Multi-omic analysis of Huntington's disease reveals a compensatory astrocyte state.

The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington's disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD.

Clusterin knockdown has effects on intracellular and secreted von Willebrand factor in human umbilical vein endothelial cells.

Alterations in von Willebrand factor (VWF) have an important role in human health and disease. Deficiency of VWF is associated with symptoms of bleeding and excesses of VWF are associated with thrombotic outcomes. Understanding the mechanisms that drive VWF regulation can lead to a better understanding of modulation of VWF levels in humans. We identified clusterin (CLU) as a potential candidate regulator of VWF based on a single cell RNA sequencing (scRNA-seq) analysis in control endothelial cells (ECs) and von Willebrand disease (VWD) endothelial colony-forming-cells (ECFCs). We found that patients with deficiencies of VWF (von Willebrand disease, VWD) had decreased CLU expression and ECs with low VWF expression also had low CLU expression. Based on these findings, we sought to evaluate the role of CLU in the regulation of VWF, specifically as it relates to VWD. As CLU is primarily thought to be a golgi protein involved in protein chaperoning, we hypothesized that knockdown of CLU would lead to decreases in VWF and alterations in Weibel-Palade bodies (WPBs). We used both siRNA- and CRISPR-Cas9-based approaches to modulate CLU in human umbilical vein endothelial cells (HUVECs) and evaluated VWF protein levels, VWF mRNA copy number, and WPB quantity and size. We demonstrated that siRNA-based knockdown of CLU resulted in decreases in VWF content in cellular lysates and supernatants, but no significant change in WPB quantity or size. A CRISPR-Cas9-based knockdown of CLU demonstrated similar findings of decreases in intracellular VWF content but no significant change in WPB quantity or size. Our data suggests that CLU knockdown is associated with decreases in cellular VWF content but does not affect VWF mRNA levels or WPB quantity or size.

Screening in serum-derived medium reveals differential response to compounds targeting metabolism.

A challenge for screening new anticancer drugs is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels, which can influence cell metabolism and drug sensitivity. A general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To address this, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We screened several small molecule libraries and found that compounds targeting metabolic enzymes were differentially effective in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.

Screening in serum-derived medium reveals differential response to compounds targeting metabolism.

A challenge for screening new candidate drugs to treat cancer is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels to propagate cells. Which nutrients are available can influence how cancer cells use metabolism to proliferate and impact sensitivity to some drugs, but a general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To enable screening of compounds to determine how the nutrient environment impacts drug efficacy, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We used this system to screen several small molecule libraries and found that compounds targeting metabolic enzymes were enriched as having differential efficacy in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.

A single F153Sß3 mutation causes constitutive integrin αIIbß3 activation in a variant form of Glanzmann thrombasthenia.

This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbß3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report ß3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sß3 substitution within the ßI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153ß3. F153 is completely conserved among ß3 of several species and all human ß-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sß3 also displays reduced levels of a constitutively activated αIIb-S153ß3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153ß3 is critical for maintaining the resting conformation of α2- and α1-helices of the ßI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the ßI-domain toward the constitutively active αIIbß3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbß3 activation. The data collectively demonstrate that disruption of F153ß3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153ß3 may be compensated by a hyperactive conformation that promotes viable hemostasis.

Quantitative analysis of Weibel-Palade bodies.

Weibel Palade bodies (WPBs) are vesicles found in endothelial cells which carry the multimeric protein von Willebrand factor (VWF). As cellular confluency has been shown to influence the number of WPBs in endothelial cells, we propose to test two methods of attaining endothelial cell confluence to inform on the relevancy of cellular culture methods when analyzing endothelial WPBs. We test these cellular culture methods in two endothelial cell types, human umbilical vein endothelial cells (HUVECs) and endothelial colony forming cells (ECFCs). One method maintains a constant incubation time of 96 hrs. while varying the seeding density. The second method maintains a constant seeding density of 30,000 cells/cm2 while varying incubation time. In comparing these two methods, we evaluate the nuclei count, total WPB count, and WPB/nuclei count for each. Our results show that there is a trend of increasing nuclei count, total WPB count, and WPB/nuclei count as incubation time and seeding density increases. However, there is no difference in WPB/nuclei quantification whether confluency is reached via a constant seeding density or a constant incubation time. In addition, we show that confluency plays a major role in WPB/nuclei generation as we demonstrate higher WPB/nuclei counts in confluent cultures compared to sub-confluent cultures.

