tumour and blood from a patient with a family history of breast cancer. Our results indicated that the prevalence of homopolymeric indels overlooked by ion semiconductor techniques is seemingly low. A careful evaluation of clinical and family history data would further help minimise this technique-bound limitation, highlighting cases in which a deeper look at these regions would be recommended.

Abstract Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-fibroblast growth factor 23 (FGF23) axis is associated with endothelial injury and cardiovascular risk. We aimed to analyze the relationship between Klotho and FGF23 serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI. Baseline levels of Klotho and FGF23, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER. A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs. 446.4 ± 171.7 pg/mL, p

Introduction Along with European integration and the harmonisation of living conditions, improvements in health have been observed over the past decades. However, sociospatial inequalities within and across member states still exist today. While drivers of these health inequalities have been widely researched on a national and regional scale, cross-border regions remain understudied. The removal of border controls within the European Union (EU) member states has facilitated economic convergence and created new opportunities, including cross-border cooperation in the healthcare systems. However, whether and how these developments have influenced the population health in the respective cross-border regions is unclear. Hence, this scoping review aims to examine the empirical literature on the changes in health outcomes over time at the population level in EU cross-border areas. Additionally, we aim to identify the type of evidence and available data sources in those studies. Finally, we will determine the research gaps in the literature.Methods and analysis We will follow the Joanna Briggs Institute methodology for this scoping review. The ‘Population–Concept–Context’ framework will be used to identify the eligibility criteria. A three-step search strategy will be conducted to find relevant studies in the databases of PubMed, Web of Science, Scopus and EBSCOhost (SocIndex). Additionally, we will search on websites of international governmental institutions for further reports and articles. The finalisation of the search is planned for August 2023. The extracted data from the scoping review will be presented in a tabular form. A narrative summary of the selected studies will accompany the tabulated results and describe how they answer the research questions.Ethics and dissemination We will exclusively use secondary data from available studies for our analysis. Therefore, this review does not require ethical approval. We aim to publish our findings at (inter-)national conferences and as an open-access, peer-reviewed journal article.

Introduction Congenital heart disease (CHD) represents the most common birth defect, affecting from 0.4% to 1.2% of children born in developed countries. The survival of these patients has increased significantly, but CHD remains one of the major causes of neonatal and childhood death. The aetiology of CHD is complex, with some evidence of both genetic and environmental causes. However, there is still lack of knowledge regarding modifiable risk factors and molecular and genetic mechanisms underlying the development of CHD. This study aims to develop a prospective cohort of patients undergoing cardiac procedures that will bring together routinely collected clinical data and biological samples from patients and their biological mothers, in order to investigate risk factors and predictors of postoperative-outcomes, as well as better understanding the effect of the surgical intervention on the early and long-term outcomes.Methods and analysis Children OMACp (OMACp, outcome monitoring after cardiac procedure in congenital heart disease) is a multicentre, prospective cohort study recruiting children with CHD undergoing a cardiac procedure. The study aims to recruit 3000 participants over 5 years (2019–2024) across multiple UK sites. Routine clinical data will be collected, as well as participant questionnaires collecting sociodemographic, NHS resource use and quality of life data. Biological samples (blood, urine and surgical waste tissue from patients, and blood and urine samples from biological mothers) will be collected where consent has been obtained. Follow-up outcome and questionnaire data will be collected for 5 years.Ethics and dissemination The study was approved by the London–Brent Research Ethics Committee on 30 July 2019 (19/SW/0113). Participants (or their parent/guardian if under 16 years of age) must provide informed consent prior to being recruited into the study. Mothers who wish to take part must also provide informed consent prior to being recruited. The study is sponsored by University Hospitals Bristol and Weston Foundation Trust and is managed by the University of Bristol. Children OMACp is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated through peer-reviewed publications, presentation at conference, meetings and through patient organisations and newsletters.Trial registration number ISRCTN17650644.

