Effects of Implantable Cardioverter-Defibrillator Leads on the Tricuspid Valve and Right Ventricle: A Randomized Trial.

BACKGROUND: There are no randomized data to inform the extent to which transvenous cardiac leads cause tricuspid regurgitation (TR). OBJECTIVES: This study sought to determine the effect of a transvenous implantable cardioverter-defibrillator (TV-ICD) on TR severity, and secondarily, on right ventricular (RV) size and function. METHODS: We evaluated TR severity before and 6 months after implantable cardioverter-defibrillator insertion in a post hoc analysis of adults randomized to receive a transvenous (n = 252) or subcutaneous implantable cardioverter-defibrillator (S-ICD) (n = 251) device. TR and RV size and systolic function were assessed by echocardiographic images analyzed in a core laboratory. RESULTS: At baseline, at least mild TR was present in 30% of individuals. At 6 months, the proportion of participants with any TR in the TV-ICD group was 42% vs 19% in the S-ICD group (P < 0.001). The proportion with moderate or severe TR was 7% in the TV-ICD group vs 2% in the S-ICD group (P = 0.021). At 6 months, the OR of at least 1 grade worsening of TR in the TV-ICD group as compared with the S-ICD group was 7.2 (95% CI: 3.3-15.8; P < 0.001). There were no differences between groups with respect to RV size or systolic function. CONCLUSIONS: Six months following TV-ICD insertion, there was a 7-fold increase in the risk of at least 1 grade worsening of TR, with 7% of individuals having TR that was moderate or severe. There was no detectable difference in RV size or function; however, longer follow-up is needed.

Genomic structures and regulation patterns at HPV integration sites in cervical cancer.

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

Minimizing total weighted latency in home healthcare routing and scheduling with patient prioritization.

We study a home healthcare routing and scheduling problem, where multiple healthcare service provider teams should visit a given set of patients at their homes. The problem involves assigning each patient to a team and generating the routes of the teams such that each patient is visited once. When patients are prioritized according to the severity of their condition or their service urgency, the problem minimizes the total weighted waiting time of the patients, where the weights represent the triage levels. In this form, the problem generalizes the multiple traveling repairman problem. To obtain optimal solutions for small to moderate-size instances, we propose a level-based integer programming (IP) model on a transformed input network. To solve larger instances, we develop a metaheuristic algorithm that relies on a customized saving procedure and a general variable neighborhood search algorithm. We evaluate the IP model and the metaheuristic on various small-, medium- and large-sized instances coming from the vehicle routing literature. While the IP model finds the optimal solutions to all the small- and medium-sized instances within three hours of run time, the metaheuristic algorithm achieves the optimal solutions to all instances within merely a few seconds. We also provide a case study involving Covid-19 patients in a district of Istanbul and derive insights for the planners by means of several analyses.

Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq.

Hundreds of loci in human genomes have alleles that are methylated differentially according to their parent of origin. These imprinted loci generally show little variation across tissues, individuals, and populations. We show that such loci can be used to distinguish the maternal and paternal homologs for all human autosomes without the need for the parental DNA. We integrate methylation-detecting nanopore sequencing with the long-range phase information in Strand-seq data to determine the parent of origin of chromosome-length haplotypes for both DNA sequence and DNA methylation in five trios with diverse genetic backgrounds. The parent of origin was correctly inferred for all autosomes with an average mismatch error rate of 0.31% for SNVs and 1.89% for insertions or deletions (indels). Because our method can determine whether an inherited disease allele originated from the mother or the father, we predict that it will improve the diagnosis and management of many genetic diseases.

A Novel Scalable Reconfiguration Model for the Postdisaster Network Connectivity of Resilient Power Distribution Systems.

The resilient operation of power distribution networks requires efficient optimization models to enable situational awareness. One of the pivotal tools to enhance resilience is a network reconfiguration to ensure secure and reliable energy delivery while minimizing the number of disconnected loads in outage conditions. Power outages are caused by natural hazards, e.g., hurricanes, or system malfunction, e.g., line failure due to aging. In this paper, we first propose a distribution-network optimal power flow formulation (DOPF) and define a new resilience evaluation indicator, the demand satisfaction rate (DSR). DSR is the rate of satisfied load demand in the reconfigured network over the load demand satisfied in the DOPF. Then, we propose a novel model to efficiently find the optimal network reconfiguration by deploying sectionalizing switches during line outages that maximize resilience indicators. Moreover, we analyze a multiobjective scenario to maximize the DSR and minimize the number of utilized sectionalizing switches, which provides an efficient reconfiguration model preventing additional costs associated with closing unutilized sectionalizing switches. We tested our model on a virtually generated 33-bus distribution network and a real 234-bus power distribution network, demonstrating how using the sectionalizing switches can increase power accessibility in outage conditions.

