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Cardiac implantable electronic devices (CIEDs) store information continuously; however, the log of these devices is rarely analyzed in forensic practice. We retrospectively reviewed all cases referred for CIED interrogation by the Los Angeles County Department of Medical Examiner-Coroner between 2001 and 2020. According to the Department's practice, CIED interrogation may be requested for decedents in which details or cause of death are not clear from autopsy and clinical history. The CIED analysis was considered informative for the coroner's investigation either if it detected an arrhythmia or malfunction likely related to decedent's terminal event or if it was essential to determine time of death or identity of decedent. A total of 57 CIEDs were evaluated during the 20-year period. In almost half of cases (26/57: 45.6%), device analysis was informative for coroner's investigation. Arrhythmias likely related to terminal event were commonly detected (21/57: 36.8%). Device malfunction was identified as the likely cause of death in almost 10% of decedents (5/57: 8.8%), including three cases of battery depletion (3/57: 5.3%), one case of misclassification of ventricular tachycardia as supraventricular tachycardia with failure to deliver therapy (1/57: 1.7%), and one case of lead failure due to a broken pacing wire (1/57: 1.7%). Not infrequently, CIED interrogation was essential for determination of time of death (9/57: 15.8%), and there was one case (1/57: 1.7%) in which interrogation was essential for identifying the decedent. Our study shows that postmortem CIED interrogation can provide unique information regarding mechanism and time of death, and decedent's identity.

Introduction Cardiac sympathetic denervation (CSD) is utilized for the management of ventricular tachycardia (VT) in structural heart disease when refractory to radiofrequency ablation (RFA) or when patient/VT characteristics are not conducive to RFA. Methods We studied consecutive patients who underwent CSD at our institution from 2009 to 2018 with VT requiring repeat RFA post-CSD. Patient demographics, VT/procedural characteristics, and outcomes were assessed. Results Ninety-six patients had CSD, 16 patients underwent RFA for VT post-CSD. There were 15 male and 1 female patients with mean age of 54.2 ± 13.2 years. Fourteen patients had nonischemic cardiomyopathy. A mean of 2.0 ± 0.8 RFAs for VT was unsuccessful before the patient undergoing CSD. The median time between CSD and RFA was 104 days (interquartile range [IQR] = 15-241). The clinical VT cycle length was significantly increased after CSD both spontaneously on ECG and/or ICD interrogation (355 ± 73 ms pre-CSD vs. 422 ± 94 ms post-CSD, p = .001) and intraprocedurally (406 ± 86 ms pre-CSD vs. 457 ± 88 ms post-CSD, p = .03). Two patients had polymorphic and 14 had monomorphic VT (MMVT) pre-CSD, and all patients had MMVT post-CSD. The proportion of mappable, hemodynamically stable VTs increased from 35% during pre-CSD RFA to 58% during post-CSD RFA (p = .038). At median follow-up of 413 days (IQR = 43-1840) after RFA, eight patients had no further VT. Conclusion RFA for recurrent MMVT post-CSD is a reasonable treatment option with intermediate-term clinical success in 50% of patients. Clinical VT cycle length was significantly increased after CSD with associated improvement in mappable, hemodynamically tolerated VT during RFA.

Aims We are studying the dialogue between β-cells and the immune system in type 1 diabetes and have identified a cell surface receptor, Signal Regulatory Protein-alpha (SIRPα) as an important component in the regulation of β-cell survival. SIRPα interacts with another protein, CD47, to mediate signalling. In the present work, we have studied the expression and role of CD47 in human islet cells in type 1 diabetes. Methods Clonal EndoC-βH1 cells were employed for functional studies. Cells were exposed to pro-inflammatory cytokines and their viability monitored by flow cytometry after staining with propidium iodide. Targeted knockdown of CD47 or SIRPα was achieved with small interference RNA molecules and the expression of relevant proteins studied by Western blotting or immunocytochemistry. Human pancreas sections were selected from the Exeter Archival Diabetes Biobank and used to examine the expression of CD47 by immunofluorescence labelling. Image analysis was employed to quantify expression. Results CD47 is abundantly expressed in both α and β cells in human pancreas. In type 1 diabetes, the levels of CD47 are increased in α cells across all age groups whereas the expression in β-cells varies according to disease endotype. Knockdown of either CD47 or SIRPα in EndoC-βH1 cells resulted in a loss of viability. Conclusions We conclude that the CD47 plays a previously unrecognised role in the regulation of β-cell viability. This system is dysregulated in type 1 diabetes suggesting that it may be targeted therapeutically to slow disease progression.

BACKGROUND AND PURPOSE Primary autoimmune cerebellar ataxia (PACA) in the absence of another triggering disease represents an emerging category of neurological illness. We report such a case whose ataxia was markedly responsive to plasma exchange. We analyzed patient serum for the presence of IgM or IgG anticerebellar neuronal antibodies. METHODS Case presentation: rat cerebellar slice cultures incubated with patient sera were studied for IgG and IgM antibody uptake, intracellular binding, and neuronal death. Patient serum was evaluated for anti-myelin associated glycoprotein (anti-MAG) and associated anti-glycolipid antibodies. RESULTS Antibodies were taken up by viable cerebellar neurons and bound to intracellular antigens. Uptake and predominantly nuclear binding of IgG were seen in granule cells whereas cytoplasmic binding of IgM was observed predominantly in Purkinje cells. Intracellular antibody accumulation was not accompanied by neuronal death, consistent with the patient's excellent clinical response to plasma exchange. Anti-MAG or other associated anti-glycolipid antibodies were not detected. CONCLUSIONS PACA may be associated with both IgG and IgM antibodies reactive with cerebellar neuronal antigens. Our patient's response to plasma exchange supports a role for antineuronal antibodies in disease pathogenesis and emphasizes the need for rapid diagnosis and treatment.

Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1 week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels.A dose of 60 mg kg-1 week-1 achieved trough serum levels >11 μmol l-1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l-1 year-1 occurred more often in patients receiving A1 -PI: 63 vs. 12%.Weight-based A1 -PI dosing reliably raises serum levels above the 11 μmol l-1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.

Objective To examine the prevalence of α1-antitrypsin deficiency (AATD) in rheumatoid arthritis (RA), and to determine whether AATD is associated with higher levels of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti–citrullinated peptide autoantibodies (ACPAs). Methods RF, ANAs, and ACPAs were measured by standard immunoturbidimetry, immunofluorescence assay, and enzyme-linked immunosorbent assay, respectively. Characterization of AAT phenotypes was performed by isoelectric focusing and immunofixation. The chi-square test with Yates' correction and the Mann-Whitney U test were used to assess the prevalence of alleles associated with AATD in RA and to compare mean antibody titers, respectively. Results Of 246 patients with RA, 24 who were heterozygous for AATD were identified, with no statistically significant difference in the prevalence of AATD between RA patients and the general population (P = 0.39). A positive association between heterozygosity for AATD and the production of ACPAs was observed (P

Predict the Impact of PVC on Myocardial FunctionIntroduction Reversible premature ventricular complexes-induced cardiomyopathy (PVC-CMP) is a well-described, multi-factorial entity. Single predictors, such as PVC burden or QRS duration, may not apply equally to all patients in contemporary unselected populations including patients with structural heart disease (SHD) or with particular origin such as epicardial (EPI) PVC. We sought to evaluate clinical criteria associated with PVC-CMP notably focusing on the EPI origin impact and ECG recognition and the value of a new composite predictor of PVC-CMP, the PVC-CMP-Index. Methods and Results We studied 107 consecutive patients (69 men; mean age = 56 ± 16 years) with frequent PVC (23.1 ± 11.5%) referred for PVC ablation. Thirty-six patients (33.6%) had an underlying SHD and 25 patients (23.4%) an EPI PVC origin. After a mean follow-up of 22.7 ± 15.3 months, 72.9% achieved a long-term successful ablation and 54.2% had PVC-CMP. PVC-CMP prevalence was significantly higher in patients with an EPI compared to endocardial PVC focus (84.0% vs. 45.1%, respectively, P < 0.001). EPI PVC origin (OR = 68.7 IC95% [3.5–1363], P = 0.005), as well as SHD (OR = 12.3 IC95% [1.6–92.6], P = 0.015), was independent predictor of PVC-CMP. While PVC burden (AUC = 0.78) or PVC-QRS width (AUC = 0.68) independently predicted PVC-CMP, the PVC-CMP-Index (values ≥39) defined as: PVC burden (0–1) × PVC-QRS width (milliseconds) × a constant C (1.28 for SHD or 2 for ECG suggesting EPI origin based on our ECG 3-step algorithm), highly correlated with PVC-CMP (AUC = 0.91, sensitivity = 93%, specificity = 80%). Conclusion We developed a new index, which incorporates PVC burden, QRS width, and presence of SHD or suspected EPI origin that best predicted PVC-CMP.

