Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV.

Objective: Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods: Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing. Results: Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7-4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%-24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9-9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%-39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12-22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001). Conclusion: Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting. Clinical Trials Registration: ISRCTN69078957.

Oral Anticoagulation Therapy in Atrial Fibrillation Patients Managed in the Emergency Department Compared to Cardiology Outpatient: Opportunities for Improved Outcomes.

INTRODUCTION: Recent registry data suggests oral anticoagulation (OAC) usage remains suboptimal in atrial fibrillation (AF) patients. The aim of our study was to determine if rates of appropriate use of OAC in individuals with AF differs between the emergency department (ED) and cardiac outpatient clinic (CO). METHODS: This was a retrospective study of consecutive AF patients over a 12-month period. Data from clinical records, discharge summaries and outpatient letters were independently reviewed by two investigators. Appropriateness of OAC was assessed according to the CHA2DS2-VASc score. RESULTS: Of 455 unique ED presentations with AF as a primary diagnosis, 115 patients who were treated and discharged from the ED were included. These were compared to 259 consecutively managed AF patients from the CO. Inappropriate OAC was significantly higher in the ED compared to the CO group (65 vs. 18%, p<0.001). Treatment in the ED was a significant multivariate predictor of inappropriate OAC (odds ratio 8.2 [4.8-17.7], p<0.001). CONCLUSIONS: This patient level data highlights that significant opportunity exists to improve disparities in the use of guideline adherent therapy in the ED compared to CO. There is an urgent need for protocol-driven treatment in the ED or streamlined early follow-up in a specialised AF clinic to address this treatment gap.

Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis.

Aims: Several techniques have been utilized for the ablation of persistent (P) and long-standing persistent (LsP) atrial fibrillation (AF); however, the best approach of substrate ablation remains poorly defined. This study aims to examine the impact of ablation approach on outcomes associated with P or LsP AF ablation by conducting a meta-analysis and regression on contemporary literature. Methods and results: A systematic literature review was conducted up to 29 July 2015 for scientific literature reporting on outcomes associated with P or LsP AF ablation. One hundred and thirteen studies reported outcomes in a total of 18 657 patients undergoing various ablation approaches for the treatment of P-LsP AF between 2001 and 2015. The point efficacy estimate of a single-AF ablation procedure without the use of anti-arrhythmic drugs was 43% (95% CI; 39-47%). Multiple procedures and/or the use of anti-arrhythmic drugs increase success to 69% (95% CI; 66-71%). Meta-regression revealed that ablation technique (P < 0.001) and left atrial size (P = 0.02) were predictive of single procedure, drug-free success. The addition of extra-pulmonary substrate approaches was associated with declining efficacy when compared to a pulmonary vein ablation alone. Conclusion: The efficacy of a single-AF ablation procedure for P or LsP AF is 43%; however, can be increased to 69% with the use of multiple procedures and/or anti-arrhythmic drugs. Current literature supports the finding that pulmonary vein antrum ablation/isolation is at least equivalently efficacious to other contemporary P-LsP ablation strategies.

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

BACKGROUND: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. METHODS AND RESULTS: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Whole-genome sequencing and epidemiological analysis do not provide evidence for cross-transmission of mycobacterium abscessus in a cohort of pediatric cystic fibrosis patients.

