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Objectives To elucidate the association between cardio-metabolic risk factors and depressive symptoms among US adults. Methods Data on 9,477 adults ≥ age 18 from the US National Health and Nutrition Examination Survey (NHANES) 2013-2018 were used. Number of cardio-metabolic risk (CMR) factors, from 0-5, was based on BMI, blood pressure, fasting blood glucose, and lipid levels. Depressive symptoms by Patient Health Questionnaire (PHQ-9) scores were categorized “no to mild symptoms” (0-9) and “clinically-significant depressive (CSD) symptoms” (10-27). Logistic regression analysis tested associations between CMR factors and CSD symptoms, adjusted for age, gender, education, income, race/ethnicity and smoking status. Results CSD symptoms were significantly associated with low HDL, abdominal obesity, and high triglycerides. Increased numbers of CMR factors were associated with increased odds of CSD symptoms, from 1.45 times for 1 CMR to 2.55 times for 5 CMRs. The cross-sectional nature of the present study has resulted in some limitations like the inability to determine the direction and causality of the effects between depression and CMR. The study data was subject to response bias and recall errors as the participants self-reported the use of medications. Conclusions In US adults, cardio-metabolic risk factors were associated with clinically-significant depressive symptoms. Public health and clinical programs should include screening for both health issues, intervention for modifiable risk factors, and support for social determinants of health.

Data about the presentation and the management of primary immune thrombocytopenia (ITP) in very elderly patients (VEPs; aged ≥80 years) are lacking. The aim of the present study was to describe ITP in this subgroup. The data source was the prospective CARMEN-France registry. Patients included between 2013 and 2018 were selected. ITP presentation and management in VEPs was compared to elderly patients (EPs; aged 65-79 years). We assessed factors associated with bleeding at ITP onset in VEPs. Of 541 patients, 184 were included: 87 in the VEP group and 97 in the EP group. The mean age was 85·7 years in the VEP group. Comorbidities were more frequent in the VEP group (67·4% vs. 47·9%). The median platelet count at ITP onset was similar but severe bleeding tended to be more frequent in VEPs (10·3% vs. 4·1%, P = 0·1) as well as mortality. Exposure to ITP drugs, response to first-line treatment, need of second-line treatment, evolution towards persistency, occurrence of bleeding, infection and thrombosis did not differ between groups. In VEPs, factors associated to bleeding were female sex [odds ratio (OR) 4·75, 95% confidence interval (CI) 1·31-17·32] and platelet count of

Pancreatic and biliary duct cancers are increasing causes of acute cholangitis (AC). We retrospectively characterize 81 cancer-associated cholangitis (CAC) compared to 49 non-cancer-associated cholangitis (NCAC). Clinical and biological presentations were similar. However, in CAC, antibiotic resistance and inadequate empirical antibiotic therapy were more frequent; more patients required ≥ 2 biliary drainages; and mortality at day 28 was higher than in NCAC. Death was associated with initial severity and CAC in a multivariate analysis. Cholangitis associated with pancreatic or biliary duct cancers requires specific empirical antimicrobial therapy; early use of biliary drainage may improve outcomes.

Background and Aims Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV‐infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. Approach and Results Children with chronic HCV infection, genotype 1‐6, with or without compensated cirrhosis, were divided into three cohorts by age—cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)—and given weight‐based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady‐state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug‐related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. Conclusions A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV‐infected children 3 to < 12 years old.

Pacemakers, implantable cardiac defibrillators, and cardiac resynchronization therapy devices are potentially life-saving treatments for a number of cardiac conditions, but are not without risk. Most concerning is the risk of a cardiac implantable electronic device (CIED) infection, which is associated with significant morbidity, increased hospitalizations, reduced survival, and increased healthcare costs. Recommended preventive strategies such as administration of intravenous antibiotics before implantation are well recognized. Uncertainties have remained about the role of various preventive, diagnostic, and treatment measures such as skin antiseptics, pocket antibiotic solutions, anti-bacterial envelopes, prolonged antibiotics post-implantation, and others. Guidance on whether to use novel device alternatives expected to be less prone to infections and novel oral anticoagulants is also limited, as are definitions on minimum quality requirements for centres and operators and volumes. Moreover, an international consensus document on management of CIED infections is lacking. The recognition of these issues, the dissemination of results from important randomized trials focusing on prevention of CIED infections, and observed divergences in managing device-related infections as found in an European Heart Rhythm Association worldwide survey, provided a strong incentive for a 2019 International State-of-the-art Consensus document on risk assessment, prevention, diagnosis, and treatment of CIED infections. This article is simultaneously published also in Eur J Cardiothorac Surg. (https://doi.org/10.1093/ejcts/ezz296) and European Heart Journal (https://doi.org/10.1093/eurheartj/ehaa010). Minor differences in style may appear in each publication, but the article is substantially the same in each journal.

TiO2 in the food industry, designated as E171, is widely used in the production of chewing gums, sweets, and icing. It is absorbed through food ingestion and the respiratory tract. There are also reports that TiO2 nanoparticles can reach the dermis through damaged epidermis. It demonstrates the ability to accumulate in some internal organs, like spleen, liver, and kidneys, depending on its size and structure. It may have pro-inflammatory, cytotoxic, and genotoxic effects. A change in the composition of the host’s intestinal microflora is also observed after exposure to high doses of TiO2. There are some differences in TiO2 intake with food around the world, but most data indicate higher consumption of this additive by children. Due to the small amount of research and the fact that most of the analyses were carried out using animal models, it is necessary to plan future observations of long-term exposure of the TiO2 molecule.

