Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer.

The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.

Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review.

This systematic review was performed to understand better the myriad presentations, various therapeutic options, response to therapy, and its clinical outcomes in hyperphosphatemic tumoral calcinosis (HTC). Full texts were selected according to strict inclusion criteria. All case reports of HTC wherein baseline phosphate was measured, treatment offered was mentioned, and information on follow-up and response to therapy that were available were included. A total of 43 of 188 eligible studies (N = 63 patients) met the inclusion criteria. A list of desired data was extracted and graded for methodological quality. A total of 63 individuals (Males = 33) were included from the 43 eligible case studies. The median age of the patients was 18 (IQR 8-32) years. The most frequently involved sites were the hip/gluteal region (34/63; 53.9%) followed by the elbow/forearm (26/63; 41.2%), and the shoulder (18/63; 28.5%). Three patients had conjunctival calcific deposits. The mean (SD) phosphate was 6.9 (1.1) mg/dL. Among the subjects, 36/63 (57.1%) underwent surgical excision with some form of medical therapy. Two patients underwent only surgical excision (2.1%). One patient was maintained on follow-up (1.6%) and 24/63 (38.1%) patients were treated with medical measures. The median (IQR) follow-up duration was 3 (1-9) years. Regression or reduction in lesion size was reported in 19/63 (30.2%) subjects; 20/63 (31.7%) showed progression, 24/63 (38.1%) had features of stable disease, and mortality was reported in 3 patients (4.7%). We report for the first time a detailed description of the clinical and therapeutic response of HTC. A combination of medical measures aimed at lowering serum phosphate appears to be the cornerstone of treatment, although clinical responses may vary.

Predictors of Delayed Hyponatraemia After Surgery for Pituitary Tumour.

Delayed hyponatraemia(DH) is a common complication following trans-sphenoidal surgery(TSS) for pituitary tumour. We evaluated the prevalence of DH following TSS, and assessed the factors associated with DH, including early post-operative diabetes insipidus(EPDI). This retrospective study included 100 TSS for pituitary tumours in 98 patients, over a period of 26 months. Subjects were divided into two groups: those who developed hyponatraemia and those who did not develop hyponatraemia, during post-operative days 4 to 14. The clinical characteristics and peri-operative parameters were compared between the two groups, to identify factors predicting DH. The mean age of the patients was 42.0±13.6 years, 58 (59%) were females and 61 (61%) had functional tumours. Thirty-six patients(36%) developed DH following TSS of whom majority(58%) were diagnosed on post-operative days 7 and 8; only 8/36 (22%) were symptomatic. Syndrome of inappropriate antidiuretic hormone secretion(SIADH) was found to be the most common aetiology of DH. On logistic regression analysis, intra-operative cerebrospinal fluid(CSF) leak (OR 5.0; 95% CI 1.9-13.8; p=0.002), EPDI (OR 3.4; 95% CI 1.3-9.2; p=0.015) and peri-operative steroid use (OR 3.6; 95% CI 1.3-9.8; p=0.014) were found to be significantly associated with DH. In conclusion, EPDI, intra-operative CSF leak and peri-operative steroid use were significant predictors of DH. EPDI predicts moderate to severe hyponatraemia with 80% specificity but has low sensitivity(47%). As most patients have asymptomatic hyponatraemia, serum sodium measurement on POD 7 to 10 would be helpful to identify DH in patients at increased risk.

Advancing the science of management of arrhythmic disease in children and adult congenital heart disease patients within the last 25 years.

This review article reflects how publications in EP Europace have contributed to advancing the science of management of arrhythmic disease in children and adult patients with congenital heart disease within the last 25 years. A special focus is directed to congenital atrioventricular (AV) block, the use of pacemakers, cardiac resynchronization therapy devices, and implantable cardioverter defibrillators in the young with and without congenital heart disease, Wolff-Parkinson-White syndrome, mapping and ablation technology, and understanding of cardiac genomics to untangle arrhythmic sudden death in the young.

Leadless epicardial pacing at the left ventricular apex: an animal study.