BACKGROUND: Mycobacterium abscessus has emerged as a major pathogen in cystic fibrosis (CF) patients and has been associated with poor clinical outcomes, particularly following lung transplant. We investigated the acquisition of this bacterium in a cohort of pediatric CF patients. METHODS: Demographic and patient location data were used to uncover epidemiological links between patients with genetically related strains of M. abscessus that had been previously typed by variable-number tandem repeat profiling. Whole-genome sequencing was applied to 27 M. abscessus isolates from the 20 patients in this cohort to provide definitive data on the genetic relatedness of strains. RESULTS: Whole-genome sequencing data demonstrated that M. abscessus isolates from 16 patients were unrelated, differing by at least 34 single-nucleotide polymorphisms (SNPs) from any other isolate, suggesting that independent acquisition events have occurred. Only 2 clusters of very closely related (<25 SNPs) isolates from different patients were seen. The first cluster contained 8 isolates, differing by a maximum of 17 SNPs, from a sibling pair who had intense exposure to each other both inside and outside the hospital. The second cluster contained 3 isolates, differing by a maximum of 24 SNPs, from 2 individuals with no apparent epidemiological links. CONCLUSIONS: We have not demonstrated cross-transmission of M. abscessus within our hospital, except between 1 sibling pair. Alternative routes of acquisition of M. abscessus infection, in particular the environment, require further investigation.

Venturing into ventricular arrhythmia storm: a systematic review and meta-analysis.

Ablation has substantial evidence base in the management of ventricular arrhythmia (VA). It can be a 'lifesaving' procedure in the acute setting of VA storm. Current reports on ablation in VA storm are in the form of small series and have relative small representation in a large observational series. The purpose of this study was to systematically synthesize the available literature to appreciate the efficacy and safety of ablation in the setting of VA storm. The medical electronic databases through 31 January 2012 were searched. Ventricular arrhythmia storm was defined as recurrent (≥ 3 episodes or defibrillator therapies in 24 h) or incessant (continuous >12 h) VA. Studies reporting data on VA storm patients at the individual or study level were included. A total of 471 VA storm patients from 39 publications were collated for the analysis. All VAs were successfully ablated in 72% [95% confidence interval (CI) 71-89%] and 9% (95% CI: 3-10%) had a failed procedure. Procedure-related mortality occurred in three patients (0.6%). Only 6% patients had a recurrence of VA storm. The recurrence of VA was significantly higher after ablation for arrhythmic storm of monomorphic ventricular tachycardia (VT) relative to ventricular fibrillation or polymorphic VT with underlying cardiomyopathy (odds ratio 3.76; 95% CI: 1.65-8.57; P = 0.002). During the follow-up (61 ± 37 weeks), 17% of patients died (heart failure 62%, arrhythmias 23%, and non-cardiac 15%) with 55% deaths occurring within 12 weeks of intervention. The odds of death were four times higher after a failed procedure compared with those with a successful procedure (95% CI: 2.04-8.01, P < 0.001). Ventricular arrhythmia storm ablation has high-acute success rates, with a low rate of recurrent storms. Heart failure is the dominant cause of death in the long term. Failure of the acute procedure carries a high mortality.

A Potential Prognostic Gene Signature Associated with p53-Dependent NTRK1 Activation and Increased Survival of Neuroblastoma Patients.

Neuroblastoma is the most common extracranial solid tumour in children, comprising close to 10% of childhood cancer-related deaths. We have demonstrated that activation of NTRK1 by TP53 repression of PTPN6 expression is significantly associated with favourable survival in neuroblastoma. The molecular mechanisms by which this activation elicits cell molecular changes need to be determined. This is critical to identify dependable biomarkers for the early detection and prognosis of tumours, and for the development of personalised treatment. In this investigation we have identified and validated a gene signature for the prognosis of neuroblastoma using genes differentially expressed upon activation of the NTRK1-PTPN6-TP53 module. A random survival forest model was used to construct a gene signature, which was then assessed across validation datasets using Kaplan-Meier analysis and ROC curves. The analysis demonstrated that high BASP1, CD9, DLG2, FNBP1, FRMD3, IL11RA, ISGF10, IQCE, KCNQ3, and TOX2, and low BSG/CD147, CCDC125, GABRB3, GNB2L1/RACK1 HAPLN4, HEBP2, and HSD17B12 expression was significantly associated with favourable patient event-free survival (EFS). The gene signature was associated with favourable tumour histology and NTRK1-PTPN6-TP53 module activation. Importantly, all genes were significantly associated with favourable EFS in an independent manner. Six of the signature genes, BSG/CD147, GNB2L1/RACK1, TXNDC5, FNPB1, B3GAT1, and IGSF10, play a role in cell differentiation. Our findings strongly suggest that the identified gene signature is a potential prognostic biomarker and therapeutic target for neuroblastoma patients and that it is associated with neuroblastoma cell differentiation through the activation of the NTRK1-PTPN6-TP53 module.