Objective: To critically evaluate an early childhood caries (ECC) intervention performed by non-dental primary healthcare providers. Methods: This mixed-methods investigation includes data from three sources: (a) a pilot non-randomized controlled trial to examine clinical outcomes at four health centres; (b) stakeholder focus group interviews; and (c) a survey of parents whose children were exposed to the intervention. The pilot study involved four Community Health Centres in rural Cambodia whereby mother-child (6-24 months of age)dyads received oral health education (OHE), toothbrushes, fluoride toothpaste and fluoride varnish on up to six occasions as part of the routine vaccination schedule. Outcomes were as follows: presence of ECC; impacts on oral health-related quality of life (OHRQoL); stakeholder perceptions of intervention delivery; and parental perceptions of fluoride varnish. Results: Participants in the intervention group had six times lower odds of developing ECC than those in the comparison group after controlling for socio-economic status (OR 0.13). Those in the intervention group also had a large reduction OHRQoL scale scores. Key knowledge and practice gaps were identified among stakeholders. Surveyed parents had favourable views of the fluoride varnish placement by medical professionals, and four out of five stated that they would recommend fluoride varnish for other children. Primary healthcare providers, commune council representatives and community health promoters supported oral health interventions being provided in CHCs. Conclusions: OHE and fluoride varnish interventions provided by non-dental primary health workers were feasible and acceptable for stakeholders in a Cambodian setting. The intervention group had lower ECC experience and better OHRQoL at 2 years of age.

IntroductionThe aim of the study was to analyse microbiological charac�teristics and clinical manifestations of cardiac device-related infective endo�carditis (CDRIE) in cardiac resynchronization therapy (CRT) recipients, and to compare the diagnostic value of modified Duke (MDC) versus modified Duke lead criteria (MDLC; including to MDC local infection and pulmonary infection or embolism as major criteria).Material and methodsThe study population comprised 765 consecutive CRT patients from a high-volume, tertiary care centre from 2002 to 2015. All patients were screened for CDRIE.ResultsDuring a median follow-up of 1692 days (range: 457–3067) 5.36% of patients (n = 41) developed CDRIE, which was accompanied by CRT pocket infection in 17.1% (n = 7) and recurrent pulmonary infection or pulmonary embolism in 29.3% (n = 12). Fever was present in 95.1% of patients (n = 39), whereas blood cultures were positive in 65.9% (n = 27). Staphylococcus was the most prevalent pathogen in 59.3% (n = 16), Gram-negative bacteria in 25.9% (n = 7). Transoesophageal echocardiography showed intracardiac veg�etations in 73.2% of patients (n = 30). Non-different pathogen types with the most common methicillin-sensitive Staphylococcus aureus were observed for early versus late CDRIE (endocarditis ≤ 6 vs. > 6 months from CRT or other de�vice-related procedure). All 3 inflammatory markers (C-reactive protein, white blood cells, procalcitonin) were normal in 4.9% of patients (n = 2). MDC versus MDLC indicated definite CDRIE in 48.8% versus 80.5%, respectively (p = 0.003).ConclusionsFever is the most common symptom of CRT-related CDRIE, and transoesophageal echocardiography allows vegetations to be visualised in nearly 3/4 of patients with CDRIE. Although the most common pathogens were Staphylococci, Gram-negative bacteria accounted for a quarter of CDRIE. Modified Duke lead criteria proved superior to MDC.

With rising antibiotic resistance, alternatives to carbapenems are needed for acute cholangitis (AC). Temocillin reaches high biliary concentrations with limited impact on microbiota. We retrospectively included 140 AC episodes and assessed the efficacy of temocillin using microbiology susceptibility testing from blood cultures. Considering all bacteria collected by episode, resistance to temocillin, PIP/TAZ and 3GC occurred in 27/140 (26%), 32 (22.8%) and 31 (22%) episodes, respectively (p = 0.7). After documentation, temocillin could have spared PIP/TAZ or carbapenems in 14/26 and 4/11 episodes. Temocillin may constitute an alternative treatment after microbiological documentation by sparing carbapenems and/or PIP/TAZ, but not as an empirical therapeutic option.

Background. The dynamic development and change of rural lifestyle patterns towards urban patterns has been noticeable since the second half of the 20th century. Nutrition, as well as the lifestyle in urban and rural areas, has undergone a process of urbanization, which is evidenced by the following an increasing number of overweight people. Objective. The aim of the study was to compare eating habits and frequency of consumption of selected groups of products between the urban and rural residents from the Subcarpathian voivodeship. Material and methods. The survey was carried out on a sample of 279 persons from urban and rural areas of Subcarpathian voivodeship. In this study, the diagnostic survey method consisting of 3 (different) parts was used. To check the significance of differences, U Mann-Whitney and Kruskal-Wallis tests were used; whereas correlations between variables were determined by the Spearman's rank of correlation coefficient and Pearson's chi-quadrat test. Results. In the part concerning eating habits, statistically significant differences occurred among others; for the circumstances of eating meals, the most commonly consumed snacks, food processing techniques and the most frequently selected fat. In the part concerning the frequency of consumption of individual product groups, significant differences occurred among others; for dairy products, grain products, fast food, alcohol. There was a correlation between the frequency of consumption of individual products and socioeconomic status. Conclusions. The quality of the diet and eating habits of urban and rural residents of Subcarpathian voivodeship does not differ significantly. The detected differences in eating habits were more influenced by the education and socioeconomic status of the examined group than the place of residence.

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial., Communications Biology, 3 (1), ISSN:2399-3642

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs, University of Colorado; Baylor College of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital of Pittsburgh; St Louis Children’s Hospital; Riley Hospital for Children; Seattle Children’s Hospital; M.D./Ph.D. Scholarship from the University of Groningen; European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Networking Grant 2019; ChilDReN National Institutes of Health Grants; Ann & Robert H. Lurie Children’s Hospital; Albireo and Mirum Pharmaceuticals

Resume Introduction En metropole, pres de 20 nouveaux cas de lepre sont diagnostiques chaque annee. L’incidence de la tuberculose en France est de 8/100 000 habitants et l’association des 2 mycobacteries a ete exceptionnellement rapportee. Nous rapportons un cas de co-infection lepre Borderline Tuberculoide (BT) et tuberculose disseminee, diagnostique en metropole. Observation Un homme presentait des plaques erythemateuses infiltrees hypoesthesiques diffuses. La biopsie montrait un granulome epithelioide lympho-histiocytaire peri-sudoral et peri-nerveux, avec des bacilles acido-alcoolo-resistants sur la coloration de Ziehl. La PCR Mycobacterium Leprae etait positive, confirmant le diagnostic de lepre, dans une forme BT. Le bilan d’extension revelait un epanchement pleural gauche a predominance lymphocytaire, une adenopathie hilaire droite a centre necrotique sans granulome histologique, une recherche de BK negative, un test quantiFERON-TB™ et une intra-dermo reaction a la tuberculine positifs. Le tableau clinique et radiologique etait en faveur d’une tuberculose disseminee. La quadritherapie anti-tuberculeuse (rifampicine, isoniazide, ethambutol et pyrazinamide) et la clofazimine permettaient une regression des lesions cutanees et extra-cutanees. Discussion Cette rare co-infection associe une lepre souvent lepromateuse evolutive depuis plusieurs annees et une tuberculose souvent pulmonaire d’apparition ulterieure. L’ hypothese physiopathologique est celle de l’immunite croisee (l’immunite anti-tuberculeuse protegeant contre une lepre ulterieure et inversement), etayee par la correlation inverse des deux prevalences et par la protection induite par la vaccination antituberculeuse. Dans la plupart des cas, le traitement antituberculeux et antilepreux permettent une amelioration des deux maladies. Un cas de lepre doit faire rechercher une tuberculose latente afin d’eviter une reactivation, a fortiori si une corticotherapie est associee.

Stereotactic biopsies of ventricular lesions may be less safe and less accurate than biopsies of superficial lesions. Accordingly, endoscopic biopsies have been increasingly used for these lesions. Except for pineal tumors, the literature lacks clear, reliable comparisons of these two methods. All 1581 adults undergoing brain tumor biopsy from 2007 to 2018 were retrospectively assessed. We selected 119 patients with intraventricular or paraventricular lesions considered suitable for both stereotactic and endoscopic biopsies. A total of 85 stereotactic and 38 endoscopic biopsies were performed. Extra procedures, including endoscopic third ventriculostomy and tumor cyst aspiration, were performed simultaneously in 5 stereotactic and 35 endoscopic cases. In 9 cases (5 stereotactic, 4 endoscopic), the biopsies were nondiagnostic (samples were nondiagnostic or the results differed from those obtained from the resected lesions). Three people died: 2 (1 stereotactic, 1 endoscopic) from delayed intraventricular bleeding and 1 (stereotactic) from brain edema. No permanent morbidity occurred. In 6 cases (all stereotactic), additional surgery was required for hydrocephalus within the first month postbiopsy. Rates of nondiagnostic biopsies, serious complications, and additional operations were not significantly different between groups. Mortality was higher after biopsy of lesions involving the ventricles, compared with intracranial lesions in any location (2.4% vs 0.3%, p = 0.016). Rates of nondiagnostic biopsies and complications were similar after endoscopic or stereotactic biopsies. Ventricular area biopsies were associated with higher mortality than biopsies in any brain area.

Aims and background Ophthalmic abnormalities are amongst the five major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudo-papilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report nine pediatric cases of ALGS with bilateral papilledema, five of which were diagnosed with ICHT. Methods The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation for other indications were also analyzed. Results Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all nine patients were normal. These nine patients were categorized into four groups: (1) a non-transplant group (n = 1), (2) a group with pretransplant papilledema persistent after liver transplantation (LT) (n = 2), (3) a group with papilledema occurring after LT with spontaneous resolution (n = 2), and (4) a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in two of the five cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT. Conclusions True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.

Aims The number of patients with heart failure (HF) and implantable cardiac electronic devices has been growing steadily. Remote monitoring care (RC) of cardiac implantable electronic devices can facilitate patient-healthcare clinical interactions and prompt preventive activities to improve HF outcomes. However, studies that have investigated the efficacy of remote monitoring have shown mixed findings, with better results for the system including daily verification of transmission. The purpose of the RESULT study was to analyse the impact of remote monitoring on clinical outcomes in HF patients with implantable cardioverter-defibrillator [ICD/cardiac resynchronization therapy-defibrillator (CRT-D)] in real-life conditions. Methods and results The RESULT is a prospective, single-centre, randomized trial. Patients with HF and de novo ICD or CRT-D implantation were randomized to undergo RC vs. in-office follow-ups (SC, standard care). The primary endpoint was a composite of all-cause death and hospitalization due to cardiovascular reasons within 12 months after randomization. We randomly assigned 600 eligible patients (299 in RC vs. 301 in SC). Baseline clinical and echocardiographic characteristics were well-balanced and similar in both arms. The incidence of the primary endpoint differed significantly between RC and SC and involved 39.5% and 48.5% of patients, respectively, (P = 0.048) within the 12-month follow-up. The rate of all-cause mortality was similar between the studied groups (6% vs. 6%, P = 0.9), whereas hospitalization rate due to cardiovascular reasons was higher in SC (37.1% vs. 45.5%, P = 0.045). Conclusion Remote monitoring of HF patients with implanted ICD or CRT-D significantly reduced the primary endpoint rate, mostly as a result of a lower hospitalization rate in the RC arm (ClinicalTrials.gov Identifier: NCT02409225).

Progressive familial intrahepatic cholestasis (PFIC) can cause intense pruritus that is refractory to medical therapy. Surgical biliary diversion techniques, including partial internal biliary diversion (PIBD), have been developed over the years to relieve pruritus without requiring liver transplantation. No clinical or genetic features can currently predict postoperative pruritus response. We present three PFIC type 2 (PIFC 2) patients who underwent transient endoscopic nasobiliary drainage (NBD) prior to PIBD surgery. Two patients repeatedly responded to NBD and presented with complete pruritus resolution after subsequent PIBD. NBD failed technically in the third patient, and PIBD was partially successful. Mild post-endoscopic biological pancreatitis occurred in 2/6 NBD procedures and resolved spontaneously. The only adverse effect observed within 7 years post-PIBD was very mild transient osmotic diarrhea.Conclusion: Our limited data suggest that NBD is a safe and effective way to predict pruritus response before performing permanent biliary diversion surgery in PFIC patients. What is Known: • Surgical biliary diversion techniques have been developed to relieve intractable pruritus in progressive familial intrahepatic cholestasis (PFIC). • No clinical or genetic features can currently predict pruritus response to surgery. What is New: • Our data suggest that nasobiliary drainage could be a safe and effective tool to predict pruritus response to biliary diversion and avoid unnecessary surgery in PFIC patients.

Reactivation of hepatitis B virus (HBV) is a known complication of immune-suppressive, cytotoxic, and biological modifier therapies in patients currently infected with HBV or who have had past exposure to HBV. Nowadays, newer and emerging forms of targeted biologic therapies are available for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions and solid-organ, bone marrow, or haematologic stem cell transplant but there is currently a lack of a systematic approach to the care of patients with or at risk of HBV reactivation. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) together with a working group of ESPGHAN members with clinical and research expertise in viral hepatitis developed an evidence-based position paper on reactivation of HBV infection in children identifying pertinent issues addressing the diagnosis, prevention, and treatment of this condition. Relevant clinical questions were formulated and agreed upon by all the members of the working group. Questions were answered and positions were based on evidence resulting from a systematic literature search on PubMed and Embase from their inception to July 1, 2019. A document was produced and the working group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. A recommendation was accepted provided upon agreement by at least 75% of the working group members. This position paper provides a comprehensive update on the diagnosis, prevention and treatment of HBV reactivation in children.

Introduction Implantable cardioverter-defibrillators (ICD) have a strong position in the prevention of sudden death. Nowadays, the most commonly used high-energy cardiac devices are transvenous ICDs. A new technology of totally subcutaneous ICDs (S-ICD) was invented and recently introduced into clinical practice in order to reduce lead-related complications of conventional ICDs. The aim of this paper is to present early experience with this new technology implemented in a few centres in Poland. Material and methods Medical records of patients who had S-ICD-related interventions in Poland were retrospectively analysed. Results During the first year of S-ICD introduction into the Polish health system 18 patients underwent surgery connected with S-ICDs. Majority of them (17 patients) were implanted de novo. In one patient surgical revision of a device implanted abroad was performed. Most of patients (78%) had S-ICDs implanted for secondary prevention. Inability of transvenous system implantation due to venous access obstruction or high risk of infection related with transvenous leads accounted for 83% of indications for S-ICD. Only in three patients were S-ICDs implanted due to young age and active mode of life. The implantations of S-ICDs were performed without important early or late complications. During follow-up one patient had episodes of ventricular arrhythmia successfully terminated with high-energy shocks. One patient died due to progression of heart failure. Conclusions S-ICD implantation procedure has been successfully and safely introduced in Polish clinical routine. Nevertheless, despite clear indications in recent ESC guidelines, this therapy is not directly reimbursed in Poland and needs individual application for refund.

CA extern - Weitere Nicht-UDE-Autoren sind nicht genannt. Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiology

vWFpp/ADAMTS13 ratio should be further studied as a useful marker for diagnosis of thrombotic microangiopathy postliver transplantation. Immunosuppressive regimen modification and plasma supplementation can lead to recovery.

We propose an algorithm to generate graphical summarising of longer text passages using a set of illustrative pictures (TIPS). TIPS is an algorithm using a voting process that uses results of individual “weak” algorithms. The proposed method includes a summarising algorithm that generates a digest of the input document. Each sentence of the text summary is used as the input for further processing by the sentence transformer separately. A sentence transformer performs text embedding and a group of CLIP similarity-based algorithms trained on different image embedding finds semantic distances between images in the illustration image database and the input text. A voting process extracts the most matching images to the text. The TIPS algorithm allows the integration of the best (highest scored) results of the different recommendation algorithms by diminishing the influence of images that are a disjointed part of the recommendations of the component algorithms. TIPS returns a set of illustrative images that describe each sentence of the text summary. Three human judges found that the use of TIPS resulted in an increase in matching highly relevant images to text, ranging from 5% to 8% and images relevant to text ranging from 3% to 7% compared to the approach based on single-embedding schema.

Background Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients’ clinical phenotypes and analyse the differential clinical course. Methods We performed a hierarchical cluster analysis based on Ward’s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients’ prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P < .001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27–3.62; HR 3.42, 95%CI 2.72–4.31; HR 2.79, 95%CI 2.32–3.35), and Cluster 1 (HR 1.88, 95%CI 1.48–2.38; HR 2.50, 95%CI 1.98–3.15; HR 2.09, 95%CI 1.74–2.51) reported a higher risk for the three outcomes respectively. Conclusions In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes.

Scant data exist on long-term outcomes, including death, in patients with complica-tions related to transvenous lead extractions (TLE).We sought to characterize the population and examine the outcomes including risk factors for in-hospital complications and 12-month mortality and morbidity related to the complications in a large administrative database of patients undergoing TLE.From the database of patients hospitalized for cardiovascular diseases and included in the Silesian Cardiovascular Database (SILCARD) registry, we selected the admissions of those who underwent TLE according to the appropriate ICD-9 codes. The patients were divided into two groups based on whether they did or did not manifest any complications during their hospitalization for the TLE procedure. Between 2007 and 2019, we found a total of 835 patients who underwent TLE. TLE-related complications occurred in 56 patients (6.7%) of the Complications-Yes group while no complications were recorded in 779 (93.3%) patients of the Complications-No group. A significant difference in the rate of all-cause mortality (23.9% vs. 6.5%; P0.001) and major adverse cardiac events (MACE) (58.7% vs. 39.4%; P = 0.01) between the Complications-Yes and Complications-No groups were recorded. Multivariable analysis of the entire study population revealed that prior dialysis, chronic kidney disease, and ventricular tachycardia were independent factors of a higher risk of TLE-related in-hospital complications. Multivariable analysis of the patients discharged from the hospital after the TLE procedure showed that TLE-related complications, a history of heart failure, and older age independently affected 12-month mortality.The presence of TLE-related in-hospital complications increased 12-month mortality.

