Use of δ18Oatm in dating a Tibetan ice core record of Holocene/Late Glacial climate.

Ice cores from the northwestern Tibetan Plateau (NWTP) contain long records of regional climate variability, but refrozen meltwater and dust in these cores has hampered development of robust timescales. Here, we introduce an approach to dating the ice via the isotopic composition of atmospheric O2 in air bubbles (δ18Oatm), along with annual layer counting and radiocarbon dating. We provide a robust chronology for water isotope records (δ18Oice and d-excess) from three ice cores from the Guliya ice cap in the NWTP. The measurement of δ18Oatm, although common in polar ice core timescales, has rarely been used on ice cores from low-latitude, high-altitude glaciers due to (1) low air pressure, (2) the common presence of refrozen melt that adds dissolved gases and reduces the amount of air available for analysis, and (3) the respiratory consumption of molecular oxygen (O2) by micro-organisms in the ice, which fractionates the δ18O of O2 from the atmospheric value. Here, we make corrections for melt and respiration to address these complications. The resulting records of water isotopes from the Guliya ice cores reveal climatic variations over the last 15,000 y, the timings of which correspond to those observed in independently dated lake and speleothem records and confirm that the Guliya ice cap existed before the Holocene. The millennial-scale drivers of δ18Oice are complex and temporally variable; however, Guliya δ18Oice values since the mid-20th century are the highest since the beginning of the Holocene and have increased with regional air temperature.

The relationship between weight-related indicators and depressive symptoms during adolescence and adulthood: results from two twin studies.

BACKGROUND: The association between weight and depressive symptoms is well established, but the direction of effects remains unclear. Most studies rely on body mass index (BMI) as the sole weight indicator, with few examining the aetiology of the association between weight indicators and depressive symptoms. METHODS: We analysed data from the Twins Early Development Study (TEDS) and UK Adult Twin Registry (TwinsUK) (7658 and 2775 twin pairs, respectively). A phenotypic cross-lagged panel model assessed the directionality between BMI and depressive symptoms at ages 12, 16, and 21 years in TEDS. Bivariate correlations tested the phenotypic association between a range of weight indicators and depressive symptoms in TwinsUK. In both samples, structural equation modelling of twin data investigated genetic and environmental influences between weight indicators and depression. Sensitivity analyses included two-wave phenotypic cross-lagged panel models and the exclusion of those with a BMI <18.5. RESULTS: Within TEDS, the relationship between BMI and depression was bidirectional between ages 12 and 16 with a stronger influence of earlier BMI on later depression. The associations were unidirectional thereafter with depression at 16 influencing BMI at 21. Small genetic correlations were found between BMI and depression at ages 16 and 21, but not at 12. Within TwinsUK, depression was weakly correlated with weight indicators; therefore, it was not possible to generate precise estimates of genetic or environmental correlations. CONCLUSIONS: The directionality of the relationship between BMI and depression appears to be developmentally sensitive. Further research with larger genetically informative samples is needed to estimate the aetiological influence on these associations.

Changes in the adult consequences of adolescent mental ill-health: findings from the 1958 and 1970 British birth cohorts.

BACKGROUND: Adolescent mental health difficulties are increasing over time. However, it is not known whether their adulthood health and socio-economic sequelae are changing over time. METHODS: Participants (N = 31 349) are from two prospective national birth cohort studies: 1958 National Child Development Study (n = 16 091) and the 1970 British Cohort Study (n = 15 258). Adolescent mental health was operationalised both as traditional internalising and externalising factors and a hierarchical bi-factor. Associations between adolescent psychopathology and age 42 health and wellbeing (mental health, general health, life satisfaction), social (cohabitation, voting behaviour) and economic (education and employment) outcomes are estimated using linear and logistic multivariable regressions across cohorts, controlling for a wide range of early life potential confounding factors. RESULTS: The prevalence of adolescent mental health difficulties increased and their associations with midlife health, wellbeing, social and economic outcomes became more severe or remained similar between those born in 1958 and 1970. For instance, a stronger association with adolescent mental health difficulties was found for those born in 1970 for midlife psychological distress [odds ratio (OR) 1970 = 1.82 (1.65-1.99), OR 1958 = 1.60 (1.43-1.79)], cohabitation [OR 1970 = 0.64 (0.59-0.70), OR 1958 = 0.79 (0.72-0.87)], and professional occupations [OR 1970 = 0.75 (0.67-0.84), OR 1958 = 1.05 (0.88-1.24)]. The associations of externalising symptoms with later outcomes were mainly explained by their shared variance with internalising symptoms. CONCLUSION: The widening of mental health-based inequalities in midlife outcomes further supports the need to recognise that secular increases in adolescent mental health symptoms is a public health challenge with measurable negative consequences through the life-course. Increased public health efforts to minimise adverse outcomes are needed.