Cardiovascular magnetic resonance of total and atrial pericardial adipose tissue: a validation study and development of a 3 dimensional pericardial adipose tissue model.

BACKGROUND: Recently pericardial adipose tissue (PAT) has been shown to be an independent predictor of atrial fibrillation (AF). Atrial PAT may influence underlying atrial musculature creating a substrate for AF. This study sought to validate the assessment of total and atrial PAT by standard cardiovascular magnetic resonance (CMR) measures and describe and validate a three dimensional atrial PAT model. METHODS: 10 merino cross sheep underwent CMR using a 1.5 Tesla system (Siemens, Sonata, Erlangen, Germany). Atrial and ventricular short axis (SA) images were acquired, using ECG -gated steady state free precession sequences. In order to quantify total volume of adipose tissue, a three dimensional model was constructed from consecutive end-diastolic images using semi-automated software. Regions of adipose tissue were marked in each slice followed by linear interpolation of pixel intensities in spaces between consecutive image slices. Total volume of adipose tissue was calculated as a total volume of the three dimensional model and the mass estimated from volume measurements. The sheep were euthanized and pericardial adipose tissue was removed and weighed for comparison to the corresponding CMR measurements. RESULTS: All CMR adipose tissue estimates significantly correlated with autopsy measurements (ICC > 0.80; p < 0.03). Intra- observer reliability in CMR measures was high, with 95% levels of agreement within 5.5% (ICC = 0.995) for total fat mass and its individual atrial (95% CI ± 8.3%, ICC = 0.993) and ventricular components (95% CI ± 6.6%, ICC = 0.989). Inter- observer 95% limits of agreement were within ± 10.7% (ICC = 0.979), 7.4% (ICC = 0.991) and 7.2% (ICC = 0.991) for atrial, ventricular and total pericardial adipose tissue, respectively. CONCLUSION: This study validates the use of a semi-automated three dimensional atrial PAT model utilizing standard (clinical) CMR sequences for accurate and reproducible assessment of atrial PAT. The measurement of local cardiac fat stores via this methodology could provide a sensitive tool to examine the regional effect of fat deposition on atrial substrate which potentially may influence AF ablation strategies in obese patients.

Photon-driven reduction of Zn2+ to Zn metal.

Easily oxidized metals are of interest as a means of storing solar energy in the form of fuels. While their efficient metal/air batteries make them attractive solar fuel candidates, the photoreduction of the corresponding metal ions remains difficult. Accordingly, this work describes the photon driven reduction of Zn(2+) by an iridium(III) photosensitizer (PS) and catalyst. [Ir(ppy)2(dtbbpy)](PF6) (ppy = 2-phenylpyridine, dtbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine) was found to be the most robust photocatalyst, and the use of ZnCl2 as the Zn(2+) starting material and acetonitrile as the solvent afforded the highest yield of Zn metal product. Under these conditions, a maximum of 430 catalyst turnover numbers were achieved. Cyclic voltammetry of ZnCl2 in different solvents and of different zinc salts in acetonitrile (MeCN) demonstrated the roles of MeCN and Cl(-) in the photoreduction mechanism. Kinetics measurements revealed a first order dependence of the initial rate on both [Ir(ppy)2(dtbbpy)](PF6) and ZnCl2. A first order decay of the reaction rate was also observed.

Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial.