Objective To model the referral, diagnostic and treatment pathway for cardiovascular disease (CVD) in the English National Health Service (NHS) to provide commissioners and managers with a methodology to optimise patient flow and reduce waiting lists.Study design A systems dynamics approach modelling the CVD healthcare system in England. The model is designed to capture current and predict future states of waiting lists.Setting Routinely collected, publicly available data streams of primary and secondary care, sourced from NHS Digital, NHS England, the Office of National Statistics and StatsWales.Data collection and extraction methods The data used to train and validate the model were routinely collected and publicly available data. It was extracted and implemented in the model using the PySD package in python.Results NHS cardiovascular waiting lists in England have increased by over 40% compared with pre- COVID-19 levels. The rise in waiting lists was primarily due to restrictions in referrals from primary care, creating a bottleneck postpandemic. Predictive models show increasing point capacities within the system may paradoxically worsen downstream flow. While there is no simple rate-limiting step, the intervention that would most improve patient flow would be to increase consultant outpatient appointments.Conclusions The increase in NHS CVD waiting lists in England can be captured using a systems dynamics approach, as can the future state of waiting lists in the presence of further shocks/interventions. It is important for those planning services to use such a systems-oriented approach because the feed-forward and feedback nature of patient flow through referral, diagnostics and treatment leads to counterintuitive effects of interventions designed to reduce waiting lists.

Over the past centuries, myology as a basic and clinical science has passed through three major stages of development: the classical period, the modern nosographic stage, and the molecular era. The classical period spans the sixteenth century up to the earlier parts of the twentieth century. During this time, several major muscle diseases were clinically and pathologically characterized, including Duchenne muscular dystrophy (DMD), myotonic dystrophy, and facio-scapulo-humeral dystrophy, by master clinicians such as Duchenne, Erb, Becker, Steinert, Landouzy, Dejerine, Meryon, and others. These accomplishments laid solid foundations for the following modern era with nosographic classification and the following molecular era. European clinicians and scientists were major contributors to the modern era in the second half of the twentieth century, which is characterized by three major discoveries. First, it was observed that substantial elevation of the serum activity of creatine kinase indicates muscle damage or destruction. Then, the adaptation of modern histo-and cytochemical techniques to the study of muscle biopsies markedly improved the diagnostic accuracy and made possible the identification of new changes and structures. Thirdly, the advent of modern biochemical techniques permitted the identification of various enzyme defects/storage diseases such as Pompe disease, McArdle's disease, and carnitine deficiency states. The molecular era was made possible by the strikingly fast development of molecular biology and its application to muscle diseases. This permitted the identification of gene defects in many inherited diseases, leading to an accurate and specific diagnosis. The growth of international collaboration in Europe was achieved through the exchange of international scientists and collaborative networks.

The Herpes Zoster (HZ) vaccination has proven both safe and effective in alleviating conditions related to HZ, leading to significant cost savings in national healthcare and social systems. In Italy, it is recommended and provided free of charge to individuals aged 65 and older. To achieve broad vaccination coverage, alongside ordinary immunization campaigns, active and catch-up campaigns were implemented. This retrospective observational study aimed to observe the vaccination coverage achieved in the Romagna Local Health Authority (LHA) during the 2023 active campaign, with a secondary goal of assessing the impact of the 2022 catch-up campaign and the 2023 active campaign compared to ordinary campaigns. As of 3 July 2023, an overall vaccine uptake of 13.5% was achieved among individuals born in 1958, with variations among the four LHA centers ranging from 10.2% to 17.7%. Catch-up and active campaigns together contributed to nearly half of the achieved coverage in Center No. 1 and a quarter in Center No. 2. Notably, individuals born in 1957, not included in the Center No. 2 catch-up campaign, reached significantly lower vaccination coverage compared to other cohorts and centers. Analyzing the use of text messages for active campaigns, it was observed that cohort groups did not show substantial differences in text-message utilization for warnings. However, having relatives who had experienced HZ-related symptoms significantly reduced the reliance on text messages as warnings. These results highlighted how catch-up and active campaigns effectively increased vaccine coverage. Nevertheless, differences in uptake among different centers within the same LHA and the limited contribution of other information sources compared to text messages suggest the necessity of designing campaigns involving all available channels and stakeholders to maximize vaccine uptake.

We present a genome assembly of Caretta caretta (the Loggerhead sea turtle; Chordata, Testudines, Cheloniidae), generated from genomic data from two unrelated females. The genome sequence is 2.13 gigabases in size. The assembly has a busco completion score of 96.1% and N50 of 130.95 Mb. The majority of the assembly is scaffolded into 28 chromosomal representations with a remaining 2% of the assembly being excluded from these.

Objectives To assess the effectiveness of injectable tissue pulmonary valve compared with standard pulmonary valve in patients requiring pulmonary valve replacement surgery.Design A multicentre, single-blind, parallel two-group randomised controlled trial. Participants were blind to their allocation. Follow-up continued for 6 months. Randomised allocations were generated by a computer using block randomisation, stratified by centre.Setting Two National Health Service secondary care centres in the UK.Participants People aged 12–80 years requiring pulmonary valve replacement.Interventions Participants were randomly allocated (1:1 ratio) to injectable pulmonary valve replacement (IPVR) without cardiopulmonary bypass (CPB) or standard pulmonary valve replacement (SPVR) with CPB.Primary and secondary outcome measures The primary outcome was chest drainage volume over the first 24 hours after surgery. Secondary outcomes included in-hospital clinical outcomes; valve and heart function 6 months postsurgery and health-related quality of life 6 weeks and 6 months postsurgery.Results Nineteen participants agreed to take part. Eleven were allocated to IPVR and eight to SPVR. The trial was stopped before the target sample size of 60 participants was reached due to challenges in recruitment. The primary analysis includes all randomised participants; there were no withdrawals. Chest drain volume 24 hours after surgery was on average 277.6 mL lower with IPVR (IPVR mean 340.0 mL; SPVR mean 633.8 mL; mean difference, −277.6; 95% CI, −484.0 to −71.2; p=0.005). There were no statistically significant differences in time to readiness for extubation (p=0.476), time to fitness for discharge (p=0.577) and time to first discharge from the intensive care unit (p=0.209). Six participants with IPVR required CPB. Safety profiles and quality of life scores were similar.Conclusions IPVR reduced chest drain volume despite >50% of participants requiring CPB. There was no evidence of any other benefit of IPVR.Trial registration number ISRCTN23538073.

Introduction Brain injury is common following open heart valve surgery. Carbon dioxide insufflation (CDI) has been proposed to reduce the incidence of brain injury by reducing the number of air microemboli entering the bloodstream in surgery. The CO2 Study will evaluate the efficacy and safety of CDI in patients undergoing planned left-sided open heart valve surgery.Methods and analysis The CO2 Study is a multicentre, blinded, placebo-controlled, randomised controlled trial. Seven-hundred and four patients aged 50 years and over undergoing planned left-sided heart valve surgery will be recruited to the study, from at least eight UK National Health Service hospitals, and randomised in a 1:1 ratio to receive CDI or medical air insufflation (placebo) in addition to standard de-airing. Insufflation will be delivered at a flow rate of 5 L/min from before the initiation of cardiopulmonary bypass until 10 min after cardiopulmonary bypass weaning. Participants will be followed up until 3 months post-surgery. The primary outcome is acute ischaemic brain injury within 10 days post-surgery based on new brain lesions identified with diffusion-weighted MRI or clinical evidence of permanent brain injury according to the current definition of stroke.Ethics and dissemination The study was approved by the East Midlands–Nottingham 2 Research Ethics Committee in June 2020 and the Medicines and Healthcare products Regulatory Agency in May 2020. All participants will provide written informed consent prior to undertaking any study assessments. Consent will be obtained by the principal investigator or a delegated member of the research team who has been trained in the study and undergone Good Clinical Practice training. Results will be disseminated through peer-reviewed publications and presentations at national and international meetings. Study participants will be informed of results through study notifications and patient organisations.Trial registration number ISRCTN30671536.

