Afatinib use in recurrent epithelial ovarian carcinoma.

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations

Investigating the Acceptability and Tolerability of tDCS in Patients with OCD - A Feasibility Study

© 2021 University of Hertfordshire.Introduction: Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disorder which often proves refractory to current treatment approaches1. Transcranial Direct Current Stimulation (tDCS), a non-invasive form of neurostimulation, with potential for development as a self-administered intervention, has shown potential as a safe and efficacious treatment for OCD in a small number of trials2. The two most promising stimulation sites are located above the orbitofrontal cortex (OFC) and the supplementary motor area (SMA). The aim of this feasibility study was to inform the development of a definitive trial, focussing on the acceptability, safety of the intervention, feasibility of recruitment, adherence and tolerability to tDCS and study assessments and the size of the treatment-effect. Due to COVID-19 this study was paused in March 2020 and restarted in July 2020, consequently facing the challenges of recruiting and continuing face-to-face research during the pandemic. This abstract presents acceptability and safety of the intervention as well as the feasibility of recruitment, adherence and tolerability of tDCS in patients with OCD. Method: Potential participants were identified from OCD clinics, primary health care services (e.g. IAPTs), charity/support networks, advertisements and trust databases across two sites (Hertfordshire Partnership and Southampton). Individuals were screened, then randomised if eligible, receiving three courses of tDCS (SMA, OFC and sham), randomly allocated and given in counterbalanced order. Each course comprised four sessions of 20-minute stimulations, delivered over two consecutive days, separated by at least a four-week washout period. Participants were evaluated at baseline, 1, 2 and 4 hours after stimulation. Follow-up assessments were conducted via telephone at 24 hours, 7 and 14 days following the last stimulation of each round with a final assessment 28 days after the third round. Intervention-related adverse events (AEs) were also recorded at each time point, using a questionnaire specific to tDCS3. Results: A total of 135 individuals were identified as potentially eligible (through clinics or self-referral), of which 36 consented to eligibility screening. Four withdrew consent/were lost to follow up, so screening was completed for 32. Subsequently, 16 were excluded through ineligibility (n=9), withdrawal (n=2) or loss to follow up (n=1), with the remaining 20 randomised. One participant withdrew prior to intervention round one and another prior to round two, both due to COVID-19 anxiety. All other participants (n=18, 90% of those randomised) completed all three intervention rounds. However, one individual was unable to attend day two of round two due to unconnected ill-health. Across all tDCS types, the most commonly reported AEs were sleepiness (18.7% of sessions), trouble concentrating (13.0%) and headache (12.2%), with other AE types present at <7% of sessions. Itching (0.8%) and scalp pain (1.0%) were reported least often. Discussion: Despite the impact of COVID-19, this study successfully restarted after suspension with few adjustments, meeting the revised target sample with minimal participant drop-out. Reasons for drop-out were unrelated to the intervention itself, with some participants delayed or experiencing pandemic-related anxiety. This study presents a safe intervention which was accepted, adhered to and tolerated by OCD patients, even amid a pandemic.Peer reviewe

Gender, time-Use, and energy expenditures in rural communities in India and Nepal

Women’s patterns of time-use, which proxy the work burdens associated with productive and reproductive activities, are an important determinant of nutrition and well-being in LMICs. However, there is a lack of empirical evidence on how patterns of time-use translate into patterns of physical activity and energy expenditure, particularly in rural areas where seasonal agricultural labour plays such an important role. We address this gap by integrating energy expenditure data derived from wearable tri-axial accelerometers with time-use data from conventional recall-based surveys. Using datasets from agricultural households in four rural communities in India and Nepal, our results show that there are significant gender differences in the patterns of time-use and energy expenditure. Men and women participate equally in productive work, however women shoulder most of the additional reproductive work burdens in rural households at the expense of leisure opportunities. Our results provide insights into women’s responses to opportunities for productive work and highlight the nature of trade-offs they fac

Combining mass spectrometry and genetic labeling in mice to report TRP channel expression

Transient receptor potential (TRP) ion channels play important roles in fundamental biological processes throughout the body of humans and mice. TRP channel dysfunction manifests in different disease states, therefore, these channels may represent promising therapeutic targets in treating these conditions. Many TRP channels are expressed in several organs suggesting multiple functions and making it challenging to untangle the systemic pathophysiology of TRP dysfunction. Detailed characterization of the expression pattern of the individual TRP channels throughout the organism is thus essential to interpret data such as those derived from systemic phenotyping of global TRP knockout mice. Murine TRP channel reporter strains enable reliable labeling of TRP expression with a fluorescent marker. Here we present an optimized method to visualize primary TRP-expressing cells with single cell resolution throughout the entire organism. In parallel, we methodically combine systemic gene expression profiling with an adjusted mass spectrometry protocol to document acute protein levels in selected organs of interest. The TRP protein expression data are then correlated with the GFP reporter expression data. The combined methodological approach presented here can be adopted to generate expression data for other genes of interest and reporter mice. • We present an optimized method to systemically characterize gene expression in fluorescent reporter mouse strains with a single cell resolution. • We methodically combine systemic gene expression profiling with an adjusted mass spectrometry protocol to document acute protein levels in selected organs of interest in mice

Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca2+ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca2+ uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca2+ uptake. Recently, MCU has been shown to modulate Ca2+ signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulationspecific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that ‘chronic’ loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca2+ uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs

Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases

Regulation of ClC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases.BackgroundClC-Ka and ClC-Kb, chloride channels participating in renal tubular Cl− transport, require the coexpression of barttin to become functional. Mutations of the barttin gene lead to the Bartter's syndrome variant BSND, characterized by congenital deafness and severe renal salt wasting. Barttin bears a proline-tyrosine motif, a target structure for the ubiquitin ligase Nedd4-2, which mediates the clearance of channel proteins from the cell membrane. Nedd4-2 is, in turn, a target of the serum- and glucocorticoid-inducible kinase SGK1, which phosphorylates and, thus, inactivates the ubiquitin ligase. ClC-Ka also possesses a SGK1 consensus site in its sequence. We hypothesized that ClC-Ka/barttin is stimulated by SGK1, and down-regulated by Nedd4-2, an effect that may be reversed by SGK1 and its isoforms, SGK2 or SGK3.MethodsTo test this hypothesis, ClC-Ka/barttin was heterologously expressed in Xenopus oocytes with or without the additional expression of Nedd4-2, SGK1, SGK2, SGK3, constitutively active S422DSGK1, or inactive K127NSGK1.ResultsExpression of ClC-Ka/barttin induced a slightly inwardly rectifying current that was significantly decreased upon coexpression of Nedd4-2, but not the catalytically inactive mutant C938SNedd4-2. The coexpression of S422DSGK1, SGK1, or SGK3, but not SGK2 or K127NSGK1 significantly stimulated the current. Moreover, S422DSGK1, SGK1, and SGK3 also phosphorylated Nedd4-2 and thereby inhibited Nedd4-2 binding to its target. The down-regulation of ClC-Ka/barttin by Nedd4-2 was abolished by elimination of the PY motif in barttin.ConclusionClC-Ka/barttin channels are regulated by SGK1 and SGK3, which may thus participate in the regulation of transport in kidney and inner ear

The delivery of practitioner led online telehealth interventions that use psychological therapies to support mental health: a systematic review protocol

The review question is: What type of practitioner led online Telehealth interventions that use psychological therapies are being delivered to support mental health and how effective are they? The review objectives are: 1. To identify and describe practitioner led online Telehealth interventions that use psychological therapies to support mental health. 2. To assess the utility and effectiveness of practitioner led online Telehealth interventions that use psychological therapies to support mental health. 3. What are the barriers and facilitators of implementing and engagement with practitioner led online Telehealth interventions that use psychological therapies to support mental health

Socioeconomic differences in recruitment and sickness absence in a large NHS health organisation: a cross-sectional study

OBJECTIVE: This study investigates the distribution of the workforce of one large National Health Service (NHS) employer in relation to socioeconomic deprivation and how sickness absence rates varied across these levels of deprivation. DESIGN: Share of the working age population that was employed at the NHS organisation mapped by area deprivation. The study used negative binomial regression models to investigate the extent to which wage level, occupational group and area deprivation were associated with sickness absence among employees. SETTING: The study used electronic staff records (2018–2019) of a large NHS organisation in the North West of England. RESULTS: In the most deprived areas, an additional person per 1000 working age population were employed at this NHS organisation compared with the most affluent areas. Employees from the most deprived quintile had 1.41 (95% CI 1.16 to 1.70) times the higher sickness rates than the employees from the least deprived quintile, when adjusting for age and sex. These differences were largely explained by differences in wage levels and occupation groups, with the lowest wage employees having 2.5 (95% CI 1.87 to 3.42) times the sickness absence rate as the highest wage group and the nursing and midwifery employees having 1.8 (95% CI 1.50 to 2.24) times the sickness absence rate as the administrative and clerical group. CONCLUSION: This large NHS organisation employed people disproportionately from deprived areas. They were considerably more likely to experience sickness absence compared with people from affluent areas. This appears to be because they were more likely to be in lower wage employment and employed in nursing and nursing assistant. Workplace health policies need to target these workers, adapting to their needs while enabling improvements in their working conditions, pay and career progression