IMPORTANCE: Obesity is a risk factor for atrial fibrillation. Whether weight reduction and cardiometabolic risk factor management can reduce the burden of atrial fibrillation is not known. OBJECTIVE: To determine the effect of weight reduction and management of cardiometabolic risk factors on atrial fibrillation burden and cardiac structure. DESIGN, SETTING, AND PATIENTS: Single-center, partially blinded, randomized controlled study conducted between June 2010 and December 2011 in Adelaide, Australia, among overweight and obese ambulatory patients (N = 150) with symptomatic atrial fibrillation. Patients underwent a median of 15 months of follow-up. INTERVENTIONS: Patients were randomized to weight management (intervention) or general lifestyle advice (control). Both groups underwent intensive management of cardiometabolic risk factors. MAIN OUTCOMES AND MEASURES: The primary outcomes were Atrial Fibrillation Severity Scale scores: symptom burden and symptom severity. Scores were measured every 3 months from baseline to 15 months. Secondary outcomes performed at baseline and 12 months were total atrial fibrillation episodes and cumulative duration measured by 7-day Holter, echocardiographic left atrial area, and interventricular septal thickness. RESULTS: Of 248 patients screened, 150 were randomized (75 per group) and underwent follow-up. The intervention group showed a significantly greater reduction, compared with the control group, in weight (14.3 and 3.6 kg, respectively; P < .001) and in atrial fibrillation symptom burden scores (11.8 and 2.6 points, P < .001), symptom severity scores (8.4 and 1.7 points, P < .001), number of episodes (2.5 and no change, P = .01), and cumulative duration (692-minute decline and 419-minute increase, P = .002). Additionally, there was a reduction in interventricular septal thickness in the intervention and control groups (1.1 and 0.6 mm, P = .02) and left atrial area (3.5 and 1.9 cm2, P = .02). CONCLUSIONS AND RELEVANCE: In this study, weight reduction with intensive risk factor management resulted in a reduction in atrial fibrillation symptom burden and severity and in beneficial cardiac remodeling. These findings support therapy directed at weight and risk factors in the management of atrial fibrillation. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000497000.

Characterization of Google Search Volumes and Trends From 2004 to 2021 for Diagnosis and Treatment of Locally Advanced Prostate Cancer.

Introduction and objective The purpose of this study is to better characterize at which point during the course of diagnosis and treatment of locally advanced prostate cancer the internet is utilized and to evaluate the search trends over time. Methods Monthly Google Trends data were collected from 2004 to 2021 for prostate cancer-specific terms. Temporal trends were analyzed by comparing average search volume indexes (aSVI) and analysis with joinpoint software of six-month percent change (6mPC). Chloropleths were created for geographic pattern comparisons. Results Search terms associated with interventions demonstrated the highest aSVI with terms such as "prostate biopsy" (aSVI: 33.59), "prostatectomy" (aSVI: 31.6), and "prostate radiation" (aSVI: 16.45). Terms associated with treatment side effects increased at a high rate with "radiation side effects" (21.4 6mPC, p<0.05) and "prostatectomy side effects" (14.4 6mPC, p<0.05). Prostate-specific antigen (PSA)-related search terms demonstrated a strong positive trend on joinpoint analysis with search terms "What is PSA?" (8.9 6mPC, p<0.05), and "What is normal PSA?" (15.1, p<0.05). Geographic patterns demonstrated higher search volumes in regard to screening and diagnostic terms in the northeast, while the southern regions demonstrated relatively higher search volumes for treatment and interventions. Conclusions The internet continues to be a growing part of the dynamics of prostate cancer management with more men utilizing the internet each year to help understand their diagnosis. Specifically, we found that the internet is used more for searches pertaining to PSA, procedures, and interventions affecting the quality of life.

Malignant priapism: case report and update on management protocols.