Practical considerations and consensus opinion for children's hospital-based inpatient hemostasis and thrombosis (HAT) consultative services: Communication from the ISTH SSC Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis.

Caring for children and adolescents with disorders of hemostasis and thrombosis (HAT) has become more specialized and requires a unique skill set that many providers are not able to obtain in standard pediatric hematology/oncology/bone marrow transplant fellowship training programs. The influx of numerous therapeutic advances and increasing medical complexity has expanded the need for experienced HAT providers and subspecialty collaboration in the inpatient setting due to the nuances in the management of patients with HAT complications and concerns. While there are data highlighting the benefits of an inpatient hemostasis, thrombosis, and anticoagulation management service in adult hospitals, there are limited pediatric data supporting such programs. In this article, we summarize the current practices of various pediatric institutions in the inpatient management of HAT patients and provide a consensus opinion for the development of a pediatric inpatient HAT service at tertiary care referral centers.

Single-cell transcriptional analysis of human endothelial colony-forming cells from patients with low VWF levels.

von Willebrand factor (VWF) plays a key role in normal hemostasis, and deficiencies of VWF lead to clinically significant bleeding. We sought to identify novel modifiers of VWF levels in endothelial colony-forming cells (ECFCs) using single-cell RNA sequencing (scRNA-seq). ECFCs were isolated from patients with low VWF levels (plasma VWF antigen levels between 30 and 50 IU/dL) and from healthy controls. Human umbilical vein endothelial cells were used as an additional control cell line. Cells were characterized for their Weibel Palade body (WPB) content and VWF release. scRNA-seq of all cell lines was performed to evaluate for gene expression heterogeneity and for candidate modifiers of VWF regulation. Candidate modifiers identified by scRNA-seq were further characterized with small-interfering RNA (siRNA) experiments to evaluate for effects on VWF. We observed that ECFCs derived from patients with low VWF demonstrated alterations in baseline WPB metrics and exhibit impaired VWF release. scRNA-seq analyses of these endothelial cells revealed overall decreased VWF transcription, mosaicism of VWF expression, and genes that are differentially expressed in low VWF ECFCs and control endothelial cells (control ECs). An siRNA screen of potential VWF modifiers provided further evidence of regulatory candidates, and 1 such candidate, FLI1, alters the transcriptional activity of VWF. In conclusion, ECFCs from individuals with low VWF demonstrate alterations in their baseline VWF packaging and release compared with control ECs. scRNA-seq revealed alterations in VWF transcription, and siRNA screening identified multiple candidate regulators of VWF.

Treatment outcomes among rural and urban patients with obstructive sleep apnea: a prospective cohort study.

STUDY OBJECTIVES: To determine whether adherence to continuous positive airway pressure (CPAP) in adults with uncomplicated obstructive sleep apnea differs by rural vs urban residential address. METHODS: In this prospective cohort study, we recruited adults who initiated CPAP for uncomplicated obstructive sleep apnea that was diagnosed by a physician using sleep specialist-interpreted diagnostic testing. Participants were classified as urban (community size > 100,000) or rural (community size < 100,000) by translating residential postal code into geographic census area. The primary outcome was mean daily hours of CPAP use compared between rural and urban patients. Secondary outcomes included the proportion of patients who were adherent to CPAP, change in Epworth Sleepiness Scale score, change in EuroQOL-5D visual analog score, and Visit-Specific Satisfaction Instrument score. All outcomes were measured 3 months after CPAP initiation. RESULTS: We enrolled 242 patients (100 rural) with a mean (standard deviation) age of 51 (13) years and a respiratory event index of 24 (18) events/h. The mean (95% confidence interval) CPAP use was 3.19 (2.8-3.58) hours/night and 35% were CPAP-adherent, with no difference between urban and rural patients. Among the 65% of patients who were using CPAP at 3 months, the mean CPAP use was 4.89 (4.51-5.28) hours/night and was not different between rural and urban patients. Improvement in the Epworth Sleepiness Scale score and patient satisfaction was similar between groups, but the EuroQOL-5D score improved to a greater extent in rural patients. Urban or rural residence was not associated with CPAP adherence according to multivariable regression analysis. CONCLUSIONS: Rural vs urban residence was not associated with differences in CPAP adherence among patients with uncomplicated OSA diagnosed by a physician using specialist-interpreted sleep diagnostic testing. CITATION: Corrigan J, Tsai WH, Ip-Buting A, et al. Treatment outcomes among rural and urban patients with obstructive sleep apnea: a prospective cohort study. J Clin Sleep Med. 2022;18(4):1013-1020.

