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Abstract Plasmodium vivax, a challenging species to eliminate, causes millions of malaria cases globally annually. Developing an effective vaccine is crucial in the fight against vivax malaria, but considering the limited number of studies focusing on the identification and development of P. vivax-specific vaccine candidates, exploring new antigens is an urgent need. The merozoite protein CyRPA is essential for P. falciparum growth and erythrocyte invasion and corresponds to a promising candidate antigen. In P. vivax, a single study with multiple vaccine candidates indicates PvCyRPA with strong association with protection, outperforming classic malaria vaccine candidates. However, little is known about the specific naturally acquired response in the Americas, as well as the antigen epitope mapping. For this reason, we aimed to investigate the cellular and humoral immune response elicited against PvCyRPA in Brazilian endemic areas to identify the existence of immunodominant regions and the potential of this protein as a single or even a multi-stage specific malaria vaccine candidate for P. vivax. The results demonstrated that PvCyRPA is naturally immunogenic in Brazilian Amazon individuals previously exposed to malaria, which presented anti-PvCyRPA cytophilic antibodies. Moreover, our data show that the protein also possesses important immunogenic regions with an overlap of B and T cell epitopes. These data reinforce the possibility of including PvCyRPA in vaccine formulations for P. vivax.

Abstract Sore throat represents one of the main causes of antibiotic overprescription in children. Its management is still a matter of debate, with countries considering streptococcal pharyngotonsillitis a benign and self-limiting condition and others advocating for its antibiotic treatment to prevent suppurative complications and acute rheumatic fever. Italian paediatricians frequently prescribe antibiotics on a clinical basis regardless of microbiological results. Moreover, broad-spectrum antibiotics are inappropriately prescribed for this condition. In this regard, an intersociety consensus conference was issued to promote the judicious use of antibiotic therapy in paediatric outpatient settings. A systematic review of the literature was performed, and updated recommendations were developed according to the GRADE methodology. Antibiotic treatment with amoxicillin (50 mg/kg/day) for 10 days is recommended in all children with proven streptococcal pharyngitis. Benzathine-penicillin could be prescribed in children with impaired intestinal absorption or inability to tolerate enteral intake and in those at high risk of suppurative complications with low compliance to oral therapy. In children with suspected amoxicillin allergy, third-generation cefalosporins for five days are recommended in low-risk patients, and macrolides are recommended in high-risk ones. Candidates for tonsillectomy due to recurrent pharyngitis could be treated with amoxicillin-clavulanic acid, clindamycin, or combined therapy with amoxicillin plus rifampicin for four days, in an attempt to avoid surgery.

Abstract Background To assess the adverse food reactions (AFR) prevalence in children with autism spectrum disorder (ASD) and in non-ASD healthy controls (NASD). Nutritional status alterations, food selectivity and adherence to Mediterranean Diet (MD) were also evaluated. Methods The NAFRA (Nutritional status and Adverse Food Reactions in children with Autism Spectrum Disorder) project was an observational, case-control, comparative study conducted at a tertriary center for pediatrics involving Caucasian patients of both sexes, aged 18 months-7 years, with a diagnosis of ASD, and matched NASD controls. Results From October 2017 to December 2023, 100 ASD patients [79 male, mean (± SD) age 49.9 months (± 15.4)] and 100 NASD controls [75 male, mean (± SD) age 49.8 months (± 17.7)] were enrolled at the Pediatric Section of the Department of Translational Medical Science of the University of Naples Federico II. A significantly higher prevalence of AFR was observed in ASD patients if compared with NASD (16% vs. 2%, p = 0.001), mainly due to a higher prevalence of food allergy (7% vs. 1%, p = 0.03). A significantly higher prevalence of food intolerance and celiac disease was also observed in ASD children. The rate of obesity was significantly higher in ASD patients compared to NASD. Food selectivity and low MD-adherence were more frequent in ASD children (26% vs. 2%, p

Abstract A transtibial prosthetic interface typically comprises a compliant liner and an outer rigid socket. The preponderance of today’s conventional liners are mass produced in standard sizes, and conventional socket design is labor-intensive and artisanal, lacking clear scientific rationale. This work tests the clinical efficacy of a novel, physics-based digital design framework to create custom prosthetic liner-socket interfaces. In this investigation, we hypothesize that the novel digital approach will improve comfort outcomes compared to a conventional method of liner-socket design. The digital design framework generates custom transtibial prosthetic interfaces starting from MRI or CT image scans of the residual limb. The interface design employs FEA to simulate limb deformation under load. Interfaces are fabricated for 9 limbs from 8 amputees (1 bilateral). Testing compares novel and conventional interfaces across four assessments: 5-min walking trial, thermal imaging, 90-s standing pressure trial, and an evaluation questionnaire. Outcome measures include antalgic gait criterion, skin surface pressures, skin temperature changes, and direct questionnaire feedback. Antalgic gait is compared via a repeated measures linear mixed model while the other assessments are compared via a non-parametric Wilcoxon sign-rank test. A statistically significant ( $$P=0.032$$ ) decrease in pain is demonstrated when walking on the novel interfaces compared to the conventional. Standing pressure data show a significant decrease in pressure on novel interfaces at the anterior distal tibia ( $$P = 0.012$$ ), with no significant difference at other measured locations. Thermal results show no statistically significant difference related to skin temperature. Questionnaire feedback shows improved comfort on novel interfaces on posterior and medial sides while standing and the medial side while walking. Study results support the hypothesis that the novel digital approach improves comfort outcomes compared to the evaluated conventional method. The digital interface design methodology also has the potential to provide benefits in design time, repeatability, and cost.

Abstract Although Surface Enhanced Raman Scattering (SERS) is widely applied for ultrasensitive diagnostics and imaging, its potential is largely limited by the difficult preparation of SERS tags, typically metallic nanoparticles (NPs) functionalized with Raman-active molecules (RRs), whose production often involves complex synthetic approaches, low colloidal stability and poor reproducibility. Here, we introduce LipoGold Tags, a simple platform where gold NPs (AuNPs) clusters form via self-assembly on lipid vesicle. RRs embedded in the lipid bilayer experience enhanced electromagnetic field, significantly increasing their Raman signals. We modulate RRs and lipid vesicle concentrations to achieve optimal SERS enhancement and we provide robust structural characterization. We further demonstrate the versatility of LipoGold Tags by functionalizing them with biomolecular probes, including antibodies. As proof of concept, we successfully detect intracellular GM1 alterations, distinguishing healthy donors from patients with infantile GM1 gangliosidosis, showcasing LipoGold Tags as advancement in SERS probes production.