AIMS: State-of-the-art pacemaker implantation technique in infants and small children consists of pace/sense electrodes attached to the epicardium and a pulse generator in the abdominal wall with a significant rate of dysfunction during growth, mostly attributable to lead failure. In order to overcome lead-related problems, feasibility of epicardial implantation of a leadless pacemaker at the left ventricular apex in a growing animal model was studied. METHODS AND RESULTS: Ten lambs (median body weight 26.8 kg) underwent epicardial implantation of a Micra transcatheter pacing system (TPS) pacemaker (Medtronic Inc., Minneapolis, USA). Using a subxyphoid access, the Micra was introduced through a short, thick-walled tube to increase tissue contact and to prevent tilting from the epicardial surface. The Micra's proprietary delivery system was firmly pressed against the heart, while the Micra was pushed forward out of the sheath allowing the tines to stick into the left ventricular apical epimyocardium. Pacemakers were programmed to VVI 30/min mode. Pacemaker function and integrity was followed for 4 months after implantation. After implantation, median intrinsic R-wave amplitude was 5 mV [interquartile range (IQR) 2.8-7.5], and median pacing impedance was 2235 Ω (IQR 1725-2500), while the median pacing threshold was 2.13 V (IQR 1.25-2.9) at 0.24 ms. During follow-up, 6/10 animals had a significant increase in pacing threshold with loss of capture at maximum output at 0.24 ms in 2/10 animals. After 4 months, median R-wave amplitude had dropped to 2.25 mV (IQR 1.2-3.6), median pacing impedance had decreased to 595 Ω (IQR 575-645), and median pacing threshold had increased to 3.3 V (IQR 1.8-4.5) at 0.24 ms. Explantation of one device revealed deep penetration of the Micra device into the myocardium. CONCLUSION: Short-term results after epicardial implantation of the Micra TPS at the left ventricular apex in lambs were satisfying. During mid-term follow-up, however, pacing thresholds increased, resulting in loss of capture in 2/10 animals. Penetration of one device into the myocardium was of concern. The concept of epicardial leadless pacing seems very attractive, and the current shape of the Micra TPS makes the device unsuitable for epicardial placement in growing organisms.

Associations Between Cardiovascular Risk Factors and Audiometric Hearing: Findings From the Canadian Longitudinal Study on Aging.

OBJECTIVES: The objectives of the study were to determine, among a population-based sample of Canadian adults, if risk factors for cardiovascular disease (alone and in combination) were associated with hearing loss. Cross-sectional and longitudinal associations (the latter with about 3 years of follow-up) were examined. Risk factors considered included diabetes, dyslipidemia, hypertension, obesity, and smoking. We also aimed to determine if associations were modified by sex and age group (45 to 54, 55 to 64, 65 to 74, and 75 to 86 years old at baseline). DESIGN: A secondary analysis of data collected for the Canadian Longitudinal Study on Aging was performed. Data were collected in two waves, the first between 2012 and 2015, and the second between 2015 and 2018. Hearing was measured using screening air-conduction pure-tone audiometry. The outcome of interest was defined as the mid-frequency (1000, 2000, 3000, and 4000 Hz) pure-tone average for both ears. Diabetes was defined based on self-reported physician diagnosis, use of diabetes medications, or a hemoglobin A1c level ≥6.5%. Dyslipidemia was determined by blood lipid profile as defined using the Canadian guidelines for the diagnosis and treatment of dyslipidemia (low-density lipoprotein cholesterol ≥3.5 mmol/L or non-high-density lipoprotein cholesterol ≥4.3 mmol/L). Hypertension was determined by self-reported physician diagnosis or an average systolic blood pressure ≥140 mm Hg or an average diastolic blood pressure ≥90 mm Hg. Obesity was defined as a waist-to-height ratio ≥0.6. Smoking history was determined by self-report (current/former/never-smoker). Two composite measures of cardiovascular risk were also constructed: a count of the number of risk factors and a general cardiovascular risk profile (Framingham) score. Independent associations between risk factors for cardiovascular disease and hearing were determined using multivariable regression models. Survey weights were incorporated into the analyses. All results were disaggregated by sex. Effect modification according to age was determined using multiplicative interaction terms between the age group and each of the risk factor variables. A complete case (listwise deletion) approach was performed for the primary analysis. We then repeated the multivariable regression analyses using multiple imputation using chained equations to determine if the different approaches to dealing with missing data qualitatively changed the outcomes. RESULTS: In longitudinal analyses, hypertension and the general cardiovascular risk profile score were associated with greater loss of hearing over the 3-year follow-up period for both sexes. In addition, smoking in males and obesity in females were associated with faster rates of hearing decline. In cross-sectional analyses, smoking, obesity, diabetes, and composite measures were each independently associated with worse hearing for both sexes (although for females, obesity was only associated with hearing loss in the 55 to 64-year-old age group). The results were similar for the complete case and multiple imputation approaches, but more cross-sectional associations were observed using multiple imputation. CONCLUSIONS: Diabetes, obesity, hypertension, and smoking were associated with hearing loss. Higher combinations of risk factors increased the risk of hearing loss. Further studies are needed to confirm age and sex differences and whether interventions to address these risk factors could slow the progression of hearing loss in older adults.

