1,271 research outputs found
Cellular and clinical impact of Haploinsufficiency for genes involved in ATR signaling
Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders--a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome--in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship
Expressed emotion and wellbeing in South Asian heritage families living in the UK
The primary aim of this paper was to understand expressed emotion (EE) and its relationship to wellbeing in South Asians (SAs) living in the UK. A total of 529 participants of South Asian heritage were recruited from the UK and completed an online survey consisting of the family questionnaire, the level of expressed emotion scale (LEE), warmth measure, the hospital anxiety and depression scale. Components of EE and wellbeing were investigated using network analysis. Overall, the participants were classified as low EE for criticism, but high for emotional overinvolvement. They scored relatively high on the warmth scale. LEE scores were in the middle range. The network analysis revealed unique associations between EE subscales and symptoms of depression and anxiety, and highlighted positive aspects of EE. The network analysis also highlighted differences in EE between parents and partner. The findings provide an overview of the interactions and influence of EE variables within this population. Future research should focus on the differences between SA ethnicities and religions; differentiating between intrusive and non-intrusive involvement may help further explain part of the variance between variables; exploring first and second-generation immigrants would help discover the impact of acculturation and intergenerational trauma on EE
The effects of high intensity interval training on quality of life: a systematic review and meta-analysis.
oai:repository.uel.ac.uk:8x31wAim:
This study aimed to ascertain the impact of high intensity interval training (HIIT) on physical, mental, and overall quality of life (QoL) through a comprehensive systematic review and meta-analysis.
Subject and Methods:
A systematic search for relevant trials was performed via PubMed, the Cochrane Library and Web of science as well as the manual screening of prior meta-analyses and their respective reference lists (PROSPERO reference: CRD42022326576). Adult controlled trials investigating the effects of a >2-week HIIT intervention with an eligible non-intervention control group were considered. As the primary outcome, studies were required to include at least one measure of physical and/or mental and/or overall QoL, on any validated QoL domain, pre and post intervention.
Results:
Twenty-two studies with twenty-four effect sizes were included; seventeen comparing HIIT and overall QoL, fourteen comparing HIIT and physical QoL and thirteen studies comparing HIIT and mental QoL. There was a statistically significant improvement in physical (SMD= 0.405, 95% CI: 0.110- 0.700, p= 0.007), mental (SMD= 0.473, 95% CI: 0.043 ā0.902, p=0.031) and overall QoL (SMD= 0.554, 95% CI 0.210-0.898, p=0.002) following a program of HIIT. Secondary analysis of 5 studies comparing HIIT against moderate intensity continuous training demonstrated no significant difference in improvement between the two modes (SMD= -0.094, CI= -0.506-0.318, p=0.655).
Conclusion:
Engaging in HIIT produces statistically significant improvements in physical, mental, and overall quality of life in clinical and non-clinical populations at a small to moderate effect size. Furthermore, HIIT appears as effective as MICT in improving overall QoL, offering a more time-efficient exercise option
Tuberculosis stigma as a social determinant of health: a systematic mapping review of research in low incidence countries
Highlights
ā¢Tuberculosis (TB)-related stigma is an important social determinant of health that can impact health-seeking practices and illness management.
ā¢Much research on TB-related stigma has been conducted in high incidence countries.
ā¢This study aimed to systematically map out the research in low incidence countries.
ā¢Few studies included stigma as a substantive topic; only one study aimed to reduce stigma.
ā¢Both TB control programmes and media reporting were implicated in the production of stigma.
ā¢Few studies theorized how stigma intersects with the social and structural determinants of health.
ā¢Future interventions to reduce stigma would benefit from a stronger theoretical underpinning in relation to stigma and the intersection with the social determinants.
