Metastatic disease of the breast and local recurrence

Multimodality primary therapies for breast cancer combined with earlier detection have led to a sharp decline in the death rate from breast cancer in the UK over the last 40 years in the face of a rising incidence. The latest UK statistics from Cancer Research UK report 55,122 new cases of breast cancer in 2015 with 11,563 deaths from breast cancer recorded in 2016. Crudely, this equates to a cure rate of around 80% for all comers and demonstrates a clear improvement in outcome with 50,285 new cases in 2011 and 11,716 deaths in 2012. Despite this good news, there are still significant numbers of women (and men) who suffer from either a local recurrence or metastatic disease following apparently successful treatment for early breast cancer (Stage I to III). Only a minority of individuals, 6.6% with the stage recorded at diagnosis, present with stage IV disease. This review considers the treatment options available to individuals with locally recurrent and advanced breast cancer (ABC).     

Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis

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Leadership Development in UK Medical Training: Pedagogical Theory and Practice

Phenomenon: The central role of clinical leadership in achieving the vision of quality and productivity could be attained by investing in its development in postgraduate medical education. Approach: A critical review of selected literature is presented. Findings: The author identifies some of the main theoretical constructs related to leadership; the pedagogical underpinning of medical leadership programs; their learning objectives; and the mixture of methods, individual and collective, to achieve them. Insights: How to best develop leadership through medical education remains an open debate. Experiential learning, reflective practice, action learning, and mentoring could provide the foundations of leadership development. Application of the aforementioned should be cautious due to limitations of the concept of leadership as currently promoted and lack of robust evaluation methodologies.     

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 × 10⁻⁸). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Electronic clinical records in primary care for estimating disease burden and management. An example of COPD

Chronic obstructive pulmonary disease (COPD) is a significant health problem in developed countries. We aimed to estimate the prevalence of COPD in a single Spanish healthcare area. We also aimed to assess if there are any differences in prevalence and spirometry use among primary care services by utilizing already registered information. We designed a cross-sectional study to determine the prevalence of COPD and the performance of spirometries in each primary care service. A total of 8,444 patients were diagnosed with COPD, with a prevalence of 2.6% for individuals older than 39 years. The prevalence increased with age and was much higher in men. Significant heterogeneity was found in the prevalence of COPD and spirometry use among primary care services. COPD was underdiagnosed and there was wide variability in spirometry use in our area. Greater efforts are needed to diagnose COPD in order to improve its clinical outcomes and to refine registries so that they can be used as reliable sources of information     

Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep

Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial‐ and muscular‐dependent pathways. This was associated with an enhanced nitric oxide‐dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN.     

基于VOSviewer的2019新型冠状病毒病中医临床诊疗可视化分析＊

目的 通过对公开发表在网络和数据库的有关中医药治疗2019新型冠状病毒肺炎（corona virus disease 2019，COVID-19）的文献进行方、药、证的可视化分析，客观全面的对COVID-19的中医药治疗进行探讨，为现代中医临床诊疗提供参考。方法 本文选用运用文献计量学方法和VOSviewer可视化软件对纳入文献中的用药情况进行数据拆分、整理和分析。结果 本研究高质量数据的主要期刊来源是核心期刊《中医杂志》；新冠临床用方以解表清热剂、开窍补益剂、辟秽祛湿剂为主；临床用药以解表药、清热解毒药、化湿祛痰药以及补益药为主；临床治病思路以六经辨证、三焦辨证和卫气营血辨证理论为指导；临床常见证型为湿、热、寒、毒相关证型；重视新冠前期预防以及后期恢复调养；治疗过程用药考究，注重养阴与祛邪并进。结论 新冠的中医临床诊治考病全面，并注重养阴与祛邪并进，可为官方制定治疗方案提供参考。