Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.

Methods And Results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information.

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated.

Methods And Results: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation.

Persistent Shoulder Pain Due to a Suprascapular Nerve Injury in the Setting of Trauma.

Suprascapular neuropathy is a rare cause of shoulder pain with an injury to the nerve intrinsically related to the anatomy and course of the suprascapular nerve. The common etiologies of a suprascapular nerve injury include repetitive overhead activity, rotator cuff pathology, and compression of the nerve at either the suprascapular or the spinoglenoid notch secondary to space-occupying lesions. Although uncommon, suprascapular nerve damage has been associated with scapular fractures previously.

Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells.

Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, associated with a prolonged QT interval and sudden death, caused by mutations in key genes regulating cardiac electrophysiology. Current strategies to study LQTS include heterologous systems or animal models. Despite their value, the overwhelming power of genetic tools has exposed the many limitations of these technologies.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi005-A from a patient carrying the KCNQ1-R190W mutation.

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a woman carrier of the heterozygous mutation c.568C > T p.R190W on the KCNQ1 gene.

Mexiletine Shortens the QT Interval in Patients With Potassium Channel-Mediated Type 2 Long QT Syndrome.

Background: Long QT syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel blockers, like mexiletine, is often utilized for patients with sodium channel-mediated type 3 long QT syndrome (LQT3). The potential role of sodium channel blockers in patients with potassium channel-mediated long QT syndrome (ie, LQT1 and LQT2) has not been investigated in detail.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi004-A from a carrier of the KCNQ1-R594Q mutation.

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a male carrier of the heterozygous mutation c.1781 G > A p.R594Q on the KCNQ1 gene.

Cardiac Sympathetic Denervation in Channelopathies.

Left cardiac sympathetic denervation (LCSD) is a surgical antiadrenergic intervention with a strong antiarrhythmic effect, supported by preclinical as well as clinical data. The mechanism of action of LCSD in structurally normal hearts with increased arrhythmic susceptibility (such as those of patients with channelopathies) is not limited to the antagonism of acute catecholamines release in the heart. LCSD also conveys a strong anti-fibrillatory action that was first demonstrated over 40 years ago and provides the rationale for its use in almost any cardiac condition at increased risk of ventricular fibrillation.

Anticipatory Waivers of Consent for Pediatric Biobanking.

As pediatric biobank research grows, additional guidance will be needed about whether researchers should always obtain consent from participants when they reach the legal age of majority. Biobanks struggle with a range of practical and ethical issues related to this question. We propose a framework for the use of anticipatory waivers of consent that is empirically rooted in research that shows that children and adolescents are often developmentally capable of meaningful deliberation about the risks and benefits of participation in research.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi007-A from a Long QT Syndrome type 1 patient carrier of two common variants in the NOS1AP gene.

We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic Long QT Syndrome (LQTS) type 1 patient, belonging to a South African (SA) founder population segregating the heterozygous mutation c.1022C > T p.A341V on the KCNQ1 gene.

Prevalence, characteristics, and risk factors of occult uterine cancer in presumed benign hysterectomy.

Background: Occult uterine cancer at the time of benign hysterectomy poses unique challenges in patient care. There is large variability and uncertainty in estimated risk of occult uterine cancer in the literature and prior research often did not differentiate/include all subtypes.

Objectives: To thoroughly examine the prevalence of occult uterine cancer in a large population-based sample of women undergoing hysterectomy for presumed benign indications and to identify associated risk factors.

Proarrhythmic proclivity of left-stellate ganglion stimulation in a canine model of drug-induced long-QT syndrome type 1.

Background: Left-stellate ganglion stimulation (LSGS) can modify regional dispersion of ventricular refractoriness, promote triggered activity, and reduce the threshold for ventricular fibrillation (VF). Sympathetic hyperactivity precipitates torsades de pointes (TdP) and VF in susceptible patients with long-QT syndrome type 1 (LQT1). We investigated the electromechanical effects of LSGS in a canine model of drug-induced LQT1, gaining novel arrhythmogenic insights.

From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2.

Aims: Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2 patients, we tested whether the commercial association Lumacaftor + Ivacaftor (LUM + IVA) could shorten the QTc in the same two patients.

Methods And Results: After hospital admission and 1 day of baseline recordings, half dose LUM + IVA was administered on Day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements.

Sphincter of Oddi Dysfunction After Gastric Bypass: Surgical or Endoscopic Therapy?

Background: Management of Sphincter of Oddi Dysfunction (SOD) requires advanced techniques (endoscopic retrograde cholangiopancreatography via gastrostomy [GERCP]) after Roux-en-Y gastric bypass (RYGB) for obesity. Transduodenal sphincteroplasty (TS) is also performed yet carries the risks of surgery. We hypothesized that TS would have increased morbidity and mortality but provide a more durable remission of symptoms.

International Triadin Knockout Syndrome Registry.

Background: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy.

Methods: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations.

PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers.

Objective: Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu.

Methods: We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC.

Ten-Year Comparison Study of Type 1 and 2 Endometrial Cancers: Risk Factors and Outcomes.

Aims: To compare baseline risk factors for type 1 vs. 2 endometrial cancers and analyze these risk factors for association with overall survival and time to recurrence.

Methods: Retrospective review of 816 consecutive endometrial cancer cases was conducted with diagnosis from January 2005 to December 2010 and clinical course until 2016.