Preparation for oxidative stress (POS) is a widespread adaptive response to harsh environmental conditions, whose hallmark is the upregulation of antioxidants. In contrast to controlled laboratory settings, animals are exposed to multiple abiotic stressors under natural field conditions. Still, the interplay between different environmental factors in modulating redox metabolism in natural settings remains largely unexplored. Here, we aim to shed light on this topic by assessing changes in redox metabolism in the mussel Brachidontes solisianus naturally exposed to a tidal cycle. We compared the redox biochemical response of mussels under six different natural conditions in the field along two consecutive days. These conditions differ in terms of chronology, immersion/emersion, and solar radiation, but not in terms of temperature. Animals were collected after being exposed to air early morning (7:30), immersed during late morning and afternoon (8:45–15:30), and then exposed to air again late afternoon towards evening (17:45–21:25), in two days. Whole body homogenates were used to measure the activity of antioxidant (catalase, glutathione transferase and glutathione reductase) and metabolic (glucose 6-phosphate dehydrogenase, malate dehydrogenase, isocitrate dehydrogenase and pyruvate kinase) enzymes, reduced (GSH) and disulfide (GSSG) glutathione levels, and oxidative stress markers (protein carbonyl and thiobarbituric acid reactive substances). Air and water temperature remained stable between 22.5 °C and 26 °C during both days. Global solar radiation (GSR) greatly differed between days, with a cumulative GSR of 15,381 kJ/m2 for day 1 and 5,489 kJ/m2 for day 2, whose peaks were 2,240 kJ/m2/h at 14:00 on day 1 and 952 kJ/m2/h at 12:00 on day 2. Compared with animals underwater, emersion during early morning did not elicit any alteration in redox biomarkers in both days. Air exposure for 4 h in the late afternoon towards evening caused oxidative damage to proteins and lipids and elicited GSH synthesis in animals that had been previously exposed to high GSR during the day. In the following day, when GSR was much lower, exposure to air under the same conditions (duration, time, and temperature) had no effect on any redox biomarker. These findings suggest that air exposure under low-intensity solar radiation is not sufficient to trigger POS in B. solisianus in its natural habitat. Thus, natural UV radiation is possibly a key environmental factor that combined to air exposure induces the POS-response to the stressful event of tidal variation in this coastal species.

Progress in muscle research has been through different phases over the past decades. Here are reviewed the advances presented at the International Congresses of Neuromuscular Diseases (ICNMD). In the ‘60 to ‘80 muscle physiology and interpretations of muscle biopsy were the major focuses, diagnosis of muscle disorders was advanced utilizing histochemical, and ultrastructural techniques, and the focus of first to IVth ICNMD was prevention and Muscle Disorders classification as major issues. After that from ‘80 to 2000 muscle neuromuscular junction (NMJ) immunology, biochemistry, molecular biology , therapeutic trials, and genetics were the major developments and represented the focus of research in following ICNMD from the Vth to the Xth. From 2000 to 2020 personalized medicine,genotype-phenotype correlation, and the use of DNA/RNA profiling , Imaging was developed and represented substantial signs of progress that were presented in ICNMD XIth to XVIIth. The future is evolving toward a major involvement of the pharmaceutical industry with new drugs and gene-delivered therapy, the use of biomarkers and robotics as well as of artificial intelligence, both for interpreting morphology, DNA, and imaging diagnostic, and such developments will be reflected in research presented in future Congresses.