Leitlinie Myokarditis der Deutschen Gesellschaft für Pädiatrische Kardiologie.

This consensus statement presents updated recommendations on diagnosis and treatment of myocarditis in childhood.

Fate After the Mustard Procedure for d-Transposition of the Great Arteries: Impact of Age, Complexity, and Atrial Tachyarrhythmias: A Single Center Experience.

Patients with dextro transposition of the great arteries (d-TGA) after atrial switch procedure are at risk to develop heart failure and arrhythmias during long-term follow-up. The present study aims to add knowledge on the fate of subjects after Mustard procedure during long-term follow-up into adulthood. A single center, retrospective chart review analysis was conducted. All subjects who had Mustard-type atrial switch procedure between 1969 and 1994 at our institution were included. A total of 92 subjects were included. Early postoperative death was reported in 2 subjects. Long-term follow-up was available in 49 survivors. Of those, 6 individuals died during further follow-up. Sudden cardiac death was the most prevalent cause for fatal outcome. Mortality during long-term follow-up was associated with the presence of additional cardiovascular malformations (complex d-TGA). Sinus node dysfunction was observed in 65% of the patients and atrial tachyarrhythmias were common in adult survivors (63%). Implantation of a pacemaker or a cardioverter defibrillator was required in 31% and 45% of those surviving into adulthood. Complications were frequently observed during follow-up after either pacemaker or cardioverter defibrillator implantation (43%) with lead failure being the most frequent complication. The aging population of patients after Mustard procedure is facing challenging problems mainly resulting from a failing systemic right ventricle, presence of associated cardiac malformations and the presence of atrial baffles associated with relevant atrial scars. Age, associated cardiac malformations, and atrial tachyarrhythmias seem to play a major role in determining the fate of patients with d-TGA after atrial switch procedures.

Enhanced bone tissue regeneration with hydrogel-based scaffolds by embedding parathyroid hormone in mesoporous bioactive glass.

OBJECTIVES: To evaluate hydrogel-based scaffolds embedded with parathyroid hormone (PTH)-loaded mesoporous bioactive glass (MBG) on the enhancement of bone tissue regeneration in vitro. MATERIALS AND METHODS: MBG was produced via sol-gel technique followed by PTH solution imbibition. PTH-loaded MBG was blended into the hydrogels and submitted to a lyophilisation process associated with a chemical crosslinking reaction to the production of the scaffolds. Characterisation of the MBG and PTH-loaded MBG scaffolds, including the scanning electron microscope (SEM) connected with an X-ray detector (EDX), Fourier transform infrared (FTIR), compression strength, rheological measurements, swelling and degradation rates, and PTH release analysis, were performed. Also, bioactivity using simulated-body fluid (SBF), biocompatibility (MTT), and osteogenic differentiation analyses (von Kossa and Alizarin Red stainings, and µ-computed tomography, µCT) of the scaffolds were carried out. RESULTS: SEM images demonstrated MBG particles dispersed into the hydrogel-based scaffold structure, which was homogeneously porous and well interconnected. EDX and FTIR revealed large amounts of carbon, oxygen, sodium, and silica in the scaffold composition. Bioactivity experiments revealed changes on sample surfaces over the analysed period, indicating the formation of carbonated hydroxyapatite; however, the chemical composition remained stable. PTH-loaded hydrogel-based scaffolds were biocompatible for stem cells from human-exfoliated deciduous teeth (SHED). A high quantity of calcium deposits on the extracellular matrix of SHED was found for PTH-loaded hydrogel-based scaffolds. µCT images showed MBG particles dispersed into the scaffolds' structure, and a porous, lamellar, and interconnected hydrogel architecture. CONCLUSIONS: PTH-loaded hydrogel-based scaffolds demonstrated consistent morphology and physicochemical properties for bone tissue regeneration, as well as bioactivity, biocompatibility, and osteoinductivity in vitro. Thus, the scaffolds presented here are recommended for future studies on 3D printing. CLINICAL RELEVANCE: Bone tissue regeneration is still a challenge for several approaches to oral and maxillofacial surgeries, though tissue engineering applying SHED, scaffolds, and osteoinductive mediators might help to overcome this clinical issue.

