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Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Context Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies. Objective This work aims to identify the genetic cause of growth failure in 3 “classical” GHI individuals. Methods A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. Results We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. Conclusion Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are potentially severe and complex disease in its management among the various allergic eye diseases. In this regard, studies clarified the etiopathogenetic mechanisms. The workup should be multidisciplinary. The treatment includes topical and systemic medications with anti-inflammatory and immunosuppressant activity. However, a definition of nationally- and internationally-shared diagnostic protocols would also be needed and validated access to therapeutic options of proven safety and efficacy to avoid the use of galenic preparations, up to now still essential in the management of moderate-severe VKC. Finally, recognizing VKC and AKC, among rare diseases, at a national and international level would be an essential step to allow the management of VKC with adequate timings and settings within the National Health System.

To evaluate the course of prenatally diagnosed and early-enrolled congenital solitary functioning kidney patients followed until adulthood and to identify risk factors for kidney injury.Among all congenital solitary functioning kidney patients followed (1993-2018), we recalled 56 patients with prenatal diagnosis and congenital solitary functioning kidney confirmation at 1-3 months of life reaching at least 18 years of age. Serum uric acid, heavy smoking (≥25 cigarettes/day) and overweight/obesity were clustered as modifiable risk factors. Kidney injury was defined by estimated glomerular filtration rate90 ml/minute/1.73 mThe mean followup period was 21.1 years (range 18-33 years). Mild kidney injury was found in 15 out of 56 patients (26.8%). The mean age at proteinuria, reduced estimated glomerular filtration rate and hypertension onset was 19.7 years (1.2 SDS), 20.7 years (2.7 SDS), and 22 years (5.6 SDS), respectively. Patients with CAKUT of congenital solitary functioning kidney and with both CAKUT of congenital solitary functioning kidney and modifiable risk factors presented survival free from kidney injury of 0% at 22.2 and 24.2 years of age, respectively. Patients with modifiable risk factors presented 42.4% of survival at 30 years. Patients without CAKUT of congenital solitary functioning kidney nor modifiable risk factors presented 100% of survival at 30 years of age (p=0.002). The presence of CAKUT of congenital solitary functioning kidney was the only significant risk factor (HR 4.9; 95% CI 1.8-14.2; p=0.003).The outcomes of congenital solitary functioning kidney in early adulthood appear better than previously reported. Prompt diagnosis of congenital solitary functioning kidney, healthy lifestyle promotion and monitoring of serum uric acid may improve the prognosis of congenital solitary functioning kidney patients.

Context Acute kidney injury (AKI) and renal tubular damage (RTD), especially if complicated by acute tubular necrosis (ATN), could increase the risk of later chronic kidney disease. No prospective studies on AKI and RTD in children with type1diabetes mellitus (T1DM) onset are available. Objectives To evaluate the AKI and RTD prevalence and their rate and timing of recovery in children with T1DM onset. Design Prospective study. Settings and patients 185 children were followed up after 14 days from T1DM onset. The patients who did not recover from AKI/RTD were followed-up 30 and 60 days later. Main outcome measures AKI was defined according to the KDIGO criteria. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin and/or tubular reabsorption of phosphate 2%. ATN was defined by RTD+AKI, prerenal (P)-AKI by AKI+FENa Results Prevalence of diabetic ketoacidosis (DKA) and AKI were 51.4% and 43.8%, respectively. Prevalence of AKI in T1DM patients with and without DKA was 65.2% and 21.1%, respectively; 33.3% reached AKI stage 2, and 66.7% of patients reached AKI stage 1. RTD was evident in 136/185 (73.5%) patients (32.4% showed ATN; 11.4%, P-AKI; 29.7%, ATD). All patients with DKA or AKI presented with RTD. The physiological and biochemical parameters of AKI and RTD were normal again in all patients. The former within 14 days and the latter within 2months. Conclusions Most patients with T1DM onset may develop AKI and/or RTD, especially if presenting with DKA. Over time the physiological and biochemical parameters of AKI/RTD normalize in all patients.

Hepatic calcifications have been increasingly identified over the past decade due to the widespread use of high-resolution Computed Tomography (CT) imaging. Calcifications can be seen in a vast spectrum of common and uncommon diseases, from benign to malignant, including cystic lesions, solid neoplastic masses, and inflammatory focal lesions. The purpose of this paper is to present an updated review of CT imaging findings of a wide range of calcified hepatic focal lesions, which can help radiologists to narrow the differential diagnosis.

Background We aimed to evaluate prevalence of acute kidney injury (AKI) and its risk factors in children hospitalized for acute gastroenteritis (AGE) to identify early predictors of AKI. Methods We retrospectively collected clinical and biochemical data of 114 children (57.9% male; mean age 2.9 ± 2.8 years) hospitalized for AGE. AKI was defined according to Kidney Disease/Improving Global Outcomes creatinine criteria. We considered basal serum creatinine as value of creatinine estimated with Hoste (age) equation assuming basal eGFRs were median age-based eGFR normative values for children ≤ 2 years of age, and eGFR 120 mL/min/1.73m2 for children > 2 years. Univariate and multivariate logistic regression models were used to explore associations with AKI. We included in multivariate analyses only variables with significant p after Bonferroni correction. Results AKI was found in 28/114 (24.6%) patients. No patients required hemodialysis, 2 (1.8%) reached AKI stage 3, 2 (1.8%) AKI stage 2, and 24 (21.0%) AKI stage 1. Mean length of stay was 3.6 ± 1.2, 5.0 ± 1.8, and 10.5 ± 5.8 days, for patients with no, mild, and severe AKI (p < 0.001), respectively. Duration of symptoms before hospitalization (OR = 2.5; 95% CI = 1.3–5.0; p = 0.006), dehydration > 5% (OR = 43.1; 95% CI = 5.4–344.1; p = < 0.001), and serum bicarbonate levels (OR = 1.6; 95% CI = 1.2–2.1; p = 0.001) were independent predictors of AKI. Conclusions About one quarter of patients hospitalized for AGE may suffer from AKI with a longer stay for patients with more severe AKI. Particular attention, however, should be paid to volemia and kidney health of patients with AGE especially in the presence of increased duration of symptoms before hospitalization, dehydration, and lower serum bicarbonate levels. Graphical abstract