Background: Malignant priapism, a rare disease with only about 500 reported cases to date, consists of persistent erection secondary to invasion or metastasis of a primary neoplasm. While treatment guidelines for priapism in non-malignant cases have been established, there is currently no guideline for treating malignant priapism. Herein, we describe three cases of malignant priapism and suggest a step-by-step approach for clinical management. Case Description: This study reports three cases of malignant priapism resulting from advanced genitourinary cancers. All patients experienced a sub-acute progression of penile pain and ultimately underwent palliative penectomy, resulting in sustained symptom relief. Conclusions: Treatment of malignant priapism needs to be individualized to the needs of the patient. No matter the primary or secondary nature of the disease, current data suggest that malignant priapism is associated with poor outcomes and emphasis should be put on palliative care. Similar to previous cases, our cases died shortly after the diagnosis of malignant priapism. Conventional procedures such as shunting may not necessarily provide symptom relief in these patients. Although new radiation techniques have shown favorable outcomes, penectomy should be considered the last resort in clinical management. Revisions to the existing management guidelines for priapism are necessary to address its occurrence in malignant contexts.

Device-detected atrial fibrillation in a large remote-monitored cohort: implications for anticoagulation and need for new pathways of service delivery.

BACKGROUND: Remote monitoring (RM) can facilitate early detection of subclinical and symptomatic atrial fibrillation (AF), providing an opportunity to evaluate the need for stroke prevention therapies. We aimed to characterize the burden of RM AF alerts and its impact on anticoagulation of patients with device-detected AF. METHODS: Consecutive patients with a cardiac implantable electronic device, at least one AF episode, undergoing RM were included and assigned an estimated minimum CHA2DS2-VASc score based on age and device type. RM was provided via automated software system, providing rapid alert processing by device specialists and systematic, recurrent prompts for anticoagulation. RESULTS: From 7651 individual, 389,188 AF episodes were identified, 3120 (40.8%) permanent pacemakers, 2260 (29.5%) implantable loop recorders (ILRs), 987 (12.9%) implantable cardioverter defibrillators, 968 (12.7%) cardiac resynchronization therapy (CRT) defibrillators, and 316 (4.1%) CRT pacemakers. ILRs transmitted 48.8% of all AF episodes. At twelve-months, 3404 (44.5%) AF < 6 min, 1367 (17.9%) 6 min-6 h, 1206 (15.8%) 6-24 h, and 1674 (21.9%) ≥ 24 h. A minimum CHA2DS2-VASc score of 2 was assigned to 1704 (63.1%) of the patients with an AF episode of ≥ 6 h, 531 (31.2%) who were not anticoagulated at 12-months, and 1031 (61.6%) patients with an AF episode duration of ≥ 24 h, 290 (28.1%) were not anticoagulated. CONCLUSIONS: Despite being intensively managed via RM software system incorporating cues for anticoagulation, a substantial proportion of patients with increased stroke risk remained unanticoagulated after a device-detected AF episode of significant duration. These data highlight the need for improved clinical response pathways and an integrated care approach to RM. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN12620001232921.

How Effective Was the 2014 AUA Cryptorchidism Guideline? A Multi-institutional Evaluation.

INTRODUCTION: In 2014, the AUA published guidelines regarding the evaluation of cryptorchidism. This multi-institutional study aims to determine if these guidelines reduced the age of referral and the utilization of ultrasound in boys with cryptorchidism. We hypothesize that delayed referral continues, and utilization of ultrasound remains unchanged. METHODS: A retrospective review of boys referred for the evaluation of cryptorchidism was performed at 4 academic institutions, collecting data for 1 year prior (2013) and 2 nonconsecutive years following guideline creation (2015 and 2019). Across these time frames, we compared median ages at evaluation and surgery, and rates of patient comorbidities, orchiopexy, and preevaluation ultrasound. RESULTS: A total of 3,293 patients were included. The median age at initial pediatric urology evaluation in all cohorts was 39 months (IQR: 14-92 months). Following publication of the AUA Guidelines, there was no difference (P = .08) in the median age at first evaluation by a pediatric urologist between 2013 and 2015, and an increase (P = .03) between 2013 and 2019. Overall, 21.2% of patients received an ultrasound evaluation prior to referral, with no significant difference between 2013 and 2015 (P = .9) or 2019 (P = .5) cohorts. CONCLUSIONS: Our data suggest that, despite publication of the AUA Guidelines on evaluation and treatment of cryptorchidism, there has been no reduction in the age of urological evaluation or the utilization of imaging in boys with undescended testis. Finding alternative avenues to disseminate these evidence-based recommendations to referring providers and exploring barriers to guideline adherence is necessary to improve care for patients with cryptorchidism.