Este artículo describe el proceso de diseño y las características de un cuestionario y una pauta de observación intradomiciliaria desarrollados para evaluar tanto transversal como longitudinalmente la relación vivienda-barrio-salud en el marco de transformaciones urbanas llevadas a cabo en poblaciones de elevada vulnerabilidad socio-territorial. Los instrumentos se desarrollaron para el estudio longitudinal multimétodos RUCAS (Regeneración Urbana, Calidad de Vida y Salud), un experimento natural cuyo objetivo principal es evaluar el impacto en salud y calidad de vida de un programa de Regeneración de Conjuntos Habitacionales en dos conjuntos de vivienda social en Chile. El diseño de los instrumentos siguió cuatro etapas principales: (1) revisión narrativa de la literatura para definir las dimensiones del estudio, y de instrumentos existentes para identificar ítems apropiados para su medición; (2) validación de contenido con expertos; (3) pre-test; y (4) estudio piloto. El cuestionario resultante, compuesto de 262 ítems, tiene en cuenta las distintas etapas del ciclo vital y cuestiones de género. La pauta de observación intradomiciliaria (77 ítems) es aplicada por el/la encuestadora. Los instrumentos abordan (i) características de la situación residencial actual que sabidamente afectan la salud y serán intervenidas por el programa; (ii) dimensiones de la salud potencialmente afectadas por la situación residencial y/o por la intervención dentro de los plazos del estudio (4 años); (iii) otras condiciones de salud y relacionadas con la salud que sean relevantes, aun cuando no se verán modificadas dentro de los plazos del estudio, y (iv) dimensiones socioeconómicas, ocupacionales y demográficas relevantes. Los instrumentos han mostrado ser una herramienta capaz de abordar la multidimensionalidad de los procesos de transformación urbana en contextos de pobreza urbana en vivienda formal.

Abstract Phosphatidylinositol 4-kinases (PI4Ks) are the first enzymes that commit phosphatidylinositol into the phosphoinositide pathway. Here, we show that Arabidopsis thaliana seedlings deficient in PI4Kβ1 and β2 have several developmental defects including shorter roots and unfinished cytokinesis. The pi4kβ1β2 double mutant was insensitive to exogenous auxin concerning inhibition of root length and cell elongation; it also responded more slowly to gravistimulation. The pi4kß1ß2 root transcriptome displayed some similarities to a wild type plant response to auxin. Yet, not all the genes displayed such a constitutive auxin-like response. Besides, most assessed genes did not respond to exogenous auxin. This is consistent with data with the transcriptional reporter DR5-GUS. The content of bioactive auxin in the pi4kß1ß2 roots was similar to that in wild-type ones. Yet, an enhanced auxin-conjugating activity was detected and the auxin level reporter DII-VENUS did not respond to exogenous auxin in pi4kß1ß2 mutant. The mutant exhibited altered subcellular trafficking behavior including the trapping of PIN-FORMED 2 protein in rapidly moving vesicles. Bigger and less fragmented vacuoles were observed in pi4kß1ß2 roots when compared to the wild type. Furthermore, the actin filament web of the pi4kß1ß2 double mutant was less dense than in wild-type seedling roots, and less prone to rebuilding after treatment with latrunculin B. A mechanistic model is proposed in which an altered PI4K activity leads to actin filament disorganization, changes in vesicle trafficking, and altered auxin homeostasis and response resulting in a pleiotropic root phenotypes.

Organ-on-a-chip platforms are utilized in global bioanalytical and toxicological studies as a way to reduce materials and increase throughput as compared to in vivo based experiments. These platforms bridge the infrastructure and regulatory gaps between in vivo animal work and human systems, with models that exemplify active biological pathways. In conjunction with the advent of increased capabilities associated with next generation sequencing and mass spectrometry based '-omic' technologies, organ-on-a-chip platforms provide an excellent opportunity to investigate the global changes at multiple biological levels, including the transcriptome, proteome and metabolome. When investigated concurrently, a complete profile of cellular and regulatory perturbations can be characterized following treatment with specific agonists. In this study, global effects were observed and analyzed following liver chip exposure to the chemical warfare agent, VX. Even though the primary mechanism of action of VX (i.e. acetylcholinesterase inhibition) is well characterized, recent in vivo studies suggest additional protein binding partners that are implicated in metabolism and cellular energetic pathways. In addition, secondary toxicity associated with peripheral organ systems, especially in human tissues, is not well defined. Our results demonstrate the potential of utilizing an organ-on-a-chip platform as a surrogate system to traditional in vivo studies. This is realized by specifically indicating significant dysregulation of several cellular processes in response to VX exposure including but not limited to amino acid synthesis, drug metabolism, and energetics pathways.