Background: Physical exercise (PE) can regulate inflammation, cardiovascular health, sarcopenia, anaemia, and bone health in the chronic kidney disease (CKD) population. Experimental and clinical studies both help us better understand the mechanisms that underlie the beneficial effects of the exercise, especially in renal anaemia and CKD-mineral bone disorders (CKD-MBDs). Here, we summarize this evidence, exploring the biological pathways involved, locally released substances, and crosstalk between tissues, but also the shortcomings of current knowledge. Summary: Anaemia: Both in healthy and CKD subjects, PE may mimic hypoxia, inhibiting PHDs; so hydroxylate HIF-α subunits may be translocated into the nucleus, resulting in dimerization of HIF-1α and HIF-1β, recruitment of p300 and CBP, and ultimately, binding to HREs at target genes to cause activation. However, in CKD subjects acute PE causes higher levels of lactate, leading to iron restriction by upregulating hepatic hepcidin expression, while chronic PE allows an increased lactate clearance and HIF-α and VEGFα levels, stimulating both erythropoiesis and angiogenesis. CKD-MBD: PE may improve bone health decreasing bone resorption and increasing bone formation throughout at least three main pathways: (a) increasing osteoprotegerin and decreasing RANKL system; (b) decreasing cytokine levels; and (c) stimulating production of myokines and adipokines. Key Messages: Future research needs to be defined to develop evidence-based exercise guidance to provide optimal benefit for CKD using exercise interventions as adjuvant therapy for CKD-related complications such as anaemia and CKD-MBD.

Abstract Background The nephrotoxic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are widely acknowledged. In particular, diclofenac is the most commonly prescribed NSAIDs, but no previous findings of electrolyte disturbances were reported following its administration. Case report We presented the case of a man who experienced significant weakness associated with severe deficiencies in potassium, calcium, and magnesium after misusing diclofenac because of severe back pain. Conclusions This case emphasizes the need of awareness about the electrolyte imbalances and electrolyte disturbances associated with the misuse of diclofenac, which is a widely available drug. This is a case report which does not need a Clinical Trial Number.

Abstract Introduction Chronic obstructive pulmonary disease (COPD) is a frequent cause of morbidity and mortality. Dysregulated and enhanced immune-inflammatory responses have been described in COPD. Recent data showed impaired immune responses and, in particular, of interferon (IFNs) signaling pathway in these patients. Aim To evaluate in peripheral lung of COPD patients, the expression of some of the less investigated key components of the innate immune responses leading to IFN productions including: IFN-receptors (IFNAR1/IFNAR2), IRF-3 and MDA-5. Correlations with clinical traits and with the inflammatory cell profile have been assessed. Methods Lung specimens were collected from 58 subjects undergoing thoracic surgery: 22 COPD patients, 21 smokers with normal lung function (SC) and 15 non-smoker controls (nSC). The expression of IFNAR1, IFNAR2, IRF-3 and MDA-5, of eosinophils and activated NK cells (NKp46+) were quantified in the peripheral lung by immunohistochemistry. Results A significant increase of IRF-3 + alveolar macrophages were observed in COPD and SC compared with nSC subjects. However, in COPD patients, the lower the levels of IRF-3 + alveolar macrophages the lower the FEV1 and the higher the exacerbation rate. The presence of chronic bronchitis (CB) was also associated with low levels of IRF-3 + alveolar macrophages. NKp46 + cells, but not eosinophils, were increased in COPD patients compared to nSC patients (p

Abstract Background Influenza infections pose significant risks for nursing home (NH) residents. Our aim was to evaluate the impact of the cantonal influenza campaign, and influenza vaccination coverage of residents and healthcare workers (HCWs) on influenza burden in NHs in a context of enhanced infection prevention and control measures (IPC) during the SARS-CoV-2 pandemic. Methods We extracted data from epidemic reports provided by our unit to NHs over two consecutive winter seasons (2021-22 and 2022-23) and used linear regression to assess the impact of resident and HCW vaccination coverage, and participation in the campaign, on residents’ cumulative influenza incidence and mortality. Results Thirty-six NHs reported 155 influenza cases and 21 deaths during the two winter seasons corresponding to 6.2% of infected residents and a case fatality ratio of 13.5%. Median vaccination coverage was 83% for residents, 25.8% for HCWs, while 87% of NHs participated in the campaign. Resident vaccination was significantly associated with a decrease in odds of death (odds ratio (OR) 0.96, 95% confidence interval (CI): 0.93–0.99). There was no significant effect of HCW vaccination coverage on resident infections and deaths. Campaign participation was associated with decreased odds of infection and death among residents (OR: 0.17, 95% CI: 0.06–0.47 and OR: 0.06, 95% CI: 0.02–0.17 respectively). Conclusion Our analysis suggests that in a context of reinforced IPC measures, influenza still represents a significant burden for NH residents. The most effective measures in decreasing resident influenza burden in NHs was participation in the cantonal influenza vaccination campaign and resident vaccination.

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

Wandering spleen is a rare condition in children that is often caused by the loss or weakening of the splenic ligaments. Its clinical presentation is variable; 64% of children with wandering spleen have splenic torsion as a complication. A 13-year-old boy who had been showing abdominal pain in the hypogastric region accompanied by vomit and an enormous tumefaction in the suprapubic region came to our observation. Considering the ovoid morphology at ultrasound exam, the echostructure and the marked reduction of parenchymal vascularization, suspicion for torsion of an ectopic spleen arose. Ultrasound evaluation has a primary role in the diagnosis of a suspected wandering spleen and, to avoid potentially life-threatening complications, immediate surgery is often times required.

Objectives: To investigate seasonality, epidemiologic characteristics, and clinical severity variations of respiratory syncytial virus (RSV)-associated hospitalizations following the easing of COVID-19 restrictions in Tuscany, Italy, up to the 2022-2023 season. Methods: From 2017 to 2023, a dynamic cohort consisting of all resident children aged ≤2 years was followed up in regional registries. The person-time incidence rate of RSV-associated hospitalizations per 1,000 person-years and risk of severe hospitalization (intensive care unit, continuous positive airway pressure, or mechanical ventilation) per 100 RSV hospitalizations were calculated. RSV seasonality was investigated with retrospective methods. Results: A total of 193,244 children were followed up. After the easing of restrictions, RSV epidemics showed earlier seasonality and shorter duration compared with pre-pandemic (2017 to 2019), with this deviation decreased in 2022-2023. In 2021-2022 and 2022-2023, the incidence rate of RSV-associated hospitalizations significantly increased compared with pre-pandemic (2022-2023 risk ratio 3.6, 95% confidence interval 3.3-4.0), with larger increases among older age groups. Among hospitalized children, only those aged ≥12 months showed an increased risk of severe hospitalization, particularly during 2021-2022 (risk ratio 4.7, 95% confidence interval 1.5-24.3). Conclusions: Our findings suggest a gradual return of RSV epidemics to the pre-pandemic pattern, although relevant increases in disease incidence persist. Reduced regular RSV exposure among older children may lead to declining immunity and increased severe outcome risks.

