University of Campania "Luigi Vanvitelli"

Introduction: Inherited retinal diseases (IRDs) are the leading cause of vision loss in the working‐age population and represent one of the most genetically heterogeneous, rare Mendelian diseases. This heterogeneity mirrors a spectrum of clinical phenotypes which vary in terms of cell/tissue involvement, disease onset, severity, and progression. Aim: To determine the genetic basis of IRD pathogenesis in a large Italian cohort (n = 2790) followed at a single referral center. Methods: We performed a retrospective epidemiological study by reviewing the clinical records and genetic data of the IRD patients followed at the Eye Clinic of the University of Campania ‘Luigi Vanvitelli’ (Naples, Italy). Almost 70% of cases were analysed by Next Generation Sequencing approaches using panels of known retinopathy genes, clinical exome or whole exome sequencing. A third of the molecular diagnoses were performed by candidate gene sequencing, APEX‐based genotyping microarrays and single molecule Molecular Inversion Probes. Results: We provided conclusive molecular diagnosis for 2036 patients (from 1683 unrelated families). The overall diagnostic success rate was 73%. We identified a total of 1327 causative sequence variations in 127 genes, including 348 novel variants, and 866 potentially actionable genotypes for therapeutic approaches. ABCA4 was the most frequently mutated gene ( n = 535; 26.3% of solved cases), followed by USH2A ( n = 228; 11.2%) and RPGR ( n = 102; 5%). About 60% of RPGR variants were detected in ORF15, a mutational hotspot refractory to NGS analyses. The other 124 genes had a lower contribution to IRD pathogenesis (e.g. CHM 3.5%, RHO 3.5%; MYO7A 3.4%; CRB1 2.7%; RPE65 2%, RP1 1.8%; GUCY2D 1.7%). Seventy‐eight genes were mutated in five patients or less. Mitochondrial DNA variants were responsible for 2.1% of cases. The combined genetic and clinical assessment uncovered novel genotype‐phenotype associations and phenotypic expansions. Conclusions: We report on the largest cohort of molecularly characterised IRD patients from Italy to date. Our findings confirm the complex genetic etiology of IRDs and reveal the high prevalence of ABCA4 and USH2A mutations. The results suggest that mutations in RPGR‐ORF15 likely account for a significant fraction of male IRD patients who remain undiagnosed after a first tier NGS analysis. This study also uncovers novel genetic associations with a spectrum of clinical phenotypes and identifies numerous cases potentially eligible for clinical trials and, ultimately, for molecular therapies. Keywords: Inherited retinal diseases, genetic epidemiology, retinitis pigmentosa, Stargardt disease, Leber Congenital Amaurosis

Autosomal dominant polycystic kidney disease (ADPKD) represents the most common inherited kidney disorder leading to kidney failure in a significant percentage of patients over time. Although previously considered as an adult disease, robust evidence demonstrated that clinical manifestations might occur during childhood and adolescence. Therefore, early identification and treatment of the disease are of cardinal importance for pediatricians to ensure the best long-term outcomes. To date, licensed treatment options are limited but promising potential therapeutic targets are emerging. Among these, an intriguing pathophysiological role for microRNAs as small molecules with a critical role in regulating gene expression has been considered possible in ADPKD. Indeed, numerous circulating microRNAs have been found to be dysregulated in ADPKD, suggesting their potential role as biomarkers and therapeutic targets. Based on this background, further detailed insights into the mechanisms of miRNAs contributing to ADPKD development might pave the way for their effective application as a targeted treatment in young patients with ADPKD. We aimed to summarize the most recent evidence in this fascinating research area, providing a comprehensive overview of the current landscape of specific microRNAs in ADPKD as a potential innovative therapeutic strategy for these young patients.