The clinical spectrum of SARS‐CoV‐2 infection is mixed. It ranges from asymptomatic cases, medium‐intensity forms with mild to moderate symptoms, to severe ones with bilateral lung involvement and respiratory distress, which can require transfer to ICUs and intubation. In most cases, the clinical picture is characterized by a persistent fever, cough, dyspnoea, expectoration, myalgias, arthralgias, headache, gastrointestinal symptoms, nasal congestion, and pharyngodynia. The spread of COVID‐19 in Europe has highlighted an atypical presentation of disease involving upper airways and, above all, dysfunction of olfactory and gustatory senses. There is ample evidence that COVID‐19 is significantly less severe in children than in adults. However, due to difficulties in assessing the disorder in children, especially among very young patients, the olfaction and gustatory dysfunctions remain open issues. This article sheds light on the upper airway involvement in pediatric COVID‐19 subjects.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in pediatric obesity. Our study aims to identify a predictive anthropometrical measure for NAFLD in obese children. METHODS We retrospectively enrolled children and adolescents with obesity. Physical, biochemical, and ultrasound assessments were available. ROC curve tests were performed to identify the best predictor of NAFLD among waist-to-height ratio (WHR), BMI z-score, and triponderal mass index (TMI, an anthropometric index recently associated with increased adiposity in children). Subsequently, a cut-off value was identified. RESULTS In total, 1900 children and adolescents (1011 with NAFLD) were included. WHR (AUC 0.62, 95% CI 0.59-0.64) was the best predictor of NAFLD compared to BMI z-score (AUC 0.58, 95% CI 0.55-0.60) and TMI (AUC 0.58, 95% CI 0.55-0.61). WHR ≥ 0.53 in boys and 0.63 in girls displayed the best sensitivity and specificity for NAFLD presence. In addition, children with high WHR showed a significantly higher risk of NAFLD (boys: OR 2.43, 95% CI 1.61-3.68, p

Background Patients affected by cystic fibrosis can present with metabolic alkalosis such as Bartter's syndrome. In this case report we want to underline this differential diagnosis and we aimed focusing on the suspect of cystic fibrosis, also in case of a negative newborn screening. Case summary In a hot August -with a mean environmental temperature of 36 °C- an 8-mo-old female patient presented with severe dehydration complicated by hypokalemic metabolic alkalosis, in absence of fever, diarrhea and vomiting. Differential diagnosis between cystic fibrosis and tubulopathies causing metabolic alkalosis (Bartter's Syndrome) was considered. We started intravenous rehydration with subsequent improvement of clinical conditions and serum electrolytes normalization. We diagnosed a mild form of cystic fibrosis (heterozygous mutations: G126D and F508del in the cystic fibrosis transmembrane conductance regulator gene). The trigger factor of this condition had been heat exposure. Conclusion When facing a patient with hypokalemic metabolic alkalosis, cystic fibrosis presenting with Pseudo-Bartter's syndrome should be considered in the differential diagnosis, even if the newborn screening was negative.

Dehydration is a significant cause of morbidity and mortality in children worldwide. Infants and young children are vulnerable to dehydration, and clinical assessment plays a pivotal role in their care. In addition, laboratory investigations can, in some children, be helpful when assessing the severity of dehydration and for guiding rehydration treatment. In this interpretation, we review the current literature and provide an evidence-based approach to recognising and managing dehydration in children.

Rationale & Objective: The objective of this study is to evaluate the effect of body mass index (BMI) on estimated glomerular filtration rate (eGFR) levels in children with congenital solitary kidney (CSK). Moreover, we evaluated if other factors could influence this relationship. Study Design: Multicenter cross-sectional study. Setting & Participants: University hospital pediatrics departments. Subjects: Two hundred eighty-one patients with CSK. Predictors: Weight, height, BMI-SDS (standard deviation score), duration of overweight/obesity, pubertal stage, systolic (SBP) and diastolic (DBP) blood pressure, eGFR, and renal ultrasound were obtained at the last follow-up visit. The population was classified on the basis of nutritional status and divided in tertiles for duration of overweight/obesity. We compared eGFR levels among these categories. A simple regression was used to correlate eGFR with BMI-SDS. To evaluate if other factors could influence the relationship between eGFR and BMI-SDS, a general linear model was performed, including gender, birth weight

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Background: The relation between glucose homeostasis and outcome in hypoxic-ischemic encephalopathy (HIE) is unclear. To investigate whether glucose abnormalities assessed by using continuous interstitial glucose monitoring (CGM) correlate with later neurological outcomes in HIE. Methods: Prospective cohort study recruiting full-term neonates who received therapeutic hypothermia for HIE. CGM devices were placed soon after birth and recorded glucose profile for 3 days. The association between hypoglycemia (≤50 mg/dL), hyperglycemia (>144 mg/dL) and primary outcome defined as death or moderate or severe disability was examined with generalized estimating equations adjusted for Apgar scores, umbilical artery pH and base deficit. Neurodevelopmental outcome was assessed between 18 and 24 months. Results: Fifty-four neonates had outcome data available for the analysis; 19 of them (35%) had adverse outcome. Longer duration of hypoglycemia (OR 7.1, 95% CI 1.8–20.3, P < 0.001) and hyperglycemia (OR 5.4, 95% CI 1.6–15.7, P < 0.001), a greater area under the hypoglycemic (OR 2.6, 95% CI 1.4–4.6, P = 0.04) and hyperglycemic (OR 6.4, 95% CI 1.9–16.3, P < 0.001) curve were significantly associated with adverse outcomes. Conclusion: Both hyper and hypoglycemia may be associated with adverse outcome in neonates with HIE. Future studies are needed to assess their prognostic association with neurological outcome. Impact: Glucose abnormalities during therapeutic hypothermia are associated with later neurological outcomes.Increased glucose variability correlates to the neurological outcome between 18 and 24 months.This study provides the first data on the continuous glucose profile in a group of HIE infants followed up to 2 years of age.Glucose homeostasis represents a key point in the management of HIE patients.Further research is needed to find the appropriate glycemic target in this population.

Background: We hypothesized that children with congenital solitary functioning kidney (CSFK) present forms of congenital urinary tract anomalies (CUTA) with higher chance of spontaneous resolution compared with patients with two kidneys. Methods: We retrospectively selected 75 consecutive children with CUTA of the CSFK and 75 matched patients with unilateral CUTA but without CSFK (controls) with prenatal suspicion of unilateral CUTA and early evaluation. We compared the spontaneous CUTA resolution and the prevalence of kidney injury between groups at last follow-up. Patients and controls were clustered under the categories of “severe” and “non-severe” CUTA. Results: The mean age at first and last follow-up was 0.17 ± 0.07 and 8.5 ± 5.2 years. Compared with controls, patients with CSFK had lower prevalence of severe CUTA at first evaluation; lower prevalence of febrile urinary tract infections, need of surgical correction, and higher rate of spontaneous CUTA resolution during follow-up; and a similar prevalence of mild kidney injury at last follow-up. CSFK compared with controls presented higher cumulative proportion of spontaneous resolution from severe CUTA (100 vs 41.8%; p < 0.001) and from the single CUTA sub-categories (severe vesicoureteral reflux, non-obstructive hydronephrosis, and megaureter). Conclusions: CSFK patients had lower prevalence of severe forms and better outcomes of their CUTA compared with controls. Impact: One-third of patients with congenital solitary functioning kidney (CSFK) present congenital urinary tract anomalies (CUTA) and manifest poorer outcomes compared with CSFK without CUTA.CSFK patients had lower prevalence of severe forms and better outcomes of their CUTA in spite of similar prevalence of kidney injury compared with controls.This adds evidence about disturbed nephrogenesis in CSFK patients and emboldens conservative management of many of their non-obstructive CUTA.