Introduction More than 30 000 cardiac surgery procedures are performed in the UK each year, however, postoperative complications and long-term failure of interventions are common, leading to repeated surgeries. This represents a significant burden on the patient and health service.Routinely, patients are discharged to their general practitioner 6 weeks postoperatively and research studies typically only report short-term outcomes up to 1 year after surgery, together this makes long-term outcomes of cardiac surgery difficult to monitor. Further, traditional research methods have yet to advance understanding of what causes early complications and why surgical interventions fail.Methods and analysis This prospective cohort study will characterise participants undergoing cardiac surgery at baseline, describe short-term, medium-term and long-term health outcomes postoperatively and collect tissue samples.All eligible adult patients undergoing cardiac surgery at the Bristol Heart Institute, UK will be approached for consent. Recruitment is expected to continue for up to 10 years resulting in the largest cohort of cardiac patients reported to date. Blood, urine and waste tissue samples will be collected during admission. Samples, along with anonymised data, will be used to investigate outcomes and inform predictive models of complications associated with cardiac surgery.Data about the surgical admission will be obtained from hospital databases and medical notes. Participants may be monitored up to 5 years postoperatively using data obtained from NHS digital. Participants will complete health questionnaires 3 months and 12 months postoperatively.The analysis of data and tissue samples to address specific research questions will require separate research protocols and ethical approval.Ethics and dissemination This study was approved by the East Midlands Nottingham 2 Research Ethics Committee.Findings will be disseminated through peer-reviewed publications and presentation at national and international meetings. Participants will be informed of results in annual newsletters.Trial registration number ISRCTN90204321.

ABSTRACT Objective: To analyse the distances between the femoral insertions of the popliteus tendon (PT) and the lateral collateral ligament (LCL) through dissections of cadaveric specimens in a mixed population. Methods: Fresh cadavers were dissected, and the anthropometric data of all specimens were recorded. The distances from the origin of the PT to the LCL in the femoral region and the diameter of each structure were measured using a digital calliper. Results: In total, 11 unpaired knees were dissected, eight men and three women, with an average age of 71.5 ± 15.2 years, weight of 57.2 ± 15.6 kg, and a mean height of 170.5 ± 8.2 cm. The distance from the center of the femoral footprint of the LCL to the PT was 10.0 ± 2.4 mm. The distances between the edges closest to each other and those more distant from each other were 3.1 ± 1.1 mm and 16.3 ± 2.4 mm, respectively. Conclusion: The distance between the midpoints of the PT and the LCL in our mixed population is smaller than the distances often reported in the literature. PLC reconstruction with separate tunnels for the LCL and PT may not be technically possible for individuals of any population. Level of Evidence III, Diagnostic studies.

Abstract ZFP57 is required to maintain the germline-marked differential methylation at imprinting control regions (ICRs) in mouse embryonic stem cells (ESCs). Although DNA methylation has a key role in genomic imprinting, several imprinted genes are controlled by different mechanisms, and a comprehensive study of the relationship between DMR methylation and imprinted gene expression is lacking. To address the latter issue, we differentiated wild-type and Zfp57 -/- hybrid mouse ESCs into neural precursor cells (NPCs) and evaluated allelic expression of imprinted genes. In mutant NPCs, we observed a reduction of allelic bias of all the 32 genes that were imprinted in wild-type cells, demonstrating that ZFP57-dependent methylation is required for maintaining or acquiring imprinted gene expression during differentiation. Analysis of expression levels showed that imprinted genes expressed from the non-methylated chromosome were generally up-regulated, and those expressed from the methylated chromosome were down-regulated in mutant cells. However, expression levels of several imprinted genes acquiring biallelic expression were not affected, suggesting the existence of compensatory mechanisms that control their RNA level. Since neural differentiation was partially impaired in Zfp57-mutant cells, this study also indicates that imprinted genes and/or non-imprinted ZFP57-target genes are required for proper neurogenesis in cultured ESCs.