Background and objectives: Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum. Methods: We devised a new live cell-based assay (CBA) for PLP1-IgG and used it to test 2 cohorts (retrospective exploratory, n = 284; prospective validation, n = 824) of patients with ADDs and controls (n = 177). Patients were classified as MS, neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other ADDs. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based assay (TBA). Complement-dependent cytotoxicity (CDC) was assessed on a live CBA and antigen specificity and conformational binding through immunoadsorption/colocalization/fixation experiments. Results: PLP1-IgG were found in 0 of 177 controls and 42 of 1104 patients with ADDs mainly diagnosed as other ADDs (19/42) with frequent myelitis/encephalomyelitis (14/19) and coexisting PNS involvement (13/19). Four of 19 patients with other ADDs fulfilled the seronegative NMOSD criteria. PLP1-IgG were also found in patients with MOGAD (11/42), more frequently with PNS involvement (p = 0.01), and in patients with MS (12/42), more frequently with atypical features (p < 0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (p < 0.001) and PLP1-IgG-positive MS had higher severity scores (MSSS, p < 0.001) compared with those PLP1-IgG-negative. Overall, PLP1-IgG were found in 24.1% of patients with CNS+PNS-ADD, 21.2% with atypical MS, 8.3% with MOGAD, 12.0% with seronegative NMOSD, and 1.4% with typical MS. Their frequency within each diagnostic subgroup was consistent between the exploratory and validation cohorts. PLP1-IgG a) colocalized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; and c) coreacted with DM20 in all 12 patients with PNS involvement tested. Discussion: Conformational PLP1-IgG predominantly identify patients with non-MS ADDs. They should be tested mainly in those with CNS + PNS ADD, coherently with DM20-IgG coreactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.

Our study offers a comprehensive Monkeypox virus (MPXV) analysis, utilizing innovative protocols to uncover potential vulnerabilities. We examine MPXV’s epidemiology, link to smallpox, genomics, mutation landscape, clinical features, diagnostics, therapeutics, FDA-approved drugs, clinical trials, and preventive strategies. We used various analytical methods to analyse genome data from the NCBI database (2019–2023) to assess sequence alignment, protein identification, and genome diversity. The phylogenomic analysis identified unique lineages and a mutation associated with human transmission, revealing that 24 MPXV proteins are particularly mutation-prone. Domain analysis confirmed conserved Ortho-poxvirus genes and critical regions, providing insights into MPXV’s structure, diversity, and host interaction. Additionally, we integrated clinical data, geospatial mapping, statistical analysis, and AI/ML for predictive insights on MPXV progression. We also explored bioinformatics tools and plant-based treatments, conducting in-silico studies to identify potential drug targets. Our research integrates epidemiological and genomic data to inform real-time preventive measures and optimize public health responses to MPXV.

Importance Integration of molecular biomarker information into systemic therapy has become standard practice in breast cancer care. However, its implementation in guiding radiotherapy (RT) is slower. Although postoperative RT is recommended for most patients after breast-conserving surgery and, depending on risk factors, following mastectomy, emerging evidence has indicated that patients with low scores on gene expression signatures or selected clinical-pathological features may have very low local recurrence rates. This narrative review explored the potential of biomarker-directed personalized RT approaches, which may optimize treatment strategies and be associated with improved patient outcomes and experiences. Observations Distinctions between prognostic and predictive biomarkers were highlighted, emphasizing the importance of analytical and clinical validity in biomarker-based studies. Findings from studies investigating the prognostic and predictive value of various genomic signatures and immunohistochemical markers for guiding breast RT were presented. These included the Adjuvant Radiotherapy Intensification Classifier and the Profile for the Omission of Local Adjuvant Radiation, which have shown potential in predicting RT benefits. The genomic-adjusted radiation dose and role of tumor-infiltrating lymphocytes were also discussed. Ongoing clinical trials exploring the use of biomarkers in ductal carcinoma in situ and invasive breast cancer to refine RT decision-making were illustrated. Conclusions and Relevance The results of this narrative review suggest that evidence-based shared decision-making is crucial to optimize treatment according to the individual’s predicted benefits and risks along with their personal preferences. Incorporation of biomarker-directed approaches in RT for breast cancer may hold promise for personalized treatment, potentially facilitating omission of RT for patients at low risk of recurrence, while identifying those who may benefit from intensified therapy. This personalized RT approach may be associated with improved clinical outcomes and quality of life and facilitate decision-making for people with breast cancer. However, there remains a need for robust clinical and analytical validation of biomarkers to ensure reliability and clinical utility for RT optimization.

