Interstellar Carbon in Translucent Sightlines

We report interstellar C II column densities or upper limits determined from weak absorption of the 2325.4029 A intersystem transition observed in six translucent sightlines with STIS. The sightlines sample a wide range of interstellar characteristics including total-to-selective extinction, R_{V} = 2.6 - 5.1; average hydrogen density along the sightline, = 3 - 14 cm^{-3}; and fraction of H in molecular form, 0 - 40%. Four of the sightlines, those toward HD 37021, HD 37061, HD 147888 and HD 207198, have interstellar gas-phase abundances that are consistent with the diffuse sightline ratio of 161 +/- 17 carbon atoms in the gas per million hydrogen nuclei. We note that while it has a gas-phase carbon abundance that is consistent with the other sightlines, a large fraction of the C II toward HD 37061 is in an excited state. The sightline toward HD 152590 has a measured interstellar gas-phase carbon abundance that is well above the diffuse sightline average; the column density of C in this sightline may be overestimated due to noise structure in the data. Toward HD 27778 we find a 3 sigma abundance upper limit of <108 C atoms in the gas per million H, a substantially enhanced depletion of C as compared to the diffuse sightline value. The interstellar characteristics toward HD 27778 are otherwise not extreme among the sample except for an unusually large abundance of CO molecules in the gas.Comment: Accepted for publication in the Astrophysical Journa

The Effects of Cardiac Fibroblasts on Cardiac Myocyte Structure and Excitation-Contraction Coupling Through Paracrine Mediators

Cardiac fibroblasts are the most numerous cells within the heart. Their traditional roles are the maintenance of the extracellular matrix to support the structure and contraction of the heart, and their activation and production of increased extracellular matrix in disease. Over the past 15 years, evidence has grown that shows fibroblasts are capable of modulating myocyte function. This is achieved through paracrine mediators, the release of biologically active soluble substances into the local environment, and through direct cell contact, involving gap junctions and mechanical connections. Fibroblasts can also modulate myocyte function indirectly through modification of the extracellular matrix which can transfer various signals to myocytes. However, research into the interaction between fibroblasts and myocytes has been largely limited to using neonatal cells and fibroblasts that have been maintained in culture. This thesis sets out to examine the paracrine effects of fibroblasts on myocyte structure and excitation contraction coupling. Adult myocytes and, where possible, fibroblasts before their activation in culture were used. The thesis also aimed to determine whether these effects are different using fibroblasts after pressure overload of the myocardium and potential mediators involved in the effects. Initial studies looked at the effect of normal rat cardiac fibroblasts isolated from healthy rat hearts, and showed that these fibroblasts reduced myocyte viability, induced myocyte hypertrophy and increased the amplitude of the Ca2+ transient. We then compared the effect of fibroblasts from pressure overloaded hearts with control fibroblasts. The pressure overloaded fibroblasts caused a similar reduction in myocyte viability and also induced myocyte hypertrophy. However, the functional effects were different and the Ca2+ transient amplitude was reduced in myocytes co-cultured with pressure overload fibroblasts. TGF-β was elevated in the both pressure overload and control fibroblasts co-cultures and was therefore investigated as the potential mediator of the effects. It was found that fibroblast derived TGF-β directly causes myocyte hypertrophy, whereas the other effects are due to more complex signalling with the involvement of secondary mediators released from the fibroblasts in response to TGF-β signalling. Finally, we investigated the paracrine effects of cultured canine fibroblasts on the electrical activity of adult myocardium using canine myocardial slices. These are thin viable slices of the left ventricle and allowed us to investigate the field potential and the conduction velocity of intact adult myocardium. It was found that fibroblasts-derived paracrine mediators altered the conduction velocity of these slices. This work supports the growing body of evidence that fibroblasts are capable of modulating myocyte structure and function and, specifically, myocyte excitation contraction coupling. We have shown that these effects are evident in adult cells and are altered using fibroblasts from normal and diseased heart. Furthermore, we have shown that TGF-β appears to be central to these effects.Open Acces

“Physical touch” contact points used in procedural touch, from educational checklists, by undergraduate medical students.