Abnormal proximal aortic origin of the brachiocephalic artery is a very rare condition. It can occur in isolation or associated with complex congenital heart disease affecting the right ventricular outflow tract. Its recognition carries relevant surgical implications for the safe conduct of cardiopulmonary bypass and for any surgical procedures that directly involve the proximal ascending aorta and its branches.

Abstract Despite international regulation, polychlorinated biphenyls (PCBs) are routinely detected at levels threatening human and environmental health. While previous research has emphasized trophic transfer as the principle pathway for PCB accumulation, our study reveals the critical role that non-trophic interactions can play in controlling PCB bioavailability and biomagnification. In a 5-month field experiment manipulating saltmarsh macro-invertebrates, we show that suspension-feeding mussels increase concentrations of total PCBs and toxic dioxin-like coplanars by 11- and 7.5-fold in sediment and 10.5- and 9-fold in cordgrass-grazing crabs relative to no-mussel controls, but do not affect PCB bioaccumulation in algae-grazing crabs. PCB homolog composition and corroborative dietary analyses demonstrate that mussels, as ecosystem engineers, amplify sediment contamination and PCB exposure for this burrowing marsh crab through non-trophic mechanisms. We conclude that these ecosystem engineering activities and other non-trophic interactions may have cascading effects on trophic biomagnification pathways, and therefore exert strong bottom-up control on PCB biomagnification up this coastal food web.

In August 2022, Italy launched a vaccination campaign to combat the spread of the monkeypox virus, which the WHO has designated as a public health emergency. Priority targets for the campaign included laboratory personnel and men who have sex with men with specific risk criteria. Primary immunization involved two doses of the Imvanex/Jynneos vaccine, followed by a single booster dose. We conducted a study in two Italian towns, Bologna and Forlì, in October and November 2022 to investigate adverse events following immunization (AEFIs) of the monkeypox vaccine through participant-based active surveillance. Participants who received the vaccine and were aged 18 and over were invited to complete an e-questionnaire by scanning a QR code during their second vaccine appointment or by email one month after the booster dose. A descriptive analysis of AEFI incidences was conducted, with the results stratified by type and severity of symptoms. A total of 135 first-dose, 50 second-dose, and 6 single-dose recipients were included, with a mean age of 36.4 ± 8.7 years. Systemic reactions after the first and second doses were reported by 39.3% and 26.0% of participants, respectively, with asthenia being the most common symptom. Local site reactions were reported by 97.0% and 100.0% of participants, respectively, with redness, swelling, and itching being the most common local AEFIs. Grade 3 or 4 AEFIs were reported for local AEFIs only by 16.8% and 14.0% of participants after the first and second doses, respectively. Our findings suggest that the monkeypox vaccine has a high tolerability profile in terms of short-term common systemic AEFIs. However, the high incidence and severity of local AEFIs highlight the need to monitor their persistence following intradermal administration of the vaccine.

Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.

Abstract We used agnostic, unsupervised machine learning to cluster a large clinical database of information on infants admitted to neonatal units in England. Our aim was to obtain insights into nutritional practice, an area of central importance in newborn care, utilising the UK National Neonatal Research Database (NNRD). We performed clustering on time-series data of daily nutritional intakes for very preterm infants born at a gestational age less than 32 weeks (n = 45,679) over a six-year period. This revealed 46 nutritional clusters heterogeneous in size, showing common interpretable clinical practices alongside rarer approaches. Nutritional clusters with similar admission profiles revealed associations between nutritional practice, geographical location and outcomes. We show how nutritional subgroups may be regarded as distinct interventions and tested for associations with measurable outcomes. We illustrate the potential for identifying relationships between nutritional practice and outcomes with two examples, discharge weight and bronchopulmonary dysplasia (BPD). We identify the well-known effect of formula milk on greater discharge weight as well as support for the plausible, but insufficiently evidenced view that human milk is protective against BPD. Our framework highlights the potential of agnostic machine learning approaches to deliver clinical practice insights and generate hypotheses using routine data.

