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Abstract Background Research in the neurosciences has highlighted the importance of intersubjective relationships in promoting neuromental development of the child. Children’s learning in early childhood occurs mainly in a dyadic context of an interaction with their parents: from this perspective, good dialogic parent–child communication is required to be promoted also through good educational practices. Dialogic Book-Sharing (DBS), a dialogic form of parent–child communication through the use of wordless picture books, provides a privileged ‘intersubjective’ space and is highly effective in promoting communication, language, attention, behavioural development and the parent–child relationship. DBS programme, successfully previously trialled in South Africa and the UK, will be applied for the first time in Italy for research purposes in Italian health, educational and maternal-child centres. Methods A multicentre randomised controlled trial is being conducted to evaluate DBS parenting intervention for children aged between 14 and 20 months. Parent–child dyads are randomly allocated to a book-sharing intervention group or to a wait-list control group. In the intervention, parents are trained in supportive book-sharing with their children by local staff of the centres. DBS intervention is carried out in small groups over a period of 4 weeks. Data are collected at baseline, post-intervention and at 6 months post-intervention with a questionnaire and video recording of parent–child interaction. Discussion DBS programme in early childhood could enhance the educational resources offered by Italian health, educational and maternal-child centres, in support of child’s development and parenting. DBS represents a strategic opportunity for bringing about positive effects, also in terms of prevention of socio-emotional and cognitive difficulties. As such it represents a promising response to the new social, health and educational needs of the post-COVID-19 pandemic era caused by the social isolation measures. Furthermore, the application of the DBS methodology is a way to promote the use of books, and thereby counteract the excessive use of technological devices already present in early childhood. Trial registration The trial is registered on the International Standard Randomised Controlled Trial Number database, registration number ISRCTN11755019 Registered on 2 November 2023. This is version 1 of the protocol for the trial.

Abstract Background BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. Methods The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. Discussion BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases. Trial registration: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

In locally advanced (LA) laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC), larynx preservation (LP) strategies aim at the cure of the disease while preserving a functional larynx, thus avoiding total laryngectomy and the associated impact on the quality of life. In the last decades, apart from transoral and open-neck organ preservation approaches, several non-surgical regimens have been investigated: radiotherapy alone, alternate, concurrent or sequential chemoradiation, and bioradiotherapy. Despite major progress, the identification of reliable and effective predictors for treatment response remains a clinical challenge. This review examines the current state of LP in LA-LHSCC and the need for predictive factors, highlighting the importance of the PRESERVE trial in addressing this gap. The PRESERVE trial represents a pivotal initiative aimed at finding the optimal therapy for laryngeal preservation specific to each patient through a retrospective analysis of data from previous LP trials and prospectively validating findings. The goal of the PRESERVE trial is to develop a comprehensive predictive classifier that integrates clinical, molecular, and multi-omics data, thereby enhancing the precision and efficacy of patient selection for LP protocols.

Abstract Background Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency

Purpose The PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population.Participants The PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry.Findings to date The open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples.Future plans The registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole.Trial registration number NCT04098315.

Abstract This study evaluated the relationship between negative symptoms, daily time use (productive/non-productive activities, PA/NPA), and negative emotions in schizophrenia-spectrum disorders (SSDs): 618 individuals with SSDs (311 residential care patients [RCPs], 307 outpatients) were surveyed about socio-demographic, clinical (BPRS, BNSS) and daily time use (paper-and-pencil Time Use Survey completed twice/week) characteristics. Among them 57 RCPs and 46 outpatients, matched to 112 healthy controls, also underwent ecological monitoring of emotions (8 times/day for a week) through Experience Sampling Method (ESM). RCPs spent significantly less time in PA than outpatients. Patients with more negative symptomatology spent more time in NPA and less in PA compared to patients with milder symptoms. Higher time spent in NPA was associated with negative emotions (p