Background Asymptomatic (“silent”) atrial fibrillation is common and associated with poor outcomes. It is important to determine the risk factors that predispose elderly individuals from the general population to atrial fibrillation (AF). However, population-based data for silent AF (SAF) are limited. Design First, to study the risk factors for symptomatic AF and SAF in an elderly (≥65 years) general population. Second, to develop a risk stratification model for predicting SAF. Methods Continuous ECG monitoring was performed for up to 30 days using a vest-based system in a cohort from NOMED-AF, a cross-sectional study based on a nationwide population sample. The independent risk factors for AF and SAF were determined using multiple logistic regression. ROC analysis was applied to validate developed risk stratification score. Results From the total cohort of 3014 subjects, AF was diagnosed in 680 individuals (mean age, 77.5±7.9; 50.1% men) with AF, and of these, 279 (41%) had SAF. Independent associations with an increased risk of AF were age, male gender, coronary heart disease, thyroid diseases, prior ischemic stroke or transient ischemic attack (ICS/TIA), diabetes, heart failure, chronic kidney disease (CKD), obesity (BMI>30) and NT-proBNP >125 ng/ml. Prior revascularization was negatively associated with risk of AF. The main risk factors for SAF were age, male gender, prior ICS/TIA, diabetes, heart failure, CKD and NT-proBNP >125 ng/ml. We developed a simple clinical risk scale (MR-DASH score) which had good prediction in the derivation cohort (AUC 0.726) and the validation cohort (AUC 0.730). Conclusions SAF is associated with various clinical risk factors in a population sample of individuals ≥65 years. Stratifying individuals from the general population according to their risk for SAF may be possible using the MR-DASH score, facilitating targeted screening programs of individuals with high risk of SAF Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Centre for Research and Development

Background Cardiac resynchronization therapy (CRT) is an effective method of treatment in patients with HF, but as complex device with three electrodes, it is prone to electrode dysfunctions and the need to replace them. However little is known about the frequency of need for leads replacement in subjects undergone CRT in a very long-term follow up. Aim To determine the frequency of leads replacement in patients undergoing CRT during long term follow-up. Methods Study population consisted of 1059 consecutive patients with CRT implanted between 2002 and 2019 in tertiary care university hospital, in a densely inhabited, urban region of Poland. The data about lead replacement was collected. Results During the median follow-up of 1661 days (IQR: 815–2792) for non-infectious reasons (dislocation, dysfunction, fracture etc.) a total of 324 leads in 251 patients (23.7%) were replaced. Median time from CRT implantation to the first lead replacement was 359 days (42–1413). The electrode replacement within first year after CRT implantation was performed in 126 subjects (50.2%), in the rest of patients (49.8%) the leads were replaced after one year of device implantation. In patients with above ten years of follow up (n=143; 13.5%) 67 subjects (46.8%) had one or more lead replacement during follow up. Patients with electrode replacement during follow-up were younger (63 vs 66 years, P Conclusions The need for leads replacement due to non-infectious reasons reaches almost 25% of patients with CRT within 4.5 years. Half of the patients have lead replacement within one year after CRT implantation and the other half during long term follow up. The duration of the first procedure (CRT device implantation) is strong predictor of lead replacement during follow up. Funding Acknowledgement Type of funding sources: None.

Background Advanced heart failure with reduced ejection fraction (HFrEF) is associated with poor prognosis. Cardiac resynchronization therapy (CRT) is an effective method of treatment for advanced HFrEF to reduce HF hospitalizations and mortality. Nonetheless, very long-term observation of HF patients undergoing CRT implantation is scarce. Aim To assess very long-term survival (≥10 years) and predictors of shorter survival (death within 10 years from CRT implantation). Methods We screened a large dataset of CRT population from a tertiary care university hospital comprising consecutive HF patients implanted with CRT from 2002 through 2019 to select those who were alive ≥10 years and those who died within 10 years since device implantation. We analyzed various patients' baseline, clinical and procedural characteristics and sought for predictors of mortality within 10 years from CRT implantation. Results Of 1059 CRT patients, 143 (13.5%) were alive ≥10 years since CRT implantation. On multivariable regression analysis the independent predictors for all-cause death up to 10 years from CRT implantation were as follows: age, HR 1.02, 95% CI 1.01–1.31; male sex, 1.27, 95% CI 1.01–1.60; primary prevention of sudden cardiac death (SCD), HR 0.72, 95% CI 0.58–0.89; ischemic cardiomyopathy, HR 1.41, 95% CI 1.76–1.70; NYHA class at implantation, HR 1.38, 95% CI 1.17–1.62; baseline left ventricle ejection fraction (EF), HR 0.97, 95% CI 0.96–0.98; severe mitral regurgitation, HR 1.38; 95% CI 1.08–1.75; baseline NT-proBNP concentration, HR 1.00, 95% CI 1.00–1.00; and creatinine level, HR 1.00, 95% CI 1.00–1.01. Conclusions In a real-life patient population with CRT only 13.5% survived over 10 years since device implantation. Independent predictors for death within 10 years since CRT implantation were older age, male sex, secondary prevention of SCD, ischemic and more advanced heart failure along with renal impairment. Funding Acknowledgement Type of funding sources: None.

Background In prior unblinded studies, cardiac neuromodulation therapy (CNT) employing a sequence of variably timed short and longer atrioventricular intervals yielded sustained reductions of systolic blood pressure (SBP) in patients with hypertension. The effects of CNT on SBP were investigated in this double‐blind randomized pilot study. Methods and Results Eligible patients had daytime ambulatory SBP (aSBP) ≥130 mm Hg and office SBP ≥140 mm Hg despite taking ≥1 antihypertensive medication, and an indication for a dual‐chamber pacemaker. Patients underwent Moderato device implantation, which was programmed as a standard pacemaker during a 1‐month run‐in phase. Patients whose daytime aSBP was ≥125 mm Hg at the end of this period were randomized (1:1, double blind) to treatment (CNT) or control (CNT inactive). The primary efficacy end point was the between‐group difference of the change in 24‐hour aSBP at 6 months. Of 68 patients initially enrolled and who underwent implantation with the Moderato system, 47 met criteria for study continuation and were randomized (26 treatment, 21 control). The mean age was 74.0±8.7 years, 64% were men, left ventricular ejection fraction was 59.2%±5.7%, and aSBP averaged 141.0±10.8 mm Hg despite the use of 3.3±1.5 antihypertensive medications; 81% had isolated systolic hypertension. Six months after randomization, aSBP was 11.1±10.5 mm Hg (95% CI, −15.2 to −8.1 mm Hg) lower than prerandomization in the treatment group compared with 3.1±9.5 mm Hg (−7.4 to 1.2 mm Hg) lower in controls, yielding a net treatment effect of 8.1±10.1 mm Hg (−14.2 to −1.9 mm Hg) ( P =0.012). There were no Moderato device– or CNT‐related adverse events. Conclusions CNT significantly reduced 24‐hour aSBP in patients with hypertension with a clinical indication for a pacemaker. The majority of patients had isolated systolic hypertension, a particularly difficult group of patients to treat. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02837445.