Background The role of allergic sensitization seems to be protective against SARS CoV2 infection. The aim of this study was to evaluate, using online surveys, the impact of COVID-19 on Italian allergic children, comparing the prevalence of AR and asthma symptoms between the first and second pandemic wave. Methods Both surveys were emailed to Italian pediatricians in April 2020 (first survey) and in March 2021 (second survey). The first one was related to the impact of COVID-19 and the most frequently reported symptoms. The second one was superimposed on the previous one, taking into account some additional aspects in the management of disease. Results A total of 99 pediatricians participated in the first survey and 267 in the second one. The first survey showed that, asthma and allergic rhinoconjunctivitis prevalence was mostly between 0 and 20% throughout the country. The second survey showed a lower prevalence of both diseases nationwide in comparison to the first one. Comparing the two surveys, statistically significant differences were reported only in the distribution of asthma prevalence in Southern Italy while no differences were highlighted in the North and in the Center. Finally regarding allergic rhinoconjunctivitis prevalence, no differences were noticed nationwide. Conclusions Allergic rhinoconjunctivitis and asthma, if under control, did not represent risk factors for the susceptibility to SARS CoV2. Therefore, it is strongly recommended to continue therapies during COVID-19 outbreak, according to the international guidelines. However, being COVID-19 a new disease, actual knowledge will undergo continuous improvements over time.

Transjugular portal vein puncture is considered the riskiest step in TIPS creation with possible incidence of portal vein puncture-related complications (PVPC). The Colapinto and the Rösch-Uchida needle sets are two different needle sets currently available. To date, there have been no randomized control trials or systematic reviews which compare the incidence of PVPC when using the two different needle sets. The aim of this literature review is to assess the rate of PVPC associated with the different needle sets used in the creation of TIPS. From the described search, 1500 articles were identified and 34 met the inclusion criteria. Outcome measured was the prevalence of PVPC using the different needle sets. Overall 212 (3.6%) PVPC were reported in 5865 patients; 142 (3.5%) reported in 4000 cases using the Rösch-Uchida set and 70 (3.7%) in 1865 patients using the Colapinto set (p = 0.69). PVPC in TIPS creation are not related to the choice of needle set used in the procedure. To our knowledge, this is the first review of its kind, the results of which support the theory that while the rate of PVPC is influenced by many factors, choice of needle set does not seem to be one of them.

Neurofibromatosis 1 (NF1) is a chronic medical disease that often presents with psychiatric disorders. We investigated suicidal ideation in NF1 patients compared to healthy controls. We also evaluated whether hopelessness, depressive symptoms and perceived disability may mediate suicidal ideation in patients with NF1.We enrolled 60 patients with NF1 and 50 healthy controls with no history of NF1. Patients underwent a full psychiatric evaluation. Psychiatric diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria. Patients and controls underwent a series of psychometric measures, namely the Columbia Suicide Severity Rating Scale, the Beck Hopelessness Scale, the Italian Perceived Disability Scale and the Beck Depression Inventory.Suicidal ideation was significantly higher in patients with NF1 (45%) than in controls (10%). Patients also presented more severe perceived disability and hopelessness and more frequent psychiatric disorders than controls. Multivariable logistic regression analysis showed that perceived disability was independently associated with the presence of suicidal ideation in patients with NF1.In conclusion, our results showed that suicidal ideation was present in almost half of patients with NF1, suggesting the importance of suicide assessment in these patients.Key pointsPatients with NF1 have an increased suicide ideation when compared to healthy controlsIncreased suicidal ideation correlates with perceived disability, but not with the presence of psychiatric disordersAssessment of suicidal ideation should be performed in patients with NF1.

Item does not contain fulltext BACKGROUND: Catheter ablation for persistent atrial fibrillation (persAF) is associated with less favorable outcomes than for paroxysmal AF. To improve success rates, left atrial (LA) substrate modification is frequently performed in addition to pulmonary vein isolation (PVI). The purpose of the study was to compare 4 different ablation approaches using radiofrequency catheter ablation (RFCA) or cryoballoon ablation (CB-A) for persAF and to evaluate the respective outcomes on a midterm follow-up of 12 months. METHODS: We did a propensity score-matched comparison of 30 patients undergoing PVI + LA posterior wall isolation (LAPWI) with CB-A, 30 patients who underwent PVI + linear ablation (roof and mitral lines) using RFCA, 60 patients with PVI alone using CB-A, and 60 patients who had PVI alone using RFCA. The endpoint was recurrence of documented atrial tachyarrhythmias (ATas) > 30 s at 1-year follow-up. RESULTS: After 12 months, freedom from ATas after a single procedure was 83.3% in the PVI + LAPWI group, 46.7% in the PVI + linear ablation group, 58.3% in the PVI-alone CB-A group, and 61.6% PVI-alone RFCA (p = 0.03). Moreover, freedom from ATas was significantly higher comparing the PVI + LAPWI group with each of the other groups. CONCLUSIONS: In this propensity-matched comparison of strategies for persAF, LAPW ablation in addition to PVI with CB-A seems to improve 1-year outcome in comparison to PVI + linear ablation using RFCA and to PVI alone using RFCA or CB-A. Randomized comparisons are eagerly awaited.

Background & Aims Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. Methods In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. Conclusions In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. Lay summary While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Background:Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods:This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (Results:Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusions:Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19.Funding:Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative.Clinical trial number:NCT04549831.

Background In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine. Methods Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published. Results The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm. Conclusions We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research.

Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. Methods We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD). Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD). Conclusions As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Gen receptor d'andrògens; Infecció vírica i genoma de l’hoste Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Gen receptor de andrógenos; Infección viral y genoma del huésped Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Androgen receptor gene; Viral infection and host genome Background While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men

