Assessing the quality of ReSPECT documentation using an accountability for reasonableness framework.

BACKGROUND: The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) form, which supports the ReSPECT process, is designed to prompt clinicians to discuss wider emergency treatment options with patients and to structure the documentation of decision-making for greater transparency. METHODS: Following an accountability for reasonableness framework (AFR), we analysed 141 completed ReSPECT forms (versions 1.0 and 2.0), collected from six National Health Service (NHS) hospitals in England during the early adoption of ReSPECT. Structured through an evaluation tool developed for this study, the analysis assessed the extent to which the records reflected consistency, transparency, and ethical justification of decision-making. RESULTS: Recommendations relating to CPR were consistently recorded on all forms and were contextualised within other treatment recommendations in most forms. The level of detail provided about treatment recommendations varied widely and reasons for treatment recommendations were rarely documented. Patient capacity, patient priorities and preferences, and the involvement of patients/relatives in ReSPECT conversations were recorded in some, but not all, forms. Clinicians almost never documented their weighing of potential burdens and benefits of treatments on the ReSPECT forms. CONCLUSION: In most ReSPECT forms, CPR recommendations were captured alongside other treatment recommendations. However, ReSPECT form design and associated training should be modified to address inconsistencies in form completion. These modifications should emphasise the recording of patient values and preferences, assessment of patient capacity, and clinical reasoning processes, thereby putting patient/family involvement at the core of good clinical practice. Version 3.0 of ReSPECT responds to these issues

Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers

General practitioners’ experiences of emergency care and treatment planning in England : a focus group study

Background: Emergency Care and Treatment Plans are recommended for all primary care patients in the United Kingdom who are expected to experience deterioration of their health. The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) was developed to integrate resuscitation decisions with discussions about wider goals of care. It summarises treatment recommendations discussed and agreed between patients and their clinicians for a future emergency situation and was designed to meet the needs of different care settings. Our aim is to explore GPs’ experiences of using ReSPECT and how it transfers across the primary care and secondary care interface. Methods: We conducted five focus groups with GPs in areas being served by hospitals in England that have implemented ReSPECT. Participants were asked about their experience of ReSPECT, how they initiate ReSPECT-type conversations, and their experiences of ReSPECT-type recommendations being communicated across primary and secondary care. Focus groups were transcribed and analysed using Thematic Analysis. Results: GPs conceptualise ReSPECT as an end of life planning document, which is best completed in primary care. As an end of life care document, completing ReSPECT is an emotional process and conversations are shaped by what a ‘good death’ is thought to be. ReSPECT recommendations are not always communicated or transferable across care settings. A focus on the patient’s preferences around death, and GPs’ lack of specialist knowledge, could be a barrier to completion of ReSPECT that is transferable to acute settings. Conclusion: Conceptualising ReSPECT as an end of life care document suggests a difference in how general practitioners understand ReSPECT from its designers. This impacts on the transferability of ReSPECT recommendations to the hospital setting

Resuscitation with pre-hospital blood products in adults with trauma-related haemorrhagic shock:the RePHILL RCT

Background: The treatment of traumatic haemorrhagic shock has been transformed through better haemorrhage control, use of tranexamic acid and use of blood products. The improved survival seen from these strategies has stimulated an interest in pre-hospital transfusion.Objectives: To determine if the clinical effectiveness of resuscitation with red blood cells and lyophilised plasma was superior to 0.9% saline for improving tissue perfusion and reducing mortality in adults with haemorrhagic shock following major trauma.Design: A multi-centre, allocation concealed, open-label, parallel group, randomised controlled trial (with internal pilot).Setting: The trial was conducted in four civilian pre-hospital critical care services who operated within the National Health Service (NHS) England Major Trauma Networks.Participants: Adults (aged ≥16 years) who had sustained traumatic injuries, were attended by a pre-hospital emergency medical team and were hypotensive (systolic blood pressure &lt;90 mmHg or absence of radial pulse) as a consequence of traumatic haemorrhage were eligible for inclusion. The exclusion criteria were known or apparently &lt;16 years, blood administered on scene prior to the arrival of the RePHILL team, traumatic cardiac arrest where (1) the arrest occurred prior to arrival of the team and/or (2) the primary cause is not hypovolaemia, refusal of blood product administration, known Jehovah’s Witness, pregnancy, isolated head injury without evidence of external haemorrhage, prisoners in the custody of HM Prison and Probation Service.Interventions: Participants were randomised to receive up to either two units each of red blood cells and lyophilised plasma or up to 1 L 0.9% saline. Treatment was administered through the intravenous or intraosseous route.Main outcome measures: The primary outcome was a composite of episode mortality and/or impaired lactate clearance. The secondary outcomes included the individual components of the primary outcome.Results: From 6 December 2016 to 2 January 2021, pre-hospital medical teams randomised 432 participants to red blood cell/lyophilised plasma (n = 209) or 0.9% saline (n = 223) out of a target sample size of 490. Most participants were white (62%), males (82%), median age 38 (interquartile range 26 to 58), involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, interquartile range 25 to 50). Prior to randomisation participants had received on average 430 ml crystalloid fluids and tranexamic acid (90%). The primary outcome occurred in 128/199 (64.3%) of participants randomised to red blood cell/lyophilised plasma and 136/210 (64.8%) randomised to 0.9% saline [adjusted risk difference –0.025% (95% confidence interval –9.0% to 9.0%), p = 0.996]. The event rates for the individual components of the primary outcome, episode mortality and lactate clearance were not statistically different between groups [adjusted average differences −3% (−12% to 7%); p = 0.57 and −5% (−14% to 5%), p = 0.33, respectively].Limitations: Recruitment stopped prematurely due to disruption caused by the COVID-19 pandemic.Future work: Identify the characteristics of patients who may benefit from pre-hospital blood products and whether alternative transfusion regimens are superior to standard care.Conclusions: The trial did not demonstrate that pre-hospital red blood cell/lyophilised plasma resuscitation was superior to 0.9% saline for trauma-related haemorrhagic shock.Trial registration: This trial is registered as ISRCTN62326938.Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 14/152/14) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 2. See the NIHR Funding and Awards website for further award information.<br/

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

BackgroundVaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries.MethodsTwenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios.ResultsWe estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases.ConclusionsThis study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future.FundingVIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication

Self-reported drunkenness among adolescents in four sub-Saharan African countries: associations with adverse childhood experiences

<p>Abstract</p> <p>Background</p> <p>Consumption of alcohol is associated with acute and chronic adverse health outcomes. There is a paucity of studies that explore the determinants of alcohol use among adolescents in sub-Saharan Africa and, in particular, that examine the effects of adverse childhood experiences on alcohol use.</p> <p>Methods</p> <p>The paper draws on nationally-representative data from 9,819 adolescents aged 12-19 years from Burkina Faso, Ghana, Malawi, and Uganda. Logistic regression models were employed to identify correlates of self-reported past-year drunkenness. Exposure to four adverse childhood experiences comprised the primary independent variables: living in a food-insecure household, living with a problem drinker, having been physically abused, and having been coerced into having sex. We controlled for age, religiosity, current schooling status, the household head's sex, living arrangements, place of residence, marital status, and country of survey. All analyses were conducted separately for males and females.</p> <p>Results</p> <p>At the bivariate level, all independent variables (except for coerced sex among males) were associated with the outcome variable. Overall, 9% of adolescents reported that they had been drunk in the 12 months preceding the survey. In general, respondents who had experienced an adverse event during childhood were more likely to report drunkenness. In the multivariate analysis, only two adverse childhood events emerged as significant predictors of self-reported past-year drunkenness among males: living in a household with a problem drinker before age 10, and being physically abused before age 10. For females, exposure to family-alcoholism, experience of physical abuse, and coerced sex increased the likelihood of reporting drunkenness in the last 12 months. The association between adverse events and reported drunkenness was more pronounced for females. For both males and females there was a graded relationship between the number of adverse events experienced and the proportion reporting drunkenness.</p> <p>Conclusions</p> <p>We find an association between experience of adverse childhood events and drunkenness among adolescents in four sub-Saharan African countries. The complex impacts of adverse childhood experiences on young people's development and behavior may have an important bearing on the effectiveness of interventions geared at reducing alcohol dependence among the youth.</p

A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP

Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity

Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk

Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness