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Neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). ARNI increase survival and quality of life; due to their hemodynamic effects, ARNI could also affect exercise tolerance. We studied the effects of ARNI on cardiopulmonary test (CPET) after six months of treatment in 35 patients [67 ± 11 years; LVEF 31 ± 6%; NT-proBNP 1822 ± 1651 pg/ml; ICD/CRT since at least 6 months in 26/35], treated with increasing doses of Sacubitril/Valsartan up to 318 ± 36 mg/die. In addition, levels of NT-proBNP, renal function, electrolytes, and echocardiocolorDoppler were assessed in the same time periods. No variations of renal function and/or potassium levels were observed; NT-proBNP decreased. Most CPET variables were improved by ARNI (p

Study objective Methadone is associated with QT interval prolongation and torsades de pointes. Expert panel recommendations advocate a pre-methadone electrocardiogram (ECG) and another ECG at 30 days of therapy in patients with risk factors. Some guidelines recommend a pre-methadone ECG and routine ECG monitoring in all methadone patients, but this is controversial due to the resources required. Availability of a convenient, less resource-intensive method of ECG monitoring for patients taking methadone is desirable. The objective of this study was to assess the accuracy of a handheld smartphone ECG (iECG) for QT measurement in patients on maintenance methadone therapy in an urban opioid treatment program. Design Prospective study. Setting Urban opioid treatment program. Patients n = 115 patients in normal sinus rhythm who were on steady-state maintenance methadone therapy INTERVENTION: Patients (n = 115) underwent a simultaneous 12-lead ECG and a single-lead iECG. Measurements and main results The first three QT and RR intervals from lead II of the 12-lead ECG and simulated lead I from the iECG were compared using the Bland-Altman analysis of measurement agreement. Mean [± standard deviation) age was 34 ± 11 years; 71% were female, 75% were white. Compared to the 12-lead ECG, the iECG was associated with a QTc bias of - 0.14 ms (SD = 12 ms, 95% CI = -2.4 to 2.1 ms). The absolute mean difference in QTc between the two methods was 9.5 ± 7.1 ms. For identification of patients with methadone-associated QTc prolongation, the iECG performed moderately well [c-statistic 0.97 (95% CI 0.91-0.99); sensitivity and specificity 75% (95% CI 43-95%) and 99% (95% CI 94-99%), respectively]. The positive and negative likelihood ratios of the iECG for identifying patients with methadone-associated QTc prolongation were 77.25 (95% CI 10.69 to 558.18) and 0.25 (95% CI 0.09 to 0.67), respectively, while the positive and negative predictive values were 90% (95% CI 56-99%) and 97% (95% CI 92-99%), respectively. The accuracy of the iECG for identifying patients with QTc prolongation was 97% (95% CI 91-99%). Conclusion A handheld smartphone ECG is accurate for QT interval measurement in patients taking maintenance methadone therapy, and its performance is moderately good for identifying patients with methadone-associated QTc prolongation.

We investigated the associations of physical activity (PA), sedentary time (ST), and diet quality with biomarkers of inflammation in 390 children (192 girls, 198 boys) aged 6–8 years. PA energy expenditure (PAEE), light PA, moderate PA (MPA), vigorous PA (VPA), moderate-to-vigorous PA (MVPA), and ST were assessed by combined movement and heart rate sensor. Finnish Children Healthy Eating Index was calculated using data from 4 d food records. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry. High-sensitivity C-reactive protein (Hs-CRP), leptin, interleukin-6 (IL-6), adiponectin, tumour necrosis factor-α, and glycoprotein acetyls were measured from fasting blood samples. PAEE, MPA, VPA, and MVPA were inversely associated with hs-CRP (β=−191 to −139, 95% CI=−0.294 to −0.024), leptin (β=−0.409 to −0.301, 95% CI=−0.499 to −0.107), IL-6 (β=−0.136 to −0.104, 95% CI=−0.240 to −0.001) and PAEE, MPA, and MVPA were inversely associated with glycoprotein acetyls (β=−0.117 to −0.103, 95% CI=−0.213 to −0.001). ST was directly associated with hs-CRP (β=0.170, 95% CI=0.070–0.269), leptin (β=0.355, 95% CI=0.265–0.445), and IL-6 (β=0.105, 95% CI=0.005–0.205). VPA was inversely associated with hs-CRP, leptin, and IL-6 in children with higher BF% (β=−0.344 to −0.181, 95% CI=−0.477 to −0.033) but not among children with lower BF% (β=−0.007–0.033, 95% CI=−0.183–0.184). In conclusion, PA was inversely and ST directly associated with circulating levels of biomarkers of inflammation among children. Furthermore, we observed that PA was inversely associated with these biomarkers for inflammation in children with a higher BF%. Highlights Systemic inflammation, as indicated by increased circulating concentrations of biomarkers for inflammation, may be important in causal pathways leading to insulin resistance, sub-clinical atherosclerosis, and eventually clinical manifestations of cardiovascular diseases. Higher levels of physical activity and lower levels of sedentary time were associated with more favourable inflammatory profile. Body fat percentage modified these associations and especially vigorous intensity physical activity was inversely associated with biomarkers of inflammation on children with higher body fat percentage but not in children with lower body fat percentage.

ObjectiveAfter a previous survey on the incidence of diabetic ketoacidosis (DKA) at onset of type 1 diabetes in children in 2013–2014 in Italy, we aimed to verify a possible decline in the incidence of DKA at onset during a national prevention campaign.DesignProspective observational study.SettingMulticentre study throughout Italy.InterventionNational awareness campaign started in November 2015 and held until December 2017.PatientsDuring 2016 and 2017 we collected data on all patients aged 0–18 years with new-onset diabetes.Main outcome measuresDKA (pH ResultsRecords (n=2361) of children with newly diagnosed type 1 diabetes were collected from 58 out of 68 (85.3%) centres of the original survey participants and 100% of the previously surveyed tertiary centres. Overall, DKA was observed in 1124 patients, with an increased rate when compared with the previous survey (47.6% vs 38.5%, p=0.002), and severe DKA in 15.3%. In children below 6 years, DKA was observed in 323 out of 617 (52.5%) and severe DKA in 16.7%; in this age group, occurrence of DKA reduced by 21.3% (p=0.009). DKA treatment according to the ISPED guidelines was adopted in 95% of the centres, with a 27% improvement (p=0.025).ConclusionsDuring a 2-year awareness campaign, DKA at onset of diabetes in children and adolescents 0–18 years is still common and increased when compared with the 2013–2014 survey.

Background: Atrial fibrillation (AF) itself may lead to functional tricuspid regurgitation (FTR) through tricuspid annulus (TA) dilation. However, the pathophysiological determinants of TA enlargement in AF patients remain to be clarified. The objectives of this study were (1) to compare the TA size and function in AF patients versus healthy subjects; (2) to identify the determinants of TA remodeling in patients with AF and FTR; and (3) to assess the relationships among right heart structures and severity of FTR in AF patients. Methods: Eighty-three consecutive patients with long-term persistent AF and FTR (61 ± 9.9 years, 67% women) were prospectively enrolled and compared with 83 sex and body surface area–matched healthy subjects. Heart chamber size and function and TA geometry were analyzed using three-dimensional echocardiography. Results: Among AF patients, 33%, 34%, and 33% had mild, moderate, and severe FTR, respectively. Right atrial (RA) dilation was detected in 93% of AF patients, while only 27% and 12% of them showed dilated or dysfunctional right ventricle (RV), respectively. End-diastolic TA area had the strongest correlation with the minimum volume of the RA (RAVmin r = 0.6981, P

Status Epilepticus (SE) is a condition resulting either from the failure of seizure termination mechanisms or from the abnormal activation of prolonged seizure mechanisms. It represents a life-threatening medical emergency associated with high morbidity and mortality that requires prompt diagnosis and treatment. SE treatment begins with a quick-acting benzodiazepine, followed by intravenous (IV) loading and a continuous infusion of antiseizure medications (ASMs). The failure of first- and second-line treatments is defined as “refractory SE” (RSE) and requires infusion of IV anaesthetics. If anaesthetics fail or SE recurs after 24 hours, SE is defined as “super refractory status epilepticus” (SRSE).

In this study natural-based complex polyphenols, obtained through a smart synthetic approach, have been evaluated for their ability to inhibit the formation of Aβ42 oligomers, the most toxic species causing synaptic dysfunction, neuroinflammation, and neuronal death leading to the onset and progression of Alzheimer's disease. In vitro neurotoxicity tests on primary hippocampal neurons have been employed to select nontoxic candidates. Solution NMR and molecular docking studies have been performed to clarify the interaction mechanism of Aβ42 with the synthesized polyphenol derivatives, and highlight the sterical and chemical requirements important for their antiaggregating activity. NMR results indicated that the selected polyphenolic compounds target Aβ42 oligomeric species. Combined NMR and docking studies indicated that the Aβ42 central hydrophobic core, namely, the 17-31 region, is the main interaction site. The length of the peptidomimetic scaffold and the presence of a guaiacol moiety were identified as important requirements for the antiaggregating activity. In vivo experiments on an Aβ42 oligomer-induced acute mouse model highlighted that the most promising polyphenolic derivative (PP04) inhibits detrimental effects of Aβ42 oligomers on memory and glial cell activation. NMR kinetic studies showed that PP04 is endowed with the chemical features of true inhibitors, strongly affecting both the Aβ42 nucleation and growth rates, thus representing a promising candidate to be further developed into an effective drug against neurodegenerative diseases of the amyloid type.

Better models to identify individuals at low risk of ventricular arrhythmia (VA) are needed for implantable cardioverter-defibrillator (ICD) candidates to mitigate the risk of ICD-related complications. We designed the CERTAINTY study (CinE caRdiac magneTic resonAnce to predIct veNTricular arrhYthmia) with deep learning for VA risk prediction from cine cardiac magnetic resonance (CMR). Using a training cohort of primary prevention ICD recipients (n = 350, 97 women, median age 59 years, 178 ischemic cardiomyopathy) who underwent CMR immediately prior to ICD implantation, we developed two neural networks: Cine Fingerprint Extractor and Risk Predictor. The former extracts cardiac structure and function features from cine CMR in a form of cine fingerprint in a fully unsupervised fashion, and the latter takes in the cine fingerprint and outputs disease outcomes as a cine risk score. Patients with VA (n = 96) had a significantly higher cine risk score than those without VA. Multivariate analysis showed that the cine risk score was significantly associated with VA after adjusting for clinical characteristics, cardiac structure and function including CMR-derived scar extent. These findings indicate that non-contrast, cine CMR inherently contains features to improve VA risk prediction in primary prevention ICD candidates. We solicit participation from multiple centers for external validation.

Background and Aims Peripheral vascular surgery patients commonly present multiple diseases and receive anticoagulants or antiplatelet drugs. Nonetheless, revascularization procedures may last many hours. Thus the risk of a long-lasting general anesthesia may increase while neuraxial blocks may expose patients to an augmented risk of bleeding [1]. Peripheral blocks last longer and guarantee hemodynamic control but may not be adequate for procedures involving the iliac artery. We present a case of a patient, who underwent revision of an iliac-femoral bypass under a combination of lumbar plexus and quadratus lumborum blocks. Methods Female 70 y.o., ASA III. Chronic legs ischemia, diabetes, multiple bypass and left toe amputation, hypertension, blindness, ischemic cardiopathy, moderate aorta stenosis. Scheduled for revision of iliac-femoral bypass of the left leg. expected to last 3 to 6 hours.General anaesthesia and neuraxial anaesthesia weren’t the best options, due to patient multimorbidity and aorta’s stenosis.With patient’s consent, we performed an ultrasound plus nerve stimulation guided lumbar plexus block with Shamrock approach [2] (Stimuplex ultra 360 – 100 mm – Bbraun) with 30 m of 0,375% ropivacaine; subsequently the needle was retracted and further 20 ml of the same mixture were deposited in the plane between psoas and quadratus lomborum muscles. Weak sedation with propofol TCI 0,6 µg/ml was administered. Results Surgery was carried out in 4 hours with complete surgical anesthesia and hemodynamic stability. After one hour in recovery room, patient was dismissed to the ward. Conclusions Shamrock approach allowed the successful combination of lumbar plexus and transmuscular quadratus lomborum block

IntroductionSudden cardiac death (SCD) is the leading cause of death in patients with myocardial infarction (MI) and can be prevented by the implantable cardioverter defibrillator (ICD). Currently, risk stratification for SCD and decision on ICD implantation are based solely on impaired left ventricular ejection fraction (LVEF). However, this strategy leads to over- and under-treatment of patients because LVEF alone is insufficient for accurate assessment of prognosis. Thus, there is a need for better risk stratification. This is the study protocol for developing and validating a prediction model for risk of SCD in patients with prior MI.Methods and AnalysisThe EU funded PROFID project will analyse 23 datasets from Europe, Israel and the US (∼225,000 observations). The datasets include patients with prior MI or ischemic cardiomyopathy with reduced LVEFEthics and disseminationLocal ethical approval was obtained. The final model will be disseminated through scientific publications and a web-calculator. Statistical code will be published through open-source repositories.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive heart condition which causes fibro-fatty myocardial scarring, ventricular arrhythmias, and sudden cardiac death. Most cases of ARVC can be linked to pathogenic mutations in the cardiac desmosome, but the pathophysiology is not well understood, particularly in early phases when arrhythmias can develop prior to structural changes. Here, we created a novel human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of ARVC from a patient with a c.2358delA variant in desmoglein-2 (DSG2). These DSG2-mutant (DSG2Mut) hiPSC-CMs were compared against two wildtype hiPSC-CM lines via immunostaining, RT-qPCR, Western blot, RNA-Seq, cytokine expression and optical mapping. Mutant cells expressed reduced DSG2 mRNA and had altered localization of desmoglein-2 protein alongside thinner, more disorganized myofibrils. No major changes in other desmosomal proteins were noted. There was increased pro-inflammatory cytokine expression that may be linked to canonical and non-canonical NFκB signaling. Action potentials in DSG2Mut CMs were shorter with increased upstroke heterogeneity, while time-to-peak calcium and calcium decay rate were reduced. These were accompanied by changes in ion channel and calcium handling gene expression. Lastly, suppressing DSG2 in control lines via siRNA allowed partial recapitulation of electrical anomalies noted in DSG2Mut cells. In conclusion, the aberrant cytoskeletal organization, cytokine expression, and electrophysiology found DSG2Mut hiPSC-CMs could underlie early mechanisms of disease manifestation in ARVC patients.

Background Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20–40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis. Methods Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance. Results The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine. Conclusion A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.

Highlights • The association of breast cancer and ileal GIST in Neurofibromatosis type 1 is extremely rare. • Laparoscopy is associated with better perioperative outcomes and shorter hospital stay. • Laparoscopic resection of small bowel GIST has shown in some studies to have oncological outcomes comparable to laparotomy., Introduction The Neurofibromatosis type I (NF1) is an autosomal dominant syndrome that affects 1/3000–1/4000 individuals. Patients with this condition are predisposed to different tumors, like neurofibromas, optic nerve gliomas, gastrointestinal stromal tumors (GIST) and breast cancers. Presentation of case A 78-year-old female patient affected by NF1 in May 2018 during follow-up for a carcinoma of the right breast had persistent anemia requiring regular blood transfusions. She presented with NF 1 with disseminated cutaneous neurofibromas, asthma, hypothyroidism, arterial hypertension and uterine prolapse. She had performed gastroscopy and colonoscopy both negative for neoplastic lesions. She was subjected to chest and abdomen CT which revealed the presence of an ileal lesion of 6.5 × 4 cm suspected of GIST. The patient underwent laparoscopic ileal resection in 120 min and was discharged on the sixth postoperative day. Discussion NF1 is caused by biallelic loss of a tumor suppressor gene. Most GISTs are localized in the stomach and small intestine. Surgery is the first line of treatment for localized disease. The main goal of surgery is complete excision with negative margins. The association between breast cancer and intestinal GIST in NF1 is reported only from two previous studies. Conclusion It is a rare case of association of breast cancer and ileal GIST in NF1. Laparoscopic resection of intestinal GIST has shown in some studies to have oncological outcomes comparable to laparotomy. Furthermore, laparoscopy is associated with better perioperative outcomes and shorter hospital stays. Further studies with a higher level of evidence are needed.

Highlights • Mesenteric cysts are rare but may cause symptoms or complications. • If so, surgical excision is considered the cornerstone of therapy. • Laparoscopic excision is feasible. • The types of mesenteric cyst are discussed though their aetiology is uncertain., Introduction The diagnosis and treatment of mesenteric cysts (MC) is a challenge due to rarity, lack of specific symptoms and variability in location and size. Mesenteric cysts are rare surgical entities that occur approximately in 1: 200,000–1: 350,000 hospitalizations. Presentation of case A 47-year-old female patient presented in August 2018 with occasional abdominal pains and an abdominal swelling palpable in the lower right quadrant. A CT scan with contrast enhancement confirmed a 11 cm mass with liquid content in the right iliac fossa, clearly separate from other intra-abdominal structures. The mass was completely excised laparoscopically. The patient was discharged on the third postoperative day. She was symptom-free at 30-day follow-up. Histology demonstrated a solitary non-pancreatic cyst of the mesentery with negative cytology for neoplastic cells. Discussion The origin of mesenteric cysts (MC) is uncertain. Imaging (by ultrasonography, CT, and MRI) can be diagnostic. Therapy for these cysts should be performed if they are symptomatic or cause complications. The treatment of choice is complete surgical excision. The advent of laparoscopy has allowed the excision of these cysts without laparotomy in the expert hands of surgeons with good experience in advanced laparoscopy. Laparoscopy is not a standard for the presence in the literature of only case reports. Conclusion MC are commonly asymptomatic and discovered incidentally. If symptomatic, surgical excision is considered the cornerstone intervention and laparoscopic resection is feasible, causing less pain, a shorter postoperative stay, and quicker recovery of the patient than open operation. Further studies with a higher level of evidence are needed.

Introduction The risk of acquiring SARS-CoV-2 in a hospital setting and the need of reorganizing the Emergency Departments (EDs) to cope with infected patients have led to a reduction of ED attendances for non-infectious acute conditions and to a different management of chronic disorders. Methods We performed a retrospective study evaluating the frequency and features of ED attendances for seizures during the lockdown period (March 10th–April 30th 2020) in the University Hospital of Trieste, Italy. We studied the possible pandemic impact on the way patients with seizures sought for medical assistance by comparing the lockdown period to a matched period in 2019 and to a period of identical length preceding the lockdown (January 18th–March 9th 2020). Results A striking decrease in total ED attendances was observed during lockdown (4664) compared to the matched control (10424) and to the pre-lockdown (9522) periods. A similar reduction, although to a lesser extent, was detected for seizure attendances to the ED: there were 37 during lockdown and 63 and 44 respectively during the two other periods. Intriguingly, during the lockdown a higher number of patients attended the ED with first seizures (p = 0.013), and more EEGs (p = 0.008) and CT brain scans (p = 0.018) were performed; there was a trend towards more frequent transport to the ED by ambulance (p = 0.061) in the lockdown period. Conclusions Our data suggest that the pandemic has affected the way patients with seizures access the Health Care System.

Background The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition. Objective The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. Methods We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls. Results The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. Conclusion This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.

Disability in leprosy is a direct consequence of damage to the peripheral nervous system which is usually worse in patients with no skin manifestations, an underdiagnosed subtype of leprosy known as primary neural leprosy. We evaluated clinical, neurophysiological and laboratory findings of 164 patients with definite and probable primary neural leprosy diagnoses. To better understand the disease progression and to improve primary neural leprosy clinical recognition we compared the characteristics of patients with short (≤12 months) and long (>12 months) disease duration. Positive and negative symptoms mediated by small-fibres were frequent at presentation (∼95%), and symptoms tend to manifest first in the upper limbs (∼68%). There is a consistent phenotypic variability between the aforementioned groups. Deep sensory modalities were spared in patients evaluated within the first 12 months of the disease, and were only affected in patients with longer disease duration (∼12%). Deep tendon reflexes abnormalities were most frequent in patients with longer disease duration (P < 0.001), as well as motor deficits (P = 0.002). Damage to large fibres (sensory and motor) is a latter event in primary neural leprosy. Grade-2 disability and nerve thickening was also more frequent in cases with long disease duration (P < 0.001). Primary neural leprosy progresses over time and there is a marked difference in clinical phenotype between patients with short and long disease duration. Patients assessed within the first 12 months of symptom onset had a non-length-dependent predominant small-fibre sensory neuropathy, whilst patients with chronic disease presented an asymmetrical all diameter sensory-motor neuropathy and patchily decreased/absent deep tendon reflexes.

Ischemic cardiomyopathy poses a significant public health burden due to the irreversible loss of functional cardiac tissue. Alternative treatment strategies include creation of three-dimensional (3D) cardiac tissues to both replace and augment injured native tissue. In this study, we utilize a net mold-based method to create a biomaterial-free 3D cardiac tissue and compare it to current methods using biomaterials. Cardiomyocytes, fibroblasts, and endothelial cells were combined using a hanging drop method to create spheroids. For the net mold patch method, spheroids were seeded into a net mold-based system to create biomaterial-free 3D cardiac patches. For the gel patch, spheroids were embedded in a collagen gel. Immunohistochemistry revealed increased alignment, vascularization, collagen I expression, cell viability, and higher density of cells in the net mold patch compared with the gel patch. Furthermore

Background Implantable cardiac monitor (ICM) revealed subclinical atrial fibrillation (SCAF) in up to 30% of cryptogenic stroke (CS) patients in randomized trials. However, real world data are limited. Objectives We investigated SCAF occurrence, treatments, clinical outcomes and predictors of SCAF in a multicenter real-world population subjected to ICM after CS. Methods From September 2016 to November 2019, 20 Italian centers collected data of consecutive patients receiving ICM after CS and followed with remote and outpatient follow-up according to clinical practice. All device-detected AF events were confirmed by the cardiologist to diagnose SCAF. Results ICM was implanted in 334 CS patients (mean age±SD 67.4±11.5 years, 129 (38.6%) females, 242 (76.1%) with CHA2DS2-VASC score≥4). During a follow-up of 23.6 (IQR 14.6-31.5) months, SCAF was diagnosed in 92 (27.5%) patients. First episode was asymptomatic in 81 (88.1%). SCAF daily burden ≥5 minutes was 22.0%, 24.1% and 31.5% at 6, 12, and 24 months after ICM implantation. Median time to first day with AF was 60 (IQR 18-140) days. Female gender, age>69 years, PR interval>160 ms and cortical-subcortical infarct type at enrolment were independently associated with an increased risk of SCAF. Conclusions In a real-world population, ICM detected SCAF in more than a quarter of CS patients. This experience confirms the relevance of implanting CS patients, for maximizing the possibilities to detect AF, following failure of Holter monitoring, according to guidelines. However, there is need to demonstrate that shift to oral anticoagulation following SCAF detection is associated with reduced risk of recurrent stroke.

A wild muskox (Ovibos moschatus) with dermatitis typical of contagious ecthyma had secondary bacterial septicemia with Corynebacterium freneyi that included laminitis, hepatitis, and suppurative encephalitis. This case supports the association between orf virus infection and fatal secondary infections, which may have contributed to population declines on Victoria Island, Canada.

Objective Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design Retrospective analysis of the Italian data set of patients with TNDM. Methods Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. Results Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; −2.27 SD) than those with KATP mutations (4.0 weeks; −1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Supplemental Digital Content is available in the text., Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm derived from plasmacytoid dendritic cells (pDCs). In this study, we investigated by immunohistochemical analysis the expression of E-cadherin (EC) on pDCs in reactive lymph nodes and tonsils, bone marrow, and in BPDCN. We compared the expression of EC in BPDCN to that in leukemia cutis (LC) and cutaneous lupus erythematosus (CLE), the latter typically featuring pDC activation. In BPDCN, we also assessed the immunomodulatory activity of malignant pDCs through the expression of several type I interferon (IFN-I) signaling effectors and downstream targets, PD-L1/CD274, and determined the extent of tumor infiltration by CD8-expressing T cells. In reactive lymph nodes and tonsils, pDCs expressed EC, whereas no reactivity was observed in bone marrow pDCs. BPDCN showed EC expression in the malignant pDCs in the vast majority of cutaneous (31/33 cases, 94%), nodal, and spleen localizations (3/3 cases, 100%), whereas it was more variable in the bone marrow (5/13, 38,5%), where tumor cells expressed EC similarly to the skin counterpart in 4 cases and differently in other 4. Notably, EC was undetectable in LC (n=30) and in juxta-epidermal pDCs in CLE (n=31). Contrary to CLE showing robust expression of IFN-I-induced proteins MX1 and ISG5 in 20/23 cases (87%), and STAT1 phosphorylation, BPDCN biopsies showed inconsistent levels of these proteins in most cases (85%). Expression of IFN-I-induced genes, IFI27, IFIT1, ISG15, RSAD2, and SIGLEC1, was also significantly (P

Objective Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases (AIDs). Although most of T1D patients are sporadic cases (S-T1D), 10% to 15% have a familial form (F-T1D) involving 2 or more first-degree relatives. This study evaluated the effect of T1D family aggregation and age onset on AIDs occurrence. Methods In this observational, cross-sectional, case-control, single center study, we enrolled 115 F-T1D and 115 S-T1D patients matched for gender, age, T1D age onset, and duration. With respect to T1D age onset (before or after 18 years), both groups were further subdivided into young- or adult-onset F-T1D and young- or adult-onset S-T1D. The presence of organ-specific antibodies and/or overt AIDs was evaluated. Results The F-T1D group had a higher percentage of AIDs (29.8% vs 18.4%, P = .04) and a significant earlier onset of AIDs at Cox regression analysis (P = .04) than the S-T1D group. Based on multivariate analysis, the adult-onset F-T1D subgroup had the highest prevalence of both additional organ-specific antibodies (60.5%) and overt AIDs (34.9%), whereas the adult S-T1D subgroup was the least frequently involved (29.1% and 12.7%, respectively). In F-T1D patients, offsprings develop T1D and AIDs earlier than their parents do. Conclusions In T1D patients, familial aggregation and adult-onset of T1D increase the risk for coexistent AIDs. These clinical predictors could guide clinicians to address T1D patients for the screening of T1D-related AIDs.

BACKGROUND to assess predictors of remission in children with Juvenile Idiopathic Arthritis (JIA), treated with intraarticular corticosteroid injection (IACI) as monotherapy or in combination with Methotrexate (MTX). METHODS a retrospective study of 43 patients diagnosed with different JIA subtypes and followed-up at a tertiary centre between 2000 and 2014. We included patients treated with IACI as monotherapy or in combination with MTX at onset or thereafter. We excluded patients treated with MTX as monotherapy or in combination with biologics. Patients were divided into two groups on the basis of assigned treatment. Primary outcomes were disease remission and duration. We performed descriptive analysis, bivariate analysis and cross-correlation analysis between variables. Statistically significant results (pvalue

Introduction: GDF-15 (Growth Differentiation Factor 15), a member of the transforming growth factor beta superfamily, has been shown to be a biomarker of mitochondrial diseases. Additionally, increased levels of GDF-15 have also been associated with all-cause death and heart failure (HF) in patients with coronary artery disease. Conflicting data exists regarding GDF-15 levels and risk of ventricular arrhythmic events. Hypothesis: In a cohort of patients with reduced left ventricular systolic function, GDF-15 identifies patients at high risk of (1) worsening HF and (2) sudden arrhythmic death. Methods: PROSe-ICD is a multicenter prospective cohort study of 1,189 patients with ischemic and non-ischemic cardiomyopathy who underwent ICD implantation for primary prevention of sudden death, designed to compare patients who sustain an appropriate ICD firing for rapid VT or VF (surrogate for sudden death) to those who do not. Worsening HF was defined as any admission for acute decompensated HF during an average follow up period of 8 years. Blood samples were obtained on average every 6 months and GDF-15 was measured with an ELISA based assay from a subset of PROSe-ICD patients with appropriate ICD shocks (n=58; 228 samples), worsening HF (n=42; 157 samples), both HF and VT/VF (n=12; 46 samples) and 237 samples from 46 controls without ICD shocks and HF, matched for age and ejection fraction. Results: GDF-15 levels were elevated in patients who had acute decompensated heart failure, but not in patients who experienced ICD shocks in the absence of worsening HF (see Figure). Differences in GDF-15 levels were relatively stable over time within individual patients, and did not predict HF events. Conclusions: Future studies need to examine whether patients with the highest GDF-15 levels have underlying mitochondrial or nuclear DNA mutations leading to mitochondrial dysfunction and worsening HF.

Introduction: The safety of vigorous exercise for individuals with appropriately-treated LQTS remains unproven, and physical activity practices in this population have not been described. Methods: LIVE-LQTS prospectively enrolled individuals age 8-60 years with overt LQTS or gene mutation carriers. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review. Results: Among 1554 participants, 804 (52%) reported exercising vigorously, 473 of these competitively, 577 (37%) exercising at moderate, and 173 (11%) at low levels. Seven percent of those working describe jobs more active than walking, including 10 in protective services and 19 in sports/coaching. Over 90% are genotype positive, 57% are phenotype positive at rest and an additional 16% have exercise-induced QT prolongation. Forty four percent have had documented ventricular arrhythmias or syncope. Eighty-four percent are appropriately treated with either beta-blockers, ICD, and/or sympathectomy, although among beta-blocked patients, only 60% are on the most effective agents. Among adults, BMI was significantly lower among the vigorous exercisers. Conclusion: While the high percentage of vigorous exercisers seen in this study may not represent all patients with LQTS due to self-selection for study participation, many patients with LQTS are engaged in vigorous exercise or competitive athletics. Prospective follow up of this cohort is ongoing and will determine safety of vigorous exercise through comparison of arrhythmic outcomes in vigorous exercisers vs moderate/low level exercisers.

Introduction: Methadone, a racemic mixture of S - and R -enantiomers, prolongs the QT interval and causes torsades de pointes. Methadone has been shown to lengthen late ventricular repolarization, represented by the T peak-Tend interval, which is modulated primarily by I Kr and I Ks . However, it is unknown whether methadone prolongs early ventricular repolarization, represented by the heart rate-corrected J-T peak (J-T peak c) interval, which is regulated primarily by L-type calcium and late sodium currents. In addition, the relationship between stereospecific serum methadone and metabolite concentrations and effects on J-T peak c and T peak -T end intervals are unknown. Hypothesis: 1) Methadone lengthens both J-T peak c and T peak -T end , and 2) Methadone effects on J-T peak c and T peak -T end correlate with serum S - and R -methadone and S - and R -metabolite [ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations. Methods: Patients (n=81) on steady state maintenance methadone therapy at an urban narcotic treatment center who had undergone a pre-methadone 12-lead ECG within the previous 6 months were identified and asked to return for a followup ECG during steady-state methadone therapy. In a subset (n=41), blood was obtained to determine serum S - and R -methadone and S - and R -EDDP concentrations. Results: Compared to baseline, methadone lengthened mean ± SD J-T peak c (225 ± 26 vs 232 ± 28 ms, p=0.02) as well as T peak - T end (80 ±14 vs 90 ± 16 ms, pS -methadone correlated with J-T peak c [R 2 = 0.41 (95% CI 0.11-0.65), p=0.007]. Serum R -methadone concentrations also correlated with J-T peak c [R 2 = 0.47 (0.17-0.68), p=0.002]. In addition, serum concentrations of S - and R -EDDP correlated with J-T peak c [R 2 = 0.39 (0.09-0.63), p=0.01] and [R 2 = 0.38 (0.07-0.62), p=0.02], respectively. There were no significant correlations between serum S - and R -methadone or S- and R-EDDP concentrations with T peak - T end intervals. Conclusions: Methadone lengthens both early and late ventricular repolarization, suggesting that methadone’s ion channel effects may extend beyond inhibition of I Kr . Serum S - and R -methadone and S -and R -EDDP concentrations are associated with effects on J-T peak c intervals.

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p p p = 0.002 and p = 0.005, respectively). No significant difference was found in d-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE.

Background Current approaches fail to separate patients at high versus low risk for ventricular arrhythmias owing to overreliance on a snapshot left ventricular ejection fraction measure. We used statistical machine learning to identify important cardiac imaging and time‐varying risk predictors. Methods and Results Three hundred eighty‐two cardiomyopathy patients (left ventricular ejection fraction ≤35%) underwent cardiac magnetic resonance before primary prevention implantable cardioverter defibrillator insertion. The primary end point was appropriate implantable cardioverter defibrillator discharge or sudden death. Patient characteristics; serum biomarkers of inflammation, neurohormonal status, and injury; and cardiac magnetic resonance‐measured left ventricle and left atrial indices and myocardial scar burden were assessed at baseline. Time‐varying covariates comprised interval heart failure hospitalizations and left ventricular ejection fractions. A random forest statistical method for survival, longitudinal, and multivariable outcomes incorporating baseline and time‐varying variables was compared with (1) Seattle Heart Failure model scores and (2) random forest survival and Cox regression models incorporating baseline characteristics with and without imaging variables. Age averaged 57±13 years with 28% women, 66% white, 51% ischemic, and follow‐up time of 5.9±2.3 years. The primary end point (n=75) occurred at 3.3±2.4 years. Random forest statistical method for survival, longitudinal, and multivariable outcomes with baseline and time‐varying predictors had the highest area under the receiver operating curve, median 0.88 (95% CI, 0.75‐0.96). Top predictors comprised heart failure hospitalization, left ventricle scar, left ventricle and left atrial volumes, left atrial function, and interleukin‐6 level; heart failure accounted for 67% of the variation explained by the prediction, imaging 27%, and interleukin‐6 2%. Serial left ventricular ejection fraction was not a significant predictor. Conclusions Hospitalization for heart failure and baseline cardiac metrics substantially improve ventricular arrhythmic risk prediction.

Aims Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Na(v)1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na(v)1.5) in ARVD/C.Methods and results We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 +/- 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of Na(v)1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 +/- 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 +/- 15 vs. 94 +/- 14 ms, P Conclusions Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na(v)1.5 and N-Cadherin clusters at junctional sites. This suggests that Na(v)1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na(v)1.5 dysfunction causes cardiomyopathy.

Background and aim: The objective of this cross-sectional study was to evaluate the degree of glycaemic control and the frequency of diabetic complications in Italian people with diabetes who were treated with continuous subcutaneous insulin infusion (CSII). Methods and results: Questionnaires investigating the organisation of diabetes care centres, individuals’ clinical and metabolic features and pump technology and its management were sent to adult and paediatric diabetes centres that use CSII for treatment in Italy. Information on standard clinical variables, demographic data and acute and chronic diabetic complications was derived from local clinical management systems. The sample consisted of 6623 people with diabetes, which was obtained from 93 centres. Of them, 98.8% had type 1 diabetes mellitus, 57.2% were female, 64% used a conventional insulin pump and 36% used a sensor-augmented insulin pump. The median glycated haemoglobin (HbA1c) level was 60 mmol/mol (7.6%). The HbA1c target (i.e. 18 years) was achieved in 43.4% of paediatric and 23% of adult participants. Factors such as advanced pump functions, higher rate of sensor use, pregnancy in the year before the study and longer duration of diabetes were associated with lower HbA1c levels. The most common chronic complications occurring in diabetes were retinopathy, microalbuminuria and hypertension. In the year before the study, 5% of participants reported ≥1 episode of severe hypoglycaemic (SH) episodes (SH) and 2.6% reported ≥1 episode of ketoacidosis. Conclusions: Advanced personal skills and use of sensor-based pump are associated with better metabolic control outcomes in Italian people with diabetes who were treated with CSII. The reduction in SH episodes confirms the positive effect of CSII on hypoglycaemia. Clinical trial registration number: NCT 02620917 (ClinicalTrials.gov).

Botulinum toxin type A (BTX-A) represent the gold standard therapy for focal dystonia and related hyperkinetic movement disorders. The main advantages of this method are low rate of complications, reversibility and efficacy in reducing spastic hypertonia or abnormal movements. The treatment is safe but it needs to be repeated periodically and some patients do not obtain effective control of the symptoms due to the onset of secondary immune resistance. For this reason we have selected 45 cases already in treatment with botulinum toxin that have been switched to incobotulinumtoxinA. At a median follow up of 8 months the greatest part of the patients, twenty-six (57.7%) remained clinically unchanged; fourteen (31.1%) had a significant clinical improvement and five (11.1%) worsened. We did not observe any general or injection site complications.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. Methods Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. Results ICU patients showed a marked increase in neutrophils (1.24 × 105 ml− 1, 0.85–2.07), lower lymphocyte (0.97 × 105 ml− 1, 0.024–0.34) and macrophages fractions (0.43 × 105 ml− 1, 0.34–1.62) compared to IMW patients (0.095 × 105 ml− 1, 0.05–0.73; 0.47 × 105 ml− 1, 0.28–1.01 and 2.14 × 105 ml− 1, 1.17–3.01, respectively) (p p p p p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p p Conclusions Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.

STUDY OBJECTIVE Methadone is associated with QT interval prolongation and torsades de pointes. The objective of this study was to (a) determine the incidence of QT interval prolongation among patients on maintenance methadone therapy in an urban opioid treatment program (OTP), (b) compare characteristics of patients who developed methadone-associated QT prolongation with those who did not develop QT prolongation, and (c) investigate the relationship between QT interval prolongation and stereospecific serum methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations. DESIGN Prospective study. SETTING Urban opioid treatment program (OTP). PATIENTS n = 93 patients on maintenance methadone therapy in an urban OTP. INTERVENTION Patients underwent a 12-lead electrocardiogram (ECG) prior to initiating methadone and again during steady-state maintenance methadone therapy. In a subset (n = 43), blood was obtained to determine serum (S)- and (R)-methadone and (S)- and (R)-EDDP concentrations, which were compared in patients who developed Bazett's-corrected QT (QTc) prolongation [≥470 ms (men) or ≥480 ms (women) and/or ≥60 ms lengthening from pretreatment value] with those who did not have QTc prolongation. MEASUREMENTS AND MAIN RESULTS Mean [± standard deviation (SD)] age was 36 ± 12 years; 73% were female, and 74% were white. QTc prolongation occurred in 14 (15.1%) patients. Patients who developed QTc prolongation were older (41 ± 13 vs. 35 ± 9 years, p = 0.03) and had a longer pre-methadone QTc compared with those who did not have QTc prolongation (429 ± 11 vs. 420 ± 20 ms, respectively, p = 0.02). Serum (S)-methadone concentrations were higher in patients with QTc prolongation compared to patients without prolongation (199 ± 81 vs. 128 ± 68 ng/ml, respectively, p = 0.01), whereas the difference in serum (R)-methadone concentrations between the groups did not reach significance (189 ± 68 vs. 125 ± 60 ng/ml, respectively, p = 0.08). Serum (R)-methadone concentrations correlated with QTc intervals [R2 = 0.15 (95% confidence interval (CI) 0.11-0.62, p = 0.0009)]. The correlation between serum (S)-methadone concentrations and QTc did not reach significance [R2 = 0.08 (95% CI -0.01 to 0.54, p = 0.06)]. Serum (S)-and (R)-EDDP concentrations were not significantly different between the groups and did not significantly correlate with QTc intervals. CONCLUSIONS Approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation. Both serum (S)- and (R)-methadone concentrations, but not (S)- or (R)-EDDP, contribute to methadone-associated QT prolongation.

Background: With the ever-increasing demand on acute healthcare, the hospital discharge process and delayed discharges are considered relevant in achieving optimal performance in clinical settings. The purpose of this paper is to review the literature to identify conceptual and operational definitions of delayed discharges, identify causes and effects of delayed discharges, and also to explore the literature for interventions aimed at decreasing the impact (in terms of reducing the number/rate of delays) of delayed discharges in acute healthcare settings. Methods: An extensive literature search yielded a total of 26 248 records. Sixty-four research articles were included in the scoping review after considering inclusion/exclusion criteria and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) search strategy. The following databases were utilized: Cochrane, EBSCO, PubMed, PubMed Central, Medline, and Web of Science. The search was carried out between January 2017 and March 2020 and covered literature ranging from 1990 to 2019. Results were reviewed by authors for duplicates and filtered using the inclusion/ exclusion criteria. Tables were created to classify the chosen articles (n = 64), allowing us to organise findings and results. Results: Conceptual and operational definitions were analysed. In turn, causes and effects of delayed discharges were extracted and represented in diagrammatic format, together with specific interventions used in acute healthcare settings to lessen the effect of delayed discharges. Operational definitions of delayed discharges were found to be more difficult to establish, particularly in the light of the vast number of different scenarios and workplace interventions uncovered in the literature. The main causes of delayed discharges were faulty organisational management, inadequate discharge planning, transfer of care problems, and age. The main effects were bed-blocking, A&E (Accident & Emergency) overcrowding, and financial implications. The main interventions included ‘discharge before noon’ initiative, ‘discharge facilitation tools,’ ‘discharge delay tracking’ mechanisms, and the role of general practitioners and social care staff. Conclusion: This paper fills a gap in the fragmented literature on delayed inpatient discharges by providing a researchbased perspective on conceptual and operational definitions, causes and effects, as well as interventions to minimize their impact. The findings and definitions are intended as points of reference for future research.

Background Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown. Methods and Results We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QTF) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTFvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QTF interval exposure. Maximum QTF (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QTF from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different. Conclusions HFpEF is associated with enhanced response to drug-induced QT interval lengthening.

A 67-year-old Brazilian man of African ancestry and his 60-year-old sister both presented with choreiform movements, although in the man these were significantly overshadowed by additional parkinsonism. The man also had a history of four epileptic seizures. Neurological examination in each also found slow saccades and a dysexecutive syndrome. Genetic tests for Huntington’s disease were negative but were positive for Huntington’s disease-like 2. There are various genetic causes of chorea diseases, and their correct identification is important for appropriate clinical management and genetic counselling.

Sirtuins are NAD+-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases.

Abstract Myotonic dystrophy is an inherited systemic disorder affecting skeletal muscle and the heart. Genetic testing for myotonic dystrophy is diagnostic and identifies those at risk for cardiac complications. The 2 major genetic forms of myotonic dystrophy, type 1 and type 2, differ in genetic etiology yet share clinical features. The cardiac management of myotonic dystrophy should include surveillance for arrhythmias and left ventricular dysfunction, both of which occur in progressive manner and contribute to morbidity and mortality. To promote the development of care guidelines for myotonic dystrophy, the Myotonic Foundation solicited the input of care experts and organized the drafting of these recommendations. As a rare disorder, large scale clinical trial data to guide the management of myotonic dystrophy are largely lacking. The following recommendations represent expert consensus opinion from those with experience in the management of myotonic dystrophy, in part supported by literature‐based evidence where available.

To ascertain the most effective approach in pregnancies complicated by mild intrahepatic cholestasis of pregnancy (mICP) by evaluating rates of adverse perinatal outcomes (APOs) and pathological placental findings.A total of 89 pregnancies complicated by mICP (defined as total serum bile acids (TSBAs) levels40 µmol/L) were included. One-drug (ursodeoxycholic acid [UDCA]) (No differences were found in demographic, obstetric, and placental characteristics. In UDCAPregnancies complicated by mICP and managed by UDCA alone present similar APO rates and placental histopathology if compared with those treated by UDCA

A 41-year-old woman with type 1 myotonic dystrophy and a family history of sudden cardiac death presented with frequent palpitations and near syncope. During an electrophysiology study, she was found to have a prolonged HV interval and easily inducible wide complex tachycardia, consistent with bundle branch reentrant ventricular tachycardia for which she underwent successful catheter ablation of the right bundle branch. The importance of clinical surveillance for conduction abnormalities and arrhythmias in patients with myotonic dystrophy is discussed.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading throughout Italy since February 2020. Limited data are available regarding indications, performance characteristics and safety of bronchoscopy (which is an aerosol generating procedure) in the context of SARS-CoV-2 outbreak. Methods: We performed a prospective, observational, multicentric study to describe the role of bronchoscopy during SARS-CoV-2 outbreak in Italy. Findings: 147 consecutive adult patients who underwent bronchoscopy between March 1st and April 15 th 2020 in five Italian hospitals were enrolled. 78/147 (53·1%) bronchoscopies were performed to detect SARS-CoV-2 in patients with negative nasopharyngeal swabs. SARS-CoV-2 was detected in 43/78 (55·1%) patients, without no difference in diagnostic yield between bronchoalveolar lavage (BAL) and bronchial washing (BW) (35/61, 57·4% and 8/17, 47·1%; p-value: 0·45). Suspected co-infections and management of obstructive atelectasis were the main indications for bronchoscopy in 31/147 (21·1%) patients with COVID-19 (respectively 11/31 (35·5%) and 7/31 (16·1%)). Suspected non-COVID-19 lower respiratory tract infections (18/38 (47·4%) and malignancy (7/38 (18·4%)) were the main indications in 38/147 (25·8%) patients without COVID-19. Overall, bronchoscopy was successfully performed for diagnostic and therapeutic purposes in 111/147 (75·5%) cases. 8/147 (5·4%) patients had mild complications related to the procedure.No procedure-related infections for patients and healthcare workers were recorded. Interpretation: bronchoscopy is a useful technique in the diagnosis of SARS-CoV-2 pneumonia in patients with negative swab. Endoscopic techniques may be safely and successfully performed for diagnostic and therapeutic purposes in the vast majority of the patients with or without SARS-CoV-2 illness. Funding: University of Milan Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the ethical committees of all the participating hospitals. Written informed consent was signed by recruited patients

To present the genetic heterogeneity of a sample of the Brazilian population with transthyretin (TTR) mutations. This cohort study was descriptive and retrospective, and enrolled patients with peripheral neuropathy of unknown cause that were found to have a mutation in the TTR gene during the process of etiological investigation, between July 1997 to January 2016. Over the study period, 129 point mutations were identified in 448 tested patients, of whom 128 were of Brazilian origin. The TTR Val30Met mutation was identified in 116 patients (90.6%); while 7 (4.7%) patients had a pathogenic non-TTR mutation and 7 (4.7%) carried non-pathogenic mutations (4.7%). The four non-TTRMet30 pathogenic mutations were TTR Aps38Tyr; TTR Ile107Val; TTR Val71Ala; and TTR Val122Ile. In the non-pathogenic group, we only found two mutations, including TTR Gly6Ser and TTR Thr119Thr. Our study depicts a scenario of greater genetic heterogeneity among Brazilian hereditary transthyretin amyloidosis (hATTR) patients with familial amyloidotic polyneuropathy (FAP). We expect that this number will grow fast over a short period of time, due to increasing availability of genetic tests, increasing knowledge of the disease and the multivariate origin of our population.

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver. 3 2 125 133

Fighting cancer is an economically expensive challenge for both health care payers, and the patients and their families and the median costs for cancer care are rapidly increasing in the last decade. Although both direct and indirect costs of medical assistance have been a frequent source of distress and contention, however analysis of the non-medical expenses incurred directly by cancer patients has not received adequate attention. Developing a deeper understanding of so-called "out-of-pocket" costs may be necessary. Out-of-pocket costs for medical care range from 7 % to 11 % of medical costs for all payers. However, the range of out-of-pocket costs shows considerable variability in different studies. In this review, we reviewed available data concerning direct and indirect medical costs, including psychosocial ones.