A cross-lagged twin study of emotional symptoms, social isolation and peer victimisation from early adolescence to emerging adulthood.

BACKGROUND: Emotional symptoms, such as anxiety and depressive symptoms, are common during adolescence, often persist over time, and can precede the emergence of severe anxiety and depressive disorders. Studies suggest that a vicious cycle of reciprocal influences between emotional symptoms and interpersonal difficulties may explain why some adolescents suffer from persisting emotional symptoms. However, the role of different types of interpersonal difficulties, such as social isolation and peer victimisation, in these reciprocal associations is still unclear. In addition, the lack of longitudinal twin studies conducted on emotional symptoms during adolescence means that the genetic and environmental contributions to these relationships during adolescence remain unknown. METHODS: Participants (N = 15,869) from the Twins Early Development Study completed self-reports of emotional symptoms, social isolation and peer victimisation at 12, 16 and 21 years old. A phenotypic cross-lagged model examined reciprocal associations between variables over time, and a genetic extension of this model examined the aetiology of the relationships between variables at each timepoint. RESULTS: First, emotional symptoms were reciprocally and independently associated with both social isolation and peer victimisation over time, indicating that different forms of interpersonal difficulties uniquely contributed to emotional symptoms during adolescence and vice versa. Second, early peer victimisation predicted later emotional symptoms via social isolation in mid-adolescence, indicating that social isolation may constitute an intermediate pathway through which peer victimisation predicts longer-term emotional symptoms. Finally, individual differences in emotional symptoms were mostly accounted for by non-shared environmental factors at each timepoint, and both gene-environment and individual-specific environmental mechanisms were involved in the relationships between emotional symptoms and interpersonal difficulties. CONCLUSIONS: Our study highlights the necessity to intervene early in adolescence to prevent the escalation of emotional symptoms over time and to consider social isolation and peer victimisation as important risk factors for the long-term persistence of emotional symptoms.

Characterising patterns of COVID-19 and long COVID symptoms: evidence from nine UK longitudinal studies.

Multiple studies across global populations have established the primary symptoms characterising Coronavirus Disease 2019 (COVID-19) and long COVID. However, as symptoms may also occur in the absence of COVID-19, a lack of appropriate controls has often meant that specificity of symptoms to acute COVID-19 or long COVID, and the extent and length of time for which they are elevated after COVID-19, could not be examined. We analysed individual symptom prevalences and characterised patterns of COVID-19 and long COVID symptoms across nine UK longitudinal studies, totalling over 42,000 participants. Conducting latent class analyses separately in three groups ('no COVID-19', 'COVID-19 in last 12 weeks', 'COVID-19 > 12 weeks ago'), the data did not support the presence of more than two distinct symptom patterns, representing high and low symptom burden, in each group. Comparing the high symptom burden classes between the 'COVID-19 in last 12 weeks' and 'no COVID-19' groups we identified symptoms characteristic of acute COVID-19, including loss of taste and smell, fatigue, cough, shortness of breath and muscle pains or aches. Comparing the high symptom burden classes between the 'COVID-19 > 12 weeks ago' and 'no COVID-19' groups we identified symptoms characteristic of long COVID, including fatigue, shortness of breath, muscle pain or aches, difficulty concentrating and chest tightness. The identified symptom patterns among individuals with COVID-19 > 12 weeks ago were strongly associated with self-reported length of time unable to function as normal due to COVID-19 symptoms, suggesting that the symptom pattern identified corresponds to long COVID. Building the evidence base regarding typical long COVID symptoms will improve diagnosis of this condition and the ability to elicit underlying biological mechanisms, leading to better patient access to treatment and services.

Pre-pandemic mental health and disruptions to healthcare, economic and housing outcomes during the COVID-19 pandemic: evidence from 12 UK longitudinal studies.

BACKGROUND: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable. AIMS: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing. METHOD: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies. RESULTS: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20-1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09-1.41) for disruption to procedures to 1.33 (95% CI 1.20-1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06-1.21) and income (OR 1.12, 95% CI 1.06 -1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00-1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18-1.32) or in one domain (OR 1.11, 95% CI 1.07-1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97-1.03). CONCLUSIONS: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities.