Summary
Tuberculosis (TB)-related stigma is an important social determinant of health. Research generally highlights how stigma can have a considerable impact on individuals and communities, including delays in seeking health care and adherence to treatment. There is scant research into the assessment of TB-related stigma in low incidence countries. This study aimed to systematically map out the research into stigma. A particular emphasis was placed on the methods employed to measure stigma, the conceptual frameworks used to understand stigma, and whether structural factors were theorized. Twenty-two studies were identified; the majority adopted a qualitative approach and aimed to assess knowledge, attitudes, and beliefs about TB. Few studies included stigma as a substantive topic. Only one study aimed to reduce stigma. A number of studies suggested that TB control measures and representations of migrants in the media reporting of TB were implicated in the production of stigma. The paucity of conceptual models and theories about how the social and structural determinants intersect with stigma was apparent. Future interventions to reduce stigma, and measurements of effectiveness, would benefit from a stronger theoretical underpinning in relation to TB stigma and the intersection between the social and structural determinants of health
CE17015
In the southwest of Ireland and the Celtic Sea (ICES Divisions VIIaS, g & j), herring are an important commercial species to the pelagic and polyvalent fleet. For a period in the 1970s and1980s, larval surveys were conducted for herring in this area. However, since 1989, acoustic surveys have been carried out, and currently are the only tuning indices available for this stock. In the Celtic Sea and VIIj, herring acoustic surveys have been carried out since 1989. Since 2004 the survey has been fixed in October and carried out onboard the RV Celtic Explorer. The geographical confines of the annual 21 day survey have been modified in recent years to include areas to the south of the main winter spawning grounds in an effort to identify the whereabouts of winter spawning fish before the annual inshore spawning migration. Spatial resolution of acoustic transects has been increased over the entire south coast survey area. The acoustic component of the survey has been further complemented since 2004 by detailed hydrographic, marine mammal and seabird surveys
Examining the relationship between work-related factors and work-family-related factors on work-family conflict
The current work-family conflict literature is characterized by limitations in focus and methodology, particularly with a failure to link work-family conflict with work-family policies. This study compares the influence of work-related factors and work-family related factors on work-family conflict in two directions. A local government organization in New Zealand was the setting. Findings show that work factors account for a significant component of both work-to-family and family-to-work conflict, although this is far greater on work-family conflict. Work-family practice use had little influence on work-family practices was found to positively associate with family-work conflict. Overall, the finds suggest managers in search of reducing employee conflict should focus directly upon work factors such as workload, rather than see to use work-family practices as the primary way to reduce conflict
miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer
Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630ās regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630ās regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patientsā response to HER-targeting drugs
Antarctica on foot: the energy expended to walk, ski and man-haul
Polar exploration often involves travelling on foot and thus is physically intensive, with long-term excursions typically resulting in weight loss. Few studies have investigated the energy expended under such circumstances. Here, we present a range of prediction equations for estimating metabolic rate from heart rate or accelerometry data for specific activities including skiing and man-hauling which can be applied to either short- or long-term excursions. We also use some of these equations to estimate the energy expended undertaking various activities by a team of explorers while attempting to traverse the Antarctic continent during the austral winter of 2013 (as part of the White Mars Project during The Coldest Journey). Calibration equations based on either accelerometry data (from which overall dynamic body acceleration, ODBA, is derived) or heart rate showed good relationships with rate of oxygen consumption, particularly when person height was included. Periods of skiing and man- hauling on The Coldest Journey were estimated to be more energetically demanding (30.0 and 31.1 kJ minā1, respectively) than walking (24.9 kJ minā1), or other outdoor work (21.9 kJ minā1). Estimates of energy expenditure during The Coldest Journey were similar to measures obtained in previous, comparative scenarios. We hope that future expeditions to Antarctica will use these prediction equations to further our understanding of the energy costs of exploring Antarctica and the nutritional requirements needed to guard against emaciation
Valvular Heart Disease in Patients with Chronic Kidney Disease
Valvular heart disease (VHD) is highly prevalent in patients with chronic kidney disease (CKD) from the early stages to end-stage renal disease (ESRD). Aortic and mitral valves are the most frequently affected, leading to aortic valve and/or mitral annular calcification, which, in turn, causes either valve stenosis or regurgitation at an accelerated rate compared with the general population. Tricuspid regurgitation is also prevalent in CKD and ESRD, and haemodialysis patients are at an increasingly high risk of infective endocarditis. As for pathophysiology, several mechanisms causing VHD in CKD have been proposed, highlighting the complexity of the process. Echocardiography constitutes the gold standard for the assessment of VHD in CKD/ESRD patients, despite the progress of other imaging modalities. With regard to treatment, the existing 2017 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines on the management of VHD addressing patients with normal kidney function are also applied to patients with CKD/ESRD
Protocol for a feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients
IntroductionOxygen is the most commonly administered drug to mechanically ventilated critically ill adults, yet little is known about the optimum oxygen saturation (SpO2) target for these patients; the current standard of care is an SpO2of 96% or above. Small pilot studies have demonstrated that permissive hypoxaemia (aiming for a lower SpO2than normal by using a lower fractional inspired oxygen concentration (FIO2)) can be achieved in the critically ill and appears to be safe. This approach has not been evaluated in a National Health Service setting. It is possible that permissive hypoxaemia may be beneficial to critically ill patients thus it requires robust evaluation.Methods and analysisTargeted OXygen therapY in Critical illness (TOXYC) is a feasibility randomised controlled trial (RCT) to evaluate whether recruiting patients to a study of permissive hypoxaemia is possible in the UK. It will also investigate biological mechanisms that may underlie the links between oxygenation and patient outcomes. Mechanically ventilated patients with respiratory failure will be recruited from critical care units at two sites and randomised (1:1 ratio) to an SpO2target of either 88%ā92% or ā„96% while intubated with an endotracheal tube. Clinical teams can adjust FIO2and ventilator settings as they wish to achieve these targets. Clinical information will be collected before, during and after the intervention and blood samples taken to measure markers of systemic oxidative stress. The primary outcome of this study is feasibility, which will be assessed by recruitment rate, protocol adherence and withdrawal rates. Secondary outcomes will include a comparison of standard critical care outcome measures between the two intervention groups, and the measurement of biomarkers of systemic oxidative stress. The results will be used to calculate a sample size, likely number of sites and overall length of time required for a subsequent large multicentre RCT.Ethics and disseminationThis study was approved by the London - Harrow Research Ethics Committee on 2 November 2017 (REC Reference 17/LO/1334) and received HRA approval on 13 November 2017. Results from this study will be disseminated in peer-reviewed journals, at medical and scientific meetings, in the NIHR Journals Library and patient information websites.Trial registration numberNCT03287466; Pre-results.</jats:sec
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