Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes

The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic de novo, rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in PKD1L1 and ZIC3 were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in LMBRD1 and DNAH17, respectively, were prioritized. In another family, an ultra-rare de novo variant in WDR47 was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in WDR47, but no further individuals with biallelic variants in DNAH17 or LMBRD1. Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes PKD1L1 and ZIC3 and suggests DNAH17, LMBRD1, and WDR47 as potential genes involved in laterality defects.Subject terms: Disease genetics, Genetic counselling, Biological sciences     

卒中医疗体系之急诊医疗服务的实施策略:美国心脏协会/美国卒中协会急诊医疗服务体系专家组和卒中委员会的政策声明

尽管卒中的预防、诊断、治疗和康复已取得一些进展,但卒中在美国仍然是第三大死亡原因和长期残疾的主要原因.每年约有70万人新发或复发卒中[1].在过去10年里,急性卒中诊治的一些进展,包括纤溶和其他短期疗法的引入,突出显示了急诊医疗服务(emergency medical services,EMS)机构和急诊医疗服务体系(emergency medical services systems,EMSS)在优化卒中医疗中的关键作用[2-7].     

Breast Nurse Intervention to Improve Adherence to Endocrine Therapy Among Breast Cancer Patients in South Ethiopia

IntroductionMany women in rural Ethiopia do not receive adjuvant therapy following breast cancer surgery despite the majority being diagnosed with estrogen-receptor-positive breast cancer and tamoxifen being available in the country. We aimed to compare a breast nurse intervention to improve adherence to tamoxifen therapy for breast cancer patients.Methods and MaterialsThe 8 hospitals were randomized to intervention and control sites. Between February 2018 and December 2019, patients with breast cancer were recruited after their initial surgery. The primary outcome of the study was adherence to tamoxifen therapy by evaluating 12-month medication-refill data with medication possession ratio (MPR) and using a simplified medication adherence scale (SMAQ) in a subjective assessment.ResultsA total of 162 patients were recruited (87 intervention and 75 control). Trained nurses delivered education and provided literacy material, gave additional empathetic counselling, phone call reminders, and monitoring of medication refill at the intervention hospitals. Adherence according to MPR at 12 months was high in both the intervention (90%) and control sites (79.3%) (P = .302). The SMAQ revealed that adherence at intervention sites was 70% compared with 44.8% in the control sites (P = .036) at 12 months. Persistence to therapy was found to be 91.2% in the intervention and 77.8% in the control sites during the one-year period (P = .010).ConclusionBreast nurses can improve cost-effective endocrine therapy adherence at peripheral hospitals in low-resource settings. We recommend such task sharing to overcome the shortage of oncologists and distances to central cancer centers.     

Beta-receptor blockader therapy in the acute stage of myocardial infarct pathophysiological basis

The causal connection between the coronary occlusion and the necrosis of the myocardium, as it is verified again and again, is not unequivocal. The favourable effects of the beta-receptorblockers in the acute phase of the infarction of the height of the ST-elevations, the later levels of the CPK and the prognosis of the patients plead for the essential causal importance of the catecholamines in the infarctional process. The catecholamines have an effect on the myocardium increasing the contraction and dissipating oxygen. Through activations of the metabolism in the vascular wall they lead to subintimal swellings and to lesions of the endothelium and increase the aggregation of the thrombocytes. With the decreasing pH, value the flexibility of erythrocytes lowers and thus the microcirculation. Via positive feed-backs the acidosis of the myocardium increases, which via activation of lysosomal enzymes leads to the necrosis of the myocardium. beta-receptorblockers reduced the myocardial contractility, the increased glycogenolysis and the increased activity of the respiratory chains. The lesion of the vascular wall, the aggregation of thrombocytes and the decrease of pH are inhibited, by means of which the spreading conditions of the necrosis deteriorate. By the early application of the beta-receptor blockers the patho-mechanisms lying still in the functional region can be inhibited, thus the danger of early disturbances of rhythm and of the early cardiogenic shock. With the deterioration of the conditions of necrotization the prognosis of the patients with infarction improves.     

Extensively drug-resistant (XDR) Neisseria gonorrhoeae causing possible gonorrhoea treatment failure with ceftriaxone plus azithromycin in Austria,April 2022

We describe a gonorrhoea case with ceftriaxone plus high-level azithromycin resistance. In April 2022, an Austrian heterosexual male was diagnosed with gonorrhoea after sexual intercourse with a female sex worker in Cambodia. Recommended treatment with ceftriaxone (1 g) plus azithromycin (1.5 g) possibly failed. Worryingly, this is the second strain in an Asian Neisseria gonorrhoeae genomic sublineage including high-level azithromycin-resistant strains that developed ceftriaxone resistance by acquisition of mosaic penA-60.001. Enhanced resistance surveillance and actions are imperative to prevent spread.     

Hodgkin Lymphoma after Disseminated Mycobacterium genavense Infection,Germany

Mycobacterium genavense infection, a rare nontuberculous mycobacteria infection, occurs in heavily immunocompromised patients (i.e., those with advanced HIV disease, genetic disorders, or acquired immunologic disorders and those undergoing immunosuppressive therapy). We report a case of disseminated M. genavense infection preceding Hodgkin lymphoma in a patient without obvious risk factors for this infection.