Resumen: Introducción y objetivos: Varón de 34 años con Síndrome de Marfan y Pectus Excavatum intervenido de aneurisma de aorta ascendente e insuficiencia aórtica mediante técnica de David I en 2007 que acude con insuficiencia mitral severa por rotura de cuerdas de velo anterior. Nuestro objetivo persigue demostrar que la toracotomía posterolateral izquierda es una alternativa factible en determinados casos seleccionados para el tratamiento de la patología de la válvula mitral. Métodos: Dadas las características anatómicas del paciente y la cirugía cardíaca previa nos planteamos cual sería la mejor vía de abordaje para este caso. Tras revisiones bibliográficas y consultas a expertos nos inclinamos por la sustitución valvular mitral vía toracotomía posterolateral izquierda. Para ello tras toracotomía posterolateral izquierda y canulación a nivel de aorta torácica descendente y vena femoral común izquierda (Seldinger) se procede a entrada en circulación extracorpórea. Ante la imposibilidad de clampaje aórtico, se decide practicar la sustitución valvular mitral a corazón latiendo y con ambiente de CO2, para ello se practica atriotomía izquierda y utilizando varios aspiradores de recuperación se consigue una visión aceptable de la válvula mitral, decidiéndose sustitución de la misma ante las dificultades técnicas que conllevaría una reparación valvular. Resultados: Se consiguió llevar a cabo el recambio mitral con buen resultado, comprobado por ecocardiografía transesofágica tras la cirugía. Conclusiones: La toracotomía posterolateral izquierda puede ser una alternativa ante pacientes con patologías concomitantes que provoquen desplazamiento del corazón hacia el hemitórax izquierdo. Abstract: Introduction and objectives: The case concerns a 34-year-old man with Marfan syndrome and Pectus Excavatum that has been previously operated on for an ascending aortic aneurysm and aortic regurgitation using the David I technique in 2007. The patient currently has severe mitral regurgitation due to rupture of the anterior chordae leaflet. The objective is to demonstrate that left posterolateral thoracotomy is a feasible alternative in certain selected cases for the treatment of mitral valve pathology. Methods: Given the anatomical characteristics of the patient, and previous cardiac surgery, posed the question of what would be the best approach for this case. After a review of the literature and expert consultations, it was decided to perform a mitral valve replacement via left posterolateral thoracotomy. To do this, after left posterolateral thoracotomy and cannulation at the level of the descending thoracic aorta and left common femoral vein (Seldinger), extracorporeal circulation was started. Given the impossibility of aortic clamping, it was decided to perform beating heart mitral valve replacement in a CO2 environment. To do this, a left atriotomy was performed and, using various recovery aspirators, an acceptable view of the mitral valve was achieved. I was decided to replace it, due to the technical difficulties that a valve repair would entail. Results: The mitral replacement was successfully performed by transoesophageal echocardiography. Conclusions: Left posterolateral thoracotomy may be an alternative for patients with concomitant pathologies that cause displacement of the heart towards the left hemithorax.

Background Neurofibromatosis Type I (NF1), also termed von Recklinghausen disease, is a rare genetic disorder that is transmitted by autosomal dominant inheritance, with complete penetrance and variable expressivity. It is caused by mutation in the NF1 gene on chromosome 17 encoding for neurofibromin, a protein with oncosuppressive activity, and it is 50% sporadic or inherited. The disease is characterized by a broad spectrum of clinical manifestations, mainly involving the nervous system, the eye and skin, and a predisposition to develop multiple benign and malignant neoplasms. Ocular diagnostic hallmarks of NF1 include optic gliomas, iris Lisch nodules, orbital and eyelid neurofibromas, eyelid café-au-lait spots. Choroidal nodules and microvascular abnormalities have recently been identified as additional NF1-related ocular manifestations. The present study was designed to describe the features and clinical significance of a new sign related to the visual apparatus in NF-1, represented by hyperpigmented spots (HSs) of the fundus oculi. Results HSs were detected in 60 (24.1%) out of 249 patients with NF1, with a positive predictive value of 100% and a negative predictive value of 44.2%. None of the healthy subjects (150 subjects) showed the presence of HSs. HSs were visible under indirect ophthalmoscopy, ultra-wide field (UWF) pseudocolor imaging and red-only laser image, near-infrared reflectance (NIR)-OCT, but they were not appreciable on UWF green reflectance. The location and features of pigmentary lesions matched with the already studied NF1-related choroidal nodules. No significant difference was found between the group of patients (n = 60) with ocular HSs and the group of patients (n = 189) without ocular pigmented spots in terms of age, gender or severity grading of the disease. A statistically significant association was demonstrated between the presence of HSs and neurofibromas (p = 0.047), and between the presence of HSs and NF1-related retinal microvascular abnormalities (p = 0.017). Conclusions We described a new ocular sign represented by HSs of the fundus in NF1. The presence of HSs was not a negative prognostic factor of the disease. Following multimodal imaging, we demonstrated that HSs and choroidal nodules were consistent with the same type of lesion, and simple indirect ophthalmoscopy allowed for screening of HSs in NF1.

The relationship between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has gained considerable scientific interest in adults over the past few years. However, this association has recently emerged in children. Several published studies have suggested a role for NAFLD as a risk factor for CKD from the earliest age, with a potential influence of the major NAFLD risk polymorphisms, resulting in an increased risk of both cardiovascular and metabolic diseases. In view of the progressive course and increased cardiometabolic risk closely related to NAFLD and CKD, we focused on the link between these diseases in childhood.

Introduction: While renal biopsy remains the gold standard for diagnosing lupus nephritis (LN), the prognostic and diagnostic role of non-invasive biomarkers for LN is currently debated. Methods: Available studies published in last 5 years (2015–2020) assessing the diagnostic and prognostic value of urinary and/or serological biomarkers in subjects with LN were analyzed in this systematic review. Results: Eighty-five studies were included (comprehending 13,496 patients with systemic lupus erythematosus [SLE], 8,872 LN, 487 pediatric LN, 3,977 SLE but no LN, 160 pediatric SLE but no LN and 7,679 controls). Most of the studies were cross-sectional (62; 73%), while 14 (17%) were prospective. In sixty studies (71%), the diagnosis of LN was biopsy-confirmed. Forty-four out of 85 (52%) investigated only serological biomarkers, 29 studies (34%) tested their population only with urinary biomarkers, and 12 (14%) investigated the presence of both. Outcome measures to assess the clinical utility of the analyzed biomarkers were heterogeneous, including up to 21 different activity scores, with the SLEDAI (in 60%) being the most used. Despite some heterogeneity, promising results have been shown for biomarkers such as urinary monocyte chemoattractant protein, urinary adiponectin, and urinary vascular cell adhesion protein 1. Discussion/Conclusion: While serum and urine biomarkers have the potential to improve diagnostic and prognostic pathways in patients with LN, the vast heterogeneity across studies severely limits their applicability in current clinical practice. With the kidney biopsy still representing the gold standard, future efforts should focus on harmonizing study inclusion criteria and outcomes, particularly in clinical trials, in order to improve comparability and facilitate the implementations of available biomarkers into the daily practice.

Objective Aim of the present study is to investigate the alterations of brain networks derived from EEG analysis in pre- and post-sleep onset conditions after 40 h of sleep deprivation (SD) compared to sleep onset after normal sleep in 39 healthy subjects. Methods Functional connectivity analysis was made on electroencelographic (EEG) cortical sources of current density and small world (SW) index was evaluated in the EEG frequency bands (delta, theta, alpha, sigma and beta). Results Comparing pre- vs. post-sleep onset conditions after a night of SD a significant decrease of SW in delta and theta bands in post-sleep onset condition was found together with an increase of SW in sigma band. Comparing pre-sleep onset after sleep SD versus pre-sleep onset after a night of normal sleep a decreased of SW index in beta band in pre-sleep onset in SD compared to pre-sleep onset in normal sleep was evidenced. Conclusions Brain functional network architecture is influenced by the SD in different ways. Brain networks topology during wake resting state needs to be further explored to reveal SD-related changes in order to prevent possible negative effects of SD on behaviour and brain function during wakefulness. Significance The SW modulations as revealed by the current study could be used as an index of an altered balance between brain integration and segregation processes after SD.

