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Sex differences in coronary physiology and in the pathogenesis of coronary artery disease (CAD) have been previously described. Contrasting data have been reported, so far, about the impact of sex on the assessment of the functional significance of intermediate coronary stenoses by fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR). The present study aimed at assessing the sex differences in the results of iFR in a cohort of patients undergoing coronary angiography . Methods We included patients undergoing coronary angiography and the functional assessment of intermediate (40 to 70%) coronary lesions in 2 centers. iFR measurement was performed by pressure-recording guidewire and automatically calculated at the core laboratory using the manufacturers' dedicated software. Quantitative parameters of the coronary lesions were calculated by an automatic edge-detection system. Minimal luminal diameter (MLD), reference diameter (RD), percent diameter stenosis, and length of the lesion were measured. Positive iFR was considered for values Results We included 325 patients undergoing coronary angiography and iFR evaluation of 371 intermediate coronary stenoses, including 20.6% of women. Females were older, displayed lower body weight and hemoglobin, lower rate of active smoking (p = 0.04), lower platelet count ( p = 0.001) and creatinine (p = 0.02). Systolic blood pressure and heart rate at admission were more elevated in women ( p = 0.001 and p = 0.05, respectively). At angiography, multivessel coronary artery disease was more uncommon (p = 0.001) and proximal lesions were more frequently assessed by iFR (p = 0.04). Mean values of iFR did not differ with sex and neither the percentage of positive iFR (19.1% vs 18.8%, p = 0.99, adjusted OR[95%CI] = 0.51[0.18–1.48], p = 0.22). Conclusion Among patients undergoing functional assessment of intermediate coronary lesions by instantaneous wave-free ratio, no impact of sex was observed on the absolute values or the rate of positivity of iFR.

Background Empathy has long been considered a multidimensional construct, encompassing cognitive, affective and behavioral domains. Deficits in empathic competences in early childhood contribute to psychopathology, and have been variably implicated in several clinical conditions, such as autism spectrum disorders (ASD) and conduct disorders. Aim To identify and describe empirically validated questionnaires assessing empathy in children and adolescents and to provide a summary of related theoretical perspectives on empathy definitional issues. Methods A systematic review of the literature was conducted. Three bibliographic databases were searched. A total of 47 studies were selected for final analysis and 16 distinct measures were identified and described. Results Questionable to excellent levels of internal consistency were observed, while few studies assessed test-retest reliability. Although construct definitions only partially overlapped, affective and cognitive domains of empathy were the commonest internal factors that were often separately evaluated. New facets of the construct (i.e., somatic empathy and sympathy) and specific clinical populations (i.e., ASD) could be specifically addressed through more recent instruments. Conclusion The combination of different assessment methods is recommended in order to foresee further improvements in this field and try to overcome the problem of limited convergence with more objective measures.

Background Electroconvulsive therapy (ECT) has been shown to induce broadly distributed cortical and subcortical volume increases, more prominently in the amygdala and the hippocampus. Structural changes after one ECT session and in the long-term have been understudied. Objective The aim of this study was to describe short-term and long-term volume changes induced in cortical and subcortical regions by ECT. Methods Structural brain data were acquired from depressed patients before and 2 h after their first ECT session, 7–14 days after the end of the ECT series and at 6 months follow up (N = 34). Healthy, age and gender matched volunteers were scanned according to the same schedule (N = 18) and patients affected by atrial fibrillation were scanned 1–2 h before and after undergoing electrical cardioversion (N = 16). Images were parcelled using FreeSurfer and estimates of cortical gray matter volume and subcortical volume changes were obtained using Quarc. Results Volume increase was observable in most of gray matter regions after 2 h from the first ECT session, with significant results in brain stem, bilateral hippocampi, right putamen and left thalamus, temporal and occipital regions in the right hemisphere. At the end of treatment series, widespread significant volume changes were observed. After six months, the right amygdala volume was still significantly increased. No significant changes were observed in the comparison groups. Conclusions Volume increases in gray matter areas can be detected 2 h after a single ECT session. Further studies are warranted to explore the underlying molecular mechanisms.

Purpose We aimed at investigating the lifetime prevalence of mood, eating and panic disorders in a large sample of obese patients referred to bariatric surgery. We also explored the patterns of psychiatric comorbidity and their relationship with Body Mass Index (BMI). Methods The sample was composed of patients consecutively referred for pre-surgical evaluation to the Obesity Center of Pisa University Hospital between January 2004 and November 2016. Clinical charts were retrieved and examined to obtain sociodemographic information, anthropometric variables and lifetime psychiatric diagnoses according to DSM-IV criteria. Results A total of 871 patients were included in the study; 72% were females, and most patients had BMI ≥ 40 kg/m2 (81%). Overall, 55% of the patients were diagnosed with at least one lifetime psychiatric disorder. Binge eating disorder (27.6%), major depressive disorder (16%), bipolar disorder type 2 (15.5%), and panic disorder (16%) were the most common psychiatric diagnoses. Mood disorders showed associations with panic disorder (OR = 2.75, 95% CI = 1.90–3.99, χ2 = 41.85, p = 0.000) and eating disorders (OR = 2.17, 95% CI 1.64–2.88, χ2 = 55.54, p = 0.000). BMI was lower in patients with major depressive disorder (44.9 ± 7.89) than in subjects without mood disorders (46.75 ± 7.99, padj = 0.017). Conclusion Bariatric patients show high rates of psychiatric disorders, especially binge eating and mood disorders. Longitudinal studies are needed to explore the possible influence of such comorbidities on the long-term outcome after bariatric surgery. Level of evidence V, cross sectional descriptive study.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.

CHARGE syndrome is a rare genetic multiple-malformation disorder characterized by wide phenotypic variability. It is often caused by heterozygous variants in CHD7 and, more rarely, SEMA3E. Although craniofacial alterations are frequent in this condition, to date craniosynostosis is not considered part of the clinical spectrum. Here, we report bi-coronal craniosynostosis in a newborn affected by CHARGE syndrome caused by the de novo heterozygous c.6157C>T, p.(Arg2053*) CHD7 variant. We found two additional subjects in the literature with different craniosynostoses and distinct CHD7 alterations. The inclusion of CHD7-related CHARGE syndrome in the group of rare causes of syndromic craniosynostoses is proposed.

Background and aims There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and results Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6–14.7 for age ≥85 vs 18–44 y); HR = 4.7; 2.9–7.7 for estimated glomerular filtration rate levels, Highlights • Impaired renal function, elevated C-reactive protein and advanced age were major indicators of death in COVID-19 patients. • These associations were substantially homogenous across all sub-groups analysed. • No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. • Death rates were higher in the Northern as opposed to Central-Southern Italian regions.

The automatic segmentation of variations in fundus images is being increasingly developed to establish retinal health, and to diagnose and monitor retinal abnormality. Fundus images can be acquired by low-cost and easy access diagnostic systems also in resource limited countries. In this paper, we focus on the segmentation of pigment signs in retinal fundus images, which is an important step in the diagnosis and monitoring of Retinitis Pigmentosa. At present, most of the existing approaches adopted for this purpose are based on the analysis of Optical Coherence Tomography (OCT) data, with only a few algorithms working on fundus images. The contribution of this paper is twofold. First, we propose a supervised segmentation technique for pigment sign detection in fundus images, which exploits the ensemble classifiers for both bagged and boosted decision trees, namely Random Forests and AdaBoost.M1. The ensemble classifiers are trained on feature vectors encoding the information of a set of regions obtained by partitioning a pre-processed image, so that each region is labeled as either normal fundus or pigment sign. Secondly, we have collected a large dataset of retinal images, in which the pigment signs have been segmented manually and we are making this publicly available to the research community. The performance of the classifiers has been evaluated on the proposed dataset and can be considered as a baseline for comparison. Our results demonstrate the high effectiveness of a machine learning approach as a suitable tool for automated Retinitis Pigmentosa analysis. The automatic segmentation of variations in fundus images is being increasingly developed to establish retinal health, and to diagnose and monitor retinal abnormality. Fundus images can be acquired by low-cost and easy access diagnostic systems also in resource limited countries. In this paper, we focus on the segmentation of pigment signs in retinal fundus images, which is an important step in the diagnosis and monitoring of Retinitis Pigmentosa. At present, most of the existing approaches adopted for this purpose are based on the analysis of Optical Coherence Tomography (OCT) data, with only a few algorithms working on fundus images. The contribution of this paper is twofold. First, we propose a supervised segmentation technique for pigment sign detection in fundus images, which exploits the ensemble classifiers for both bagged and boosted decision trees, namely Random Forests and AdaBoost.M1. The ensemble classifiers are trained on feature vectors encoding the information of a set of regions obtained by partitioning a pre-processed image, so that each region is labeled as either normal fundus or pigment sign. Secondly, we have collected a large dataset of retinal images, in which the pigment signs have been segmented manually and we are making this publicly available to the research community. The performance of the classifiers has been evaluated on the proposed dataset and can be considered as a baseline for comparison. Our results demonstrate the high effectiveness of a machine learning approach as a suitable tool for automated Retinitis Pigmentosa analysis.

A 26-year-old male with a two-year history of FLC developed progressive somnolence and disorientation. Treatment history for FLC had included cytotoxic chemotherapy, lenvatinib, and immunotherapy. A CT scan confirmed extensive stage FLC with numerous liver, lung, and pelvic metastasis. Laboratory results showed bilirubin 0.3 mg/dL, creatinine 0.4 mg/dl, leukocytes of 9.5x109 /L, hemoglobin 11.2 g/dL, platelets 369x109 /L, and ammonia 247 µmol/L (reference range: 0-32 µmol/L). Plasma amino acid analysis revealed relatively low citrulline (14 µmol/L), arginine (32 µmol/L), and ornithine (35 µmol/L). Urinary orotic acid excretion was markedly elevated at 149 mmol/mol creat (reference range: 0.68-3.52 mmol/mol creat).

Breast cancer is the most common invasive cancer in women, affecting more than 10% of women worldwide. Microscopic analysis of a biopsy remains one of the most important methods to diagnose the type of breast cancer. This requires specialized analysis by pathologists, in a task that i) is highly time- and cost-consuming and ii) often leads to nonconsensual results. The relevance and potential of automatic classification algorithms using hematoxylin-eosin stained histopathological images has already been demonstrated, but the reported results are still sub-optimal for clinical use. With the goal of advancing the state-of-the-art in automatic classification, the Grand Challenge on BreAst Cancer Histology images (BACH) was organized in conjunction with the 15th International Conference on Image Analysis and Recognition (ICIAR 2018). A large annotated dataset, composed of both microscopy and whole-slide images, was specifically compiled and made publicly available for the BACH challenge. Following a positive response from the scientific community, a total of 64 submissions, out of 677 registrations, effectively entered the competition. From the submitted algorithms it was possible to push forward the state-of-the-art in terms of accuracy (87%) in automatic classification of breast cancer with histopathological images. Convolutional neuronal networks were the most successful methodology in the BACH challenge. Detailed analysis of the collective results allowed the identification of remaining challenges in the field and recommendations for future developments. The BACH dataset remains publically available as to promote further improvements to the field of automatic classification in digital pathology., Accepted for publication at Medical Image Analysis (Elsevier). Publication licensed under the Creative Commons CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

Background: Shp1, a tyrosine-phosphatase-1 containing the Src-homology 2 (SH2) domain, is involved in inflammatory and immune reactions, where it regulates diverse signalling pathways, usually by limiting cell responses through dephosphorylation of target molecules. Moreover, Shp1 regulates actin dynamics. One Shp1 target is Src, which controls many cellular functions including actin dynamics. Src has been previously shown to be activated by a signalling cascade initiated by the cytosolic-phospholipase A2 (cPLA2) metabolite glycerophosphoinositol 4-phosphate (GroPIns4P), which enhances actin polymerisation and motility. While the signalling cascade downstream Src has been fully defined, the mechanism by which GroPIns4P activates Src remains unknown. Methods: Affinity chromatography, mass spectrometry and co-immunoprecipitation studies were employed to identify the GroPIns4P-interactors; among these Shp1 was selected for further analysis. The specific Shp1 residues interacting with GroPIns4P were revealed by NMR and validated by site-directed mutagenesis and biophysical methods such as circular dichroism, isothermal calorimetry, fluorescence spectroscopy, surface plasmon resonance and computational modelling. Morphological and motility assays were performed in NIH3T3 fibroblasts. Results: We find that Shp1 is the direct cellular target of GroPIns4P. GroPIns4P directly binds to the Shp1-SH2 domain region (with the crucial residues being Ser 118, Arg 138 and Ser 140) and thereby promotes the association between Shp1 and Src, and the dephosphorylation of the Src-inhibitory phosphotyrosine in position 530, resulting in Src activation. As a consequence, fibroblast cells exposed to GroPIns4P show significantly enhanced wound healing capability, indicating that GroPIns4P has a stimulatory role to activate fibroblast migration. GroPIns4P is produced by cPLA2 upon stimulation by diverse receptors, including the EGF receptor. Indeed, endogenously-produced GroPIns4P was shown to mediate the EGF-induced cell motility. Conclusions: This study identifies a so-far undescribed mechanism of Shp1/Src modulation that promotes cell motility and that is dependent on the cPLA2 metabolite GroPIns4P. We show that GroPIns4P is required for EGF-induced fibroblast migration and that it is part of a cPLA2/GroPIns4P/Shp1/Src cascade that might have broad implications for studies of immune-inflammatory response and cancer. [Figure not available: see fulltext.]

Magneto-rheological elastomers (MRE), consisting of elastomeric matrix containing ferromagnetic particles, are a kind of smart material, whose mechanical properties are controllable via applied magnetic fields. In this paper, the possibility of adopting these materials to realize vibration isolators for lightweight structures is evaluated. Such isolators must be stiff enough in the vertical direction, to support the structure weight, while they must have a low horizontal stiffness to isolate ground vibrations originated by different sources. To meet these requirements, an isolation system, constituted by MRE pads and ball transfer units (BTU), is proposed. The BTUs support the structure weight allowing it to move in any horizontal direction, while the MRE pads provide a controllable horizontal restoring force. Therefore, the pad stiffness may be chosen considering only the horizontal isolation characteristics, regardless of the vertical ones. The paper describes the isolator layout, the criteria followed to make up a set of MRE specimens and the experimental set-up adopted to characterize them. The dynamic behaviour of the isolated structure and the isolator performances are described by means of numerical simulations. The analytical description of the isolator restoring force was deduced adopting a generalized Maxwell model in parallel with a Bouc–Wen element whose coefficients were identified from the experimental test results.

Abnormal joint kinematics are commonly reported in the acute and chronic stages of recovery after anterior cruciate ligament (ACL) injury and have long been mechanistically implicated as a primary driver in the development of post-traumatic osteoarthritis (PTOA). Though strongly theorized, it is unclear to what extent biomechanical adaptations after ACL injury culminate in the development of PTOA, as data that directly connects these factors does not exist. Using a pre-clinical, non-invasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on joint kinematics and the pathogenetic mechanisms involved in the development of PTOA. Thirty-two, sixteen-week-old Long-Evans rats were exposed to a non-invasive ACL injury. Marker-less deep learning software (DeepLabCut) was used to track animal movement for sagittal-plane kinematic analyses and micro computed tomography was used to evaluate subchondral bone architecture at days 7, 14, 28 and 56 following injury. There was a significant decrease in peak knee flexion during walking (p

Background. Optimization of the techniques and larger accessibility to mechanical reperfusion have significantly improved the outcomes of patients with ST-segment elevation myocardial infarction (STEMI). However, suboptimal results have been observed in certain higher-risk subsets of patients, as in advanced age, where the benefits of primary PCI are more debated. We evaluated the impact of systematic primary percutaneous coronary intervention (PCI) and an optimized STEMI network on the long-term prognosis from a single centre experience. Methods. We included STEMI patients included in the FAST-STEMI network between 2016 and 2019. Ischemia duration was defined as the time from symptoms onset to coronary reopening (pain-to-balloon, PTB). The primary study endpoint (PE) was a composite of mortality and recurrent MI at long-term follow-up. Indywidual outcome endpoints were also assessed. Results. We included 253 patients undergoing primary PCI and discharged alive. Mean age was 67.2 ± 12.5 years, 75.1% males and 19.8% diabetics. At a median follow-up of 581 [307–922] days, the primary endpoint occurred in 24 patients (7.9%), of whom 5.5% died. The occurrence of a cardiovascular event was significantly associated with advanced age (p < 0.001), renal failure (p = 0.03), lower ejection fraction at discharge (p = 0.04) and longer in-hospital stay (p = 0.01). The median PTB was 198 minutes [IQR: 125–340 min], that was significantly longer among patients experiencing the PE (p = 0.01). A linear relationship was observed between age and PTB (r = 0.13, p = 0.009). However, both age ≥ 75 years and PTB above the median emerged as independent predictors of the primary endpoint (age: HR [95%CI] = 5.56 [2.26–13.7], p < 0.001, PTB: HR [95%CI] = 3.59 [1.39–9.3], p = 0.01). Similar results were observed for overall mortality. Conclusion. The present study shows that among STEMI patients undergoing primary PCI in a single centre, the duration of ischemia and advance age are independently associated to long-term mortality and recurrent myocardial infarction. However, longer time to reperfusion was observed among elderly patients.

Proximal interstitial deletions of chromosome 9p13 have been described only in a few patients with developmental delay, moderate intellectual disability, craniofacial dysmorphism, short stature, genital anomalies, and precocious puberty. To corroborate and expand these findings, we report on two novel syndromic male patients with 9p13 deletions suffering from a similar form of tremor and compare them with literature data. Despite genomic variability in deletion sizes, all patients displayed homogeneous dysmorphism and clinical manifestations, including very invalidating tremor. Furthermore, we outlined a region of around 2 Mb shared in common by all patients with nearly 70 genes, among which NPR2 might have a role in the phenotype. These data delineate interstitial 9p13 deletion syndrome with tremor as a major feature.

Bone morphogenetic protein 15 (BMP15) encodes an oocyte factor with a relevant role for folliculogenesis as homodimer or cumulin heterodimer (BMP15-GDF9). Heterozygous BMP15 variants in the precursor or mature peptide had been associated with primary ovarian insufficiency (POI), but the underlying mechanism remains elusive and a double dose of BMP15 was suggested to be required for adequate ovarian reserve. We uncovered two homozygous BMP15 null variants found in two girls with POI and primary amenorrhea. Both heterozygous mothers reported physiological menopause. We then performed western blot, immunofluorescence, and reporter assays to investigate how previously reported missense variants, p.Y235C and p.R329C, located in the precursor or mature domains of BMP15, may affect protein function. The p.R329C variant demonstrates an impaired colocalization with growth/differentiation factor 9 (GDF9) at confocal images and diminished activation of the SMAD pathways at western blot and reporter assays in COV434 follicular cell line. In conclusion, BMP15 null mutations cause POI only in the homozygous state, thus discarding the possibility that isolated BMP15 haploinsufficiency can cause evident ovarian defects. Alternatively, heterozygous BMP15 missense variants may affect ovarian function by interfering with cumulin activity. Our data definitely support the fundamental role of BMP15 in human ovarian folliculogenesis.

Objective To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). Methods This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. Results Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. Conclusions Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

The potent oral inhibitor of BCL2, venetoclax (VEN), used to treat adults with chronic lymphocytic leukaemia, has been approved in US for the treatment of naïve patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy and recently in Europe, too. However, the drug has been used for years in combination with hypomethylating agents (HMAs) in patients not eligible to other treatment option, according to the so-called off-label use. We collected real-world data about patients treated with VEN + HMAs in the context of a pharmacovigilance project focused on the evaluation of the safety and effectiveness of drugs used for unapproved indication in Italian hospitals. From March to December 2020, 24 patients started treatment with VEN combined with HMAs. 21 patients have been assessed for response. Eleven (52%) patients reached complete remission (CR), and three patients (14%) CR with partial hematological recovery (CRh), with a median duration of response of 4.5 months (range 0.5–12.5). 19 patients experienced at least 1 adverse drug reaction (ADR), mostly serious, including 3 deaths (9% of ADRs; 12.5% of patients) in febrile neutropenia. Hematological toxicities and infections (cytopenia, neutropenia, febrile neutropenia, sepsis), were the most reported ADRs (84.4%). In general, neutropenic fever occurred more frequently in patients treated with decitabine (7 out of 9, 78%) compared to azacitidine (5 out of 15, 33%; p = 0.03), whereas response assessment did not differ based on used HMA (p = 0.1). These results confirm the benefit-risk profile of VEN in a real-world setting of patients with no adequate therapeutic options.

Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.

Summary We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly., We report a neurodevelopmental disorder with microcephaly in seven affected individuals with the same de novo variant in the ARPC4 gene. The recurrent variant in ARPC4, a subunit of the complex that catalyzes F-actin network formation, is associated with decreased F-actin in cells from affected individuals.

Background Vitamin D displays a broad spectrum of cardioprotective effects, preventing oxidative stress, inflammation and thrombosis and improving endothelial function. Previous studies have associated vitamin D deficiency with more extended and severe coronary artery disease (CAD) and worse outcome, and especially among patients with ST-segment elevation myocardial infarction (STEMI). Few data have been reported on the association of vitamin D levels with the features of infarct-related lesions and PCI outcomes. Aim We aimed at assessing the relationship between vitamin D and angiographic findings and the procedural results of primary percutaneous coronary intervention (pPCI) in STEMI. Methods A consecutive cohort of patients admitted for STEMI treated with pPCI were included. The levels of 25(OH)D were assessed at admission by chemiluminescence immunoassay kit LIAISON® Vitamin D assay. Hypovitaminosis D was defined for 25(OH)D Results We included in our study 450 patients, divided according to tertiles values of 25(OH)D. Lower vitamin D was associated to higher use of diuretics (p=0.02), higher levels of white blood cells and glycemia (p Conclusion The present study shows that among patients with STEMI undergoing pPCI, lower levels of vitamin D indepently predict the occurrence of slowflow/no-reflow phenomenon. Future dedicated studies will shed light on the prognostic implications of hypovitaminosis D in these patients and the potential therapeutic perspectives. Funding Acknowledgement Type of funding sources: None.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved., Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

The adoption of Deep Learning (DL) algorithms into the practice of ophthalmology could play an important role in screening and diagnosis of eye diseases in the coming years. In particular, DL tools interpreting ocular data derived from low-cost devices, as a fundus camera, could support massive screening also in resource limited countries. This paper explores a fully automatic method supporting the diagnosis of the Retinitis Pigmentosa by means of the segmentation of pigment signs in retinal fundus images. The proposed approach relies on an U-Net based deep convolutional network. At the present, this is the first approach for pigment signs segmentation in retinal fundus images that is not dependent on hand-crafted features, but automatically learns a hierarchy of increasingly complex features directly from data. We assess the performance by training the model on the public dataset RIPS and comparisons with the state of the art have been considered in accordance with approaches working on the same dataset. The experimental results show an improvement of 15% in F-measure score.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). NPC1 and NPC2 genes were studied following an algorithm recently published. Eighty-four different NPC1 and five NPC2 alleles were identified. Only two NPC1 alleles remained non detected. Sixty-two percent of NPC1 alleles were due to missense variants. The most frequent NPC1 mutation was the p.F284Lfs*26 (5.8% of the alleles). All NPC2 mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel NPC1 mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient’s fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.

Purpose The co-occurrence of obesity, eating and mood disorders has been frequently reported in clinical and epidemiological settings. This study aimed to explore the prevalence of night-eating obese patients referred for bariatric surgery and to identify associated psychopathology and psychiatric comorbidity. Methods The sample was composed of 121 obese patients consecutively enrolled between November 2010 and May 2012 during psychiatric evaluations for bariatric intervention. Clinical features and psychiatric diagnoses were collected. Night-eating was investigated through the administration of the Night-eating Questionnaires (NEQ) and was defined as the presence of self-reported evening hyperphagia and/or nocturnal ingestions. Binge-eating and purging behaviors and general psychopathology were respectively assessed using the Bulimic Investigatory Test, Edinburgh and the Symptom Checklist-90-Revised. Results Night-eating was reported by twenty subjects (16.5%). Patients with night-eating behavior were significantly more frequently diagnosed with bipolar spectrum disorders and with comorbid eating and mood disorders in comparison with other patients. Night-eating patients showed significantly more binging/purging behaviors and greater severity of somatization, obsessive–compulsive symptoms, phobic anxiety, psychoticism and sleep disorders. Patients with bipolar disorder type 1 or 2 scored significantly higher than those without mood disorders at NEQ total score, mood/sleep and nocturnal ingestions subscales, but also scored significantly higher than other patients with mood disorders at the latter subscale. Conclusion Patients with evening hyperphagia and/or nocturnal ingestions should be carefully evaluated to detect possible bipolar spectrum disorders and other eating disorders. Prompt management of these conditions should be provided before bariatric interventions. Level of evidence V, cross-sectional descriptive study.

Background Standardised checklists of items to be addressed in clinical study protocols and publications are promoting transparency in research. However, particular specifications for exceptional cases, such as children with minor parents are missing. This study aimed to examine the level of transparency regarding recruitment and informed consent approaches in publications of clinical trials recruiting children with minor parents in sub-Saharan Africa. We thereby focused particularly on the transparency about consenting persons (i.e. proxy decision-makers) and assessed the need to expand reporting guidelines for such exceptional cases. Methods We conducted a secondary analysis of clinical trial publications previously identified through a systematic review. Multiple scientific databases were searched up to March 2019. Clinical trial publications addressing consent and potentially recruiting children with minor parents in sub-Saharan Africa were included. 44 of the in total 4382 screened articles met our inclusion criteria. A descriptive analysis was performed. Results None of the included articles provided full evidence on whether any recruited children had minor parents and how consent was obtained for them. Four proxy decision-maker types were identified (parents; parents or guardians; guardians; or caregivers), with further descriptions provided rarely and mostly in referenced clinical trial registrations or protocols. Also, terminology describing proxy decision-makers was often used inconsistently. Conclusions Reporting the minimum maternal age alongside maternal data provided in baseline demographics can increase transparency on the recruitment of children with minor mothers. The CONSORT checklist should require clinical trial publications to state or reference exceptional informed consent procedures applied for special population groups. A standardized definition of proxy decision-maker types in international clinical trial guidelines would facilitate correct and transparent informed consent for children and children with minor parents. Study registration CRD42018074220.

Despite the availability of a lot of effective disease-modifying drugs, multiple sclerosis (MS) (in particular the progressive forms) still represents an important unmet medical need, because of issues in terms of effectiveness, duration of response, safety, and patient compliance. An increasing body of evidence from randomized clinical trials and real-world data suggest that rituximab is a highly effective alternative in both relapsing and progressive MS, with a low discontinuation rate, related to a good benefit/risk profile, and a good compliance. To date, the use of rituximab in patients with multiple sclerosis is not in accordance with the authorized product information (off-label use). However, the use of this medicine is widespread in several countries, and in some cases, it is the most commonly used disease-modifying drug for MS subtypes. This use could be officially recognized by national regulatory authorities, according to specific procedures, to ensure equal access for patients to a safe and effective option.

Background DSM-5 and ICD-11 define mixed depression as the presence of non-overlapping symptoms of opposite polarity during a major depressive episode. However, such a definition has generated controversy. Methods 2720 patients with major depression, enrolled in BRIDGE–II–MIX cross-sectional study, were subdivided in clusters using a k-medoids algorithm based on 32 clinical features. Clinical variables were compared among clusters. Stepwise logistic regression and random forest predictor importance estimates were used to identify which features best predicted cluster membership. Data-driven criteria were compared with DSM-5 mixed specifier and previously proposed research-based criteria (RBDC). Results Two clusters were identified (MDE ± MX), mainly reflecting differences in current manic symptoms. As expected, MDE + MX showed higher rates of comorbidities and bipolar features, more previous depressive episodes and suicide attempts, shorter duration of current MDE and lower age at onset. Seven clinical features among the original 32 proved to be the best predictors of cluster membership. Derived criteria perfectly allocated subjects in clusters, requiring at least four features out of the following seven: irritability, emotional lability, psychomotor agitation, distractibility, mood reactivity, absence of reduced appetite, and absence of psychomotor retardation. RBDC showed a better performance than DSM-5 in identifying MDE + MX subjects. Conclusion Our results strongly suggest a predominant role for overlapping “manic” symptoms in defining mixed depressive states. Mixed depression is better identified by the presence of excitatory features shared with mania and atypical features rather than by non-overlapping manic symptoms.

Background: Glioma, most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. Evaluate the association of polymorphisms related of to the cell cycle, integrity and DNA repair with gliomas, as well as lifestyle habits, comorbidities, survival and response to treatment. Methods: Were studied 303 individuals distributed into: Study Group - 100 patients with gliomas, regardless of the degree of malignancy, and Control Group - 203 individuals without clinical signs of the disease. These polymorphisms were genotyped by TaqMan® SNP Genotyping Assay. Significance level was set at 5%. Results: Smoking, alcohol consumption, systemic arterial hypertension (SAH) and diabetes mellitus (DM) prevailed in patients, compared to controls (P=0.0088, P=0.0001, P=0.0001, P=0.0011, respectively). In the logistic regression analysis, alcohol consumption and SAH were identified as independent risk factors for gliomas (P=0.0001, P=0.0027, respectively). Patients with low-grade gliomas showed survival in one year (92.0±6.8%), compared to patients with high-grade gliomas (24.0±5.3; P=0.011). Conclusion: Polymorphisms involved in cell cycle, telomere protection and stability and DNA repair are not associated with gliomas. On the other hand, alcohol consumption and SAH stand out as independent risk factors for the disease. Low-grade gliomas, response to treatment and the combination of chemotherapy with Temozolomide and radiation therapy show increased survival of patients.

Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or multiplex ligation-dependent probe amplification and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.

BackgroundStructural variants (SVs) affecting non-coding cis-regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the PITX1 locus leading to its misregulation in the forelimb by its native enhancer element Pen. This study aims to elucidate the genetic cause of an unsolved family with a mild form of Liebenberg syndrome and investigate the role of promoters in long-range gene regulation.MethodsHere, we identify SVs by whole genome sequencing (WGS) and use CRISPR-Cas9 genome editing in transgenic mice to assign pathogenicity to the SVs.ResultsIn this study, we used WGS in a family with three mildly affected individuals with Liebenberg syndrome and identified the smallest deletion described so far including the first non-coding exon of H2AFY. To functionally characterise the variant, we re-engineered the 8.5 kb deletion using CRISPR-Cas9 technology in the mouse and showed that the promoter of the housekeeping gene H2afy insulates the Pen enhancer from Pitx1 in forelimbs; its loss leads to misexpression of Pitx1 by the pan-limb activity of the Pen enhancer causing Liebenberg syndrome.ConclusionOur data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease.

The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here we identified 17 individuals from 14 unrelated families with both with new and previously characterised variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in C. elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.

Background and Objectives: Emotional dysregulation is central to the problem of the overlap between attention-deficit/hyperactivity disorder (ADHD) and cyclothymia. The aim of the study was to evaluate comorbidity rates between ADHD and cyclothymic disorder and to explore demographic and clinical differences among the groups, focusing on affective temperament and emotional dysregulation. Materials and Methods: One hundred sixty-five outpatients attending the Second Psychiatry Unit at the Santa Chiara University Hospital (Pisa) were consecutively recruited: 80 were diagnosed with ADHD, 60 with cyclothymic disorder, and 25 with both conditions. Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-M) and the 40-item version of Reactivity, Intensity, Polarity, and Stability questionnaire (RI-PoSt-40) were administered. Results: Cyclothymic patients were more frequently female and older with respect to the ADHD groups. Both comorbid and non-comorbid ADHD patients showed significantly lower educational attainment and more frequently had substance use disorders. Panic disorder was common in non-comorbid cyclothymic patients, who showed significantly higher rates of familial panic disorder, major depressive disorder and suicide attempts in comparison with patients only diagnosed with ADHD. Cyclothymic patients without ADHD were also characterized by fewer hyperthymic temperamental traits, higher depressive and anxious dispositions, and a greater negative emotionality. No significant differences among groups were observed for cyclothymic temperament and overall negative emotional dysregulation, but comorbid patients with both conditions scored the highest in these subscales. This group also showed significantly higher affective instability with respect to ADHD patients without cyclothymia and was less frequently diagnosed with bipolar disorder type II than patients from both the other groups. Conclusions: ADHD and cyclothymia often co-occur and show similar levels of emotional dysregulation. However, cyclothymic patients may be more prone to negative emotionality in clinical settings. Subjects with “sunny” cyclothymic features might escape the attention of clinicians unless ADHD is present.

Mood and anxiety disorders are the most common neuropsychiatric syndromes associated with Parkinson’s disease (PD). The aim of our study was to estimate the prevalence of lifetime and current anxiety disorders in patients with Parkinson’s Disease (PD), to explore possible distinctive neurological and psychiatric features associated with such comorbidity. One hundred patients were consecutively recruited at the Movement Disorders Section of the Neurological Outpatient Clinic of the University of Pisa. According to the MINI-Plus 5.0.0, 41 subjects were diagnosed with lifetime anxiety disorder (22 with panic disorder) and 26 were diagnosed with current anxiety disorders. Patients with anxiety disorders were more frequently characterized by psychiatric symptoms preceding PD, lifetime major depression and antidepressant treatments. They showed more anxious temperamental traits and scored higher at Parkinson Anxiety Scale (PAS) and persistent anxiety subscale. Current anxiety disorders were associated with more severe psychopathology, depressive symptomatology, and avoidant behavior. Among anxiety subtypes, patients with lifetime panic disorder showed higher rates of psychiatric symptoms before PD, lifetime unipolar depression, current psychiatric treatment, and a more severe psychopathology. Given the overall high impact of anxiety on patients’ quality of life, clinicians should not underestimate the extent of different anxiety dimensions in PD.

The hippocampus’s dorsal and ventral parts are involved in different operative circuits, which functions vary in time during the night and day cycle. These functions are altered in epilepsy. Since energy production is tailored to function, we hypothesized that energy production would be space- and time-dependent in the hippocampus and that such organizing principle would be modified in epilepsy. Using metabolic imaging and metabolite sensing ex vivo, we show that the ventral hippocampus favors aerobic glycolysis over oxidative phosphorylation as compared to the dorsal part in the morning in control mice. In the afternoon, aerobic glycolysis is decreased, and oxidative phosphorylation increased. In the dorsal hippocampus, the metabolic activity varies less between these two times but is weaker than in the ventral. Thus, the energy metabolism is different along the dorsoventral axis and changes as a function of time in control mice. In an experimental model of epilepsy, we find a large alteration of such spatio-temporal organization. In addition to a general hypometabolic state, the dorsoventral difference disappears in the morning, when seizure probability is low. In the afternoon, when seizure probability is high, the aerobic glycolysis is enhanced in both parts, the increase being stronger in the ventral area. We suggest that energy metabolism is tailored to the functions performed by brain networks, which vary over time. In pathological conditions, the alterations of these general rules may contribute to network dysfunctions.SIGNIFICANCE STATEMENTThe dorsal part of the hippocampus is involved in spatial learning and memory processes, while the ventral is implicated in motivational and emotional behavior. These functions change during the night and day cycle, and they are altered in epilepsy. Here we show that energy production (glycolysis versus oxidative phosphorylation) varies along the dorsoventral axis in a circadian manner ex vivo in control mice. These rules are altered in experimental epilepsy. Thus, energy production may be tailored to the function performed by hippocampal subdivisions and to the time of the day. Alterations in epilepsy may contribute to seizure generation and cognitive deficits.

Fertility preservation represents one important goal of cancer patients’ management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.

Aim: Instantaneous wave-free ratio (iFR) has emerged as the strategy of choice for the assessment of intermediate coronary lesions. The impact of preprocedural β-blockers therapy on the iFR was the aim of this study. Methods: We included patients undergoing functional assessment of intermediate (40%-70%) coronary lesions in 2 centers. The iFR measurement was performed by pressure-recording guidewire and calculated at the core laboratory using the manufacturers’ dedicated software. Minimal luminal diameter, reference diameter, percent diameter stenosis, and length of the lesion were measured. Positive iFR was considered for values Results: We included 197 patients undergoing functional evaluation of 223 coronary lesions. Patients on β-blockers (69%) had more frequently hypertension ( P = .05); previous myocardial infarction ( P = .01); therapy with clopidogrel ( P = .02), statins, and aspirin; and acute coronary syndrome at presentation ( P < .001, respectively). Mean iFR values were slightly higher in patients on β-blockers (0.94 ± 0.06 vs 0.92 ± 0.06, P = .11). The rate of positive iFR was significantly lower with β-blockers (14.9% vs 27.5%, P = .04). On multivariate analysis, β-blockers use was a predictor of the significance of coronary stenoses (odds ratio [OR] = 0.48; 95% CI = 0.23-0.98; P = .05) together with lesion length (OR = 1.04; 95% CI = 1.01-1.07; P = .007). Conclusion: Among patients undergoing iFR, preprocedural β-blockers are associated with higher absolute values and a lower rate of positive iFR.

ObjectiveTo describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy.MethodsWe investigated by Sanger and targeted resequencing the SYN1 gene in 12 individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened.ResultsIn all families with bathing epilepsy, we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in SYN1, 9 of which are novel. Conversely, none of the individuals with hot-water epilepsy displayed SYN1 variants. In mutated individuals, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail clipping, haircutting, or watching someone take a shower. Unprovoked seizures and a variable degree of developmental delay were also common.ConclusionBathing epilepsy is genetically distinct reflex epilepsy caused mainly by SYN1 mutations.

Background Increasing attention has been recently paid to precursors of bipolar disorder (BD). Symptoms of attention-deficit/hyperactivity disorder (ADHD) have been reported among the most common prodromes of BD. The aim of this study was to estimate the risk of BD in youths affected by ADHD based on prospective studies. Methods A systematic review was conducted according to the PRISMA guidelines. A meta-analysis of single proportions was performed to compute the overall occurrence of BD in ADHD individuals. Binary outcome data were used to calculate risk estimates of BD occurrence in ADHD subjects versus Healthy Controls (HC). Results An overall proportion of BD occurrence of 10.01% (95%-confidence interval [CI]: 6.47%-15.19%; I2 = 82.0%) was found among 1248 patients with ADHD over 10 prospective studies. A slightly higher proportion was found when excluding one study based on jack-knife sensitivity analysis (11.96%, 95%-CI: 9.15%-15.49%; I2 = 54.1%) and in three offspring studies (12.87%, 95%-CI: 8.91%-18.23%). BD occurrence was not significantly associated with mean follow-up duration (p-value = 0.2118). A greater risk of BD occurrence in ADHD versus HC from six studies was found (risk ratio: 8.97, 95%-CI: 4.26-18.87, p-value Limitations Few prospective studies have been retrieved in our search and most were not specifically aimed at assessing BD in followed-up ADHD patients. Conclusions Greater clinical attention should be paid to ADHD as an early precursor of BD since a substantial proportion of ADHD patients is expected to be diagnosed with BD during the developmental age.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.

Oculo-auriculo-vertebral-spectrum (OAVS, OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.

Retinitis Pigmentosa is an eye disease that presents with a slow loss of vision and then evolves until blindness results. The automatic detection of the early signs of retinitis pigmentosa acts as a great support to ophthalmologists in the diagnosis and monitoring of the disease in order to slow down the degenerative process. A large body of literature is devoted to the analysis of Retinitis Pigmentosa. However, all the existing approaches work on Optical Coherence Tomography (OCT) data, while hardly any attempts have been made working on fundus images. Fundus image analysis is a suitable tool in daily practice for an early detection of retinal diseases and the monitoring of their progression. Moreover, the fundus camera represents a low-cost and easy-access diagnostic system, which can be employed in resource-limited regions and countries. The fundus images of a patient suffering from retinitis pigmentosa are characterized by an attenuation of the vessels, a waxy disc pallor and the presence of pigment deposits. Considering that several methods have been proposed for the analysis of retinal vessels and the optic disk, this work focuses on the automatic segmentation of the pigment deposits in the fundus images. The image distortions are attenuated by applying a local {\color{blue}pre-processing}. Next, a watershed transformation is carried out to produce homogeneous regions. Working on regions rather than on pixels makes the method very robust to the high variability of pigment deposits in terms of color and shape, so allowing the detection even of small pigment deposits. The regions undergo a feature extraction procedure, so that a region classification process is performed by means of an outlier detection analysis and a rule set. The experiments have been performed on a dataset of images of patients suffering from retinitis pigmentosa. Although the images present a high variability in terms of color and illumination, the method provides a good performance in terms of sensitivity, specificity, accuracy and the F-measure, whose values are 74.43, 98.44, 97.90, 59.04, respectively.