Background & Aims: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). Methods: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. Results: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. Conclusions: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy. Clinical Trials Registration: EudraCT 2016-001177-32. Lay summary: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Thoracic aortic diseases contribute to a major part of cardiac surgeries. The severity of pathologies varies significantly from emergency and life-threatening to conservatively managed conditions. Life-threatening conditions include type A aortic dissection and rupture. Aortic aneurysm is an example of a conservatively managed condition. Pathologies that affect the arterial wall can have a profound impact on the presentation of such cases. Several risk factors have been identified that increase the risk of emergency presentations such as connective tissue disease, hypertension, and vasculitis. The understanding of aortic pathologies is essential to improve management and clinical outcomes.

Introduction: Surgical treatment of biliary atresia (BA) is still based on sequential strategy with Kasai hepatoportoenterostomy (KP) followed by liver transplantation (LT), in case of complicated secondary biliary cirrhosis. Concerns have been expressed regarding the risks of LT related to previous KP, suggesting primary LT as an exclusive treatment of BA.Methods: Single-center retrospective analysis including 393 pediatric patients who underwent LT for BA from 1993 to 2018, categorized into two groups: with (KP) or without (NoKP) previous KP. Pre-LT clinical condition was estimated considering age at LT, time on waiting list, pediatric end-stage liver disease score (PELD), and presence of portal vein hypoplasia. Post-LT outcome was evaluated considering patient and graft survival rates, and need for early reoperation due to abdominal or graft-related complications (Results: Two-hundred ninety-six patients (75.3%) were categorized in the KP group, and 97 (24.7%) in the NoKP group. Median age at LT was 1.14 years in the KP group and 0.85 years in the NoKP group (p < 0.0001). PELD score was significantly less severe in KP patients (p < 0.05). One-year patient survival rates were 96.9 and 96.8% in the KP and NoKP groups, respectively (p = 0.43), and the corresponding graft survival was 92.5 and 94.8% (p = 0.97). The need for early reoperation was more frequent in the KP group (29.8%) vs. NoKP group (12.4%, p = 0.01). The rate of bowel perforation was non-significantly higher in the KP group (8.1%) vs. NoKP group (3.1%, p = 0.11).Conclusions: The sequential strategy including KP and LT allowed performing LT in patients with significant older age and better clinical conditions, when compared to those transplanted without previous KP. Patient and graft survivals were not impacted by previous KP. Although previous KP was associated with an increased rate of post-LT surgical complications, bowel perforation and bleeding did not occur significantly more frequently. Such results support the current strategy based on sequential treatment.

Background: Low pH is an important factor facilitating entry of enveloped viruses including coronaviruses and further fusion with the host epithelial cell membrane. pH in the pulmonary environment can be maintained by supplying a negative electric charge. The main objective was to check if earthing (direct or indirect connection to Earth) changes the pH of the respiratory tract.Methods: Nine participants were evaluated and pH measurements were taken on the mucous membrane of the throat before and after 15 minutes of earthing.Results: Mean pH before earthing was 5.83±0.43 and after earthing was 6.33± 0.43 (p=0.000323). Conclusions: Earthing is able to supply a negative charge resulting in alkalization of the pulmonary environment. The increased pH value in the respiratory tract reduces the pH-dependent entry of coronaviruses into epithelial cells. Earthing can have an impact on the course of respiratory tract infection both viral and bacterial decreasing the susceptibility of the development of fatal forms of SARS (Severe Acute Respiratory Syndrome).

The burden of paediatric HCV infection across Europe is unknown, as are current policies regarding monitoring and treatment. This collaborative study aimed to collect aggregate data to characterise the population of ≤18-year olds with HCV infection in specialist follow up in a twelve-month period (2016) across the PENTAHep European consortium, and investigate current policies around monitoring and treatment. A cross-sectional, web-based survey was distributed in April 2017 to 50 paediatricians in 19 European countries, covering patients' profile, and monitoring and treatment practices. Responses were received from 38/50 clinicians collectively caring for 663 children with chronic HCV infection of whom three-quarters were aged ≥6 years and 90% vertically-infected. HCV genotype 1 was the most common (n 380; 57.3%), followed by genotype 3, 4 and 2. Seventeen children (3%) with chronic HCV infection were diagnosed with cirrhosis and 6 were reported to have received liver transplantation for HCV-related liver disease. The majority (n 425; 64.1%) of the European children with HCV infection remained treatment-naive in 2016. Age affected clinicians' attitudes towards treatment; 94% reported being willing to use direct-acting antivirals, if available, in adolescents (aged ≥11 years), 78% in children aged 6-10 and 42% in those 3 to 5 years of age (Pearson correlation coefficient -0.98; p 0.0001). This survey provides the largest characterisation of the population of children in clinical follow-up for chronic HCV infection in Europe, alongside important contextual information on their management and treatment. Discussion is needed around strategies and criteria for use of direct-acting antivirals in these children. This article is protected by copyright. All rights reserved

The major therapeutic goal for immune thrombocytopenia (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. 80% of patients possess anti-integrin αIIbβ3 (GPIIbIIIa) IgG autoantibodies causing platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in ~50% of patients to recover a normal platelet count after anti-CD20 Rituximab-mediated B cell depletion and splenectomy suggest that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SC) reside in other anatomical compartments. We analyzed >3,300 single IgG-SC from spleen, bone marrow and/or blood of 27 patients with ITP revealing high inter-individual variability in affinity for GPIIbIIIa with variations over 3 logs. IgG-SC dissemination and range of affinities were however similar per patient. Longitudinal analysis of autoreactive IgG-SC upon treatment with anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-GPIIbIIIa IgG-SC in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.