Background: Double external defibrillation (DED) has been used as a final effort to terminate refractory ventricular fibrillation/pulseless ventricular tachycardiac (rVF/pVT). Data surrounding time to DED and patient-centered outcomes remains limited. Objectives: This study summarizes patient-level data from case-series of observed survival and neurologic outcomes following the use of DED for rVF/pVT among those with data regarding time to DED. Methods: We conducted a literature search of PubMed, MEDLINE (OVID interface), and Scopus from January 1, 2000, through January 5, 2020. The literature was screened according to inclusion and exclusion criteria. Two investigators independently conducted the literature search, study selection, and data extraction. Results: Our database search identified 3139 records. Of these, 1660 studies were eliminated following inspection of the titles and 22 studies underwent full-text screening, three included in the final analysis, describing a total of 29 cases. All studies were considered to have critical risk of bias. For the critical outcomes of survival to discharge and neurologically intact survival we identified that patients who received DED before 30 min from collapse compared to those who received DED after 30 min had better survival to discharge (33.3% [5/15] vs. 7.1% [1/14]) and neurologically intact survival (20.0% [3/15] vs. 7.1% [1/14]). Overall, 20.6% of patients survived to discharge, 13.8% with neurologically intact survival. It is noteworthy that the patients who were discharged with a CPC of 1 received two, four, five, and three standard shocks before receiving DED, and the time between their onset of cardiac arrest to their first DED attempt was recorded to be 15, 26, 26, and 32 min, respectively. Conclusion: We would like to indicate that there is not enough evidence to suggest that early use of pre-hospital DED is associated with improved outcomes. Further research should strive to address these issues before conclusions can be drawn.

Congenital diabetes mellitus is a rare disorder characterized by hyperglycemia that occurs shortly after birth. We define "Diabetes of Infancy" if hyperglycemia onset before 6 months of life. From the clinical point of view, we distinguish two main types of diabetes of infancy: transient (TNDM), which remits spontaneously, and permanent (PNDM), which requires lifelong treatment. TNDM may relapse later in life. About 50% of cases are transient (TNDM) and 50% permanent. Clinical manifestations include severe intrauterine growth retardation, hyperglycemia and dehydration. A wide range of different associated clinical signs including facial dysmorphism, deafness and neurological, cardiac, kidney or urinary tract anomalies are reported. Developmental delay and learning difficulties may also be observed. In this paper we review all the causes of congenital diabetes and all genes and syndromes involved in this pathology. The discovery of the pathogenesis of most forms of congenital diabetes has made it possible to adapt the therapy to the diagnosis and in the forms of alteration of the potassium channels of the pancreatic Beta cells the switch from insulin to glibenclamide per os has greatly improved the quality of life. Congenital diabetes, although it is a very rare form, has been at the must of research in recent years especially for pathogenesis and pharmacogenetics. The most striking difference compared to the more frequent autoimmune diabetes in children (type 1 diabetes) is the possibility of treatment with hypoglycemic agents and the apparent lower frequency of chronic complications.

Measles outbreaks were recently reported in Europe due to low immunization rates. In this scenario, identifying the reasons of no vaccination is crucial to set up strategies to improve immunization rate. A cross-sectional study was conducted to investigate the determinants of missed vaccination in children living in Southern Italy, during the 2016 outbreak. A standardized face-to-face questionnaire was used to record demographic data, immunization status, and reasons for missed vaccination. A total of 1141 children (median age 86months, male 47.2%) was enrolled, 77.8% of the children were adequately vaccinated for age, 6.3% were incompletely vaccinated for age, and 15.9% did not receive any vaccine dose. Vaccination rate and reasons for not vaccinating significantly varied according to age, with children ≤ 24months showing the lowest rate (67.8%). Reasons for not vaccinating included fear for side effects (51%), presence of underlying chronic conditions (12.2%), skip scheduled appointment (12.2%), refusal of vaccination (10.3%), acute illnesses (7.2%), and allergy to eggs (4.6%). The presence of underlying condition was a risk factor for inadequate immunization (p < 0.0001). Only 4.7% of conditions were true contraindications to vaccine administration. Conclusion: We reported inadequate measles immunization rate in Southern Italy, with lowest rates in children ≤ 2years or with underlying conditions. Only a minority had true contraindications to vaccine uptake. Implementation strategies addressed to health-care professionals and families should focus on the reported determinants to increase measles vaccination coverage.What is Known:• Measles is a viral, highly communicable disease, preventable by vaccine.• Measles elimination in Europe failed as demonstrated by outbreaks in several countries, due to low immunization rates.What is New:• Inadequate measles immunization rate due to false contraindications in Southern Italy, with lowest rates in children ≤ 2years.• The presence of underlying disease is a risk factor for inadequate immunization.

The hemangioma is the most common solid lesion of the liver. Therefore, radiologists must know the typical and atypical imaging findings of this lesion in order to reach a correct diagnosis and avoid diagnostic errors. However, only few papers have comprehensively described the entire spectrum of atypical and uncommon imaging features. In this updated review, we provide the imaging features of hepatic hemangioma, in both typical and atypical forms, as well as its association with abnormalities in the adjacent hepatic parenchyma and other hepatic lesions, and its complications.

BackgroundNonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD.AimsWe examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors.MethodsWe recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system.ResultsThe overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75–0.88] vs. 0.77 [0.70–0.84] without SNPs; p = 0.047).ConclusionsNAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD.

Purpose The aim of this study was to assess the novel advanced magnetic resonance imaging findings of acute stage cortical laminar necrosis developing after complicated cardiovascular or abdominal surgery. Materials and methods This institutional review board-approved study included patients with postoperative stroke due to cortical laminar necrosis imaged with magnetic resonance in the acute stage. Brain magnetic resonance imaging examinations were obtained on a 3T magnetic resonance scanner within 48 hours of the neurological symptoms, including diffusion-weighted images (b value, 1000 s/mm2) and arterial spin labelling using a pseudo-continuous arterial spin labelling method in four patients. Conventional and advanced magnetic resonance images were analysed to assess the imaging features in acute stage cortical laminar necrosis. Results The final population consisted of 14 patients (seven men and seven women, mean age 61 years, range 32–79 years) diagnosed with stroke and acute phase cortical laminar necrosis. All the patients presented with cortical lesions showing restricted diffusion on diffusion-weighted images and hypointensity on the apparent diffusion coefficient map. Cortical hyperintensity on T2-weighted or fluid-attenuated inversion recovery images was found in three (21%) and six (43%) patients, respectively. Reduced perfusion was noted in three out of four patients imaged with arterial spin labelling, while in one case no corresponding perfusion abnormality was noted on the arterial spin labelling maps. Arterial spin labelling abnormalities were much more extensive than diffusion restriction in two patients, and they were associated with a poor outcome. Conclusion Cortical hyperintense abnormalities on diffusion-weighted imaging may be the only sign of developing cortical laminar necrosis injury. The acquisition of arterial spin labelling helps to identify perfusion alterations and the extension of the ischaemic injury.