IntroductionMagnesium Sulphate (MgSO4) is commonly used in human medicine for the management of perioperative pain in different types of procedures. However, in veterinary medicine, the use of MgSO4 has not been evaluated for its analgesic efficacy in dogs, which has generated conflicts of opinion in this area of veterinary anesthesiology. The aim of this study was to evaluate the perioperative analgesic efficacy of MgSO4 in combination with Ketamine in dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO). Our hypothesis is that MgSO4 plus ketamine have a synergistic action in the management of intra-and postoperative pain.MethodsTwenty adult mixed breed dogs with average age 5.9 ± 2.6 years and weight 27.8 ± 9.2 kg were included in this prospective, clinical, randomized study. Dogs were randomly assigned to two groups. The MK group received ketamine (0.5 mg/kg as starting bolus followed by continuous infusion rate at 1 mg/kg/h). At the end of the ketamine bolus, MgSO4 (50 mg/kg over 15 min) was administered by the same route, followed by a constant rate infusion (CRI) at 15 mg/kg/h, IV. K group received a bolus of ketamine followed by a CRI at the same dosage described in MK group. Main cardiorespiratory parameters were recorded 10 min before the start of surgery (BASE), after the ketamine bolus (T1) and the MgSO4 bolus (T2), during the skin incision (SKIN), the osteotomy (OSTEOTOMY) and skin suturing (SUTURE). In the postoperative period, the short form of Glasgow Composite Pain scale (SF-CMPS) was used to assess pain at 30, 60, 120, and 180 min after extubation (Post30, Post60, Post120, and Post180, respectively). The main blood electrolytes (Mg2+, Ca2+, Na+, K+) were analyzed at BASE, T2, OSTEOTOMY, SUTURE and T3 (one hour after stopping MgSO4 infusion). Number of rescue analgesia and administration times were recorded both in the intra-and postoperative period.ResultsIn K group 7 out of 10 dogs required intraoperatory rescue analgesia compared to MK group (3/10). Furthermore, mean arterial pressure (MAP) and heart rate (HR) were significantly higher at OSTEOTOMY compared to BASE time in both groups. In the postoperative period, at T120, ICMPS-SF score was higher in K group than MK group.ConclusionThe administration of MgSO4 could guarantee better analgesia in the perioperative period in dogs undergoing TPLO, performing a synergistic action with ketamine.

In a steep slope with limited soil thickness, a rootstock comparison was established in 1999 with the Pinot Blanc variety and the rootstocks SO4, 1103 Paulsen 140 Ruggeri, Börner and two clones of 420 A in 5 randomised repetitions. From 2018, in the 20th year of the vineyard's existence, small-scale vinifications were carried out in three consecutive years and the wines were evaluated sensorially. In addition, ascertainments were carried out in the experimental vineyard to determine the growth strength of the rootstocks and their drought tolerance. Hardly any statistically significant differences could be found in the evaluations. At the tastings of the wines, a tendency towards atypical aging of the wines from Paulsen 1103 and 420 A clone SMA was noticeable. Furthermore, rootstocks 1103 Paulsen and 140 Ruggeri showed a tendency towards more growth and better drought stress tolerance compared to the other rootstocks. Both clones of rootstock 420 A fell sharply in their vegetation development in the field replicates with somewhat less favourable soil conditions, which was not observed to a comparable extent by the other rootstocks.

Anderson–Fabry disease (AFD) is a lysosomal storage disorder, depending on defects in alpha galactosidase A activity, due to a mutation in the galactosidase alpha gene. Cardiovascular involvement represents the leading cause of death in AFD. Cardiac imaging plays a key role in the evaluation and management of AFD patients. Echocardiography is the first-line imaging modality for the identification of the typical features of AFD cardiomyopathy. Advanced echocardiography that allows assessment of myocardial deformation has provided insights into the cardiac functional status of AFD patients. The present review highlights the value and the perspectives of advanced ultrasound imaging in AFD.

Epilepsy is a severe and common neurological disease that causes sudden and irregular seizures, necessitating patient-specific detection models for effective management. The proposed methodology, Epilepsy Tracking META-Set Analysis, establishes portability rules that identify similar patients, enabling the transfer of these detection models from one patient to another. Main issue is to identify clusters of patients analyzing a set of meta-features of each patient in terms of clinical descriptors, performance metrics of a machine learning model for seizure detection, and data complexity measures. The investigation of complexity measures represents a novelty in such a medical field, allowing to compare patients and to support automated seizure detection methods. The proposed methodology is validated using the well-known Epileptic Seizure EEG Database from the Epilepsy Center of the University Hospital of Freiburg and demonstrates promising results in transferring detection models to new cases.

Abstract Evidence about feeding practices’ consequences in small for gestational age newborns is not well established because they are less likely to initiate and continue breastfeeding than other newborns. Our aim was to study current knowledge about the benefits of exclusive human milk diet after 2 years of age in small for gestational age newborns. A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline criteria. Pubmed and Scopus were searched for studies published from databases inception until June 2, 2023. Included articles were analysed and synthesised. Risk of bias and level of evidence assessments were performed. They were enrolled small for gestational age newborns fed by breastfeeding, breast milk or donor milk. The systematic review included 9 articles which were related to 4 health domains: neurodevelopment, cardiovascular, somatic growth and bone mineralization and atopy. Extracted data support a beneficial effect of breastfeeding on these outcomes. Better quality of evidence and longer follow-up are needed.

The paper analyses the topic to understand how the legal and judicial practices in two Amazonian municipalities (Apuí and Lábrea) respond to the dynamics of environmental crimes in the region. The research project is a based in a qualitative and quantitative methodology. This paper discusses the initial results from interviews gathered in the city of Manaus with a Judge from the Amazonas State, a Prosecutor from Public Ministry, a Federal Police Commissar, and a member of the Environmental Agency of Amazonas. Thus, it is possible to understand: a) the context of environmental crimes in the cities of Apuí and Lábrea, b) the responses of criminal justice institutions to the occurrence of environmental crimes in the region. El artículo analiza el tema para comprender cómo las prácticas legales y judiciales en dos municipios amazónicos (Apuí y Lábrea) responden a la dinámica de los delitos ambientales en la región. El proyecto de investigación se basa en una metodología cualitativa y cuantitativa. Las entrevistas fueran realizadas en la ciudad de Manaus con un juez del estado de Amazonas, un fiscal del Ministerio Público, un comisario de la Policía Federal y un miembro de la Agencia Ambiental de Amazonas. Así, es posible comprender: a) el contexto de los delitos ambientales en las ciudades de Apuí y Lábrea, b) las respuestas de las instituciones de justicia penal ante la ocurrencia de delitos ambientales en la región.