Abstract CSF shunting with adjustable valve is the treatment of idiopathic normal pressure hydrocephalus. The opening pressure valve setting is left to the neurosurgeon’s experience. Aqueductal CSF stroke volume by phase-contrast magnetic resonance measures the CSF passing through the Sylvian aqueduct and it changes with intracranial hydrodynamics. We sought to identify a window of stroke volume differences associated with the best clinical outcome and lowest rate of complications. The records of 69 patients were reviewed. At every clinical check, stroke volume, opening pressure valve, clinical outcome, and CSF overdrainage were analyzed. The correlation between stroke volume differences and negative outcome was also analyzed. The median follow-up was 2.3 years (range 0.3–10.4 years). The odds of negative outcome between two consecutive checks significantly increased by 16% (95%CI 4–28%, p = 0.006). Taking the lowest risk group as reference, the odds ratio of negative outcome was 1.16 (95%CI 0.51–2.63, p = 0.726) for SV differences less than − 37.6 µL, while it was 1.96 (95%CI 0.97–3.98, p = 0.062) for stroke volume changes above + 23.1 µL. Maintaining stroke volume values within a definite range might help maximize clinical benefit and avoid the risk of CSF overdrainage.

Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.

ABSTRACT BACKGROUND: Frailty is consensually understood to be a clinical syndrome in which minimal stressors can lead to negative outcomes such as hospitalization, early institutionalization, falls, functional loss and death. Frailty is more prevalent among patients with chronic kidney disease (CKD), and those on dialysis are the frailest. Depression contributes towards putting patients with CKD into the frailty cycle. OBJECTIVE: To assess frailty and its relationship with depression among patients with CKD undergoing hemodialysis. DESIGN AND SETTING: Observational and quantitative cross-sectional study conducted in a renal therapy unit, located in the interior of the state of São Paulo, Brazil. METHODS: This investigation took place in 2019, among 80 patients. The following instruments were applied: a sociodemographic, economic and health condition characterization and the Subjective Frailty Assessment (SFA) and Patient Health Questionnaire-9 (PHQ-9). RESULTS: Among the patients, there was higher prevalence of females, individuals with a steady partner and retirees, and their mean age was 59.63 (± 15.14) years. There was high prevalence of physical frailty (73.8%) and depression (93.7%). Depression was associated with frailty, such that patients with depression were 9.8 times more likely to be frail than were patients without depression (odds ratio, OR = 9.80; 95% confidence interval, CI, 1.93-49.79). CONCLUSION: Based on the proposed objective and the results achieved, it can be concluded that depression was associated with the presence of frailty among patients with CKD on hemodialysis.

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.

OBJETIVO: Comparar a prevalência da fragilidade com o perfil sociodemográfico e a avaliação subjetiva de saúde de idosos cadastrados em Centros de Referência de Assistência Social em um município do interior paulista. MÉTODOS: Estudo comparativo e transversal, baseado no método quantitativo de investigação. Foram avaliados 247 idosos utilizando-se: questionário para caracterização do idoso, Avaliação Subjetiva de Saúde e Escala de Fragilidade de Edmonton. As entrevistas foram realizadas no domicílio. Todos os cuidados éticos foram observados. A pesquisa foi aprovada sob CAAE 00867312.8.0000.5504. RESULTADOS: Dos idosos avaliados, 41,7% não apresentaram fragilidade e 36,8% possuíam algum nível (seja fragilidade leve, moderada ou severa). Houve diferença estatisticamente significativa entre fragilidade e: número de doenças relatadas e avaliação subjetiva de saúde (p