Aim: This study assessed the prevalence of wrongly diagnosed non-febrile urinary tract infections in patients who had not been toilet trained and presented with poor feeding and, or, failure to thrive. The diagnostic value of these signs in predicting non-febrile UTIs was also explored. Methods: We focused on 59 outpatients (56.7% male) with these criteria, who had positive urine cultures and were referred to our Italian University hospital from January 2017 to January 2019. None were on antibiotics and all underwent urine cultures by bladder catheterisation. Wrongly diagnosed non-febrile UTIs were defined by sterile urine cultures. The predictive value was evaluated using logistic regression. Results: The mean age was 8.5±5.7months and 72.9% had wrongly diagnosed non-febrile UTIs. Poor feeding was significantly higher among the 16 patients with true non-febrile UTIs (P=.04). It was significantly predictive of non-febrile UTIs (odds ratio 4.1, 95% confidence interval 1.1-16.6), especially when leucocyturia was present (odds ratio 9.7, 95% confidence interval 2.3-40.7). Conclusion: Wrongly diagnosed non-febrile UTIs were high in children with poor feeding and, or, failure to thrive. Only poor feeding and, in particular, the combination of poor feeding and leucocyturia, significantly increased the odds of non-febrile UTI.

Asthma is the most frequent chronic disease in childhood. Chest tightness, cough, wheezing and dyspnoea during or after exercise may be unique manifestations of asthma in up to 90% of subjects. Physical activity may be reduced by uncontrolled asthma symptoms and parental beliefs, impairing physical fitness of asthmatic children. Clinicians working in the field of allergy are aware of evidence supporting the benefits of physical activity for patients with asthma. Treatment of asthma is required in order to obtain its control and to avoid any limitation in sports and active play participation. As exercise performance in children with controlled asthma is not different from that of healthy controls, any exercise limitation cannot be accepted. Overweight and obesity may interfere with asthma and exercise, leading to dyspnoea symptoms. Evidences on the effect of insulin resistance on airway smooth muscle and on bronchial hyperactivity are presented. CONCLUSION: Exercise is part of the strategy to obtain the best control of asthma in childhood, but we have to optimise the asthma control therapy before starting exercise programming. Furthermore, it is crucial to give best attention on the effects of obesity and insulin resistance, because they could in turn influence patients' symptoms.

Background Double/dual defibrillation (DD) has been proposed as an alternative treatment for refractory ventricular fibrillation (VF). This topic has been poorly researched and data on survival rates are limited. Objective This systematic review and meta-analysis evaluates whether DD improves outcomes among patients with refractory VF in- and out-of-hospital cardiac arrest compared with standard defibrillation. Methods A literature search was conducted on July 20, 2019 using MEDLINE via PubMed, Embase, Scopus, and the Cochrane Database of Systematic Reviews. We gave all results as a pooled odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was assessed by calculating the I2 statistic and was deemed significant for a p value of Results We included 27 records, of which 4 cohort studies totaling 1061 patients were included in the quantitative analysis. Of these, 20.5% (n = 217) received the intervention. DD had no effect on return of spontaneous circulation (OR 0.68; 95% CI 0.44–1.04; I2 = 41%, p = 0.08) (GRADE: Very low), survival to admission (OR 0.77; 95% CI 0.51–1.17; I2 = 18%, p = 0.22) (GRADE: Very low), or survival to discharge (OR 0.66; 95% CI 0.38–1.15; I2 = 0%, p = 0.14) (GRADE: Very low). Conclusions DD did not improve any outcomes of interest. Therefore, it is imperative that a well-designed study in this area be conducted. Ideally, conducting a randomized controlled trial in this population should be attempted to obtain a higher level of scientific evidence.

Introduction Neurofibromatosis type 1 (NF1) is a multisystemic disease caused by the mutation of Nf1 gene located on chromosome 17q11.2. The mutation determines the loss of function of the protein neurofibromin with consequent uncontrolled cellular proliferation. Patients are characterized by a wide range of dermatological, neurological, and ophthalmological symptoms. Purpose The aim of the study was to evaluate, through pattern visual evoked potentials (p-VEPs) and frequency doubling technology (FDT) Matrix perimetry, the objective and psychophysical functionality of the optic pathways in a group of NF1 patient. Methods The study group consisted of 26 patients affected by NF1 and 17 healthy controls. Each patient underwent a complete ophthalmological examination, p-VEPs with the evaluation of amplitude and latency of the P100 wave, and FDT perimetry, with the evaluation of central sensitivity (CS), mean deviation (MD), pattern standard deviation (PSD) and glaucoma hemifield test (GHT). Results NF1 patients showed a statistically significant alteration in the transmission of visual impulse. P-VEPs results highlighted a reduced amplitude and an increased latency of the P100 wave, suggesting an involvement of the visual pathway. Visual field analysis showed a significant reduction in all the observed parameters as well (CS, MD, PSD, and GHT). Conclusion The present study showed, in NF1 patients, a qualitative and quantitative alteration in the conduction of stimuli through the visual pathways. The observed alterations are present, although, only at a subclinical level. None of the patients included in the study showed any manifest visual deficit nor had any concomitant pathology that might have affected the outcome of the study. In conclusion, electrophysiological exams and computer perimetry may take part, alongside a wider array of exams, in the differential diagnosis and later monitoring of NF1.

Background In the coming decades, diabetes mellitus might affect 628 million individuals. Its final impact on male fertility and reproductive outcomes should be considered since the number of adolescents and young adults presenting diabetes is rising. Resveratrol (RES), a polyphenol, is a biological modulator with multitarget and multi-action characteristics. Objectives to evaluate if RES is effective against the male reproductive damage caused by type 1 diabetes (DM1), focusing on sperm DNA integrity and reproductive outcome. Materials and methods At 30 dpp (days postpartum), male rats were divided into 7 groups: Sham control (SC); RES vehicle (RV); RES (R); STZ-diabetic (D; induced at 30dpp with 65 mg/kg of streptozotocin); STZ-diabetic + insulin (DI); STZ-diabetic + RES (DR); STZ-diabetic + insulin +RES (DIR). DR, DIR, and R groups received 150mg RES/kg b.w./day by gavage (from 33 to 110dpp). DI and DIR received insulin (from day 5 after DM1 induction until 110dpp). Blood glucose was monitored in different time points. Animals were mated with healthy females. Euthanasia occurred at 110 dpp. Results DM1 increased lipid peroxidation (testis and epididymis) and sperm DNA fragmentation, alterations of chromatin structure, reduced mitochondrial mass and acrosome integrity, causing a decline in fertility and pregnancy rates. RES improved the parameters. Discussion RES, as an adjuvant, activates specific reactions against hyperglycemia, the main trigger of most complications of diabetes, by controlling oxidative stress, probably as a result of SIRT1 activation. We present here more evidences showing its valuable role in diminishing diabetes seriousness to male reproduction, not only to spermatogenesis in the first instance, but also to sperm overall quality and fertility outcomes, regardless of insulin treatment. Conclusion RES attenuated lipid peroxidation and sperm DNA damage in DM1-induced animals, which positively reflected on male fertility. Our results show RES potential against DM1 complications in male reproduction.