Background Dysgeusia is a distortion of the sense of taste whose prevalence and relationship with nutritional status in Metabolic dysfunction-associated Steatotic Liver Disease (MASLD)-related advanced chronic liver disease (ACLD) have never been systematically explored. Methods 200 MASLD patients [60 ≤ F3 fibrosis, 70 compensated ACLD (cACLD), and 70 decompensated (dACLD)] were enrolled. At baseline, the Child–Pugh (CP) score was determined. Dietary habits, body composition, and frailty were evaluated. The European Working Group (EWGSOP2) criteria defined sarcopenia. Dysgeusia was assessed by the Dysgeusia-Total-Score (DTS). A visual analog scale identified appetite impairment (VASAI). During a 6-month follow-up, liver-related decompensation events (LRDEs) were recorded. Results The prevalence of dysgeusia increased with the liver disease progression, appearing significantly higher in ACLD compared with ≤ F3 (65.7% vs 5%, p:0.003), as well as in dACLD compared to cACLD patients (58.5 vs 7.1% p < 0.0001). On 41 dACLD patients presenting dysgeusia, 37 (90.2%) showed a significant impairment of appetite levels. In dACLD, the CP score was positively correlated with both DTS (R:0.742) and VASAI (R:0.704), as well as DTS was directly correlated with VASAI (R:0.765) (all p < 0.0001). Compared with dACLD patients without dysgeusia, dysgeusia-affected dACLD patients presented a lower daily protein intake (g/kg/die) (1.55 ± 0.192 vs 1.34 ± 0.15, p < 0.0001). Sarcopenia (70.7 vs 41.3%) and frailty (69.29 vs 37.9%) were significantly more prevalent in dysgeusia-affected dACLD individuals (both p < 0.0001). These patients showed a higher risk of LRDEs occurrence during the follow-up [HR:2.205; C.I. 95%:1.186–4.099; p:0.01]. Logistic regression analysis revealed dysgeusia (aOR: 3.32), appetite impairment (aOR:1.32), sarcopenia (aOR: 3.75), and frailty (aOR:3.03) significantly associated with this outcome (all p < 0.0001). Conclusions Dysgeusia appears predominant in MASLD-dACLD and, via appetite impairment, in a close relationship with malnutrition, sarcopenia, and frailty, negatively influencing patients' outcomes.

Background Management of recurrent endometrial carcinoma (EC) represents a challenge. Although a complete resection of visible disease at secondary surgery (R0) is recommended, the impact of R0 on survival outcomes is unclear and pooled data are lacking. Objective To quantitatively assess the impact of R0 on survival outcomes in women with EC recurrence. Search Strategy A systematic review and meta‐analysis was performed searching eight electronic databases from their inception up to January 2024. Selection Criteria All peer‐reviewed studies that assessed quantitatively the impact of R0 on survival outcomes in women at first EC recurrence were included. Data Collection and Analysis Hazard ratio (HR) with 95% confidence interval (CI) for death of any cause and secondary recurrent or progressive disease in women with EC recurrence who underwent R0 compared to non‐optimal secondary surgical cytoreduction (R1) were pooled and assessed at both univariable and multivariable analyses. Main Results Three studies with 442 patients were included. At univariate analysis, in women with EC recurrence and R0 compared to women with EC recurrence and R1, pooled HR was 0.451 (95% CI: 0.319–0.638) for death from any cause, and 0.517 (95% CI: 0.298–0.895; p = 0.019) for recurrent or progressive disease. At multivariate analysis, in women with EC recurrence and R0 compared to women with EC recurrence and R1, pooled HR was 0.447 (95% CI: 0.255–0.783; p = 0.005) for death from any cause, and 0.585 (95% CI: 0.359–0.952; p = 0.031) for recurrent or progressive disease. Conclusion In women with EC recurrence, R0 is an independent prognostic factor, decreasing the risk of death from any cause by approximatively 55%, and of recurrent or progressive disease by approximatively 40%, compared to R1.

We have assessed antiviral activity and induction of protective immunity of fusion-inhibitory lipopeptides derived from the C-terminal heptad-repeat domain of SARS-CoV-2 spike glycoprotein in transgenic mice expressing human ACE2 (K18-hACE2). The lipopeptides block SARS-CoV-2 infection in cell lines and lung-derived organotypic cultures. Intranasal administration in mice allows the maintenance of homeostatic transcriptomic immune profile in lungs, prevents body-weight loss, decreases viral load and shedding, and protects mice from death caused by SARS-CoV-2 variants. Prolonged administration of high-dose lipopeptides has neither adverse effects nor impairs peptide efficacy in subsequent SARS-CoV-2 challenges. The peptide-protected mice develop cross-reactive neutralizing antibodies against both SARS-CoV-2 used for the initial infection and recently circulating variants, and are completely protected from a second lethal infection, suggesting that they developed SARS-CoV-2-specific immunity. This strategy provides an additional antiviral approach in the global effort against COVID-19 and may contribute to development of rapid responses against emerging pathogenic viruses.