O artigo tem como objetivo apresentar a Revolução Haitiana (1791-1804) a partir de uma tripla interseção: seu papel no quadro das grandes revoluções que, ao longo dos séculos XVII e XVIII, modificaram as bases da cidadania; o impacto do movimento para as Independências americanas e para o abolicionismo; e, por último, suas relações com o Brasil escravista que, a despeito do itinerário distinto da Independência e do processo de abolição, sofreu fortes impactos advindas do movimento haitiano

The exchange of knowledge and best practices in adult immunization are essential to improve vaccination strategies across the European region. Italy has made groundbreaking progress in the field, being one of the first countries to propose a life-course vaccination schedule, broadening the traditional focus on childhood immunization to include adults. All vaccines included in Italy’s vaccination schedule are free of charge. Moreover, the country’s National Immunization Plan sets clear coverage targets, immunization priorities, and actions to reduce disparities. However, the fragmentation of its National Health System following the constitutional reform of 2001 has led to an increased complexity and regional inequalities regarding immunization. Other challenges the country faces include growing vaccine hesitancy, data gaps and underserved populations. This review describes Italy’s adult immunization system, from policy to implementation. The successes, challenges and lessons learned were shared during the first Adult Immunization Board country meeting in Italy, where local experts, healthcare providers, public health representatives, and policymakers engaged in collaborative discussions and shared insights through case studies and presentations (December 2023). These insights are reviewed and discussed in this manuscript.

Tarsocrural osteochondrosis (OCD) is a developmental orthopedic disease commonly affecting young Standardbreds, with different fragment localization and size. Clinically, it is characterized by variable synovial effusion in the absence of lameness, whose determinants are ill-defined. We hypothesized that localization and physical characteristics of the osteochondral fragments like dimensions, multifragmentation, and instability influence joint effusion and correlate with synovial markers of cartilage degradation and inflammation. Clinical data, synovial fluid and intact osteochondral fragments were collected from 79 Standardbred horses, aged between 12 and 18 months, operated for tarsocrural OCD. The severity of tarsocrural joint effusion was assessed semi-quantitatively. The osteochondral fragment site was defined radiographically at the distal intermediate ridge of the tibia (DIRT), medial malleolus (MM) of the tibia, and/or lateral trochlear ridge (LTR) of the talus. Size, stability, and arthroscopic appearance (unique or multi-fragmented aspect) of the fragments were determined intra-operatively. Synovial concentrations of C-terminal cross-linked telopeptides of type II collagen (CTX-II), leukotriene B4 (LTB4), and prostaglandin E2 (PGE2) were quantified. Tarsocrural synovial effusion was significantly affected by localization and stability of the fragments, with MM-located and unstable fragments being associated with highest joint effusion. Concentrations of CTX-II, LTB4, and PGE2 positively correlated with the severity of synovial effusion. This study underlines characteristics of the osteochondral fragments determining higher synovial effusion in OCD-affected tarsocrural joints and suggests both inflammation and extra-cellular matrix degradation are active processes in OCD pathology.

IntroductionSchizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling.MethodsWe conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, D-serine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics.ResultsD-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed.DiscussionThis result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis.

Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

Objectives: The COVID-19 pandemic significantly changed respiratory viruses’ epidemiology due to non-pharmaceutical interventions and possible viral interactions. This study investigates whether the circulation patterns of respiratory viruses have returned to pre-pandemic norms by comparing their peak timing and duration during the first three SARS-CoV-2 seasons to pre-pandemic times. Methods: Global Influenza Surveillance and Response System data from 194 countries (2014-2023) was analyzed for epidemic peak timing and duration, focusing on pre-pandemic and pandemic periods across both hemispheres and the intertropical belt. The analysis was restricted to countries meeting specific data thresholds to ensure robustness. Results: In 2022/2023, the northern hemisphere experienced earlier influenza and respiratory syncytial virus (RSV) peaks by 1.9 months (P

In the Americas, P. vivax is the predominant causative species of malaria, a debilitating and economically significant disease. Due to the complexity of the malaria parasite life cycle, a vaccine formulation with multiple antigens expressed in various parasite stages may represent an effective approach. Based on this, we previously designed and constructed a chimeric recombinant protein, PvRMC-1, composed by PvCyRPA, PvCelTOS, and Pvs25 epitopes. This chimeric protein was strongly recognized by naturally acquired antibodies from exposed population in the Brazilian Amazon. However, there was no investigation about the induced immune response of PvRMC-1. Therefore, in this work, we evaluated the immunogenicity of this chimeric antigen formulated in three distinct adjuvants: Stimune, AddaVax or Aluminum hydroxide (Al(OH)3) in BALB/c mice. Our results suggested that the chimeric protein PvRMC-1 were capable to generate humoral and cellular responses across all three formulations. Antibodies recognized full-length PvRMC-1 and linear B-cell epitopes from PvCyRPA, PvCelTOS, and Pvs25 individually. Moreover, mice’s splenocytes were activated, producing IFN-γ in response to PvCelTOS and PvCyRPA peptide epitopes, affirming T-cell epitopes in the antigen. While aluminum hydroxide showed notable cellular response, Stimune and Addavax induced a more comprehensive immune response, encompassing both cellular and humoral components. Thus, our findings indicate that PvRMC-1 would be a promising multistage vaccine candidate that could advance to further preclinical studies.

Cellular movement is essential for many vital biological functions where it plays a pivotal role both at the single cell level, such as during division or differentiation, and at the macroscopic level within tissues, where coordinated migration is crucial for proper morphogenesis. It also has an impact on various pathological processes, one for all, cancer spreading. Cell migration is a complex phenomenon and diverse experimental methods have been developed aimed at dissecting and analysing its distinct facets independently. In parallel, corresponding analytical procedures and tools have been devised to gain deep insight and interpret experimental results. Here we review established experimental techniques designed to investigate specific aspects of cell migration and present a broad collection of historical as well as cutting-edge computational tools used in quantitative analysis of cell motion.

RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype.

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.

Starting from the regional air quality forecasts produced by the Copernicus Atmosphere Monitoring Service (CAMS), we propose a novel post-processing approach to improve and downscale results on a finer scale. Our approach is based on the combination of ensemble model output statistics (EMOS) with a spatio-temporal interpolation process performed through the stochastic partial differential equation–integrated nested laplace approximation (SPDE-INLA). Our interpolation approach includes several spatial and spatio-temporal predictors, including meteorological variables. A use case is provided that scales down the CAMS forecasts on the Italian peninsula. The calibration is focused on the concentrations of several air quality pollutants (PM10, PM2.5, NO2, and O3) at a daily resolution from a set of 750 monitoring sites, distributed throughout the Italian country. Our results show the key role that conditioning variables play in improving the forecast capabilities of ensemble predictions, thus allowing for a net improvement in the calibration with respect to ordinary EMOS strategies. From a deterministic point of view, the performance of the predictive model shows a significant improvement in the performance of the raw ensemble forecast, with an almost-zero bias, significantly reduced root mean square errors, and correlations that are almost always higher than 0.9 for each pollutant; moreover, the post-processing approach is able to significantly improve the prediction of exceedances, even for very low thresholds, such as those recently recommended by the World Health Organisation. This is particularly significant if a forecasting approach is used to predict air quality conditions and plan adequate human health protection measures, even for low alert thresholds. From a probabilistic point of view, the quality of the forecast was verified in terms of reliability and credible intervals. After post-processing, the predictive probability density functions were sharp and much better calibrated than the raw ensemble forecast. Finally, we present some additional results based on a set of gridded (4 km × 4 km) maps covering the entire Italian country for the detection of areas where pollution peaks occur (exceedances of the current and/or proposed regulatory thresholds).