Background and aim: To compare cardiometabolic risk profile and preclinical signs of target organ damage in youth with normal and elevated blood pressure (BP), according to the American Academy of Pediatrics (AAP) guidelines. Methods and results: This cross-sectional multicenter study included 2739 youth (5-17 year-old; 170 normal-weight, 610 overweight and 1959 with obesity) defined non hypertensive by the AAP guidelines. Anthropometric, biochemical and liver ultrasound data were available in the whole population; carotid artery ultrasound and echocardiographic assessments were available respectively in 427 and 264 youth. Elevated BP was defined as BP >= 90th to = 120/80 to

Primary hepatic malignancies in non-cirrhotic liver include a wide spectrum of tumors, which are classified based on their cells of origin. Hepatocellular carcinoma is the most common primary malignant tumor, followed by intrahepatic cholangiocarcinoma. Beside these tumors, other primary malignancies in the non-cirrhotic liver are quite rare. Accurate diagnosis is often difficult with imaging alone and biopsy with further histopathological analysis is often necessary. However, many of these tumors exhibit suggestive or characteristic imaging features due to their different cellular components, allowing radiologists to suggest the correct diagnosis. Thus, the aim of this article is to provide an overview of imaging presentation of primary malignant liver tumors that develop in the non-cirrhotic liver, including potential differential diagnoses. Such knowledge is essential as it may contribute to accurate radiological diagnosis and improved patient outcome.

Introduccion La sifilis constituye un problema de salud mundial. Objetivo: establecer la prevalencia de sifilis y la distribucion segun estadio en pacientes asistidos en el Servicio de Dermatologia de Junio 2010 a Junio 2018, y comparar las caracteristicas epidemiologicas que pudieran influir en el aumento de la prevalencia. Metodos Estudio de cohorte retrospectivo de pacientes ≥ 15 anos, con diagnostico de sifilis adquirida. Para el analisis de los datos se consideraron dos periodos: P1: 2010-2015 y P2: 2015-2018, de acuerdo al aumento de prevalencia observado en la vigilancia mensual, y la comparacion entre variables considerando sifilis temprana y tardia. Resultados Se incluyeron 1582 pacientes, 51% (805) en P1 y 49% (777) en P2. La prevalencia de sifilis global en nuestro servicio fue de 7,1 %, con un alto porcentaje de pacientes embarazadas y puerperas (54% del total de las mujeres). La prevalencia en P1 fue de 5,8%, y 9,3 % en P2 (p < 0,01). En P2 la sifilis temprana ascendio a un 53% (p< 0,01), disminuyeron los tratamientos completos y aumentaron los casos sin seguimiento. La sifilis temprana se asocio con menor edad, ausencia de pareja estable, y mas consultas espontaneas y tratamientos completos. Conclusion Observamos un aumento sostenido de la prevalencia de sifilis adquirida, con un incremento de la sifilis temprana, que implica mayor riesgo de transmision. Tambien se evidencio menor adherencia al tratamiento y controles necesarios. La alta tasa de sifilis gestacional pone en alerta el deficit importante en los controles prenatales en nuestro sistema de salud. Introduction Syphilis constitutes a global health problem. Objective: to establish the prevalence of syphilis and the distribution according to stage in patients assisted in the Dermatology Service from June 2010 to June 2018, and compare the epidemiological characteristics that could influence the increase in prevalence. Methods Retrospective cohort study of patients ≥ 15 years, with diagnosis of acquired syphilis. For the analysis of the data, two periods were considered: P1: 2010-2015 and P2: 2015-2018, according to the increase in prevalence observed in the monthly surveillance, and the comparison between variables considering early and late syphilis. Results 1582 patients were included, 51% (805) in P1 and 49% (777) in P2. The prevalence of global syphilis in our service was 7.1%, with a high percentage of pregnant and postpartum patients (54% of all women). The prevalence in P1 was 5.8%, and 9.3% in P2 (p

Summary Background The Butantan Institute has manufactured a lyophilised tetravalent live-attenuated dengue vaccine Butantan-DV, which is analogous to the US National Institutes of Health (NIH) TV003 admixture. We aimed to assess the safety and immunogenicity of Butantan-DV. Methods We did a two-step, double-blind, randomised placebo-controlled phase 2 trial at two clinical sites in Sao Paulo, Brazil. We recruited healthy volunteers aged 18–59 years; pregnant women, individuals with a history of neurological, heart, lung, liver or kidney disease, diabetes, cancer, or autoimmune diseases, and individuals with HIV or hepatitis C were excluded. Step A was designed as a small bridge-study between Butantan-DV and TV003 in DENV-naive participants. In step A, we planned to randomly assign 50 dengue virus (DENV)-naive individuals to receive two doses of Butantan-DV, TV003, or placebo, given 6 months apart. In step B, we planned to randomly assign 250 participants (DENV-naive and DENV-exposed) to receive one dose of Butantan-DV or placebo. Participants were randomly assigned, by computer-generated block randomisation (block sizes of five); participants in step A were randomly assigned (2:2:1) to receive Butantan-DV, TV003, or placebo and participants in step B were randomly assigned (4:1) to receive Butantan-DV or placebo. Participants and study staff were unaware of treatment allocation. The primary safety outcome was the frequency of solicited and unsolicited local and systemic adverse reactions within 21 days of the first vaccination, analysed by intention to treat. The primary immunogenicity outcome was seroconversion rates of the DENV-1-4 serotypes measured 91 days after the first vaccination, analysed in the per-protocol population, which included all participants in step A, and all participants included in step B who completed all study visits with serology sample collection. This trial is registered with ClinicalTrials.gov , NCT01696422 . Findings Between Nov 5, 2013, and Sept 21, 2015, 300 individuals were enrolled and randomly assigned: 155 (52%) DENV-naive participants and 145 (48%) DENV-exposed participants. Of the 155 DENV-naive participants, 97 (63%) received Butantan-DV, 17 (11%) received TV003, and 41 (27%) received placebo. Of the 145 DENV-exposed participants, 113 (78%) received Butantan-DV, three (2%) received TV003, and 29 (20%) received placebo. Butantan-DV and TV003 were both immunogenic, well-tolerated, and no serious adverse reactions were observed. In step A, rash was the most frequent adverse event (16 [845] of 19 participants in the Butantan-DV group and 13 [76%] of 17 participants in the TV003 group). Viraemia was similar between the Butantan-DV and TV003 groups. Of the 85 DENV-naive participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis and thus were included in the per-protocol analysis population, 74 (87%) achieved seroconversion to DENV-1, 78 (92%) to DENV-2, 65 (76%) to DENV-3, and 76 (89%) to DENV-4. Of the 101 DENV-exposed participants in the Butantan-DV group who attended all visits for sample collection for seroconversion analysis, 82 (81%) achieved seroconversion to DENV-1, 79 (78%) to DENV-2, 83 (82%) to DENV-3, and 78 (77%) to DENV-4. Interpretation Butantan-DV and TV003 were safe and induced robust, balanced neutralising antibody responses against the four DENV serotypes. Efficacy evaluation of the Butantan-DV vaccine is ongoing. Funding Intramural Research Program US NIH National Institute of Allergy and Infectious Diseases, Brazilian National Bank for Economic and Social Development, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, and Fundacao Butantan.