Introduction: Despite being a fundamental form of human interaction, touch has received little focus in the literature, particularly as a tool in primary care consultations. The GMC outlines, in Outcomes for Graduates, that clinicians need to practice person-centred care, integrating safety and sensitivity into every consultation with a patient. As described by Cocksedge, George and Chew-graham, 2013, touch may be “procedural touch” (part of a clinical task) or “expressive touch” (physical contact unrelated to a procedure). Methods: A qualitative study was conducted to identify which anatomical locations are most touched in clinical examinations and procedures by clinicians. Physical Examinations and Procedures were identified via the GMC Medical Licensing Assessment (MLA) content map. Data was collected from Objective Structure Clinical Examination (OSCE) checklists from reputable digital sources and analysed quantitatively. Results: 37 checklists were analysed, with the Upper Limb, and Head and Neck, bodily regions being the most frequently touched across procedures and examinations. There were discrepancies between procedures and examinations, in terms of the proportion of required palpation such as otoscopy and examination of the ear. The blood transfusion procedural checklist lacked significant physical touch, which possibly contrasts the patient’s feelings around the daunting experience. Conclusion: This research illustrates the frequent interaction with the upper limb for physical interaction between patients and clinicians during examinations or procedures, and the importance of educating students to demonstrate compassion and provide reassurance in a socially acceptable manner, while simultaneously assessing patients for signs of illness in the consultation. The hand emerged as a primary site of physician- patient interaction, so may warrant targeted research into how medical students are educated on the use of touch in their clinical practice. The project findings emphasize the necessity for further inquiry into the perspectives of medical students on the inclusion of expressive and procedural touch in their skills education

Reduced Na+ and higher K+ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Brugada syndrome (BrS) is associated with ventricular tachycardia originating particularly in the right ventricle (RV). We explore electrophysiological features predisposing to such arrhythmic tendency and their possible RV localization in a heterozygotic Scn5a+/− murine model. Nav1.5 mRNA and protein expression were lower in Scn5a+/− than wild-type (WT), with a further reduction in the RV compared with the left ventricle (LV). RVs showed higher expression levels of Kv4.2, Kv4.3 and KChIP2 in both Scn5a+/− and WT. Action potential upstroke velocity and maximum Na+ current (INa) density were correspondingly decreased in Scn5a+/−, with a further reduction in the RV. The voltage dependence of inactivation was shifted to more negative values in Scn5a+/−. These findings are predictive of a localized depolarization abnormality leading to slowed conduction. Persistent Na+ current (IpNa) density was decreased in a similar pattern to INa. RV transient outward current (Ito) density was greater than LV in both WT and Scn5a+/−, and had larger time constants of inactivation. These findings were also consistent with the observation that AP durations were smallest in the RV of Scn5a+/−, fulfilling predictions of an increased heterogeneity of repolarization as an additional possible electrophysiological mechanism for arrhythmogenesis in BrS

Diagnosis, treatment, and survival from kidney cancer: real‐world National Health Service England data between 2013 and 2019

Objectives: To report the NHS Digital (NHSD) data for patients diagnosed with kidney cancer (KC) in England. We explore the incidence, route to diagnosis (RTD), treatment, and survival patterns from 2013 to 2019. Materials and Methods: Data was extracted from the Cancer Data NHSD portal for International Classification of Diseases, 10th edition coded KC; this included Cancer Registry data, Hospital Episode Statistics, and cancer waiting times data. Results: Registrations included 66 696 individuals with KC. Incidence of new KC diagnoses increased (8998 in 2013, to 10 232 in 2019), but the age‐standardised rates were stable (18.7–19.4/100 000 population). Almost half of patients (30 340 [45.5%]) were aged 0–70 years and the cohort were most frequently diagnosed with Stage 1–2 KC (n = 26 297 [39.4%]). Most patients were diagnosed through non‐urgent general practitioner referrals (n = 16 814 [30.4%]), followed by 2‐week‐wait (n = 15 472 [28.0%]) and emergency routes (n = 11 796 [21.3%]), with older patients (aged ≥70 years), Stage 4 KCs, and patients with non‐specified renal cell carcinoma being significantly more likely to present through the emergency route (all P &lt; 0.001). Invasive treatment (surgery or ablation), radiotherapy, or systemic anti‐cancer therapy use varied with disease stage, patient factors, and treatment network (Cancer Alliance). Survival outcomes differed by Stage, histological subtype, and social deprivation class (P &lt; 0.001). Age‐standardised mortality rates did not change over the study duration, although immunotherapy usage is likely not captured in this study timeline. Conclusion: The NHSD resource provides useful insight about the incidence, diagnostic pathways, treatment, and survival of patients with KC in England and a useful benchmark for the upcoming commissioned National Kidney Cancer Audit. The RTD data may be limited by incidental diagnoses, which could confound the high proportion of ‘emergency’ diagnoses. Importantly, survival outcomes remained relatively unchanged

Olly! (OnLine Learning for You!): Browser based instant messaging for online learning

This paper outlines the design principles and software architecture of Olly! (OnLine Learning for You!). Olly! is an open source, browser based instant messaging tool designed specifically for conducting classes online. Built on the AJAX scripting model, it is crossbrowser compatible and universally available to anyone with access to a computer. Data generated by the tool (text based conversations, file uploads, etc.) is retained by the institution offering the service. While currently a prototype, the future development of Olly! will produce a release candidate for use in a variety of online learning applications