Phasing DNA Methylation.

Haplotyping enables the study of allele-specific events. Heterozygous variants, primarily single nucleotide variants (SNVs), enable the assignment of the paternal and maternal origin of the chromosomes and are widely employed to phase sequencing reads to their haplotype of origin. Certain long-read technologies enable the detection of both the DNA sequence and DNA modifications. These long reads and their inherent methylation information are suitable for genome-wide haplotyping and allele-specific DNA methylation analysis. Here, we describe the workflow to phase reads and DNA methylation using nanopore sequencing.

Genome-wide detection of imprinted differentially methylated regions using nanopore sequencing.

Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. Direct nanopore sequencing of DNA provides a means to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here, we used publicly available nanopore sequencing data for 12 standard B-lymphocyte cell lines to acquire the genome-wide mapping of imprinted intervals in humans. Using the sequencing data, we were able to phase 95% of the human methylome and detect 94% of the previously well-characterized, imprinted DMRs. In addition, we found 42 novel imprinted DMRs (16 germline and 26 somatic), which were confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mouse (Mus musculus), rhesus monkey (Macaca mulatta), and chimpanzee (Pan troglodytes) suggested that 17 of these imprinted DMRs are conserved. Some of the novel imprinted intervals are within or close to imprinted genes without a known DMR. We also detected subtle parental methylation bias, spanning several kilobases at seven known imprinted clusters. At these blocks, hypermethylation occurs at the gene body of expressed allele(s) with mutually exclusive H3K36me3 and H3K27me3 allelic histone marks. These results expand upon our current knowledge of imprinting and the potential of nanopore sequencing to identify imprinting regions using only parent-offspring trios, as opposed to the large multi-generational pedigrees that have previously been required.

A review of applications of operational research in healthcare coordination in disaster management.

Many disasters that have happened in the last decades, including the latest COVID-19 pandemic, have caused a shortage of healthcare resources and change in healthcare operations. Given these impacts, the Operational Research (OR) community has applied various approaches to improve the emergency medical responses. Coordination of healthcare facilities is one of the emergency medical response strategies to ensure the continued provision of medical services during disasters. Although the existing literature reviews of OR approaches have included the perspective of healthcare management, they focused mostly on the application of OR in disaster operations and logistics management. The importance of coordination in healthcare systems during disasters is well recognised in the literature, but to the best of our knowledge there has been no review of the published research in this area. This study provides a focused literature review of the OR contributions in the coordination in healthcare systems during disasters. Definitions of the terms in use in this field are provided. An overall descriptive statistics of the reviewed articles is given, followed by the review of the presented research problems, disaster types, and developed methodologies. The main characteristics of models for the coordination in the healthcare system are described. Measures of coordination effectiveness that denote healthcare resilience are discussed. Based on our findings, we suggest future research directions in the context of existing models extension, and application and development of other methodologies with the aim to provide a solid basis for OR research in the healthcare disaster management.

Megabase-scale methylation phasing using nanopore long reads and NanoMethPhase.

The ability of nanopore sequencing to simultaneously detect modified nucleotides while producing long reads makes it ideal for detecting and phasing allele-specific methylation. However, there is currently no complete software for detecting SNPs, phasing haplotypes, and mapping methylation to these from nanopore sequence data. Here, we present NanoMethPhase, a software tool to phase 5-methylcytosine from nanopore sequencing. We also present SNVoter, which can post-process nanopore SNV calls to improve accuracy in low coverage regions. Together, these tools can accurately detect allele-specific methylation genome-wide using nanopore sequence data with low coverage of about ten-fold redundancy.

Transcriptome and Network Dissection of Microsatellite Stable and Highly Instable Colorectal Cancer.