This is the first bottom‐up review of the lived experience of postpartum depression and psychosis in women. The study has been co‐designed, co‐conducted and co‐written by experts by experience and academics, drawing on first‐person accounts within and outside the medical field. The material initially identified was shared with all participants in a cloud‐based system, discussed across the research team, and enriched by phenomenological insights. The subjective world of postpartum depression is characterized by a sudden onset (“being hit with a ton of bricks”), unbearable loneliness and sadness that are often suffered in silence, inability to feel positive emotions, grieving over the loss of self, feelings of being bad mothers (haunted by a suffocating burden of guilt due to that), inability to concentrate, lack of control of thoughts (“feeling like a tightrope walker without control over thoughts and emotions”), insecurity (up to needing to be nurtured and mothered themselves), and thoughts of death (“contemplating death as a glimmer of hope to escape the living nightmare”). In addition to these themes, the subjective world of postpartum psychosis is characterized by difficulty in articulating thoughts (“feeling the brain in a centrifuge”); perceptual abnormalities and unusual beliefs disrupting the sense of personal unity (with, in a few cases, thoughts of harming themselves or their baby, so that women may feel that they are “sinking in the depths of hell”); losing trust (“ploughing through the fog and losing trust and safety”), and stripping down relationships. Much of the isolation, guilt and disorientation experienced in these conditions relates to sociocultural and family environments, especially a gulf between how women feel and a web of norms and expectations surrounding motherhood. In most cases, stigma is related to a lack of knowledge of what postpartum depression or psychosis are. Stigma and lack of knowledge are core drivers impacting health care in terms of seeking professional help, accessing mental health services, and receiving pharmacological or psychological treatments. The narratives described in this paper should inform clinical practice, research and public health education. This study brings voice to the unspoken and unheard, and fosters relational connections within which different mothering experiences may be expressed and understood. This is vital to challenging negative sociocultural attitudes towards postpartum depression and psychosis, and providing the most supportive care to women experiencing such pervasive psychiatric disorders at a critical, fragile time in their lives.

Objective Bosentan (BOS) is approved for treating pulmonary arterial hypertension (PAH) and preventing digital ulcers (DU) in systemic sclerosis (SSc). Our study aimed to evaluate whether BOS prescribed for DU could reduce the incidence of PAH in a large SSc cohort from the SPRING registry. Methods Patients with SSc from the SPRING registry, meeting ACR/EULAR 2013 classification criteria with data on PAH onset, DU status, BOS exposure, and at least a one-year follow-up between 2015 and 2020, and no known PAH at baseline were included. PAH was diagnosed with right heart catheterization during the follow-up, and its incidence rate (IR) was calculated. Kaplan-Meier curves were determined, and multivariate regression identified PAH risk factors. Results Among 727 eligible patients with SSc, followed for a median of 2.0 years, 54 (7.4%) developed PAH [IR 3.71 per 100 patients/years]. Patients with DU who were never exposed to BOS had a higher incidence of PAH [IR 4.90 per 100 patients/years] compared to those exposed to BOS, whose rates matched those without DU and who were never exposed to BOS. Risk factors independently associated with PAH development included DU (HR 1.85), age (HR 1.05), modified Rodnan Skin Score (mRSS) >4 (HR 2.07), ILD (HR 2.29), and acetylsalicylic acid treatment (HR 1.78). Conclusion In our cohort, DU were confirmed as a leading risk factor for PAH development, and BOS use for DU prevention may reduce this risk. Only patients with DU who were not on BOS had an increased PAH incidence.