Direction-dependent conduction abnormalities in the chronically stretched atria.

AIMS: There is increasing evidence of the role direction-dependent conduction plays in the arrhythmogenic interaction between ectopic triggers and abnormal atrial substrates. We thus sought to characterize direction-dependent conduction in chronically stretched atria. METHODS AND RESULTS: Twenty-four patients with chronic atrial stretch due to mitral stenosis and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, and coronary sinus (CS) characterized direction-dependent conduction along linear catheters and across the crista terminalis. Bi-atrial electroanatomic maps were created in both sinus rhythm and an alternative wavefront direction by pacing from the distal CS. This allowed an assessment of conduction velocities, electrogram, and voltage characteristics during wavefronts propagating in different directions.  While differing wavefront directions caused changes in both chronic atrial stretch and reference patients (P< 0.001 for all), these direction-dependent changes were greater in chronic atrial stretch compared with reference patients, who exhibited greater slowing in conduction velocities (P= 0.09), prolongation of bi-atrial activation time (P= 0.04), increase in number (P< 0.001) and length (P< 0.001) of lines of conduction block, increase in fractionated electrograms (P< 0.001), and decrease in voltage (P= 0.08) during left-to-right compared with right-to-left atrial activation. These direction-dependent changes were associated with a greater propensity for chronically stretched atria to develop atrial fibrillation (P= 0.02). CONCLUSIONS: Atrial remodelling in chronic atrial stretch exacerbates physiological direction-dependent conduction characteristics. Our data suggest that the greater direction-dependent conduction seen in patients with chronic atrial stretch may promote arrhythmogenesis due to ectopic triggers from the left atrium.

Preferential conduction patterns along the coronary sinus during atrial fibrillation in humans and their modification by pulmonary vein isolation.

INTRODUCTION: Correlation function analysis applied to endocardial electrograms has earlier been used for analysis of agreement between signals and direction of activation during atrial fibrillation (AF). This study was aimed at evaluating whether preferential activation patterns along the coronary sinus (CS) exist in patients with AF. METHODS: Twenty-seven patients (57 ± 10 years old) admitted for electrophysiological (EP) study (10 patients) and/or AF ablation (17 patients) were studied, 8 with permanent and 19 with persistent AF. Unipolar signals were recorded during 60 seconds from a 10-pole CS catheter during AF at baseline (BL) and after isolation of left and right pulmonary veins and after additional lines in the left atrium (LA) (End). Correlation function analysis was applied to signals from each pair of adjacent electrodes, and graphs of cumulated time delay were made to enable interpretation of direction of activation. RESULTS: Correlation between paired signals was highest in the distal and middle parts of CS and lowest in the proximal CS. In 21 patients, correlation values greater than 0.8 between closely spaced electrodes suggested uniform propagation of the fibrillatory waves. In 18 of 21 patients, preferential conduction pattern along CS was seen. Of those, 15 patients had left-to-right conduction, and 3 had right-to-left conduction. During ablation, atrial fibrillation cycle length increased from 184 ± 32 milliseconds at BL to 193 ± 39 milliseconds after pulmonary vein isolation and 215 ± 39 milliseconds at the end of ablation (P = .03, BL vs End). Because of ablation, preferential conduction along CS changed in 4 patients from left to right at BL to simultaneous CS activation or right to left. In 1 of 3 patients with simultaneous activation at BL, the direction changed to right to left. No direction change was observed in any of the 3 patients with right-to-left activation at BL. CONCLUSIONS: Atrial activation during AF exhibits a high degree of organization in distal and middle CS. Preferential conduction patterns observed in most patients may indicate either relatively dominant stable reentry circuits in the LA or activation spread from a focal source. The changes in preferential conduction during ablation of AF may reflect modification of AF substrate and indicate persistent right atrial sources not affected by ablation in the LA only.