Abstract Background Females are generally less prone to cardiovascular (CV) events than males, but this protection is trumped by diabetes. The mechanism behind the increased relative risk in females with diabetes is not fully understood. Insulin resistance (IR) is suggested to be a more important contributor to CV morbidity in females than in males. We aim to investigate differences in the association between IR indexes (Homeostatic Model Assessment of IR - HOMA-IR, visceral adiposity index – VAI, and triglycerides/high-density lipoprotein-cholesterol - TG/HDL-C index), and a first non-fatal myocardial infarction (MI) across different glycaemic states. Methods IR indexes were calculated in a population with (n = 696) and without (n = 707) a first non-fatal MI, free from known diabetes. MI cases were investigated at least six weeks after the event. All participants were categorized by an oral glucose tolerance test as having normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Comparison of proportion of glycaemic states by sex was tested by chi-square test. The associations between sex, a first non-fatal MI, IR indexes, and traditional CV risk factors were analysed by multivariate logistic regression models. Continuous variables were logarithmically transformed. Results Of the total population 19% were females and 81% males, out of whom 47% and 50% had a first non-fatal MI, respectively. Compared with males, females were older, less often smokers, with lower body mass index and higher total cholesterol and high-density lipoprotein cholesterol levels. The proportion of glycaemic states did not differ between the sexes (p = 0.06). Females were less insulin resistant than males, especially among cases and with normal glucose tolerance. In logistic regression models adjusted for major CV risk factors including sex, the associations between VAI and TG/HDL-C index and a first non-fatal MI remained significant only in females (odds ratios and 95% confidence intervals: 1.7, 1.0-2.9, and 1.9, 1.1–3.4 respectively). Conclusions These results support the assumption that IR indexes based on anthropometrics and lipid panel, i.e., VAI and TG/HDL-C, could be a better measure of IR and CV-predictor for non-fatal MI in females, even without glycaemic perturbations.

ABSTRACTIntroduction Diabetic patients are at a higher risk of getting pneumococcal disease and are therefore recommended to get vaccinated. The aim of our systematic review is the retrieval and analysis of all available evidence on the effect of pneumococcal vaccination on the risk of hospitalization and death in adult patients with diabetes.Research design and methods MEDLINEand EMBASE were searched from inception until January 2023. We included all studies investigating whether pneumococcal vaccination reduces the risk of dying or being hospitalized in diabetic patients. The Newcastle-Ottawa scale was used to assess risk of bias. Results Only two studies, encompassing a total of 68,246 subjects, were considered eligible for inclusion and of high quality. In both studies polysaccharide pneumococcal vaccination was associated with a reduction of the risk of hospitalization or death in adult diabetic patients (aHR: 0.76 in one study, aOR: 0.97 in the other one). However, in neither of the two included studies the lower risk was statistically significant.Conclusions Further research is needed due to the potentially major clinical implications for diabetic patients. The results of this systematic review can serve as a foundation for future studies, indicating the importance of continuing research in this area to improve patient outcomes.

Gunshot wound morphology and gunshot residues (GSRs) evaluation have been poorly investigated in veterinary forensic pathology. The aims of the present study were to assess the gunshot wound morphology in animals and evaluate the detectability of lead deriving from GSRs using colorimetric techniques. To these aims, cadavers were divided into four different groups. Group A comprised eight animals who died from firearm-related injuries, while groups B and C included dog limbs shot using different shooting ranges; group D comprised dog limbs stabbed with a screwdriver. Morphological analysis was performed on all entry gunshot wounds. Lead residues were investigated using a Bullet Hole Testing Kit (BTK) and Rhodizonate Sodium histochemical staining (NaR-s). Gunshot wounds in group A showed an abrasion ring associated with hemorrhages and tissue necrosis. Groups B and C showed injuries related to the shooting range. NaR-s showed positive results in both animals that died from gunshot wounds and experimentally shot limbs. However, the number of positive cases and the pattern of lead distribution varied with the shooting range. Positive results by BTK were limited to close-contact shots in group B limbs. Our results suggest that both pathological examination and NaR tests represent valid tools for investigating gunshot wounds in veterinary pathology.

Background: Varicella infections follow a benign course in around 90% of cases, with more severe forms occurring in adults. To identify potential pockets of susceptibility and to improve targeted immunization strategies, this study aims to critically assess immunological status by evaluating varicella seroprevalence among adults (18–99 years) in the province of Florence (Italy), nearly a decade after Tuscany introduced the vaccination program. Methods: A convenience sample of 430 subjects aged 18 to 94 years (mean age 51.8 ± 18.8 years), stratified by age and sex (53.7% of subjects were female; N = 231), was collected between 2018 and 2019. Sero-analytical analyses were conducted utilizing EUROIMMUN Anti-VZV ELISA (IgG) kits. Results: Most of them were of Italian nationality (87.4%; N = 376). Among the 430 tested samples, 385 (89.5%) were positive and 39 (9.1%) were negative. The remaining six sera (1.4%), confirmed as equivocal, were excluded from further analysis. No significant differences were found based on sex (p-value = 0.706) or nationality (p-value = 0.112). The application of trend tests (Mantel–Haenszel; Kendall Tau-b) showed a significant trend (p < 0.024 and p < 0.032, respectively), with an increasing probability of finding a positive anti-varicella serological status passing from a lower age group (84.2%) to a higher one (93.0%). By considering the female population aged 18–49 years, the seroprevalence of anti-varicella antibodies was found to be 88.4%, with a susceptibility of 11.6%, highlighting the risk of acquiring infection during pregnancy. Conclusions: The introduction of varicella vaccination has had a significant impact on public health in Tuscany and in Italy more generally. However, further efforts should be made to reduce the number of individuals still susceptible in adulthood, with particular attention given to women of childbearing age and the promotion of vaccination through mass and social media and institutional websites.

The automotive industry is continuously looking for innovative solutions to improve vehicle aerodynamics and efficiency. The research introduces a significant breakthrough in the field of automotive aerodynamics by employing shape memory alloys as bistable actuators for spoilers and moving flaps. The main novelty of this research lies in the development of a bistable actuator made of shape memory alloys as a precise and accurate control mechanism for spoilers and movable flaps. The shape memory alloys, with their unique ability to maintain two stable configurations and switch rapidly from one to the other in response to thermal or mechanical stimuli, allow precise and rapid adjustment of aerodynamic surfaces. The main advantage of this technology is its ability to improve vehicle aerodynamics by optimising both drag and downforce, thereby improving vehicle performance and fuel efficiency. This research shows the promising potential of a single composition of NiTi as a revolutionary technology in the automotive industry, revolutionising the way spoilers and moving flaps are used to achieve superior vehicle performance.