[Development of the use of artificial intelligence in the management of chronic inflammatory bowel disease]. / Mise au point de l'utilisation de l'intelligence artificielle dans la prise en charge des maladies inflammatoires chroniques de l'intestin.

Complexity of inflammatory bowel diseases (IBD) lies on their management and their biology. Clinics, blood and fecal samples tests, endoscopy and histology are the main tools guiding IBD treatment, but they generate a large amount of data, difficult to analyze by clinicians. Because of its capacity to analyze large number of data, artificial intelligence is currently generating enthusiasm in medicine, and this technology could be used to improve IBD management. In this review, after a short summary on IBD management and artificial intelligence, we will report pragmatic examples of artificial intelligence utilisation in IBD. Lastly, we will discuss the limitations of this technology.

Contact force guided radiofrequency current application at developing myocardium.

INTRODUCTION: Catheter contact is a key determinant for lesion size in radiofrequency catheter ablation (RFA). Monitoring of contact force (CF) during RFA has been shown to improve efficacy of RFA in experimental settings as well as in adult patients. Coronary artery narrowing after RFA has been described in experimental settings as well as in children and adults and may be dependent from catheter contact. The value of CF monitoring concerning these issues has not been systematically studied yet. Value of high versus low CF during RFA in piglets was studied to assess lesion size and potential coronary artery involvement mimicking RFA in small children. METHODS: RFA with continuous CF monitoring was performed in 24 piglets (median weight 18.5 kg) using a 7 F TactiCath Quartz radiofrequency (RF) ablation catheter (Abbott). A total of 7 lesions were induced in each animal applying low (10-20 g) or high (40-60 g) CF. RF energy was delivered with a target temperature of 65°C at 30 W for 30 s. Coronary angiography was performed prior and immediately after RF application. Animals were assigned to repeat coronary angiography followed by heart removal after 48 h (n = 12) or 6 months (n = 12). Lesions with surrounding myocardium were excised, fixated, and stained. Lesion volumes were measured by microscopic planimetry. RESULTS: A total of 148 RF lesions were identified in the explanted hearts. Only in the subset of lesions at the AV annulus 6 month after ablation, lesion size and number of lesions exhibiting transmural extension were higher in the high CF group compared to low CF. In all other locations CF had no impact on lesion size and mural extension after 48 h as well as after 6 months. Additional parameters such as lesion size index and force time integral were also not related to lesion size. Coronary artery damage was present in two animals after 48 h and in one after 6 months and was not related to CF. CONCLUSION: In our experimental setting, lesion size in piglets was not related to catheter CF. Transmural extension of the RF lesions involving the layers of the coronary arteries was frequently noted irrespective of CF. Coronary artery narrowing was present in 3/24 animals and was not related to CF. In infants and toddlers, low CF (10-20 g) may be of adequate effect. Impact of CF monitoring during conventional RF ablation in children requires further investigation.

Repeat radiofrequency catheter ablation of atrial tachycardias in patients with congenital heart disease.