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide with high number of mortality every year. Microsatellite instability (MSI) is a considerable feature of CRC which affects prognosis and treatment. High level of MSI or MSI-high (MSI-H) colorectal cancer has better prognosis and immunotherapy response, while microsatellite stable (MSS) CRC has better response to 5-fluorouracil (5-FU)-based chemotherapy. More studies are needed, specifically on MSS CRC which has worse prognosis, to further reveal biological differences and similarities between MSS and MSI colorectal cancer, which may equip us with the knowledge to develop more promising therapeutic approaches to target both types or be more effective for each type. Methods: We aimed to find affected biological processes and their regulators in both type, MSS and MSI-H, of CRC; as well as reveal specific ones in each type. We applied meta- and network analysis on freely available transcriptome data in MSS and MSI-H colorectal cancer from gene expression omnibus (GEO) database to detect common differentially expressed genes (DEGs) and critical biological processes and predict their most significant regulators. Results: Our results demonstrate considerable up and downregulation in cell cycle and lipid catabolism processes, respectively; and introduced MYC and FOXM1 as two central and up-stream regulators of DEGs in both type of CRC. Chemokine-mediated processes displayed up-regulation in MSI-H type, while metastasis-related processes showed more activation in MSS CRC. Additionally, DACH1 and TP53 were detected as two important transcription factors that differentially expressed just in MSS and MSI-H, respectively. Conclusion: Our results can explain why MSI and MSS CRC display different immunotherapy response, prognosis, and metastasis feature. Moreover, our predicted up-stream regulators in the regulatory networks may be promising therapeutic targets.

Transcriptome mining of non-BRCA1/A2 and BRCA1/A2 familial breast cancer.

About 10% of all breast cancer cases are the familial type. Mutations in two highly penetrance breast cancer susceptibility genes, BRCA1 and BRCA2, can only explain 20% to 25% of genetic susceptibility to breast cancer, and most familial breast cancer cases have intact BRCA1 and BRCA2 genes that refer to non-BRCA1/A2 or BRCAX familial breast cancer. Despite extensive studies, more than 50% of genetic susceptibility to breast cancer remained to be disclosed. Finding the differences between these two types of breast cancer (non-BRCA1/A2 and BRCA1/A2) at genomic, transcriptomic, and proteomic levels can help us to elucidate fundamental molecular processes and develope more promising therapeutic targets. Here, we used expression data of 391 patients with familial breast cancer including 195 non-BRCA1/A2 and 196 BRCA1 and/or BRCA2 cases from four independent studies by means of meta-analysis to find differences in gene expression signature between these two types of familial breast cancer. As well as, we applied comprehensive network analysis to find crucial protein complexes and regulators for each condition. Our results revealed significant overexpression of cell cycle processes in BRCA1/A2 patients and significant overexpression of estrogen axis in non-BRCA1/A2 patients. Moreover, we found FOXM1 as the central regulator of cell cycle processes and GATA3, FOXA1, and ESR1 as the main regulators of estrogen axis.

Novel frameshift mutation in the KCNQ1 gene responsible for Jervell and Lange-Nielsen syndrome.

OBJECTIVES: Jervell and Lange-Nielsen syndrome is an autosomal recessive disorder caused by mutations in KCNQ1 or KCNE1 genes. The disease is characterized by sensorineural hearing loss and long QT syndrome. MATERIALS AND METHODS: Here we present a 3.5-year-old female patient, an offspring of consanguineous marriage, who had a history of recurrent syncope and congenital sensorineural deafness. The patient and the family members were screened for mutations in KCNQ1 gene by linkage analysis and DNA sequencing. RESULTS: DNA sequencing showed a c.1532_1534delG (p. A512Pfs*81) mutation in the KCNQ1 gene in homozygous form. The results of short tandem repeat (STR) markers showed that the disease in the family is linked to the KCNQ1 gene. The mutation was confirmed in the parents in heterozygous form. CONCLUSION: This is the first report of this variant in KCNQ1 gene in an Iranian family. The data of this study could be used for early diagnosis of the condition in the family and genetic counseling.

Three-dimensional echocardiography of a tricuspid valve papillary fibroelastoma.

Papillary fibroelastomas (PFE) on tricuspid valve (TV) are rare, accounting for fewer than 11% of all PFE. Most often they are asymptomatic, and detect on mitral valve. We report a case of a typical chest pain found to be due to papillary fibroelastoma of the tricuspid valve.

Combining white blood cell count and thrombosis for predicting in-hospital outcomes after acute myocardial infraction.