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations.

Fabry disease (FD), also known as Anderson-Fabry disease, is a hereditary disorder of glycosphingolipid metabolism, caused by a deficiency of the lysosomal alpha-galactosidase A enzyme. This causes a progressive accumulation of glycosphingolipids in tissues and organs which represents the main pathogenetic mechanism of FD. The disease is progressive and multisystemic and is characterized by early symptoms and late complications (renal, cardiac and neurological dysfunction). Fatigue and exercise intolerance are early common symptoms in FD patients but the specific causes are still to be defined. In this narrative review, we deal with the contribution of cardiac and pulmonary dysfunctions in determining fatigue and exercise intolerance in FD patients.

Digital beauty filters are pervasive in social media platforms. Despite their popularity and relevance in the selfies culture, there is little research on their characteristics and potential biases. In this article, we study the existence of racial biases on the set of aesthetic canons embedded in social media beauty filters, which we refer to as the Beautyverse . First, we provide a historic contextualization of racial biases in beauty practices, followed by an extensive empirical study of racial biases in beauty filters through state-of-the-art face processing algorithms. We show that beauty filters embed Eurocentric or white canons of beauty, not only by brightening the skin color, but also by modifying facial features.

BackgroundHormone receptor-positive tumors are unlikely to exhibit a complete pathological tumor response. The association of CDK 4/6 inhibitor plus hormone therapy has changed this perspective.Case presentationIn this study, we retrospectively reviewed the charts of patients with a diagnosis of luminal A/B advanced/metastatic tumors treated with a CDK 4/6 inhibitor-based therapy. In this part of the study, we present clinical and ultrasound evaluation. Eight female patients were considered eligible for the study aims. Three complete and five partial responses were reported, including a clinical tumor response of 50% or more in five out of nine assessed lesions (55%). All patients showed a response on ultrasound. The mean lesion size measured by ultrasound was 27.1 ± 15.02 mm (range, 6–47 mm) at the baseline; 16.08 ± 14.6 mm (range, 0–40 mm) after 4 months (T1); and 11.7 ± 12.9 mm (range, 0–30 mm) at the 6 months follow-up (T2). Two patients underwent surgery. The radiological complete response found confirmation in a pathological complete response, while the partial response matched a moderate residual disease.ConclusionThe evaluation of breast cancer by ultrasound is basically informative of response and may be an easy and practical tool to monitor advanced tumors, especially in advanced/unfit patients who are reluctant to invasive exams.

New evidence suggests that Sars-CoV2 infection during pregnancy may result in complications such as hypertension, nephropathy, thrombocytopenia, and liver damage. A pre-eclampsia-like syndrome has also been proposed in pregnant women with severe SARS-CoV-2 infection, which meets the pre-eclampsia criteria but resolves without delivery, with improvement in respiratory symptoms. 31-year-old, second pregnancy, in Emergency Room for PROM (premature rupture of membranes), has Sars-CoV2 infection and has not been vaccinated. Normal examinations and mild hypertension were present upon admission, but no treatment was administered. Vaginal Leukocytic Delivery 12 hours after admission, newborn Apgar score 9/10, weight 3.250 kg. At 20 hours after delivery, epigastric pain VAS 8-9 for 20 minutes, systolic/diastolic hypertension peak, increase in transaminases, LDH, ALP, Bilirubin, Dimer, platelet and fibrinogen drop. Neurological and respiratory objectivity were negative, and renal indices were within normal limits, so nifedipine 30mgx2/day + methyldopa 500 mgx2/day was started. Abdominal ultrasound revealed a thin perihepatic fluid stratum. A prophilaxis of dexamethasone 12mg twice a day and magnesium sulfate was introduced. At 32 hours after delivery, the laboratory detected an increase in transaminases, LDH, and worsening of thrombocytopenia. The patient is always eupnoic, and the diuresis is adequate. Blood tests improved gradually after 56 hours postpartum. Methyldopa and steroids are escalating. On day 7, discharge with normalized platelet and bilirubin counts and a decreasing trend in transaminases, LDH, and PAL. At the one-week follow-up, liver enzymes and coagulation were completely normal, and blood pressure was well controlled with methyldopa. We conclude that the simultaneous presence of the two diseases could have had a synergistic or opportunistic effect, resulting in severe clinical manifestations via interaction with the Renin-Angiotensin-Aldosterone system.

IntroductionMouse models of radiation injury are critical to the development of medical countermeasures (MCMs) against radiation. Now that MCMs against hematopoietic acute radiation syndrome (H-ARS) have achieved regulatory approval, attention is shifting to develop MCMs against the adverse effects of gastrointestinal acute radiation syndrome (GI-ARS) and delayed effects of acute radiation exposure (DEARE). The C57L/J mouse model of partial body irradiation (PBI) with 2.5% bone marrow shielding (BM2.5) is being leveraged to examine both GI-ARS and DEARE effects. Within days of PBI, mice may develop H- and GI-ARS followed several months later by DEARE as a multi-organ injury, which typically involves the lung and kidney (L- and K-DEARE, respectively). The objective of this manuscript is to describe the dose response relationship and progression of radiation injury in the C57L/J mouse and to evaluate its suitability for use in DEARE MCM testing.Materials and methodsIn two separate studies conducted over 2 years, male and female C57L/J mice were exposed to PBI BM2.5 with one hindlimb shielded from radiation, representing ~2.5% bone marrow shielding/sparing. Mice were X-ray irradiated at doses ranging from 9 to 13 Gy at 10 to 12 weeks of age for the purposes of assessing ARS survival at 30 days and DEARE survival at 182 days post-irradiation. Clinical indicators of ARS and DEARE were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging (MRI) of lung, and histopathology of selected tissues.ResultsC57L/J mice developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in dose dependent mortality at doses ≥11 Gy between 1- and 15-days post-irradiation. In animals that survived ARS, DEARE associated mortality occurred in dose dependent fashion at ≥9 Gy for both sexes between 60- and 159-days post-irradiation with histopathology examinations indicating lung injury as the primary cause of death in moribund animals.ConclusionThe PBI BM2.5 C57L/J mouse model reliably produced known H- and GI-ARS effects at doses greater than those resulting in DEARE effects. Because of this, the C57L/J mouse can be used to test MCMs against L-DEARE injury, while avoiding ARS associated mortality.