INTRODUCTION: Atrial tachycardias (AT) in patients with congenital heart disease (CHD) are significantly contributing to morbidity and mortality. Aim of this study was to evaluate the long-term course of CHD patients requiring repeat ablation procedures (RAP) of AT. PATIENTS AND METHODS: All 144 patients with CHD who had undergone ablation of AT at our center between January 2003 and October 2018 were enrolled. Patients were classified according to the complexity of CHD: complex CHD (cCHD), moderate CHD (mCHD), and simple CHD (sCHD). RESULTS: A total of 101 RAP were performed in 64 patients. One RAP was performed in n = 40, two in n = 13, three in n = 10, and five in n = 1. Acute success rate was 82% (83/101) and was not associated with the complexity of CHD (p = 1.0). Number of procedures was lower in patients with sCHD than in patients with mCHD and cCHD (sCHD 1.3 ± 0.6, mCHD 1.8 ± 1.0, and cCHD 1.8 ± 1.1, p = .04). RAP were most frequent in patients after Fontan palliation or Atrial switch procedure (2.0 ± 1.1 [n = 41] vs. 1.6 ± 0.9 all others, p = .016) and in patients with multiple unstable AT's (2.5 ± 1.1 [n = 11] vs. 1.7 ± 1.0, p = .008). Major complications occurred in 4/101 procedures. Complete follow-up was available in 125 patients. Since last RAP 73% of the patients were in sinus/atrial rhythm and 34/125 patients (27%) with AT recurrence did not require re-ablation with mean follow-up of 52 ± 40 months. CONCLUSIONS: Recurrences after ablation of AT in CHD patients were frequent. After RAP promising long-term results could be achieved. Data encourage repetitive ablation procedures in this patient population.

The prevalence of vertebral fractures among Indian perimenopausal women and its association with ovarian biomarkers.

INTRODUCTION: There is dearth of data on prevalent vertebral fractures in perimenopausal women in India and limited literature on the utility of FSH, AMH and estradiol in evaluating bone health them. The objective was to study the prevalence of vertebral fractures (VF) and to assess the utility of FSH, estradiol and AMH in predicting them in Indian perimenopausal women MATERIALS AND METHODS: It was a cross-sectional study. Perimenopausal women aged 40-49 years underwent assessment for prevalent vertebral fractures, bone mineral density (BMD) and trabecular bone score (TBS). Utility of serum FSH, estradiol and AMH in predicting prevalent vertebral fractures was also assessed. RESULTS: A total of 300 perimenopausal women with mean (SD) age of 43.2 (2.8) years was recruited and 18% had moderate-severe VF. Mean (SD) serum AMH was lower in perimenopausal women with VF as compared to those without fractures [0.752 (0.594) vs 1.023 (0.704) P = 0.006]. AMH showed significant positive correlation with TBS (r = 0.3; P < 0.001) and BMD at the femoral neck (r = 0.2; P < 0.001) and lumbar spine (r = 0.3; P < 0.001).On ROC analysis, AMH demonstrated good performance in predicting prevalent VF with an AUC of 0.800 (95% CI 0.705-0.880) and a sensitivity of 85% and specificity of 60% at a cut-off of 1.12 ng/mL. On an exploratory multivariate logistic regression analysis, AMH significantly predicted prevalent fractures with an adjusted OR (OR) of 1.85 (95% CI: 1.03-3.00; P = 0.04). The performance of FSH and estradiol in predicting prevalent fractures was sub-optimal. CONCLUSION: About one-fifth of the study subjects had prevalent vertebral fractures. AMH may be a menstrual cycle independent biomarker and may reflect bone loss in perimenopausal women. Further prospective studies are needed to validate these findings.

Proximal Hip Geometry, Trabecular Bone Score, Bone Mineral Density and Bone Mineral Parameters in Patients With Cryptogenic and Hepatitis B Related Cirrhosis- A Study From the Indian Subcontinent.

The impact of cryptogenic cirrhosis on skeleton has not been studied in Indian context. So this study investigated bone health in male patients with early cryptogenic cirrhosis as defined by Child-Turcot-Pugh A (CTP-A) categorization and compared it with patients diagnosed to have hepatitis B related chronic liver disease (CLD) on treatment and age, sex-matched healthy controls. It was a cross-sectional study, in which thirty male subjects were recruited in each group. Bone mineral density (BMD), trabecular bone score (TBS), hip structural analysis (HSA) and bone mineral parameters were assessed. The mean ±SD age of the study subjects was 39.3 ± 9.2 years. The mean 25-hydroxy vitamin D was significantly lower in subjects with cryptogenic cirrhosis as compared to controls (p = 0.001). Subjects with cryptogenic cirrhosis had significantly lower (1.297 ± 0.099) TBS as compared to hepatitis-B related CLD (1.350 ± 0.094) control subjects (1.351 ± 0.088) (p = 0.04). BMD at the hip and lumbar spine was also significantly lower in subjects with cryptogenic cirrhosis as compared to hepatitis-B related CLD and healthy age matched controls (p < 0.05). Most components of HSA were significantly affected in subjects with cryptogenic cirrhosis as compared to control subjects (p < 0.05). Patients with cryptogenic cirrhosis had significantly low TBS and BMD lumbar spine and hip as well as poor proximal hip geometry which may be good predictor of future fragility fractures.