ObjectivesTo investigate changes in daily mental health (MH) service use and mortality in response to the introduction and the lifting of the COVID-19 ‘lockdown’ policy in Spring 2020.DesignA regression discontinuity in time (RDiT) analysis of daily service-level activity.Setting and participantsMental healthcare data were extracted from 10 UK providers.Outcome measuresDaily (weekly for one site) deaths from all causes, referrals and discharges, inpatient care (admissions, discharges, caseloads) and community services (face-to-face (f2f)/non-f2f contacts, caseloads): Adult, older adult and child/adolescent mental health; early intervention in psychosis; home treatment teams and liaison/Accident and Emergency (A&E). Data were extracted from 1 Jan 2019 to 31 May 2020 for all sites, supplemented to 31 July 2020 for four sites. Changes around the commencement and lifting of COVID-19 ‘lockdown’ policy (23 March and 10 May, respectively) were estimated using a RDiT design with a difference-in-difference approach generating incidence rate ratios (IRRs), meta-analysed across sites.ResultsPooled estimates for the lockdown transition showed increased daily deaths (IRR 2.31, 95% CI 1.86 to 2.87), reduced referrals (IRR 0.62, 95% CI 0.55 to 0.70) and reduced inpatient admissions (IRR 0.75, 95% CI 0.67 to 0.83) and caseloads (IRR 0.85, 95% CI 0.79 to 0.91) compared with the pre lockdown period. All community services saw shifts from f2f to non-f2f contacts, but varied in caseload changes. Lift of lockdown was associated with reduced deaths (IRR 0.42, 95% CI 0.27 to 0.66), increased referrals (IRR 1.36, 95% CI 1.15 to 1.60) and increased inpatient admissions (IRR 1.21, 95% CI 1.04 to 1.42) and caseloads (IRR 1.06, 95% CI 1.00 to 1.12) compared with the lockdown period. Site-wide activity, inpatient care and community services did not return to pre lockdown levels after lift of lockdown, while number of deaths did. Between-site heterogeneity most often indicated variation in size rather than direction of effect.ConclusionsMH service delivery underwent sizeable changes during the first national lockdown, with as-yet unknown and unevaluated consequences.

Background Living donor liver transplantation is a treatment option for unresectable hepatic tumors in children. Methods We enrolled 45 living donor transplantations performed between 1993 and 2018 for liver malignacies, which included hepatoblastoma (n = 33), hepatocellular carcinoma (n = 10), hepatic angiosarcoma (n = 1), and rhabdomyosarcoma (n = 1). Results No mortality or major morbidities were encountered in any donor, and the complication rate was 9%. In the hepatoblastoma group, 5-year overall and event-free survival rate in recipients was 87.4% and 75.8%, respectively, and mortality was significantly higher in patients after rescue transplantation (p = .001). Inferior vena cava replacement in these recipients appeared to be associated with reduced mortality (p = .034), but this was not confirmed when rescue patients were excluded (p = .629). In hepatocellular carcinoma group, both 5-year overall and event-free survival rates were 75.4% each, and invasion of hepatic veins was significantly associated with increased risk of recurrence and death (p = .028). The patient with rhabdomyosarcoma died from EBV-induced lymphoma 2 months after transplantation. The patient with angiosarcoma was in complete remission at the last follow-up. Overall, 5-year graft survival rate was 81.3%, and one patient underwent re-transplantation due to chronic rejection. Conclusions Pediatric oncological liver transplantation has become a key player in the management of malignancies with cancer cure in 84% of patients in this series. Living donor liver transplantation for pediatric recipients with unresectable tumors might be a beneficial surgical option, which is technically safe for donors and recipients, thus, allowing timely planning according to chemotherapy protocols.

Significance Bioelectronic modulation of the autonomic nervous system innervating the spleen represents a new therapeutic avenue. Studies in rodents suffer from the limitation that stimulation parameters and anatomy are not directly applicable to humans. This work demonstrates the translation of biological mechanisms in a large animal model with similar anatomical, histological, and functional characteristics for derivation of human-relevant parameters. Here, we show the scientific process for translating a bioelectronic medicine to clinical readiness. The results presented can be used in three ways: 1) as a system to demonstrate the species translation of neuroimmune modulation, 2) as an exemplar of how translational models can reveal additional potential mechanisms, and 3) as a general methodology to determine human-relevant stimulation parameters., Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve–induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

Background: Silent atrial fibrillation (SAF) is common and is associated with poor outcomes. Aims: to study the risk factors for AF and SAF in the elderly (≥65 years) general population and to develop a risk stratification model for predicting SAF. Methods: Continuous ECG monitoring was performed for up to 30 days using a vest-based system in a cohort from NOMED-AF, a cross-sectional study based on a nationwide population sample. The independent risk factors for AF and SAF were determined using multiple logistic regression. ROC analysis was applied to validate the developed risk stratification score. Results: From the total cohort of 3014 subjects, AF was diagnosed in 680 individuals (mean age, 77.5 ± 7.9, 50.1% men) with AF, and, of these, 41% had SAF. Independent associations with an increased risk of AF were age, male gender, coronary heart disease, thyroid diseases, prior ischemic stroke or transient ischemic attack (ICS/TIA), diabetes, heart failure, chronic kidney disease (CKD), obesity, and NT-proBNP &gt, 125 ng/mL. The risk factors for SAF were age, male gender, ICS/TIA, diabetes, heart failure, CKD, and NT-proBNP &gt, 125 ng/mL. We developed a clinical risk scale (MR-DASH score) that achieved a good level of prediction in the derivation cohort (AUC 0.726) and the validation cohort (AUC 0.730). Conclusions: SAF is associated with various clinical risk factors in a population sample of individuals ≥65 years. Stratifying individuals from the general population according to their risk for SAF may be possible using the MR-DASH score, facilitating targeted screening programs of individuals with a high risk of SAF.