Reducing the number of unnecessary laboratory tests within hospital through the use of educational interventions.

BACKGROUND: The growing number of laboratory investigation requests is placing an increased burden upon NHS resources. Around a quarter of all tests are unnecessary repeats, and almost a third have no impact on patient management. Doctors recognise that tests should only be performed when clinically indicated, but a culture persists of undertaking unnecessary repeat investigations. METHODS: A cohort study was undertaken at a district general hospital to observe the impact of introducing educational interventions in the form of a poster and a series of educational lectures, encouraging clinicians to consider whether an investigation was clinically indicated. Data was collected from nine different sites across the hospital run by different medical teams regarding the number of tests undertaken and the impact on patient care. RESULTS: Data from over 13,000 tests and over 2000 patients was analysed from nine different sites across the hospital. There was a significant reduction (33%, p = 0.0001) in the number of blood tests performed. This reduction in testing saved £7006 over the course of 1 month, in addition to other benefits. There was a reduction in testing in eight out of the nine sites in which the study was undertaken, demonstrating good generalisability of results. There was no significant increase in length of admission or mortality. CONCLUSION: Educational interventions to doctors have a significant and safe impact in reducing the number of unnecessary investigations, providing cost saving benefits to the NHS.

Remote Monitoring Alert Burden: An Analysis of Transmission in >26,000 Patients.

OBJECTIVES: This study sought to determine the remote monitoring (RM) alert burden in a multicenter cohort of patients with a cardiac implantable electronic device (CIED). BACKGROUND: RM of CIEDs allows timely recognition of patient and device events requiring intervention. Most RM involves burdensome manual workflow occurring exclusively on weekdays during office hours. Automated software may reduce such a burden, streamlining real-time alert responses. METHODS: We retrospectively analyzed 26,713 consecutive patients with a CIED undergoing managed RM utilizing PaceMate software between November 2018 and November 2019. Alerts were analyzed according to type, acuity (red indicates urgent, and yellow indicates nonurgent) and CIED category. RESULTS: In total, 12,473 (46.7%) patients had a permanent pacemaker (PPM), 9,208 (34.5%) had an implantable cardioverter-defibrillator (ICD), and 5,032 (18.8%) had an implantable loop recorder (ILR). Overall, 82,797 of the 205,804 RM transmissions were alerts, with the remainder being scheduled transmissions. A total of 14,638 (54.8%) patients transmitted at least 1 alert. Permanent pacemakers were responsible for 25,700 (31.0%) alerts, ICDs for 15,643 (18.9%) alerts, and ILRs for 41,454 (50.1%) alerts, with 3,935 (4.8%) red alerts and 78,862 (95.2%) yellow alerts. ICDs transmitted 2,073 (52.7%) red alerts; 5,024 (32.1%) ICD alerts were for ventricular tachyarrhythmias and antitachycardia pacing/shock delivery. CONCLUSIONS: In an RM cohort of 26,713 patients with CIEDs, 54.8% of patients transmitted at least 1 alert during a 12-month period, totaling over 82,000 alerts. ILRs were overrepresented, and ICDs were underrepresented, in these alerts. The enormity of the number of transmissions and the growing ILR alert burden highlight the need for new management pathways for RM.