Disappearance of the last tropical glaciers in the Western Pacific Warm Pool (Papua, Indonesia) appears imminent.

The glaciers near Puncak Jaya in Papua, Indonesia, the highest peak between the Himalayas and the Andes, are the last remaining tropical glaciers in the West Pacific Warm Pool (WPWP). Here, we report the recent, rapid retreat of the glaciers near Puncak Jaya by quantifying the loss of ice coverage and reduction of ice thickness over the last 8 y. Photographs and measurements of a 30-m accumulation stake anchored to bedrock on the summit of one of these glaciers document a rapid pace in the loss of ice cover and a ∼5.4-fold increase in the thinning rate, which was augmented by the strong 2015-2016 El Niño. At the current rate of ice loss, these glaciers will likely disappear within the next decade. To further understand the mechanisms driving the observed retreat of these glaciers, 2 ∼32-m-long ice cores to bedrock recovered in mid-2010 are used to reconstruct the tropical Pacific climate variability over approximately the past half-century on a quasi-interannual timescale. The ice core oxygen isotopic ratios show a significant positive linear trend since 1964 CE (0.018 ± 0.008‰ per year; P < 0.03) and also suggest that the glaciers' retreat is augmented by El Niño-Southern Oscillation processes, such as convection and warming of the atmosphere and sea surface. These Papua glaciers provide the only tropical records of ice core-derived climate variability for the WPWP.

Geo-social gradients in predicted COVID-19 prevalence in Great Britain: results from 1 960 242 users of the COVID-19 Symptoms Study app.

Understanding the geographical distribution of COVID-19 through the general population is key to the provision of adequate healthcare services. Using self-reported data from 1 960 242 unique users in Great Britain (GB) of the COVID-19 Symptom Study app, we estimated that, concurrent to the GB government sanctioning lockdown, COVID-19 was distributed across GB, with evidence of 'urban hotspots'. We found a geo-social gradient associated with predicted disease prevalence suggesting urban areas and areas of higher deprivation are most affected. Our results demonstrate use of self-reported symptoms data to provide focus on geographical areas with identified risk factors.

Anxiety and depression symptoms after COVID-19 infection: results from the COVID Symptom Study app.

BACKGROUND: Mental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (eg, obesity and comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study. METHODS: We assessed anxiety and depression symptoms using two validated questionnaires in 413148 individuals between February and April 2021; 26998 had tested positive for SARS-CoV-2. We adjusted for physical and mental prepandemic comorbidities, body mass index (BMI), age and sex. FINDINGS: Overall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2-positive (30.4%) vs SARS-CoV-2-negative (26.1%) individuals. This association was small compared with the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants (≤40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) versus more distant (>120 days) infection, suggesting a short-term effect. INTERPRETATION: A small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than prepandemic.

Helping parents to help children overcome fear: The influence of a short video tutorial.

OBJECTIVES: Anxiety runs in families, and its transmission is largely environmental. However, studies rarely explore this process in clinically anxious parents or ask participants to face a genuine fear. We also do not know whether this process is modifiable. This study will explore these questions using a sample of clinically anxious parents. DESIGN: Experimental design comparing clinically anxious parents with non-anxious parents, and exploring the effects of a tutorial intervention versus a control group. METHODS: Parents with and without anxiety disorders and their children (5-9 years) participated (N = 72). Children chose two fearful animal stimuli. Parents helped the child approach the first in graded steps. The following parental behaviours were recorded: positive/negative verbal information; positive/negative modelling; encouragement/praising of approach/avoidance behaviours. Half the parents were then randomly assigned to a short video tutorial advising how to help children cope with fearful situations. The remainder watched a control video. The approach task was repeated with the second stimulus. RESULTS: Parenting behaviours fell into two categories: 'approach parenting' (encouraging/praising/modelling approach; positive verbal information) and 'avoidance parenting' (encouraging/praising/modelling avoidance; negative verbal information). The parenting tutorial increased 'approach parenting' and decreased 'avoidance parenting' and was associated with increased child approach towards fearful stimuli. This was not moderated by parent or child anxiety. CONCLUSIONS: Parenting, particularly 'avoidance parenting', is associated with children's approach and avoidance. A short video tutorial modified these parenting behaviours and reduced avoidance. These effects were apparent regardless of parent or child anxiety level. PRACTITIONER POINTS: Avoidance and approach parenting may influence children's response to fearful stimuli. Avoidance parenting may be more problematic than lack of approach parenting. Approach and avoidance parenting are amenable to manipulation by short video tutorial. Parenting improvement resulted in increased approach behaviour in children.

