Risk factors related to familial hemorrhagic stroke

Stroke is the fourth leading cause of death in the United States and is a leading cause of long-term disability. More than 795,000 people have a stroke annually. Ischemic strokes account for 87% of all strokes, and hemorrhagic strokes account for 13% of all strokes. Although family history is an indicator for both types of stroke, ischemic strokes are more closely related to environmental risk factors, such as diet, exercise and smoking. Hemorrhagic strokes also aggregate within families but often occur at younger ages indicating a possible genetic link. The purpose of this study was to identify similarities and differences of the biological risk factors associated with hemorrhagic stroke, such as hypertension, diabetes mellitus and/or high cholesterol, and environmental risk factors, such as exercise, alcohol consumption, smoking, and perceived stress within and between families with a history of hemorrhagic stroke. Methods: 14 individuals (8 with hemorrhagic stroke, 6 without hemorrhagic stroke) participated from 4 families with a family history of hemorrhagic stroke were recruited from stroke support groups in the southeast, social media and Casa Colina Hospital and Medical Center in Pomona, California. Participants completed medical and family history questionnaires, as well as, the Health Promoting Lifestyle Profile (HPLPII) and the Perceived Stress Scale (PSS). Results: Nonparametric statistical analysis and visual representation were utilized to compare biological risk factors associated with hemorrhagic stroke within and between families and to measure the strength and direction of association that exists between groups. Hypertension was the most salient biological risk factor among all study participants (87%), followed by high cholesterol (42.9%) and diabetes mellitus (14.3%). General stress and alcohol consumption was reported in all families (50% and 57% of participants, respectively). Mann-Whitney U Test indicated that PSS scores were significantly higher for participants with hemorrhagic stroke (=24.33) than for participants without hemorrhagic stroke (=15.67), U=4.0, p=.028). Conclusion: There is not one clear biological or environmental factor identified as the cause of familial hemorrhagic stroke; however, hypertension seems aggregate within families with a history of hemorrhagic stroke suggesting that it may be a major risk factor. In addition, perceived stress was significantly higher in participants with hemorrhagic stroke compared to those without hemorrhagic stroke suggesting that it is also a risk factor for familial hemorrhagic stroke

The development of a core outcome set for studies of pregnant women with multimorbidity