Feeding and eating disorders (FEDs) are a heterogeneous grouping of disorders at the mind‐body interface, with typical onset from childhood into emerging adulthood. They occur along a spectrum of disordered eating and compensatory weight management behaviors, and from low to high body weight. Psychiatric comorbidities are the norm. In contrast to other major psychiatric disorders, first‐line treatments for FEDs are mainly psychological and/or nutrition‐focused, with medications playing a minor adjunctive role. Patients, carers and clinicians all have identified personalization of treatment as a priority. Yet, for all FEDs, the evidence base supporting this personalization is limited. Importantly, disordered eating and related behaviors can have serious physical consequences and may put the patient's life at risk. In these cases, immediate safety and risk management considerations may at least for a period need to be prioritized over other efforts at personalization of care. This paper systematically reviews several key domains that may be relevant to the characterization of the individual patient with a FED aimed at personalization of management. These domains include symptom profile, clinical subtypes, severity, clinical staging, physical complications and consequences, antecedent and concomitant psychiatric conditions, social functioning and quality of life, neurocognition, social cognition and emotion, dysfunctional cognitive schemata, personality traits, family history, early environmental exposures, recent environmental exposures, stigma, and protective factors. Where possible, validated assessment measures for use in clinical practice are identified. The limitations of the current evidence are pointed out, and possible directions for future research are highlighted. These also include novel and emerging approaches aimed at providing more fine‐grained and sophisticated ways to personalize treatment of FEDs, such as those that utilize neurobiological markers. We additionally outline remote measurement technologies designed to delineate patients’ illness and recovery trajectories and facilitate development of novel intervention approaches.

L’INTELLIGENZA ARTIFICIALE PER POTENZIARE LA RICERCA QUALITATIVA: RIFLESSIONI METODOLOGICHE SU UNO STUDIO PILOTA Abstract Qualitative analysis is essential in research across diverse fields, offering in-depth insights that often cannot be captured through quantitative methods. However, managing large volumes of qualitative data presents challenges, including its labour intensive nature and the potential for interpretive biases. In this study, we introduce and show a methodology step by step that integrates artificial intelligence (AI) in the analysis of qualitative data, with a focus on textual responses extracted from survey questions. Specifically, our approach employs AI techniques, utilizing Word2Vec for word embedding extraction and K-Means clustering to streamline the analysis of qualitative textual data, while ultimately integrating the researcher’s interpretation of the identified clusters to improve the relevance of the analysis. Moreover, the present article discusses the relevance and significance of this approach as well as its ethical and methodological challenges by means of an empirical illustration taken from a study on teachers’ sensemaking regarding a range of different educational activities.

Literature evidenced an association of maternal sleep disturbances and maternal obstructive sleep apnea with significant obstetric complications. Moreover, the maternal sleep disturbances effect on feto-placental circulation had not been extensively examined. Our objective is to explore the possible maternal sleep disturbances impact on the feto-placental indices evaluated through the Doppler study. A systematic review of the following databases was performed: PubMed, EMBASE, Cochrane Library and Google Scholar from the beginning to June 2024. Only studies that enrolled pregnant women with signs and symptoms of maternal sleep disturbances or obstructive sleep apnea diagnosis, which analysed the feto-placental Doppler parameters, were considered eligible (PROSPERO ID: CRD42024553926). We included a total of four studies with 1715 cases of pregnant women. Various instrumental and non-instrumental diagnostic methods were adopted for detection of maternal sleep disturbances. The ultrasound exam was performed mainly in the third trimester of pregnancies, and all the studies explored the uterine Doppler parameters. Only two studies explore the foetal Doppler parameters. Only one study disclosed that maternal sleep disturbances are related to altered uterine Doppler indices with probable placental dysfunction. This review did not evidence a significant influence of maternal sleep disturbances and obstructive sleep apnea on foetal Doppler indices. Moreover, one large prospective study showed a possible impact of maternal sleep disturbances on uterine Doppler with a potential impairment of the placentation function. Additional studies with detailed data and larger samples are needed to throw light on this relationship and its impact on the foetal outcomes.

Patients with Mild Cognitive Impairment (MCI) may exhibit poorer performance in visuomotor tasks than healthy individuals, particularly under conditions with high cognitive load. Few studies have examined reaching movements in MCI and did so without assessing susceptibility to distractor interference. This proof-of-concept study analyzed the kinematics of visually guided reaching movements towards a target dot placed along the participants’ midsagittal/reaching axis. Movements were performed with and without a visual distractor (flanker) at various distances from the reaching axis. Participants were instructed to avoid “touching” the flanker during movement execution. The whole sample included 11 patients with MCI due to Alzheimer’s disease, 10 healthy older adults, and 12 healthy young adults, all right-handed. Patients with MCI performed reaching movements whose trajectories deviated significantly away from the flanker, especially when it was 1 mm away, with less consistent trajectories than controls. Also, our results suggest that trajectory curvature may discriminate between patients with MCI and healthy older adults. The analysis of reaching movements under conditions of visual interference may enhance the diagnosis of MCI, underscoring the need for multidimensional assessments incorporating both cognitive and motor domains.