Preliminary assessment of paediatric electrophysiology cardiac implantable electronic device resources around the world.

BACKGROUND: The Pediatric and Congenital Electrophysiology Society (PACES) is a global organisation committed to the care of children and adults with CHD and arrhythmias. OBJECTIVE: To evaluate the global needs and potential inequities as it relates to cardiac implantable electronic devices. METHODS: ARROW (Assessment of Rhythm Resources arOund the World) is an online survey about cardiac implantable electronic devices, sent electronically to physicians within the field of Cardiology, Pediatric Cardiology, Electrophysiology and Pediatric Electrophysiology. RESULTS: ARROW received 42 responders from 28 countries, 50% from low-/middle-income regions. The main differences between low-/middle- and high-income regions include availability of expertise on paediatric electrophysiology (50% versus 93%, p < 00.5) and possibility to perform invasive procedures (35% versus 93%, p < 0.005). Implant of devices in low-income areas relies significantly on patient's resources (71%). The follow-up of the devices is on the hands of paediatric cardiologist/electrophysiologist in higher resources centres (93% versus 50%, p < 0.05). CONCLUSIONS: The ARROW survey represents an initial assessment of the geographical characteristics in the field of Pediatric Electrophysiology. The next step is to make this "state of the art" more extensive to other aspects of the expertise. The relevance of collecting this data before the World Congress of Pediatric Cardiology and Cardiac Surgery (WCPCCS) in 2023 in Washington DC was emphasised in order to share the resulting information with the international community and set a plan of action to assist the development of arrhythmia services for children within developing regions of the world.

Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy.

BACKGROUND: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. METHODS: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. RESULTS: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. CONCLUSIONS: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Distinct opposing associations of upper and lower body fat depots with metabolic and cardiovascular disease risk markers.

BACKGROUND: To examine the associations of total and regional adiposity with metabolic and cardiovascular disease (CVD) risk markers. METHODS: This cross-sectional study included 1080 (53.8% men, aged 39-44 years) individuals from South India. Anthropometry (height, weight, waist and hip circumference), body composition assessment using dual-energy X-ray absorptiometry (DXA), blood pressure (BP), and plasma glucose, insulin and lipids were measured. Regression analysis was used to examine associations of standardized fat measurements with type 2 diabetes (T2D), insulin resistance (IR), hypertension and hypertriglyceridemia and continuous measurements of BP, glucose, insulin, HOMA-IR and lipids. Contour plots were constructed to visualize the differential effect of upper and lower fat depots. RESULTS: DXA-measured fat depots were positively associated with metabolic and CVD risk markers. After adjusting for fat mass index, upper body fat remained positively, while lower body fat was negatively associated with risk markers. A one standard deviation (SD) increase in android fat showed higher odds ratios (ORs) for T2D (6.59; 95% CI 3.17, 13.70), IR (4.68; 95% CI 2.31, 9.50), hypertension (2.57; 95% CI 1.56, 4.25) and hypertriglyceridemia (6.39; 95% CI 3.46, 11.90) in men. A 1 SD increase in leg fat showed a protective effect with ORs for T2D (0.42; 95% CI 0.24, 0.74), IR (0.31; 95% CI 0.17, 0.57) and hypertriglyceridemia (0.61; 95% CI 0.38, 0.98). The magnitude of the effect was greater with DXA-measured fat compared with anthropometry. CONCLUSION: At any level of total body fat, upper and lower body fat depots demonstrate opposite risk associations with metabolic and CVD risk markers in Asian Indians.