INTRODUCTION: Admission white blood cell (WBC) count and thrombosis in myocardial infarction (TIMI) risk score have been associated with adverse outcomes after acute myocardial infarction (AMI). This study investigated the joint effect of WBC count and TIMI risk score on predicting in-hospital outcomes in patients with AMI. MATERIALS AND METHODS: WBC count and TIMI risk score were measured at the time of hospital admission in 70 patients with AMI. Echocardiogram was done on prior to discharge by a cardiologist and ejection fraction (EF) was determined according to the Simpson formula. Patients were stratified into tertiles (low and high) based on WBC count and TIMI risk score. RESULTS: Patients with a high WBC count had a 5.0-fold increase in-hospital congestive heart failure and 2.2 increases in mortality compared with those with a low WBC count. Patients with a high TIMI risk score had a 10-fold increase in congestive heart failure presentation and mortality compared with those with a low TIMI risk score. When a combination of different strata for each variable was analyzed, a stepwise increase in mortality was seen. There were a few number of patients with a high WBC count and low TIMI risk score or with a low WBC count and high TIMI risk score. These patients had an intermediate risk, whereas those with a high WBC count and TIMI risk score had the highest risk. CONCLUSION: These findings suggested that a simple combination of WBC count and TIMI risk score might provide further information for predicting outcomes in patients with AMI.

Infective endocarditis presents as isolated splenomegaly.

Sub acute left-sided bacterial endocarditis is a serious condition that may be overlooked due to highly variable clinical manifestations. We present the case of a 45-year-old man who presented with complaints of fullness in his abdomen and splenomegaly that referred to the surgery clinic. He underwent diagnostic splenectomy. 3 month after splenectomy endocarditis was diagnosed. We recommend echocardiography in the work up of isolated splenomegaly.

Anxiety and depression symptoms in chest pain patients referred for the exercise stress test.

INTRODUCTION: As chest pain is an important symptom of coronary artery disease (CAD), the presentation of the symptom often prompts referral to a cardiologist for further investigation. The aim of the present study is to determine the prevalence of anxiety and depressive symptoms in patients referred to a cardiology outpatient clinic for performing the stress test. PATIENTS AND METHODS: Two hundred and fifty consecutive outpatients referred for evaluation of chest pain by the stress test at a government cardiology clinic from April 2010 to November 2010 were asked to participate in the study. We estimated the prevalence of anxiety and depression symptoms, as assessed by the Hospital Anxiety and Depression Scale, in a sample of patients with chest pain. RESULTS: The prevalence of anxiety and depressive symptoms was estimated to be 42% and 31%, respectively, in the total chest pain population. Males with abnormal test were depressed but females experienced more anxiety symptoms. Patients with negative tests had significantly higher scores for anxiety and higher depression scores than those with positive tests. Eleven percent of the patients with positive tests were women and 23% were men. CONCLUSION: Determining a patient's anxiety disorder history may assist the clinician in identifying, especially, women with angina who are at a lower risk of underlying CAD.

A colossal atrial myxoma.

Atrial myxomas are the most common benign primary tumor of the heart. These cardiac growths can masquerade as mitral stenosis and infective endocarditis. A 35-year-old man presented with complaints of nonspecific symptoms. Echocardiogram revealed a large atrial myxoma occupying the left atrium. Excision revealed a 14 × 8 × 6 cm3 tumor attached to a 4 × 3 × 2 cm3 stalk of septal tissue. We describe a giant left atrial myxoma. We were not able to find another myxoma as big as this one in the literature, so we are reporting it.

A case control study of cardiovascular health in chemical war disabled Iranian victims.

BACKGROUND: Sulfur mustard (SM) is an alkylating chemical warfare agent that was widely used during Iran-Iraq war between 1983 and 1988. SM exposure leads to various late complications. The aim of this study was to determine the late cardiovascular effects of SM in war-disabled Iranian victims. MATERIALS AND METHODS: This was a retrospective cohort case control study on 50 patients with symptoms of SM exposure and 50 cases who had been in Iran-Iraq war, without chemical injury. We performed exercise stress test and echocardiography for all of patients. RESULTS: The study group comprised 100 males of mean age 45.6 ± 6.2 years. In chemical war injury group, two patients (4%) had positive exercise stress test. On coronary angiography, they were found to have coronary artery disease. One patient had severe mitral regurgitation and normal coronary angiography; he was referred for mitral valve replacement. Left ventricular (LV) diastolic abnormality was detected in 23% of these subjects. In another group, 5% had LV diastolic abnormality (P = 0.02) and all of them had normal stress test. CONCLUSIONS: Cardiovascular abnormalities are another late complication in chemical war disabled Iranian victims. Diastolic dysfunction was the most common abnormality in both groups of patients.