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report.

BACKGROUND: Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. OBJECTIVE: To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. PATIENTS/METHODS: A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55-79.8 years, on emicizumab a median 213 days; range, 51-1229 days) with hemophilia A (35.3% with past or current inhibitor). RESULTS: Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every-week or every-2-week dosing, but some had alternative dosing frequency. CONCLUSIONS: Real-world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.

Re-Examining the idea of internal morality in medicine.

This article considers the idea of medicine's internal morality as it is understood by its various proponents. Although the use of the phrase 'internal morality' in relation to medicine predates Edmund Pellegrino, he can be credited with cementing its place in the vocabulary of medical ethics. Yet, while 'internal morality' and its related terms are now readily recognizable, they are used to denote irreconcilable ideas. Our aims, therefore, are to, firstly, clarify and, secondly, evaluate the different uses of 'internal morality', showing that there is little agreement on its definition. Thirdly, we argue that the terminology relating to 'internal morality' requires substantial revision, and that the term itself should be jettisoned. Finally, we briefly set out our own account of how morality should be understood in relation to the practice of medicine along similar but clearer lines to Pellegrino.

FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

Childhood asthma and cardiovascular morbidity and mortality in adulthood: The Busselton Health Study.

BACKGROUND: Long-term childhood asthma studies that investigate adult outcomes other than respiratory morbidity are lacking. This study examines the associations of childhood asthma and the occurrence of cardiovascular disease (CVD) events and mortality in adulthood. METHODS: A cohort of 4430 school children (aged 17 years) who attended the Busselton Health Study between 1967 and 1983 were analyzed. Self-reported history of doctor-diagnosed asthma was determined based on the questionnaire. Subsequent CVD events (hospital admissions or death) up to 2014 were identified using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on CVD events and mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analyzed. RESULTS: A total of 462 (10%) of the cohort had childhood asthma. During follow-up, 867 participants experienced a CVD event and 22 participants died from CVD. Childhood asthma was not associated with the risk of CVD events in adulthood (HR, 1.12; 95% CI: 0.91-1.39; p = .2833) and this persisted after adjustment for confounders. Childhood asthma was not associated with coronary heart disease events (HR, 0.72; 95% CI: 0.40-1.30; p = .2761), heart failure events (HR, 0.55; 95% CI: 0.07-4.13; p = .5604) or CVD mortality (HR, 0.91; 95% CI: 0.21-3.89; p = .8987) in adulthood. CONCLUSION: Childhood asthma is not associated with the risk of CVD events and mortality in adulthood.

Improvements in Communication and Coordination of Care in a Hemophilia Treatment Center.

INTRODUCTION: In response to the increasing complexity of care for patients with bleeding disorders, we established new clinical teams for our hemophilia treatment center (HTC). AIMS: We undertook a quality improvement project to improve the coordination and communication with our patients by establishing primary assignments of clinical staff to individual patients (primary teams). METHODS: A quality improvement project group was formed that established the goals and assignment of primary teams. Patients were surveyed for their knowledge of their primary teams as well as their ability to schedule and contact their primary providers. As a measure of the effects on clinical staff, a balancing survey was also conducted among providers impacted by the clinical assignment of teams. RESULTS: Our results demonstrate improvements across both coordination and communication as reported by patients. Additionally, the assignment of primary teams was met with high satisfaction and improvement in coordination and communication as reported by the clinical staff members of the HTC. CONCLUSIONS: Initiation of a quality improvement project and the creation of a primary team system were feasible at a large HTC and resulted in improvements in both patient-reported and staff-reported outcomes of coordination and communication of care.

The Seismic Shift in End-of-Life Care: Palliative Care Challenges in the Era of Medical Assistance in Dying.

Background: Concerns regarding personal, professional, administrative, and institutional implications of medical assistance in dying (MAiD) are of particular interest to palliative and hospice care providers (PHCPs), who may encounter additional moral distress and professional challenges in providing end-of-life (EOL) care in the new legislative and cultural era. Objective: To explore PHCPs' encountered challenges and resource recommendations for caring for patients considering MAiD. Design: Qualitative thematic analysis of audio-recorded semistructured interviews with PHCPs. Setting/Subjects: Multidisciplinary PHCPs in acute, community, residential, and hospice care in Vancouver, Canada, with experience supporting patients who have made MAiD inquiries or requests. Measurements: Interviews were deidentified, transcribed verbatim, and coded by four researchers using a common coding scheme. Key themes were analyzed. Results: Twenty-six PHCP participants included physicians (n = 7), nurses (n = 12), social workers (n = 5), and spiritual health practitioners (n = 2). Average interview length was 52 minutes (range 35-90). Analysis revealed four broad challenges associated with providing EOL care after MAiD legalization: (1) moral ambiguity and provider distress, (2) family distress, (3) interprofessional team conflict, and (4) impact on palliative care. Participants also recommended three types of resources to support clinicians in delivering quality EOL care to patients contemplating MAiD: (1) education and training, (2) pre- and debriefing for team members, and (3) tailored bereavement support. Conclusions: PHCPs encountered multilevel MAiD-related challenges, but noted improvement in organizational policies and coordination. Resources to enhance training, pre- and debriefing, and tailored bereavement may further support PHCPs in providing high-quality EOL care as they navigate the legislative and cultural shifts.

Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma.

OBJECTIVE: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma. BACKGROUND: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. METHODS: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. RESULTS: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. CONCLUSION: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Evidence on physical activity and falls prevention for people aged 65+ years: systematic review to inform the WHO guidelines on physical activity and sedentary behaviour.

BACKGROUND: Exercise prevents falls in older adults. Regular updates of estimated effects of exercise on falls are warranted given the number of new trials, the increasing number of older people globally and the major consequences of falls and fall-related injuries. METHODS: This update of a 2019 Cochrane Review was undertaken to inform the World Health Organization guidelines on physical activity and sedentary behaviour. Searches were conducted in six databases. We included randomised controlled trials evaluating effects of any form of physical activity as a single intervention on falls in people aged 60+ years living in the community. Analyses explored dose-response relationships. The certainty of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: This review included 116 studies, involving 25,160 participants; nine new studies since the 2019 Cochrane Review. Exercise reduces the rate of falls by 23% (pooled rate ratio (RaR) 0.77, 95% confidence interval (CI) 0.71 to 0.83, 64 studies, high certainty evidence). Subgroup analysis showed variation in effects of different types of exercise (p < 0.01). Rate of falls compared with control is reduced by 24% from balance and functional exercises (RaR 0.76, 95% CI 0.70 to 0.82, 39 studies, high certainty evidence), 28% from programs involving multiple types of exercise (commonly balance and functional exercises plus resistance exercises, RaR 0.72, 95% CI 0.56 to 0.93, 15 studies, moderate certainty evidence) and 23% from Tai Chi (RaR 0.77, 95% CI 0.61 to 0.97, 9 studies, moderate certainty evidence). The effects of programs that primarily involve resistance training, dance or walking remain uncertain. Interventions with a total weekly dose of 3+ h that included balance and functional exercises were particularly effective with a 42% reduction in rate of falls compared to control (Incidence Rate Ratio (IRR) 0.58, 95% CI 0.45 to 0.76). Subgroup analyses showed no evidence of a difference in the effect on falls on the basis of participant age over 75 years, risk of falls as a trial inclusion criterion, individual versus group exercise, or whether a health professional delivered the intervention. CONCLUSIONS: Given the strength of this evidence, effective exercise programs should now be implemented at scale.

Childhood asthma increases respiratory morbidity, but not all-cause mortality in adulthood: The Busselton Health Study.

BACKGROUND: Long-term childhood asthma studies that investigate adult outcomes other than lung function are lacking. This study examines the associations of childhood asthma and the occurrence of respiratory events and all-cause mortality in adulthood. METHODS: A cohort of 4430 school children (aged to 17 years) who attended the Busselton Health Study between 1967 and 1983 were analysed. Self-reported history of asthma was determined using questionnaires. Participants were followed until 2014 for respiratory disease-related events (hospital admissions or death) and all-cause mortality using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on respiratory events and all-cause mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analysed. RESULTS: A total of 462 (10%) of the cohort had childhood asthma. During follow-up 791 participants experienced a respiratory event and 140 participants died. Childhood asthma was associated with an increased risk of respiratory events in adulthood (unadjusted HR 1.84, 95% CI 1.52 to 2.23; P < 0.0001). The result remained significant after adjusting for adult-onset asthma, FEV1, body mass index, smoking, dusty job, hay fever, and respiratory symptoms (adjusted HR 1.68, 95% CI 1.07 to 2.64; P = 0.0247). Childhood asthma was not associated with all-cause mortality in adulthood (unadjusted HR 1.08, 95% CI 0.63 to 1.84; P = 0.7821). CONCLUSION: Childhood asthma is associated with increased risk of respiratory disease-related hospital admissions and death but not all-cause mortality in adulthood.