Acknowledgements We would like to thank the following individuals, organisations and many others for helping with the recruitment of the Delphi surveys: 4M Mentor Mothers, African and Caribbean Support Northern Ireland, Alopecia UK, Ammalife, Association of South Asian Midwives, Attention Deficit Hyperactivity Disorder UK, Autism Connected, Balachandran Kumarendran, Birthrights, Black Female Doctors UK, Black Mothers Matter, Bliss, Breast Cancer Now, Bristol, North Somerset and South Gloucestershire Maternity Voices Partnership, British Adult Congenital Cardiac Nurse Association, British Association of Perinatal Medicine, British Human Immunodeficiency Virus Association, British Intrapartum Care Society, British Maternal and Fetal Medicine Society, British Thyroid Foundation, Cardiff Lupus Support Group, Cardiomyopathy UK, Chelsea and Westminster Maternity Voices Partnership, Community of Cultures Sheffield Maternity Cooperation, Core Outcome Measures in Effectiveness Trials Initiative, Crohn's and Colitis Canada, Crohn's and Colitis UK, Dads Matter, Diabetes UK, Disability Maternity Care (Australia), Elly Charity, E69 MOTIVE Trial, Epilepsy Foundation of America, Epilepsy Society, Fair Treatment for the Women of Wales, Fibromyalgia Action UK, General Practitioners Championing Perinatal Care, Global Kidney Foundation, Graham Mcllroy, Haemophilia Foundation Australia, Hereditary Spastic Paraplegia Support Group, Institute of Health Visiting, International League Against Epilepsy (Africa), Irish Neonatal Health Alliance, Juvenile Diabetes Research Foundation, Katie's Team, Kidney Patient Involvement Network, Kidney Wales, LGBT Mummies, MacDonald Obstetric Medicine Society, Malaysian Obstetric Medicine, Maternity and Midwifery Forum, MIDIRS Midwifery Digest, Midlands Maternal Medicine Network, Milena Forte, MQ Mental Health Research, Multiple Sclerosis Australia, Mums Like Us, Mum's Pride, Mumsnet, Muslim Women's Network UK, National Childbirth Trust, National Human Immunodeficiency Virus Nurses Association, National Kidney Federation, National Rheumatoid Arthritis UK, Newport Yemeni Community Association, Niina Kolehmainen, Obsessive Compulsive Disorder Action, Obstetric Anaesthetists' Association, Organisation for Sickle Cell Anaemia Relief and Thalassaemia Support Birmingham, Parathyroid UK, Parent Voices in Wales, Parents 1st 83 , Positive East, Positive Life Northern Ireland, Postural Tachycardia Syndrome UK, Psoriasis Association, Raham Project, Royal College of Midwives, Royal Surrey County Hospital Maternity Voices Partnership, Scottish 86 Perinatal Network, Scottish Research Nurse, Midwife & Coordinators' Network, Section for Women's Mental Health Institute of Psychiatry, Psychology and Neuroscience (King's College London), Sjogern's India, Society of Obstetric Medicine of Australia and New Zealand, Society of Obstetric Medicine (India), Somerville Heart Foundation, Sophia Forum, South African Nephrology Society, South Asian Health Foundation, South London Applied Research Collaboration Maternal and Perinatal Mental Health Research Patient and Public Involvement, Stockport Foundation Trust, Taraki, The Black Wellbeing Collective, The International Marcé Society for Perinatal Mental Health, The Pituitary Foundation, Thyroid Patients Canada, Tommy's, Turner Syndrome Support Society UK, UK Audit and Research Collaborative in Obstetrics and Gynaecology, UK Preconception Early-and Mid-Career Researchers Network, UK Teratology Information Service, University of Bristol Centre for Academic Primary Care and Patient and Public Involvement Panel, Vasculitis Ireland Awareness, Verity Polycystic Ovarian Syndrome UK, Wales Perinatal Mental Health Network. We would also like to thank Clare Evans for her input in reviewing this manuscript Funding This work was funded by the Strategic Priority Fund “Tackling multimorbidity at scale” programme (grant number MR/W014432/1) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. BT was funded by the National Institute for Health Research (NIHR) West Midlands Applied Research Collaboration. The views expressed are those of the author and not necessarily those of the funders, the NIHR or the UK Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Key outcomes for reporting in studies of pregnant women with multiple long-term conditions and their children : a qualitative study

Funding: This work was funded by the Strategic Priority Fund “Tackling multimorbidity at scale” programme (grant number MR/W014432/1) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. BT was funded by the National Institute for Health Research (NIHR) West Midlands Applied Research Collaboration.Background Maternal multiple long-term conditions are associated with adverse outcomes for mother and child. We conducted a qualitative study to inform a core outcome set for studies of pregnant women with multiple long-term conditions. Methods Women with two or more pre-existing long-term physical or mental health conditions, who had been pregnant in the last five years or planning a pregnancy, their partners and health care professionals were eligible. Recruitment was through social media, patients and health care professionals’ organisations and personal contacts. Participants who contacted the study team were purposively sampled for maximum variation. Three virtual focus groups were conducted from December 2021 to March 2022 in the United Kingdom: (i) health care professionals (n=8), (ii) women with multiple long-term conditions (n=6), and (iii) women with multiple long-term conditions (n=6) and partners (n=2). There was representation from women with 20 different physical health conditions and four mental health conditions; health care professionals from obstetrics, obstetric/maternal medicine, midwifery, neonatology, perinatal psychiatry, and general practice. Participants were asked what outcomes should be reported in all studies of pregnant women with multiple long-term conditions. Inductive thematic analysis was conducted. Outcomes identified in the focus groups were mapped to those identified in a systematic literature search in the core outcome set development. Results The focus groups identified 63 outcomes, including maternal (n=43), children’s (n=16) and health care utilisation (n=4) outcomes. Twenty-eight outcomes were new when mapped to the systematic literature search. Outcomes considered important were generally similar across stakeholder groups. Women emphasised outcomes related to care processes, such as information sharing when transitioning between health care teams and stages of pregnancy (continuity of care). Both women and partners wanted to be involved in care decisions and to feel informed of the risks to the pregnancy and baby. Health care professionals additionally prioritised non-clinical outcomes, including quality of life and financial implications for the women; and longer-term outcomes, such as children’s developmental outcomes. Conclusions The findings will inform the design of a core outcome set. Participants’ experiences provided useful insights of how maternity care for pregnant women with multiple long-term conditions can be improved.Publisher PDFPeer reviewe

The development of a core outcome set for studies of pregnant women with multimorbidity

Background: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. Methods: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders, and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last five years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. Results: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care, and development of new mental health conditions. The six child outcomes were: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight, and separation of baby from mother for health care needs. Conclusions: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group

Maternal and child outcomes for pregnant women with pre-existing multiple long-term conditions: protocol for an observational study in the UK

Introduction: One in five pregnant women has multiple pre-existing long-term conditions in the UK. Studies have shown that maternal multiple long-term conditions are associated with adverse outcomes. This observational study aims to compare maternal and child outcomes for pregnant women with multiple long-term conditions to those without multiple long-term conditions (0 or 1 long-term conditions). Methods and analysis: Pregnant women aged 15–49 years old with a conception date between 2000 and 2019 in the UK will be included with follow-up till 2019. The data source will be routine health records from all four UK nations (Clinical Practice Research Datalink (England), Secure Anonymised Information Linkage (Wales), Scotland routine health records and Northern Ireland Maternity System) and the Born in Bradford birth cohort. The exposure of two or more pre-existing, long-term physical or mental health conditions will be defined from a list of health conditions predetermined by women and clinicians. The association of maternal multiple long-term conditions with (a) antenatal, (b) peripartum, (c) postnatal and long-term and (d) mental health outcomes, for both women and their children will be examined. Outcomes of interest will be guided by a core outcome set. Comparisons will be made between pregnant women with and without multiple long-term conditions using modified Poisson and Cox regression. Generalised estimating equation will account for the clustering effect of women who had more than one pregnancy episode. Where appropriate, multiple imputation with chained equation will be used for missing data. Federated analysis will be conducted for each dataset and results will be pooled using random-effects meta-analyses. Ethics and dissemination: Approval has been obtained from the respective data sources in each UK nation. Study findings will be submitted for publications in peer-reviewed journals and presented at key conferences

Maternal and child outcomes for pregnant women with pre-existing multiple long-term conditions: protocol for an observational study in the UK

Introduction One in five pregnant women has multiple pre-existing long-term conditions in the UK. Studies have shown that maternal multiple long-term conditions are associated with adverse outcomes. This observational study aims to compare maternal and child outcomes for pregnant women with multiple long-term conditions to those without multiple long-term conditions (0 or 1 long-term conditions).Methods and analysis Pregnant women aged 15–49 years old with a conception date between 2000 and 2019 in the UK will be included with follow-up till 2019. The data source will be routine health records from all four UK nations (Clinical Practice Research Datalink (England), Secure Anonymised Information Linkage (Wales), Scotland routine health records and Northern Ireland Maternity System) and the Born in Bradford birth cohort. The exposure of two or more pre-existing, long-term physical or mental health conditions will be defined from a list of health conditions predetermined by women and clinicians. The association of maternal multiple long-term conditions with (a) antenatal, (b) peripartum, (c) postnatal and long-term and (d) mental health outcomes, for both women and their children will be examined. Outcomes of interest will be guided by a core outcome set. Comparisons will be made between pregnant women with and without multiple long-term conditions using modified Poisson and Cox regression. Generalised estimating equation will account for the clustering effect of women who had more than one pregnancy episode. Where appropriate, multiple imputation with chained equation will be used for missing data. Federated analysis will be conducted for each dataset and results will be pooled using random-effects meta-analyses.Ethics and dissemination Approval has been obtained from the respective data sources in each UK nation. Study findings will be submitted for publications in peer-reviewed journals and presented at key conferences

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc