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Objectives This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the child's immunological profile with their mothers. Methods A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years. Results 134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-β2 glycoprotein-I (anti-β2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-β2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-β2GPI IgG were correlated with the same mother's antibodies before 6 months of age (p<0.05). Conclusion Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.

Atmospheric particulate matter (PM) has multiple adverse effects on human health, high temperatures are also associated with adverse health outcomes, and the frequency of cardiovascular events (CVEs) varies with season. We investigated a hypothesized increase in PM-related accident and emergency (A&E) presentations for CVE with high temperature, warm season, days of high influenza incidence, and in people with a cancer diagnosis, using a time-stratified case-crossover study design. Outcomes were associations of A&E presentation for CVE with atmospheric PM ≤ 10 μm (PM10), season, and air temperature. PM10 levels in the municipality of residence (exposure variable) were estimated by modeling data from local monitoring stations. Conditional logistic regression models estimated odds ratios (OR) with 95% confidence intervals (CI) for presentations in relation to supposed influencers, adjusting for confounders. Study participants were all who presented at the A&E of a large hospital near Milan, Italy, for a CVE (ICD-9: 390–459) from 1st January 2014 to 31st December 2015. There were 1349 A&E presentations for CVE in 2014–2015 and 5390 control days. Risk of A&E presentation was significantly increased on hot days with OR 1.34 (95%CI 1.05–1.71) per 10 μg/m3 PM10 increment (as mean PM10 on day of presentation, and 1 and 2 days before (lags 0–2)), and (for lag 0) in autumn (OR 1.23, 95%CI 1.09–1.37) and winter (OR 1.18, 95%CI 1.01–1.38). Risks were also significantly increased when PM10 was on lag 1, in people with a cancer diagnosis in the spring and summer months (1.88, 95%CI 1.05–3.37), and on days (lags 0–2) of high influenza incidence (OR 2.34, 95%CI 1.01–5.43). PM10 levels exceeded the 50 μg/m3 “safe” threshold recommended by the WHO and Italian legislation for only 3.8% of days during the warm periods of 2014–2015. Greater risk of A&E presentation for CVE in periods of high PM10 and high temperature suggests that “safe” thresholds for PM10 should be temperature-dependent and that the adverse effects of PM10 will increase as temperatures increase due to climate change.

The objective of this study was to determine the HLA class II associations of the anticardiolipin (aCL) and anti-b2GPI (ab2GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). A cohort of 577 European SLE patients was enrolled. aCL and ab2GPI were measured by ELISA methods. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 loci was performed by the polymerase chain reaction–sequence specific oligonucleotide probes (PCR–SSOP) method. aCL of IgG, IgM and IgA isotypes were detected in 22.8%, 14% and 13.9% of patients, respectively. IgG and IgM ab2GPI were detected in 20% of patients. aCL showed positive association with HLA DRB1*04, DRB1*0402, DRB1*0403, DRB1*07, DRB3*0301, DQA1*0201, DQA1*0301, DQB1*0302, and negative association with DQA1*0501, DRB3*0202. ab2GPI showed positive association with DRB1*0402, DRB1*0403, DQB1*0302. DRB1*0402 carried the highest relative risk for the presence of both aCL (RR = 8.1) and ab2GPI (RR = 4.6). Our results confirm the already described associations of aCL with HLA DR4 and DR7, but also demonstrate that, among the alleles at the DRB1*04 locus, the *0402 was most represented both in aCL and in ab2GPI positive patients. In addition, HLA class II associations of ab2GPI are for the first time extensively examined in a large cohort of European SLE patients.

Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1 , ITPR1 , MAB21L1 , PXDN , and PITX2 ) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.

Hereditary ataxia (HA) is a heterogeneous group of complex neurological disorders, which represent a diagnostic challenge due to their diverse phenotypes and genetic etiologies. Next-generation sequencing (NGS) has revolutionized the field of neurogenetics, improving the identification of ataxia-associated genes. Notwithstanding, repeat expansions analysis remains a cornerstone in the diagnostic workflow of these diseases. Here we describe the molecular characterization of a consecutive single-center series of 70 patients with genetically uncharacterized HA. Patients’ samples were analyzed for known HA-associated repeat expansions as first tier and negative ones were analyzed by whole exome sequencing (WES) as second tier. Overall, we identified pathogenic/likely pathogenic variants in 40% ( n  = 28/70) and variants of unknown significance (VUS) in 20% ( n  = 14/70) of cases. In particular, 10 patients (14.3%, n  = 10/70) presented pathogenic repeat expansions while 18 cases (30%, n  = 18/60) harbored at least a single nucleotide variant (SNV) or a copy number variant (CNV) in HA or HSP-related genes. WES allowed assessing complex neurological diseases (i.e., leukodystrophies, cerebrotendinous xanthomatosis and atypical xeroderma pigmentosum), which are not usually referred as pure genetic ataxias. Our data suggests that the combined use of repeat expansion analysis and WES, coupled to detailed clinical phenotyping, is able to detect the molecular alteration underpinning ataxia in almost 50% cases, regardless of the hereditary pattern. Indeed, NGS-based tests are fundamental to acknowledge novel HA-associated genes useful to explain the remaining wide fraction of negative tests. Nowadays, this gap is problematic since these patients could not benefit from an etiological diagnosis of their disease that allows prognostic trajectories and prenatal/preimplantation diagnosis.

Objectives Clinical presentation of pediatric celiac disease (CD) is heterogeneous and ever-evolving. Our aim is to highlight its changes throughout the years. Methods Data about clinical presentation of CD in children diagnosed between 1990 and 2020 at the CD Center of Maggiore Hospital, Bologna, were collected. Patients were stratified into groups based on the date [P1 (1990–2011), P2 (2012–2020)] and age [G1 (< 2 years), G2 (2–5), G3 (6–11), G4 (12–18)] at diagnosis, then investigated by comparing CD clinical presentation in different periods and ages. Results 1081 children were selected. Mean age at diagnosis increases from 5.9 to 6.6 years from P1 to P2. Gastrointestinal Symptoms (GIs) are predominant, with a decline of diarrhea (47%VS30%) and an increase of constipation (4%VS19%) ( p  < 0.001). Among Extraintestinal symptoms (EIs) a decrease of anemia (76%VS43%, p  = 0,001) is observed. Failure to Thrive (FTT) is stable throughout the years ( p  = 0.03), while screenings show a trend of increment (19%VS23%). GIs’ frequency decline from G1 to G4 ( p  = 0,001), with reduction of diarrhea ( p  < 0.001), and rise of recurrent abdominal pain ( p  = 0,02). EIs are more frequent at older ages, FTT in younger patients. Conclusions Changes in clinical presentation of CD have occurred in the last 30 years. We observe a reduction of severe and classic gastroenterologic symptoms and a rise of atypical ones, together with a growth of serological screenings and higher age at diagnosis. Awareness about CD clinical trends is crucial for a proper approach and early diagnosis.

Purpose This study aimed to assess the real-world management of achondroplasia in Italy. Methods Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery. Results In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2–5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians’ reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers. Conclusion This survey provides insight into the real-world management of individuals with achondroplasia in Italy.

Background Sleep abnormalities have been reported in Charcot–Marie–Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients’ series. Methods Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. Results ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p  = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p  = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p  < 0.001). Conclusions Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients’ management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.