Background: Multipurpose prevention technologies are needed to provide protection against HIV and sexually transmitted infections. Gel-based vaginal microbicides inserted via an applicator are prone to leakage. A novel device for vaginal drug delivery was developed to contain gel-based formulations, aiming to improve gel retention and reduce leakage. The objectives of this study were to assess acceptability and performance of a nonwoven vaginal delivery device. Methods: A nonwoven vaginal delivery device was prepared, pre-saturated with a commercially available water-based lubricant, with a finger pocket for insertion and string for removal. Quantitative and qualitative methods were used to collect data from interviews with 40 women and 10 male partners recruited from a sexual and reproductive health clinic in Durban, KwaZulu-Natal, South Africa. Women wore one device in the clinic and one device overnight or with their partner during intercourse. The primary endpoint was acceptability including comfort, ease of insertion and removal, and opinions on device attributes. Results: Most women said the device was ‘easy’ to insert and remove. Six women reported leakage after insertion and 34 reported having sexual intercourse while wearing the device. One woman was lost-to-follow-up and five women only wore the device overnight because their partners did not agree to intercourse with the inserted device. The best-liked attribute was the device’s lubrication (22 women, 7 men); the least-liked was the removal string (9 women, 8 men). Conclusions: Data are promising for further development of this nonwoven device for vaginal drug delivery. Plain English summary Multipurpose prevention technologies (MPTs) that protect against HIV and sexually transmitted infections (STIs) are urgently needed. A variety of vaginal gel-based products are actively being researched; however, these products can often have challenges with vaginal leakage and retention. This research investigates the acceptability and performance of a nonwoven device to deliver vaginal gel formulations. The gel used in this study was a currently available marketed personal lubricant. In South Africa, 40 women (and 10 male partners) were recruited and given the opportunity to comment on various device attributes after insertion, overnight wear and sexual intercourse with their male partners. Generally, participants found the device easy to use and acceptable, where many factors possibly contributed to the device’s acceptability (i.e., similarity to tampons, saturation with lubricant, minimal leakage, ease of insertion, comfort during intercourse and the male partners’ willingness to have vaginal intercourse with the device in place). Further studies of the vaginal delivery device for acceptability, safety and efficacy using a gel-based formulation with an active ingredient are warranted.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naive or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.

Posterior urethral valve (PUV) is the most common congenital cause of bladder outflow obstruction in male neonates. We report a preterm neonate with PUV who presented as nonimmune fetal hydrops with intestinal obstruction in the antenatal period. The mother of our patient is a 33-year-old woman who started her prenatal care at our hospital at 30 weeks' gestation. Her sonogram done at 32 weeks in our hospital revealed fetal hydrops. It showed polyhydramnios, mild pyelectasis of right kidney, normal left kidney, and fetal ascites. Amniocentesis revealed bile stained amniotic fluid. Ultrasound during the procedure showed dilated fetal bowel loops with increased echoes. Following delivery at 32 weeks postnatal exam showed ascites with absence of skin edema, pleural, or pericardial effusion. The abdominal sonogram showed distended urinary bladder and bilateral hydroureteronephrosis. Bladder catheterization was done which relieved the bladder outlet obstruction. Voiding cystourethrogram was done later which confirmed PUV and bilateral grade 5 vesicoureteral reflux. The formation of urinary ascites in PUV serves as a pop-off mechanism to relieve the intravesical and intrarenal pressure. When this happens by mechanisms other than bladder rupture, it can lead on to transient intestinal obstruction and hepatic synthetic defects.

Background: Motor cortex stimulation (MCS) is an intracranial, invasive method for treatment of chronic pain. Main indications for MCS are central post stroke pain, neuropathic facial pain, phantom limb pain and brachial plexus or spinal cord injury pain. Spinal cord stimulation (SCS) with burst waveform has been proved to be more effective than tonic mode in chronic pain. Necessity to replace depleted batteries of motor cortex tonic stimulators gave us an opportunity of applying burst stimulation. The objective of the pilot study was to evaluate the effects of burst stimulation applied on motor cortex in patients with chronic pain syndromes as well as comparison to tonic mode. Materials and methods: We have evaluated 6 patients (females N=3, males N=3) belonging to the group of 14 cases (females N=5, males N=9) who had undergone surgical procedure of MCS in years 2005-2017. Selected for the study were 6 patients with thalamic pain N=3, with facial pain N=3 (anaesthesia dolorosa and neuropathic trigeminal neuralgia). The patients were subjected to both modes of stimulation then they chose which one was better in relieving pain: tonic or burst. Pain intensity was assessed with the visual analogue scale (VAS) before the replacement of implanted pulse generator (IPG) and after the stimulation with tonic and burst modes. Results: In the study, 5 out of 6 patients with MCS found burst mode more effective than tonic mode. Baseline VAS score in patients that had at least 3 months depleted battery of tonic IPG was 95 mm. After implantation of a new IPG mean VAS score on tonic stimulation was 72 mm, on burst 53 mm. Conclusions: The most preferred option of MCS in selected group of patients was burst stimulation. This study has shown, that the burst stimulation of cerebral cortex is a promising modality when tonic stimulation is not sufficient in refractory, neuropathic pain.

Atrial lead implantation commonly constitutes a technical problem, especially in patients with improper structure of the right atrium. The atrial lead displacement requires reimplantation, what creates a risk of infection and periprocedural complications, particularly in patients with the heart failure. To minimise the risk of complications, it is essential to asses potential difficulties before the procedure. The article concerns the patient with many burdens (right and left ventricular systolic dysfunction, tricuspid valve regurgitation, paroxysmal atrial fibrillation and atrial flutter, catheter ablation of both types of the arrhythmias, CRT device implantation), who was repeatedly hospitalized due to atrial lead displacement and who underwent implantation of Medtronic SelectSecure 3830 lead, what finally provided to stable placement of the lead in the right atrium.