Introduction The safety of ventricular tachycardia (VT) ablation in patients with laminated left ventricular (LV) thrombus has not been examined. Methods Patients with laminated LV thrombus on transthoracic echocardiogram who underwent scar-mediated VT ablation at two centers from 2010 to 2013 were retrospectively analyzed. All patients had failed medical therapy. Acute procedural outcomes, complications, and clinical outcomes at 1 year were assessed. Results Eight patients (four ischemic, four nonischemic cardiomyopathy) underwent VT ablation in the presence of laminated intracavitary thrombus. Six out of eight (75%) had electrical storm (ES). The mapping and ablation approach was LV endocardial-only in three patients, epicardial-only in two, combined epicardial-RV endocardial in two, and combined epicardial-LV endocardial in one. Major complication (ischemic stroke) occurred in one patient 9 days post-procedure. There was no procedural mortality. Complete acute procedural success (noninducibility of any VT after ablation) was achieved in five (63%), and partial success (ablation of only clinical VT) in an additional three (37%). At 1 year, freedom from VT and survival were achieved in six (75%) and seven (88%) patients, respectively. Conclusion Initial data suggest that ablation of VT in the presence of intracavitary thrombus is feasible, is associated with a similar success rate to historical studies in patients without thrombus, and has an acceptable risk of complications given the high-risk nature of patients with ES. Further data are needed; however, the presence of a laminated thrombus should not necessarily preclude ablation in patients who have failed medical therapy for VT in whom ablation is otherwise indicated.

Key points Tonic contractions of rabbit urethra are associated with spontaneous electrical slow waves that are thought to originate in pacemaker cells termed interstitial cells of Cajal (ICC). ICC pacemaker activity results from their ability to generate propagating Ca2+ waves, although the exact mechanisms of propagation are not understood. In this study, we have identified spontaneous localised Ca2+ events for the first time in urethral ICC; these were due to Ca2+ release from the endoplasmic reticulum (ER) via ryanodine receptors (RyRs) and, while they often remained localised, they sometimes initiated propagating Ca2+ waves. We show that propagation of Ca2+ waves in urethral ICC is critically dependent upon Ca2+ influx via reverse mode NCX. Our data provide a clearer understanding of the intracellular mechanisms involved in the generation of ICC pacemaker activity. Abstract Interstitial cells of Cajal (ICC) are putative pacemaker cells in the rabbit urethra. Pacemaker activity in ICC results from spontaneous propagating Ca2+ waves that are modulated by [Ca2+]o and whose propagation is inhibited by inositol tri-phosphate receptor (IP3R) blockers. The purpose of this study was to further examine the role of Ca2+ influx and Ca2+ release in the propagation of Ca2+ waves. Intracellular Ca2+ was measured in Fluo-4-loaded ICC using a Nipkow spinning disc confocal microscope at fast acquisition rates (50 fps). We identified previously undetected localised Ca2+ events originating from ryanodine receptors (RyRs). Inhibiting Ca2+ influx by removing [Ca2+]o or blocking reverse mode sodium–calcium exchange (NCX) with KB-R 7943 or SEA-0400 abolished Ca2+ waves, while localised Ca2+ events persisted. Stimulating RyRs with 1 mm caffeine restored propagation. Propagation was also inhibited when Ca2+ release sites were uncoupled by buffering intracellular Ca2+ with EGTA-AM. This was reversed when Ca2+ influx via NCX was increased by reducing [Na+]o to 13 mm. Low [Na+]o also increased the frequency of Ca2+ waves and this effect was blocked by tetracaine and ryanodine but not 2-aminoethoxydiphenyl borate (2-APB). RT-PCR revealed that isolated ICC expressed both RyR2 and RyR3 subtypes. We conclude: (i) RyRs are required for the initiation of Ca2+ waves, but wave propagation normally depends on activation of IP3Rs; (ii) under resting conditions, propagation by IP3Rs requires sensitisation by influx of Ca2+ via reverse mode NCX; (iii) propagation can be maintained by RyRs if they have been sensitised to Ca2+.