Abstract Background The pupillary dilation reflex (PDR) is an objective indicator of analgesic levels in anesthetized patients. Through measurement of the PDR during increasing tetanic stimulation (10–60 mA), it is possible to obtain the pupillary pain index (PPI), a score that assesses the level of analgesia. Objectives The depth of analgesia during opioid-sparing anesthesia (OSA) with continuous infusion of dexmedetomidine in addition to general anesthesia was assessed. Design Observational prospective feasibility pilot study Setting This study was performed in the operating rooms of the Spedali Civili University-affiliated hospital of Brescia, Italy. Patients Forty-five adults who underwent elective open (5-cm incision) surgery under general anesthesia (78% inhalation anesthesia), from Feb. 18th to Aug. 1st, 2019, were enrolled. Exclusion criteria were as follows: implanted pacemaker or ICD, ophthalmological comorbidities, chronic opioid use, peripheral neuropathy, other adjuvant drugs, epidural analgesia, or locoregional block. Main outcome measures The first aim was to verify the feasibility of applying a study protocol to evaluate the depth of analgesia during intraoperative dexmedetomidine administration using an instrumental pupillary evaluation. The secondary outcome was to evaluate appropriate analgesia, drug dosage, anesthesia depth, heart rate, blood pressure, transient side effects, postoperative nausea and vomiting (PONV), and pain numerical rating scale (NRS) score. Results Thirty out of 50 patients (60%) treated with dexmedetomidine during the study period were included in the DEX group (8 males, age 42 ± 13 years, BMI 45 ± 8), and 15 other patients were included in the N-DEX group (8 males, age 62 ± 13 years, BMI 26 ± 6). Patients who underwent bariatric, abdominal, or plastic surgery were enrolled. At least 3 pupillary evaluations were taken for each patient. PPI ≤ 3 was observed in 97% of patients in the DEX group and 53% in the N-DEX group. Additionally, the DEX group received less than half the remifentanil dose than the N-DEX group (0.13 ± 0.07 vs 0.3 ± 0.11 mcg kg−1 min−1). The average dose of dexmedetomidine administered was 0.17 ± 0.08 mcg kg−1 h−1. Conclusion The feasibility of applying the protocol was verified. An OSA strategy involving dexmedetomidine may be associated with improved analgesic stability: a randomized controlled trial is necessary to verify this hypothesis. Trial registration Trial.gov registration number: NCT05785273

Background: Parkinson’s disease (PD) is an advancing neurodegenerative disorder characterized by spinal anomalies and muscular weakness, which may restrict daily functional capacities. A gender-focused examination of these effects could provide valuable insights into customized rehabilitation strategies for both sexes. Purpose: This study investigates the influence of spinal alignment on lower-limb function during the sit-to-stand (STS) movement in patients with Parkinson’s disease compared to healthy individuals. Methods: A cross-sectional study was conducted with 43 consecutive patients with PD (25 males and 18 females; average age 73.7 ± 7.1 years) and 42 healthy controls (22 males and 20 females; average age 69.8 ± 6.0 years). Assessments included the International Physical Activity Questionnaire (IPAQ), Hoehn and Yahr staging, and measurements of vertical deviations from several spinal landmarks. Lower-limb muscle power during the STS task was evaluated using the Muscle Quality Index (MQI). Results: Both absolute (Watts) and relative (Watts/Kg) muscle power in the lower limbs were notably decreased in the PD group compared to the control group. Within the PD cohort, muscle power showed a negative relationship with age and a positive association with the degree of lumbar lordosis (PL-L3). Importantly, gender-specific analysis revealed that male patients with PD had significantly higher lower-limb muscle power compared to female patients with PD, highlighting the need for gender-tailored therapeutic approaches. Conclusions: The findings suggest that preserving lumbar lordosis is crucial for maintaining effective lower-limb muscle biomechanics in individuals with Parkinson’s disease.

Abstract Background Cancer stem-like cells (CSCs) are a subpopulation of tumor cells responsible for tumor initiation, metastasis, chemoresistance, and relapse. Recently, CSCs have been identified in Uveal Melanoma (UM), which represents the most common primary tumor of the eye. UM is highly resistant to systemic chemotherapy and effective therapies aimed at improving overall survival of patients are eagerly required. Methods Herein, taking advantage from a pan Fibroblast Growth Factor (FGF)-trap molecule, we singled out and analyzed a UM-CSC subset with marked stem-like properties. A hierarchical clustering of gene expression data publicly available on The Cancer Genome Atlas (TCGA) was performed to identify patients’ clusters. Results By disrupting the FGF/FGF receptor (FGFR)-mediated signaling, we unmasked an FGF-sensitive UM population characterized by increased expression of numerous stemness-related transcription factors, enhanced aldehyde dehydrogenase (ALDH) activity, and tumor-sphere formation capacity. Moreover, FGF inhibition deeply affected UM-CSC survival in vivo in a chorioallantoic membrane (CAM) tumor graft assay, resulting in the reduction of tumor growth. At clinical level, hierarchical clustering of TCGA gene expression data revealed a strong correlation between FGFs/FGFRs and stemness-related genes, allowing the identification of three distinct clusters characterized by different clinical outcomes. Conclusions Our findings support the evidence that the FGF/FGFR axis represents a master regulator of cancer stemness in primary UM tumors and point to anti-FGF treatments as a novel therapeutic strategy to hit the CSC component in UM.