Atrial Fibrillation and Obesity: Reverse Remodeling of Atrial Substrate With Weight Reduction.

OBJECTIVES: This study sought to evaluate the effect of weight loss on the atrial substrate for atrial fibrillation (AF). BACKGROUND: Whether weight loss can reverse the atrial substrate of obesity is not known. METHODS: Thirty sheep had sustained obesity induced by ad libitum calorie-dense diet over 72 weeks. Animals were randomized to 3 groups: sustained obesity and 15% and 30% weight loss. The animals randomized to weight loss underwent weight reduction by reducing the quantity of hay over 32 weeks. Eight lean animals served as controls. All were subjected to the following: dual-energy x-ray absorptiometry, echocardiogram, cardiac magnetic resonance, electrophysiological study, and histological and molecular analyses (fatty infiltration, fibrosis, transforming growth factor ß1, and connexin 43). RESULTS: Sustained obesity was associated with increased left atrium (LA) pressure (p < 0.001), inflammation (p < 0.001), atrial transforming growth factor ß1 protein (p < 0.001), endothelin-B receptor expression (p = 0.04), atrial fibrosis (p = 0.01), epicardial fat infiltration (p < 0.001), electrophysiological abnormalities, and AF burden (p = 0.04). Connexin 43 expression was decreased in the obese group (p = 0.03). In this obese ovine model, 30% weight reduction was associated with reduction in total body fat (p < 0.001), LA pressure (p = 0.007), inflammation (p < 0.001), endothelin-B receptor expression (p = 0.01), atrial fibrosis (p = 0.01), increase in atrial effective refractory period (cycle length: 400 and 300 ms; p < 0.001), improved conduction velocity (cycle length: 400 and 300 ms; p = 0.01), decreased conduction heterogeneity (p < 0.001), and decreased AF inducibility (p = 0.03). Weight loss was associated with a nonsignificant reduction in epicardial fat infiltration in posterior LA (p = 0.34). CONCLUSIONS: Weight loss in an obese ovine model is associated with structural and electrophysiological reverse remodeling and a reduced propensity for AF. This provides evidence for the direct role of obesity in AF substrate and the role of weight reduction in patients with AF.

Long-term mechanical consequences of permanent right ventricular pacing: effect of pacing site.

INTRODUCTION: Long-term right ventricular apical (RVA) pacing has been associated with adverse effects on left ventricular systolic function; however, the comparative effects of right ventricular outflow tract (RVOT) pacing are unknown. Our aim was therefore to examine the long-term effects of septal RVOT versus RVA pacing on left ventricular and atrial structure and function. METHODS: Fifty-eight patients who were prospectively randomized to long-term pacing either from the right ventricular apex or RVOT septum were studied echocardiographically. Left ventricular (LV) and atrial (LA) volumes were measured. LV 2D strain and tissue velocity images were analyzed to measure 18-segment time-to-peak longitudinal systolic strain and 12-segment time-to-peak systolic tissue velocity. Intra-LV synchrony was assessed by their respective standard deviations. Interventricular mechanical delay was measured as the difference in time-to-onset of systolic flow in the RVOT and LV outflow tract. Septal A' was measured using tissue velocity images. RESULTS: Following 29 ± 10 months pacing, there was a significant difference in LV ejection fraction (P < 0.001), LV end-systolic volume (P = 0.007), and LA volume (P = 0.02) favoring the RVOT-paced group over the RVA-paced patients. RVA-pacing was associated with greater interventricular mechanical dyssynchrony and intra-LV dyssynchrony than RVOT-pacing. Septal A' was adversely affected by intra-LV dyssynchrony (P < 0.05). CONCLUSIONS: Long-term RVOT-pacing was associated with superior indices of LV structure and function compared with RVA-pacing, and was associated with less adverse LA remodeling. If pacing cannot be avoided, the RVOT septum may be the preferred site for right ventricular pacing.