Clinical Profile and Mutations Associated with Multiple Endocrine Neoplasia-Type1 (MEN1) and Their First-Degree Relatives at Risk of Developing MEN1: A Prospective Study.

Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.

Pediatric catheter ablation at the beginning of the 21st century: results from the European Multicenter Pediatric Catheter Ablation Registry 'EUROPA'.

AIMS: Contemporary data from prospective multicentre registries on catheter ablation in pediatric patients are sparse. Aim of the European Pediatric Catheter Ablation Registry EUROPA was to contribute data to fill this gap of knowledge. METHODS AND RESULTS: From July 2012 to June 2017, data on catheter ablation in pediatric patients (≤18 years of age) including a 1-year follow-up from five European pediatric EP centres were collected prospectively. A total of 683 patients (mean age 12.4 ± 3.9 years, mean body weight 50.2 ± 19 kg) were enrolled. Target tachycardia was WPW/atrioventricular-nodal re-entrant tachycardia (AVRT) in 380 (55.7%) patients, AVNRT in 230 (33.8%) patients, ventricular tachycardia (VT) in 24 (3.5) patients, focal atrial tachycardia (FAT) in 20 (2.9%) patients, IART in 14 (2%) patients, and junctional ectopic tachycardia in 3 (0.45) patients. Overall procedural success was 95.6%. Compared with all other substrates, success was significantly lower in FAT patients (80%, n = 16, P = 0.001). Mean procedure duration was 136 ± 67 min and mean fluoroscopy time was 4.9 ± 6.8 min. Major complications occurred in 0.7% of the patients. No persisting AV block requiring permanent pacing was reported. At 1-year follow-up (605/683 patients, 95%), tachycardia recurrence was reported in 7.8% of patients. Recurrence after VT ablation (33%) was significantly higher (P = 0.001) than after ablation of all other substrates. CONCLUSION: The present study proves overall high efficacy and safety of catheter ablation of various tachycardia substrates in pediatric patients. Of note, complication rate was exceptionally low. Long-term success was high except for patients after VT ablation.

DXA Measured Visceral Adipose Tissue, Total Fat, Anthropometric Indices and its Association With Cardiometabolic Risk Factors in Mother-Daughter Pairs From India.

Visceral fat is the pathogenic fat depot associated with diabetes, dyslipidemia, and cardiovascular diseases. Estimation of visceral adipose tissue (VAT) by dual energy-X-ray absorptiometry (DXA) is a newer technique with less radiation exposure, shorter scanning time, and lower cost. In this study, we attempted to look at relationship between cardiometabolic risk factors and VAT, total body fat percent (TBF%) and anthropometry. We also studied the changes in body composition and metabolic parameters with menopause. The familial resemblance of VAT and TBF% in mother-daughter pair was also compared. This was a cross sectional community study of 300 women (150 postmenopausal mothers and 150 premenopausal daughters). Body composition indices by DXA and metabolic parameters were assessed. The association between DXA-VAT, TBF%, anthropometric measures, and cardiometabolic risk factors were studied by correlation, receiver operating characteristics curves, and logistic regression analysis. VAT indices were significantly higher and lean indices lower in postmenopausal women as compared to premenopausal women. One fourth of postmenopausal women were categorized as metabolically obese normal weight. DXA-VAT was a better predictor of cardiometabolic risk factors as compared to waist circumference, body mass index, and TF% in postmenopausal women (AUC:0.68 vs 0.62, 0.60 & 0.5, respectively), whereas body mass index had a better prediction in premenopausal women(AUC:0.68). VAT area >100 cm² had a significant association with the presence of ≥2 cardiometabolic risk factors (p = 0.04, OR: 2.2, CI:1.0-4.7) in the postmenopausal women. Daughters of the mothers with higher TBF% were found to have a higher TBF% compared to daughters of mothers with normal TBF% (36.2 ± 4.2 vs 32.2 ± 4.4, p = 0.03), similar resemblance was not seen for VAT. The study showed that the VAT increases and lean mass decreases with age and menopause. DXA measured VAT is a better predictor of cardiometabolic risk in postmenopausal women but not in premenopausal women. Total body fat may have a familial resemblance, but not the VAT which is determined by age, menopause, and probable life style factors.