Background and Purpose GoSlo-SR compounds are efficacious BK (KCa1.1) channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions. Experimental Approach A combination of electrophysiology, molecular biology and synthetic chemistry was used to examine the effects of two novel channel agonists on BK channels from bladder smooth muscle cells and in HEK cells expressing BKα alone or in combination with either β1 or β4 subunits. Key Results GoSlo-SR-5-6 shifted the voltage required for half maximal activation (V1/2) of BK channels approximately −100 mV, irrespective of the presence of regulatory β subunits. The deaminated derivative, GoSlo-SR-5-130, also shifted the activation V1/2 in smooth muscle cells by approximately −100 mV; however, this was reduced by ∼80% in HEK cells expressing only BKα subunits. When β1 or β4 subunits were co-expressed with BKα, efficacy was restored. GoSlo-SR-5-130 caused a concentration-dependent reduction in spontaneous bladder contraction amplitude and this was abolished by iberiotoxin, consistent with an effect on BK channels. Conclusions and Implications GoSlo-SR-5-130 required β1 or β4 subunits to mediate its full effects, whereas GoSlo-SR-5-6 worked equally well in the absence or presence of β subunits. GoSlo-SR-5-130 inhibited spontaneous bladder contractions by activating BK channels. The novel BK channel opener, GoSlo-SR-5-130, is approximately fivefold more efficacious on BK channels with regulatory β subunits and may be a useful scaffold in the development of drugs to treat diseases such as overactive bladder.

Work in the authors’ laboratory is supported by the European Union’s Seventh Framework Programme PEVNET [FP7/2007-2013] under grant agreement number 261441; a JDRF Career Development Award (5-CDA-2014-221-A-N) to SJR and grants from Diabetes UK (12/0004505 and 15/0005156). The research was also performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by the Juvenile Diabetes Research Foundation International (JDRF, JDRF 25-2013-268) and with JDRF research grants awarded to the nPOD-V consortium, JDRF 25-2012-516 and JDRF 25-2012-770.

Type 1 diabetes mellitus (T1DM) is caused by the selective deletion of pancreatic β-cells in response to an assault mounted within the pancreas by infiltrating immune cells. However, this apparently clear and focussed annunciation conceals a stark reality in which the cellular and molecular events leading to β-cell loss remain poorly understood in humans. This reflects the difficulty of studying these processes in living individuals and the fact that, using pathological specimens, islet inflammation has been analysed in fewer than 200 recent-onset cases of T1DM worldwide, over the past century. Nevertheless, insights have been gained and the composition of the islet infiltrate is being disclosed. This is shown to be primarily lymphocytic in nature, with populations of both CD8+ and CD4+ T cells displaying an autoreactivity against specific islet antigenic peptides. The T cells are often accompanied by influent CD20+ B cells, although new data imply that the proportions of these individual cell types vary and that patients fall into at least two distinct categories having either a hyper-immune (CD20Hi) or a pauci-immune (CD20Lo) phenotype. The overall rate of β-cell decline appears to correlate with these two phenotypes such that hyper-immune patients lose β-cells more quickly and tend to develop disease at an earlier age than those with the pauci-immune profile. In this article, we review the evidence which underpins our current understanding of the aetiology of T1DM and highlight both the established features as well as areas of on-going ambiguity and debate.

Estimation of proportion mature-at-age is an important component of the estimation of stock productivity. Current methods estimate maturity-at-age in each year or cohort independently. However, cohorts that are alive in the population at the same time are expected to experience similar conditions and therefore have similar maturity trajectories. Methods to take advantage of this information using binomial time series models with over-dispersion are presented to improve the estimation of maturity-at-age, with applications to example populations of Atlantic cod, Gadus morhua Linnaeus, and American plaice, Hippoglossoides platessoides (Fabricius). An auto-correlated beta-binomial model fit the data well compared to other models investigated and improved forecasts of maturities for both populations. Use of an auto-correlated beta-binomial model should lead to improvements in projections of stock status and, hence, improvements in fisheries management advice.