Abstract Background Traumatic cervical spinal cord injury (SCI) results in reduced sensorimotor abilities that strongly impact on the achievement of daily living activities involving hand/arm function. Among several technology-based rehabilitative approaches, Brain-Computer Interfaces (BCIs) which enable the modulation of electroencephalographic sensorimotor rhythms, are promising tools to promote the recovery of hand function after SCI. The “DiSCIoser” study proposes a BCI-supported motor imagery (MI) training to engage the sensorimotor system and thus facilitate the neuroplasticity to eventually optimize upper limb sensorimotor functional recovery in patients with SCI during the subacute phase, at the peak of brain and spinal plasticity. To this purpose, we have designed a BCI system fully compatible with a clinical setting whose efficacy in improving hand sensorimotor function outcomes in patients with traumatic cervical SCI will be assessed and compared to the hand MI training not supported by BCI. Methods This randomized controlled trial will include 30 participants with traumatic cervical SCI in the subacute phase randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and the hand MI training not supported by BCI. Both interventions are delivered (3 weekly sessions; 12 weeks) as add-on to standard rehabilitation care. A multidimensional assessment will be performed at: randomization/pre-intervention and post-intervention. Primary outcome measure is the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) somatosensory sub-score. Secondary outcome measures include the motor and functional scores of the GRASSP and other clinical, neuropsychological, neurophysiological and neuroimaging measures. Discussion We expect the BCI-based intervention to promote meaningful cortical sensorimotor plasticity and eventually maximize recovery of arm functions in traumatic cervical subacute SCI. This study will generate a body of knowledge that is fundamental to drive optimization of BCI application in SCI as a top-down therapeutic intervention, thus beyond the canonical use of BCI as assistive tool. Trial registration Name of registry: DiSCIoser: improving arm sensorimotor functions after spinal cord injury via brain-computer interface training (DiSCIoser). Trial registration number: NCT05637775; registration date on the ClinicalTrial.gov platform: 05-12-2022.

Objective: The most severe type of male infertility is non-obstructive azoospermia (NOA), where there is no sperm in the ejaculate due to failure of spermatogenesis, affecting 10%–20% of infertile men with azoospermia. Genetic studies have identified dozens of NOA genes. The main aim of the present study is to identify a novel monogenic mutation that may cause NOA. Materials and methods: We studied the pedigree of a consanguineous family with three NOA and one fertile brother by a family-based exome-sequencing, segregation analysis, insilico protein modeling and single-cell RNA sequencing data analysis. Results: Bioinformatics analysis followed by sanger sequencing revealed that three NOA brothers were homozygous for a rare missense variant in Cyclin Dependent Kinase Regulatory Subunit Associated Protein 2 (Centrosomin) CDK5RAP2 (NM_018249:exon26:c.A4003T:p.R1335W, rs761196443). Protein modeling demonstrated that CDK5RAP2, Arg1335Trp resided nearby the Microtubule Associated Protein RP/EB Family Member 1 (EB1/MAPRE1) interaction site. As a consequence of the R1335W mutation, the positively charged Arginine was replaced by to the hydrophobic tryptophan residue, possibly leading to local instability in the structure and perturbation in the CDK5RAP2-MAPRE1 interaction. Conclusion: Our study reports a novel missense variant of CDK5RAP2 that segregates in homozygosity with male infertility and NOA in a consanguineous family. In silico structural predictions and gene expression data indicate a potential role of the CDK5RAP2 variant in causing defective centrosomic maturation during spermatogenesis.

Abstract Background Beckwith-Wiedemann syndrome (BWS, OMIM #130,650) is a pediatric overgrowth disorder involving a predisposition to tumor development. Although the clinical management of affected patients is well established, it is less clear how to handle with the cases of siblings of affected patients, since the prevalence of the condition in twins (1:1000) is ten times higher than in singletones (1:10000). Case presentation We report the case of a premature twin patient who during her follow-up develops a clinical phenotype compatible with BWS, genetically confirmed in blood. However, the methylation alteration characteristic of the condition was also found in the almost phenotypically normal sibling, making it challening her management. Conclusion Through our case report we highlight how the diagnosis of BWS can be made without any prenatal suspicion and we propose a review of the literature on how to manage siblings of affected patients in twinning situation.

Abstract Background Ulnar nerve entrapment at the elbow is the second most common cause of nerve entrapment in the upper limb. Surgical techniques mainly include simple decompression, decompression with anterior transposition and medial epicondylectomy. Methods We performed decompression with anterior transposition and protected ulnar nerve by adipofascial flap (a random flap with radial based vascularization, harvested through the avascular plane of Scarpa’s fascia. We analyzed patients who underwent ulnar nerve ante-position from 2015 to 2022 according to inclusion and exclusion criteria for a total of 57 patients. All patients included were graded on the McGowan's classification Messina criteria and the British Medical Research Council modified by Mackinnon and Dellon. Results The average McGowan’s score was 2.4 (± 0.6), Messina’s criteria 91.2% indicated a satisfactory or excellent result, sensibility at 6 months was 98.5% S3 or more. A preferential technique has not yet been defined. Conclusions The adipofascial flap offers numerous advantages in providing a pliable, vascular fat envelope, which mimics the natural fatty environment of peripheral nerves and creates favorable micro-environmental conditions to contribute to neural regeneration via axon outgrowth.

Abstract The T2K experiment presents new measurements of neutrino oscillation parameters using $$19.7(16.3)\times 10^{20}$$ 19.7 ( 16.3 ) × 10 20 protons on target (POT) in (anti-)neutrino mode at the far detector (FD). Compared to the previous analysis, an additional $$4.7\times 10^{20}$$ 4.7 × 10 20 POT neutrino data was collected at the FD. Significant improvements were made to the analysis methodology, with the near-detector analysis introducing new selections and using more than double the data. Additionally, this is the first T2K oscillation analysis to use NA61/SHINE data on a replica of the T2K target to tune the neutrino flux model, and the neutrino interaction model was improved to include new nuclear effects and calculations. Frequentist and Bayesian analyses are presented, including results on $$\sin ^2\theta _{13}$$ sin 2 θ 13 and the impact of priors on the $$\delta _{\textrm{CP}}$$ δ CP measurement. Both analyses prefer the normal mass ordering and upper octant of $$\sin ^2\theta _{23}$$ sin 2 θ 23 with a nearly maximally CP-violating phase. Assuming the normal ordering and using the constraint on $$\sin ^2\theta _{13}$$ sin 2 θ 13 from reactors, $$\sin ^2\theta _{23}=0.561^{+0.021}_{-0.032}$$ sin 2 θ 23 = 0 . 561 - 0.032 + 0.021 using Feldman–Cousins corrected intervals, and $$\varDelta {}m^2_{32}=2.494_{-0.058}^{+0.041}\times 10^{-3}~\text {eV}^2$$ Δ m 32 2 = 2 . 494 - 0.058 + 0.041 × 10 - 3 eV 2 using constant $$\varDelta \chi ^{2}$$ Δ χ 2 intervals. The CP-violating phase is constrained to $$\delta _{\textrm{CP}}=-1.97_{-0.70}^{+0.97}$$ δ CP = - 1 . 97 - 0.70 + 0.97 using Feldman–Cousins corrected intervals, and $$\delta _{\textrm{CP}}=0,\pi $$ δ CP = 0 , π is excluded at more than 90% confidence level. A Jarlskog invariant of zero is excluded at more than $$2\sigma $$ 2 σ credible level using a flat prior in $$\delta _{\textrm{CP}},$$ δ CP , and just below $$2\sigma $$ 2 σ using a flat prior in $$\sin \delta _{\textrm{CP}}.$$ sin δ CP . When the external constraint on $$\sin ^2\theta _{13}$$ sin 2 θ 13 is removed, $$\sin ^2\theta _{13}=28.0^{+2.8}_{-6.5}\times 10^{-3},$$ sin 2 θ 13 = 28 . 0 - 6.5 + 2.8 × 10 - 3 , in agreement with measurements from reactor experiments. These results are consistent with previous T2K analyses.

Malaria is a serious health problem worldwide affecting mainly children and socially vulnerable people. The biological particularities of P. vivax, such as the ability to generate dormant liver stages, the rapid maturation of gametocytes, and the emergence of drug resistance, have contributed to difficulties in disease control. In this context, developing an effective vaccine has been considered a fundamental tool for the efficient control and/or elimination of vivax malaria. Although recombinant proteins have been the main strategy used in designing vaccine prototypes, synthetic immunogenic peptides have emerged as a viable alternative for this purpose. Considering, therefore, that in the Brazilian endemic population, little is known about the profile of the humoral immune response directed to synthetic peptides that represent different P. vivax proteins, the present work aimed to map the epitope-specific antibodies’ profiles to synthetic peptides representing the linear portions of the ookinete and sporozoite cell passage protein (CelTOS), thrombospondin-related adhesive protein (TRAP), and cysteine-rich protective antigen (CyRPA) proteins in the acute (AC) and convalescent phases (Conv30 and Conv180 after infection) of vivax malaria. The results showed that the studied subjects responded to all proteins for at least six months following infection. For IgM, a few individuals (3–21%) were positive during the acute phase of the disease; the highest frequencies were observed for IgG (28–57%). Regarding the subclasses, IgG2 and IgG3 stood out as the most prevalent for all peptides. During the follow-up, the stability of IgG was observed for all peptides. Only one significant positive correlation was observed between IgM and exposure time. We conclude that for all the peptides, the immunodominant epitopes are recognized in the exposed population, with similar frequency and magnitude. However, if the antibodies detected in this study are potential protectors, this needs to be investigated.

Elucidation of pathways regulating parasite cell death is believed to contribute to identification of novel therapeutic targets for protozoan diseases, and in this context, apoptosis-like cell death has been reported in different groups of protozoa, in which metacaspases seem to play a role. In the genus Plasmodium, apoptotic markers have been detected in P. falciparum and P. berghei, and no study focusing on P. vivax cell death has been reported so far. In the present study, we investigated the susceptibility of P. vivax to undergo apoptotic cell death after incubating mature trophozoites with the classical apoptosis inducer staurosporine. As assessed by flow cytometry assays, staurosporine inhibited parasite intraerythrocytic development, which was accompanied by a decrease in cell viability, evidenced by reduced plasmodial mitochondrial activity. However, typical signs of apoptosis, such as DNA fragmentation, chromatin condensation, and nuclear segregation, were not detected in the parasites induced to cell death, and no significant alteration in metacaspase gene expression (PvMCA1) was observed under cell death stimulus. Interestingly, dying parasites positively modulated cell death (eryptosis) of host erythrocytes, which was marked by externalization of phosphatidylserine and cell shrinkage. Our study shows for the time that P. vivax blood stages may not be susceptible to apoptosis-like processes, while they could trigger eryptosis of parasitized cells by undergoing cell death. Further studies are required to elucidate the cellular machinery involved in cell death of P. vivax parasites as well as in the modulation of host cell death.

Climate changes may include variations in salinity concentrations at sea by changing ocean dynamics. These variations may be especially challenging for marine photosynthetic organisms, affecting their growth and distribution. Chlamydomonas spp. are ubiquitous and are often found in extreme salinity conditions. For this reason, they are considered good model species to study salinity adaptation strategies. In the current study, we used an integrated approach to study the Chlamydomonas sp. CCMP225 response to salinities of 20‰ and 70‰, by combining physiological, morphological, and transcriptomic analyses, and comparing differentially expressed genes in the exponential and stationary growth phases under the two salinity conditions. The results showed that the strain is able to grow under all tested salinity conditions and maintains a surprisingly high photosynthetic efficiency even under high salinities. However, at the highest salinity condition, the cells lose their flagella. The transcriptomic analysis highlighted the up- or down-regulation of specific gene categories, helping to identify key genes responding to salinity stress. Overall, the findings may be of interest to the marine biology, ecology, and biotechnology communities, to better understand species adaptation mechanisms under possible global change scenarios and the potential activation of enzymes involved in the synthesis of bioactive molecules.

Long-term patient monitoring is required for detection of episodes of atrial fibrillation, one of the most widespread cardiac pathologies. Today, the most used non-invasive technique is Holter electrocardiographic (ECG) monitoring, which can often prove ineffective because of the short duration of recordings (e.g., one day). Other techniques such as photo-plethysmography are adopted by smartwatches for much longer duration monitoring, but this has the disadvantage of offering only intermittent measurements. This study proposes an Internet of Things (IoT) sensor that can provide a very long period of continuous monitoring. The sensor consists of an ECG-integrated Analog Front End (MAX30003), a microcontroller (STM32F401RE), and an IoT narrowband module (STEVAL-STMODLTE). The instantaneous heart rate is extracted from the ECG recording in real time. At intervals of two minutes, the sequence of inter-beat intervals is transmitted to an IoT cloud platform (ThingSpeak). Settled atrial fibrillation event recognition software runs on the cloud and generates alerts when it recognizes such arrhythmia. Performances of the proposed sensor were evaluated by generating analog ECG signals from a public dataset of ECG signals with atrial fibrillation episodes, the MIT-BIH Atrial Fibrillation Database, each recording lasting approximately 10 h. Software implementing the Lorentz algorithm, one of the best detectors of atrial fibrillation, was implemented on the cloud platform. The accuracy, sensitivity, and specificity in recognizing atrial fibrillation episodes of the proposed system was calculated by comparison with a cardiologist’s reference data. Across all patients, the proposed method achieved an accuracy of 0.88, a sensitivity 0.71, and a specificity 0.99. The results obtained suggest that the developed system can continuously record and transmit heart rhythms effectively and efficiently and, in addition, offers considerable performance in recognizing atrial fibrillation episodes in real time.