Preventing family transmission of anxiety: Feasibility RCT of a brief intervention for parents.

OBJECTIVES: Children of anxious parents are at high risk of anxiety disorders themselves. The evidence suggests that this is due to environmental rather than genetic factors. However, we currently do little to reduce this risk of transmission. There is evidence that supporting parenting in those with mental health difficulties can ameliorate this risk. Therefore, the objective of this study was to test the feasibility of a new one-session, group-based, preventive parenting intervention for parents with anxiety disorders. DESIGN: Feasibility Randomized Controlled Trial. METHODS: A total of 100 parents with anxiety disorders, recruited from adult mental health services in England (and child aged 3-9 years), were randomized to receive the new intervention (a 1-day, group workshop), or to treatment as usual. Children's anxiety disorder and anxiety symptoms were assessed to 12 months by outcome assessors who were blind to group allocation. Exploratory analyses were conducted on an intention to treat basis, as far as possible. RESULTS: A total of 51 participants were randomized to the intervention condition and 49 to the control condition (82% and 80% followed to 12 months, respectively). The attendance rate was 59%, and the intervention was highly acceptable to parents who received it. The RCT was feasible, and 12-month follow-up attrition rates were low. Children whose parents were in the control condition were 16.5% more likely to have an anxiety disorder at follow-up than those in the intervention group. No adverse events were reported. CONCLUSIONS: An inexpensive, light-touch, psycho-educational intervention may be useful in breaking the intergenerational cycle of transmission of anxiety disorders. A substantive trial is warranted. PRACTITIONER POINTS: Anxiety disorders run in families, but we currently do little to help anxious parents to raise confident children. A brief group workshop was highly acceptable to such parents and was very inexpensive to run. Children of parents who took part in the brief intervention were 16.5% less likely to have an anxiety disorder, 1 year later, than children whose parents were in the control group. This was a feasibility study, and while it showed that both the intervention and the research were feasible, the study needs replicating with a much larger sample. Many parents faced barriers to attending the workshop, and future efforts should focus on widening accessibility. We were unable to obtain sufficient self-report data from children, so the outcomes are based on parent report only.

Research Review: Childhood chronic physical illness and adult emotional health - a systematic review and meta-analysis.

BACKGROUND: Childhood chronic physical illness is associated with a greater vulnerability for emotional problems (i.e. depression and anxiety) in childhood. However, little is known about life-long effects of childhood chronic physical illness on mental health. The present study aims to systematically review evidence for associations between eight chronic physical illnesses with childhood onset (arthritis, asthma, cancer, chronic renal failure, congenital heart disease, cystic fibrosis, type 1 diabetes, and epilepsy) and adult emotional problems. METHODS: A database search of MEDLINE, PsycARTICLES, PsycINFO, and ScienceDirect was undertaken, and random effects meta-analyses were used to synthesise evidence from eligible studies. RESULTS: In total, 37 studies were eligible for the systematic review (n = 45,733) and of these, 34 studies were included in the meta-analyses (n = 45,358). There were overall associations between childhood chronic physical illness and adult depression (OR = 1.31; 95% CI [1.12, 1.54]) and anxiety (OR = 1.47; 95% CI [1.13, 1.92]). Separate meta-analyses for childhood asthma, type 1 diabetes and cancer were also conducted, with cancer being significantly associated with adult depression (OR = 1.19; 95% CI [1.00, 1.42]). CONCLUSIONS: The effects of childhood chronic physical illness on the risk of emotional problems persist beyond childhood and adolescence. Mental health prevention and intervention strategies targeting children with chronic physical illnesses can have long-term benefits.

Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population.

OBJECTIVES: Diabetic cardiomyopathy (DCM) is an established complication of diabetes mellitus. In West Virginia, the especially high incidence of diabetes and heart failure validate the necessity of developing new strategies for earlier detection of DCM. Since most DCM patients remain asymptomatic until the later stages of the disease when the fibrotic complications become irreversible, we aimed to explore biomarkers that can identify early-stage DCM. METHODS: The patients were grouped into 4 categories based on clinical diabetic and cardiac parameters: Control, Diabetes (DM), Diastolic dysfunction (DD), and Diabetes with diastolic dysfunction (DM+DD), the last group being the preclinical DCM group. RESULTS: Echocardiography images indicated severe diastolic dysfunction in patients with DD+DM and DD compared to DM or control patients. In the DM and DM+DD groups, TNFα, isoprostane, and leptin were elevated compared to control (p<0.05), as were clinical markers HDL, glucose and hemoglobin A1C. Fibrotic markers IGFBP7 and TGF-ß followed the same trend. The Control group showed higher beneficial levels of adiponectin and bilirubin, which were reduced in the DM and DM+DD groups (p<0.05). CONCLUSION: The results from our study support the clinical application of biomarkers in diagnosing early stage DCM, which will enable attenuation of disease progression prior to the onset of irreversible complications.

Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway.

Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of ß-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased ß-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, ß-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.

A Meta-Analysis of Transdiagnostic Cognitive Behavioural Therapy in the Treatment of Child and Young Person Anxiety Disorders.

BACKGROUND: Previous meta-analyses of cognitive-behavioural therapy (CBT) for children and young people with anxiety disorders have not considered the efficacy of transdiagnostic CBT for the remission of childhood anxiety. AIM: To provide a meta-analysis on the efficacy of transdiagnostic CBT for children and young people with anxiety disorders. METHODS: The analysis included randomized controlled trials using transdiagnostic CBT for children and young people formally diagnosed with an anxiety disorder. An electronic search was conducted using the following databases: ASSIA, Cochrane Controlled Trials Register, Current Controlled Trials, Medline, PsycArticles, PsychInfo, and Web of Knowledge. The search terms included "anxiety disorder(s)", "anxi*", "cognitive behavio*, "CBT", "child*", "children", "paediatric", "adolescent(s)", "adolescence", "youth" and "young pe*". The studies identified from this search were screened against the inclusion and exclusion criteria, and 20 studies were identified as appropriate for inclusion in the current meta-analysis. Pre- and posttreatment (or control period) data were used for analysis. RESULTS: Findings indicated significantly greater odds of anxiety remission from pre- to posttreatment for those engaged in the transdiagnostic CBT intervention compared with those in the control group, with children in the treatment condition 9.15 times more likely to recover from their anxiety diagnosis than children in the control group. Risk of bias was not correlated with study effect sizes. CONCLUSIONS: Transdiagnostic CBT seems effective in reducing symptoms of anxiety in children and young people. Further research is required to investigate the efficacy of CBT for children under the age of 6.

Sodium/Potassium ATPase Alpha 1 Subunit Fine-tunes Platelet GPCR Signaling Function and is Essential for Thrombosis.

Background: Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and ß subunits, is crucial in maintaining intracellular sodium and potassium gradients. However, the role of NKA in platelet function and thrombosis remains unclear. Methods: We utilized wild-type (WT, α1+/+) and NKA α1 heterozygous (α1+/-) mice, aged 8 to 16 weeks, of both sexes. An intravital microscopy-based, FeCl3-induced carotid artery injury thrombosis model was employed for in vivo thrombosis assessment. Platelet transfusion assays were used to evaluate platelet NKA α1 function on thrombosis. Human platelets isolated from healthy donors and heart failure patients treated with/without digoxin were used for platelet function and signaling assay. Complementary molecular approaches were used for mechanistic studies. Results: NKA α1 haplodeficiency significantly reduced its expression on platelets without affecting sodium homeostasis. It significantly inhibited 7.5% FeCl3-induced thrombosis in male but not female mice without disturbing hemostasis. Transfusion of α1+/-, but not α1+/+, platelets to thrombocytopenic WT mice substantially prolonged thrombosis. Treating WT mice with low-dose ouabain or marinobufagenin, both binding NKA α1 and inhibiting its ion-transporting function, markedly inhibited thrombosis in vivo. NKA α1 formed complexes with leucine-glycine-leucine (LGL)-containing platelet receptors, including P2Y12, PAR4, and thromboxane A2 receptor. This binding was significantly attenuated by LGL>SFT mutation or LGL peptide. Haplodeficiency of NKA α1 in mice or ouabain treatment of human platelets notably inhibited ADP-induced platelet aggregation. While not affecting 10% FeCl3-induced thrombosis, NKA α1 haplodeficiency significantly prolonged thrombosis time in mice treated with an ineffective dose of clopidogrel. Conclusion: NKA α1 plays an essential role in enhancing platelet activation through binding to LGL-containing platelet GPCRs. NKA α1 haplodeficiency or inhibition with low-dose ouabain and marinobufagenin significantly inhibited thrombosis and sensitized clopidogrel's anti-thrombotic effect. Targeting NKA α1 emerges as a promising antiplatelet and antithrombotic therapeutic strategy.

PeRsOnaliSed care Planning for oldER people with frailty (PROSPER): protocol for a randomised controlled trial.

BACKGROUND: Frailty is common in older age and is characterised by loss of biological reserves across multiple organ systems. These changes associated with frailty mean older people can be vulnerable to sudden, dramatic changes in health because of relatively small problems. Older people with frailty are at increased risk of adverse outcomes including disability, hospitalisation, and care home admission, with associated reduction in quality of life and increased NHS and social care costs. Personalised Care Planning offers an anticipatory, preventative approach to supporting older adults to live independently for longer, but it has not been robustly evaluated in a population of older adults with frailty. METHODS: Following an initial feasibility study, this multi-centre, individually randomised controlled trial aims to establish whether personalised care planning for older people improves health-related quality of life. It will recruit 1337 participants from general practices across Yorkshire and Humber and Mid-Mersey in the North of England. Eligible patients will be aged 65 and over with an electronic frailty index score of 0.21 or above, living in their own homes, without severe cognitive impairment and not in receipt of end-of-life care. Following confirmation of eligibility, informed consent and baseline data collection, participants will be individually randomised to the PeRsOnaliSed care Planning for oldER people with frailty (PROSPER) intervention or usual care in a 2.6:1 allocation ratio. Participants will not be blinded to allocation, but data collection and analysis will be blinded. The intervention will be delivered over 12 weeks by a Personal Independence Co-ordinator worker based within a voluntary sector organisation, Age UK. The primary outcomes are health-related quality of life, measured using both the physical and mental components of the Short-Form 12 Item Health Questionnaire at 12 months after randomisation. Secondary outcomes comprise activities of daily living, self-management capabilities and loneliness, admission to care homes, hospitalisations, and health and social care resource use at 12 months post randomisation. Parallel cost-effectiveness and process evaluations will be conducted alongside the trial. DISCUSSION: The PROSPER study will evaluate the effectiveness and cost-effectiveness of a personalised care planning approach for older people with frailty and inform the process of its implementation. TRIAL REGISTRATION: ISRCTN16123291 .  Registered on  28 August 2020.

Early vocational rehabilitation and psychological support for trauma patients to improve return to work (the ROWTATE trial): study protocol for an individually randomised controlled multicentre pragmatic trial.

BACKGROUND: Moderately severe or major trauma (injury severity score (ISS) > 8) is common, often resulting in physical and psychological problems and leading to difficulties in returning to work. Vocational rehabilitation (VR) can improve return to work/education in some injuries (e.g. traumatic brain and spinal cord injury), but evidence is lacking for other moderately severe or major trauma. METHODS: ROWTATE is an individually randomised controlled multicentre pragmatic trial of early VR and psychological support in trauma patients. It includes an internal pilot, economic evaluation, a process evaluation and an implementation study. Participants will be screened for eligibility and recruited within 12 weeks of admission to eight major trauma centres in England. A total of 722 participants with ISS > 8 will be randomised 1:1 to VR and psychological support (where needed, following psychological screening) plus usual care or to usual care alone. The ROWTATE VR intervention will be provided within 2 weeks of study recruitment by occupational therapists and where needed, by clinical psychologists. It will be individually tailored and provided for ≤ 12 months, dependent on participant need. Baseline assessment will collect data on demographics, injury details, work/education status, cognitive impairment, anxiety, depression, post-traumatic distress, disability, recovery expectations, financial stress and health-related quality of life. Participants will be followed up by postal/telephone/online questionnaires at 3, 6 and 12 months post-randomisation. The primary objective is to establish whether the ROWTATE VR intervention plus usual care is more effective than usual care alone for improving participants' self-reported return to work/education for at least 80% of pre-injury hours at 12 months post-randomisation. Secondary outcomes include other work outcomes (e.g. hours of work/education, time to return to work/education, sickness absence), depression, anxiety, post-traumatic distress, work self-efficacy, financial stress, purpose in life, health-related quality of life and healthcare/personal resource use. The process evaluation and implementation study will be described elsewhere. DISCUSSION: This trial will provide robust evidence regarding a VR intervention for a major trauma population. Evidence of a clinically and cost-effective VR intervention will be important for commissioners and providers to enable adoption of VR services for this large and important group of patients within the NHS. TRIAL REGISTRATION: ISRCTN: 43115471. Registered 27/07/2021.