In 2018, a truck-driver strike in Sao Paulo, Brazil, provided conditions for conducting a real-world experiment on the relationship between vehicle emissions, air quality, and public health. During the strike, no truck traffic, a 40–70% bus-traffic reduction, and a reduction in auto traffic was observed. The objective of this study is to evaluate the effects of vehicle-traffic reduction on the air quality and public health in Sao Paulo by taking advantage of the truck-driver strike. The corresponding analysis was based on the comparison of the air quality (NOx (nitrogen oxides), PM10 (particle matter of diameter less than 10 μm), and O3 (ozone) concentrations) during the strike and that registered on days having similar meteorological conditions. A relative-risk function was used to associate the decrease in the PM10 concentration during the strike with avoided mortality. The results demonstrated that, on workdays, the reduction in vehicle traffic during the strike was responsible for a 29.4%–40.9% improvement in NOx air quality and 19.2%–21.4% in PM10 concentration. The reduction in the PM10 concentration resulted in the prevention of between six and eight deaths during the strike, which implies between 321 and 442 avoided deaths in a year. In terms of the O3 concentration, no difference was identified between strike days and the comparative ones. An analysis of different sites of the city revealed that the greatest air-quality improvement was observed near an arterial road and near a bus terminal. Air-quality improvement was also detected in a park that was distant from the main roads. The results of the study provide evidence for supporting cleaner transportation investments and traffic restriction policies.

Double defibrillation (DD) has been proposed as an alternative treatment for patients with refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) out-of-hospital cardiac arrest (OHCA) nonresponsive to the best current standard of care. Treatment results are promising, but the efficacy and safety of the procedure remain unclear. Currently, there is a paucity of evidence in the literature on DD suggesting the optimal strategy for treating this challenging patient population. Thus, we aim to perform a scoping review to explore the current literature addressing resuscitative parameters, survival rates, and neurological outcomes in refractory VF/pVT OHCA patients treated with DD as well as to identify gaps in the literature that may require further research. Here, we discuss the anticipated study protocol.

Introduction In this systematic review and meta‐analysis of propensity score‐matched cohort studies, we quantitatively summarize whether venoarterial extracorporeal membrane oxygenation (VA‐ECMO) used as extracorporeal cardiopulmonary resuscitation (ECPR), compared with conventional cardiopulmonary resuscitation (CCPR), is associated with improved rates of 30‐day and long‐term favorable neurological outcomes and survival in patients resuscitated from in‐ and out‐of‐hospital cardiac arrest. Methods We searched MEDLINE via PubMed, Embase, Scopus, and Google Scholar for eligible studies on January 14, 2019. All searches were limited to studies published between January 2000 and January 2019. Two investigators independently evaluated the quality (or certainty) of evidence according to GRADE guidelines. Pooled results are presented as relative risks (RRs) with 95% confidence intervals (CIs). Results Six cohort studies using propensity score‐matched analysis were included, totaling 1108 matched patients. Pooled analyses showed that ECPR was likely associated with improved 30‐day and long‐term favorable neurological outcome in adults compared to CCPR for in‐ and out‐of‐hospital cardiac arrest (RR = 2.02, 95% CI = 1.29–3.16; I2 = 20%, P = 0.002; very low‐quality evidence) and (RR = 2.86, 95% CI = 1.64–5.01; I2 = 0%, P = 0.0002; moderate‐quality evidence), respectively. When we analyzed in‐ and out‐of‐hospital cardiac arrest separately, ECPR was likely associated with improved 30‐day favorable neurological outcome compared to CCPR for in‐hospital cardiac arrest (RR = 2.18, 95% CI = 1.24–3.81; I2 = 9%, P = 0.006; very low‐quality evidence), but not for out‐of‐hospital cardiac arrest (RR = 2.61, 95% CI = 0.56–12.20; I2 = 59%, P = 0.22; very low‐quality evidence). ECPR was also likely associated with improved long‐term favorable neurological outcome compared to CCPR for in‐hospital cardiac arrest (RR = 2.50, 95% CI = 1.33–4.71; I2 = 0%, P = 0.005; moderate‐quality evidence) and out‐of‐hospital cardiac arrest (RR = 4.64, 95% CI = 1.41–15.25; I2 = 0%, P = 0.01; moderate‐quality evidence). Conclusions Our analysis suggests that VA‐ECMO used as ECPR may improve long‐term favorable neurological outcomes and survival when compared to the best standard of care in a selected patient population. Therefore, it is imperative for well‐designed randomized clinical trials to obtain a higher level of scientific evidence to ensure optimal outcomes for cardiac arrest patients.

Study objectives The purpose of this review is to provide a brief overview of new life-saving interventions and novel techniques that have been proposed as viable treatment options for patients presenting with refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) out-of-hospital cardiac arrest (OHCA). Methods We conducted a comprehensive literature search of PubMed recent, Medline and Embase databases via the Ovid interface and Google Scholar from inception to July 2019. Eligible studies were observational in nature reporting outcomes of extracorporeal membrane oxygenation (ECMO), esmolol, double sequential defibrillation (DSD), and stellate ganglion block (SGB). Two investigators conducted the literature search, study selection, and data extraction. Any disagreements were resolved by consensus. Results Our database search identified 5331 records. We included in our review 23 articles that met our inclusion criteria. The selected studies included 16 observational studies on ECMO, 2 observational studies on esmolol, and 5 observational studies on DSD. Conclusion We would like to suggest that there is not enough evidence in the existing literature to support at large-scale the effects of these techniques in the treatment of refractory VF/pVT OHCA. Randomized studies are warranted to evaluate the significant effects of these approaches against the best current standard of care.

Highlights • We reported the case of Benign Metastasizing Leiomyomatosis (BML) in a female patient emphasizing the cardiac findings. • BML is a rare disorder that affects fertile aged women with a past medical history of treatment of uterine leiomyoma. • We suggest that benign metastasizing leiomyoma should be remembered as a differential diagnoses when a hysterectomized premenopausal woman presents with an intra cardiac mass., Introduction Cardiac intracavitary growth of metastasizing tumour is unusual. Benign Metastasizing Leiomyoma (BML) from the uterus to the heart is extremely rare. It affects premenopausal women with a history of uterine leiomyoma. Presentation of case We report a case of a 42-year-old woman who presented three tumours in the right side of the heart, two years after a hysterectomy due to leiomyomatosis. The cardiac tumours were resected and the diagnosis was uterine leiomyoma. Discussion The patient developed cardiac failure due to three masses at the right side of the heart. Cardiac involvement in BML is usually asymptomatic and rare. The heart masses were surgically removed and a peri ovarian mass was detected and also removed. Although histologically benign, BML exhibits metastatic qualities. Conclusion It suggests that BML should be included as a differential diagnosis when a female patient presents an intra cardiac mass and a history of hysterectomy.