IntroductionThe RISKMet project aims to: (1) identify risk factors for metabolic syndrome (MetS) by comparing patients with and without MetS; (2) characterise patients treated with second-generation antipsychotics (SGAs) about MetS diagnosis; (3) study behavioural patterns, including physical activity (PA) and dietary habits, in patients and healthy individuals using a prospective cohort design.MethodThe RISKMet project investigates MetS in individuals treated with SGAs, focusing on both adult and paediatric populations. The study utilizes a case-control design to examine potential risk factors for MetS, categorizing participants as MetS+ considered as "Cases" and MetS- considered as "Controls" matched by sex and age. The evaluation of factors such as MetS, lifestyle habits, and environmental influences is conducted at two time points, T0 and T3, after 3 months. Subsequently, the project aims to assess body parameters, including physical examinations, and blood, and stool sample collection, to evaluate metabolic markers and the impact of SGAs. The analysis includes pharmacological treatment data and genetic variability. Behavioural markers related to lifestyle, eating behaviour, PA, and mood are assessed at both T0 and T3 using interviews, accelerometers, and a mobile app. The study aims to improve mental and physical well-being in SGA-treated individuals, establish a biobank for MetS research, build an evidence base for physical health programs, and develop preventive strategies for SGA-related comorbidities.ConclusionsThis project innovates MetS monitoring in psychiatry by using intensive digital phenotyping, identifying biochemical markers, assessing familial risks, and including genetically similar healthy controls.Study registration numberISRCTN18419418 at www.isrctn.com.

Partindo da assertiva de que muitos resultados de processos urbanísticos não são consentaneamente percebidos pelos cidadãos, o objetivo do trabalho consiste em analisar a produção científica recente sobre relações entre percepção e produtos físicos e abstratos daqueles fenômenos. Os procedimentos metodológicos adotados foram baseados em diagnóstico bibliométrico de artigos publicados em periódicos científicos de julho de 2015 a junho de 2020, com o recorte geográfico na América Latina, justificado pela maior aproximação com a realidade brasileira. Os resultados alcançados pela pesquisa são abordados em duas fases principais. A primeira – métricas encontradas – possibilita a classificação dos textos em três categorias analíticas, as quais são detalhadas na segunda – conteúdos tratados. Como resposta à questão investigativa, identifica-se maior incidência de preocupações sobre aspectos socioespaciais, seguidas por aquelas relacionadas a características socioambientais, sendo reduzidas as dirigidas a condições socioeconômicas. Por fim, conclui-se pelo ainda insuficiente aprofundamento do estado da arte da percepção de processos urbanísticos, notadamente daqueles derivados do planejamento e desenho de cidades, o que compromete a compreensão dos seus produtos tanto físicos, em termos de paisagem e morfologia urbana, quanto abstratos, vinculados à mobilidade e locomoção, conformando desafios para a melhoria da gestão de urbes contemporâneas.

IntroductionLong-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits.MethodsMuscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control.ResultsMVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT.DiscussionElectrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.

Abstract Background Cholangiocarcinoma (CC) is a rare and aggressive disease with limited therapeutic options and a poor prognosis. All available public records of cohorts reporting transcriptomic data on intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) were collected with the aim to provide a comprehensive gene expression‐based classification with clinical relevance. Methods A total of 543 patients with primary tumor tissues profiled by RNAseq and microarray platforms from seven public datasets were used as a discovery set to identify distinct biological subgroups. Group predictors developed on the discovery sets were applied to a single cohort of 131 patients profiled with RNAseq for validation and assessment of clinical relevance leveraging machine learning techniques. Results By unsupervised clustering analysis of gene expression data we identified both in the ICC and ECC discovery datasets four subgroups characterized by a distinct type of immune infiltrate and signaling pathways. We next developed class predictors using short gene list signatures and identified in an independent dataset subgroups of ICC tumors at different prognosis. Conclusions The developed class‐predictor allows identification of CC subgroups with specific biological features and clinical behavior at single‐sample level. Such results represent the starting point for a complete molecular characterization of CC, including integration of genomics data to develop in clinical practice.

Abstract Individuals with Angelman syndrome (AS) present with severe intellectual disability alongside a social phenotype characterised by social communication difficulties and an increased drive for social engagement. As the social phenotype in this condition is poorly understood, we examined patterns of social attention and social modulation of attention in AS. Twenty-four individuals with AS and twenty-one young children with similar mental age were shown videos featuring unfamiliar actors who performed simple actions across two conditions: a playful condition, in which the actor showed positive facial emotions, and a neutral condition, in which the actor showed a neutral facial expression. During the passive observation of the videos, participants’ proportion of time spent watching the two areas of interest (faces and actions) was examined using eye-tracking technology. We found that the playful condition elicited increased proportion of fixations duration to the actor’s face compared to the neutral condition similarly across groups. Additionally, the proportion of fixations duration to the action area was similar across groups in the two conditions. However, children with AS looked towards the actor’s face for a shorter duration compared to the comparison group across conditions. This pattern of similarities and differences provides novel insight on the complex social phenotype of children with AS.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

Background: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). Methods: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. Results: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. Conclusions: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.

Background Schizophrenia spectrum disorders (SSD) compromise psychosocial functioning, including daily time use, emotional expression and physical activity (PA).Objective We performed a cohort study aimed at investigating: (1) the differences in PA, daily activities and emotions between patients with SSD and healthy controls (HC); (2) the strength of the association between these variables and clinical features among patients with SSD.Methods Ninety-nine patients with SSD (53 residential patients, 46 outpatients) and 111 matched HC were assessed for several clinical variables, and levels of functioning by means of standardised clinical measures. Self-reported daily activities and emotions were assessed with a smartphone application for ecological momentary assessment (EMA), and PA levels were assessed with a wearable accelerometer for 7 consecutive days.FindingsPatients with SSD, especially those living in residential facilities, spent more time being sedentary, and self-reported more sedentary and self-care activities, experiencing higher levels of negative emotions compared with HC. Moreover, higher functioning levels among patients were associated with more time spent in moderate-to-vigorous activity.Conclusions Sedentary behaviour and negative emotions are particularly critical among patients with SSD and are associated with more impaired clinical outcomes.Clinical implications Mobile-EMA and wearable sensors are useful for monitoring the daily life of patients with SSD and the level of PA. This population needs to be targeted with specific rehabilitative programmes aimed at improving their commitment to structured daily activities.

A profissão docente exige conhecimentos e habilidades para fundamentar a sua prática. Tais exigências são construídas à medida que o docente passa por processos de formação inicial e continuada e, também, conforme vai desenvolvendo a sua carreira. Nessa direção, o objetivo desse estudo é catalogar o que dizem as pesquisas realizadas nos cursos de Pós-Graduação Stricto Sensu brasileiros acerca das características do bom professor da área de saúde. Metodologicamente, foi constituído a partir da catalogação e da análise das teses e dissertações disponíveis na Biblioteca Digital Brasileira de Teses e Dissertações (BDTD) e no Catálogo de Teses e Dissertações da CAPES de 2012 até 2022. Trata-se de uma pesquisa de natureza básica com abordagem qualitativa. É classificada como exploratória e descritiva com procedimentos técnicos documental e bibliográfico. Os resultados apresentam que os estudantes dão pouca importância para a titulação dos professores, porém as reconhecem. Um bom professor é classificado pelo seu conhecimento prático, postura acolhedora, flexível e pela disposição de observar e compreender demandas específicas dos estudantes, atuando pedagogicamente sobre elas. Salienta-se a importância da capacitação pedagógica para a docência, porém constata-se pouco interesse das instituições em ofertar formação aos docentes. Conclui-se que as 8 teses e dissertações analisadas pactuam que, para o bom desenvolvimento e exercício das competências e habilidades inerentes ao exercício profissional, faz-se necessário que o ensino em saúde lance mão de metodologias inovadoras que possibilitem a interação entre o estudante e os diferentes cenários em que eles estão inseridos, viabilizando a contextualização e aplicabilidade dos conhecimentos.

Abstract Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR

Abstract Introduction The role of glycemic control, both prior and during hospitalization, on mortality from COVID-19 in diabetic patients is debated. Furthermore, it is not clear whether hyperglycemia has a direct effect or requires inflammatory mechanisms. Objective To identify predictors of clinical outcomes (in-hospital mortality, length of hospitalization, respiratory failure, need for intensive care), considering hyperglycemia, inflammation markers and clinical history. Methods Retrospective observational study of 291 diabetic patients hospitalized with COVID-19 in the Spedali Civili di Brescia from February 1th 2020 to March 31th 2021, with also outpatient electronic records. Glucose, inflammatory parameters, creatinine were collected within 24 h after admission to the hospital. A causal mediation analysis allowed the estimation of the direct and indirect effects of hyperglycemia on mortality. Results Glucose at admission ≥ 165 mg/dL and reduced renal function were associated with an increased risk of in-hospital mortality and length of hospitalization (all p

Abstract Background In persons living with HIV (PLWH), the burden of non-communicable chronic diseases increased over time, because of aging associated with chronic inflammation, systemic immune activation, and long-term exposure to the combination antiretroviral therapy (ART). Methods To explore the association of chronological age, age at first ART, and exposure to ART with non-communicable chronic diseases, we performed a cross-sectional analysis to evaluate the prevalence of comorbidities in patients enrolled in the SCOLTA Project, stratified by groups of chronological age (50–59 and 60–69 years) and by years of antiretroviral treatment (ART, ≤ 3 or > 3 years). Results In 1394 subjects (23.8% women), mean age at enrollment was 57.4 (SD 6.5) years, and at first ART 45.3 (SD 10.7). Men were older than women both at enrollment (57.6 vs 56.8, p = 0.06) and at first ART (45.8 vs 43.6, p = 0.0009). ART duration was longer in women (13.1 vs 11.7 years, p = 0.01). The age- and sex-adjusted rate ratios (aRRs, and 95% confidence interval, CI) showed that longer ART exposure was associated with dyslipidemia (aRR 1.35, 95% CI 1.20–1.52), hypertension (aRR 1.52, 95% CI 1.22–1.89), liver disease (aRR 1.78, 95% CI 1.32–2.41), osteopenia/osteoporosis (aRR 2.88, 95% CI 1.65–5.03) and multimorbidity (aRR 1.36, 95% CI 1.21–1.54). These findings were confirmed in strata of age, adjusting for sex. Conclusions Our data suggest that longer ART exposure was associated with increased risk of dyslipidemia, hypertension, and osteopenia/osteoporosis, hence the presence of multimorbidity, possibly due to the exposition to more toxic antiretrovirals. We observed different comorbidities, according to ART exposure and age.

BackgroundNew statistical methodologies were developed in the last decade to face the challenges of estimating the effects of exposure to multiple chemicals. Weighted Quantile Sum (WQS) regression is a recent statistical method that allows estimating a mixture effect associated with a specific health effect and identifying the components that characterize the mixture effect.ObjectivesIn this study, we propose an extension of WQS regression that estimates two mixture effects of chemicals on a health outcome in the same model through the inclusion of two indices, one in the positive direction and one in the negative direction, with the introduction of a penalization term.MethodsTo evaluate the performance of this new model we performed both a simulation study and a real case study where we assessed the effects of nutrients on obesity among adults using the National Health and Nutrition Examination Survey (NHANES) data.ResultsThe method showed good performance in estimating both the regression parameter and the weights associated with the single elements when the penalized term was set equal to the magnitude of the Akaike information criterion of the unpenalized WQS regression. The two indices further helped to give a better estimate of the parameters [Positive direction Median Error (PME): 0.022; Negative direction Median Error (NME): −0.044] compared to the standard WQS without the penalization term (PME: −0.227; NME: 0.215). In the case study, WQS with two indices was able to find a significant effect of nutrients on obesity in both directions identifying sodium and magnesium as the main actors in the positive and negative association, respectively.DiscussionThrough this work, we introduced an extension of WQS regression that improved the accuracy of the parameter estimates when considering a mixture of elements that can have both a protective and a harmful effect on the outcome; and the advantage of adding a penalization term when estimating the weights.

Introduction The success of keratoplasty strongly depends on the health status of the transplanted endothelial cells. Donor corneal tissues are routinely screened for endothelial damage before shipment; however, surgical teams have currently no means of assessing the overall viability of corneal endothelium immediately prior to transplantation. The aim of this study is to validate a preoperative method of evaluating the endothelial health of donor corneal tissues, to assess the proportion of tissues deemed suitable for transplantation by the surgeons and to prospectively record the clinical outcomes of a cohort of patients undergoing keratoplasty in relation to preoperatively defined endothelial viability.Methods and analysis In this multicentre cohort study, consecutive patients undergoing keratoplasty (perforating keratoplasty, Descemet stripping automated endothelial keratoplasty (DSAEK), ultra-thin DSAEK (UT-DSAEK) or Descemet membrane endothelial keratoplasty) will be enrolled and followed-up for 1 year. Before transplantation, the endothelial viability of the donor corneal tissue will be evaluated preoperatively through trypan blue staining and custom image analysis to estimate the overall percentage of trypan blue-positive areas (TBPAs), a proxy of endothelial damage. Functional and structural outcomes at the end of the follow-up will be correlated with preoperatively assessed TBPA values.Ethics and dissemination The protocol will be reviewed by the ethical committees of participating centres, with the sponsor centre issuing the final definitive approval. The results will be disseminated on ClinicalTrials.gov, at national and international conferences, by partner patient groups and in open access, peer-reviewed journals.Trial registration number NCT05847387.