Closed-loop electrical stimulation to prevent focal epilepsy progression and long-term memory impairment.

Interictal epileptiform discharges (IEDs) are ubiquitously expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes as most therapeutics target seizures. We show in a model of progressive hippocampal epilepsy that IEDs produce pathological oscillatory coupling which is associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expands the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human subjects with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation. One-Sentence Summary: Targeted closed-loop electrical stimulation prevents spread of the epileptic network and ameliorates long-term spatial memory deficits.

Impact of inherited bleeding disorders on maternal bleeding and other pregnancy outcomes: A population-based cohort study.

INTRODUCTION: Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH. AIM: To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy. METHODS: We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes. RESULTS: We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10-10.16) in 2010-10.72 (95% CI 10.69-10.75) in 2018 (p for trend = .35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5-3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5-5.9) and red cell transfusion (OR 2.8; 95% CI 1.1-7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50 IU/mL in third trimester. CONCLUSION: Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls.

An integrated smoking cessation and alcohol intervention among Hong Kong Chinese young people: Study protocol for a feasibility randomized controlled trial.

INTRODUCTION: Young smokers always partake in both smoking and drinking. However, drinking undermines their likelihood to attempt quitting smoking or to successfully abstain from smoking. Hence, this trial will examine the feasibility of implementing an integrated smoking cessation and alcohol intervention in young Hong Kong Chinese people. Effect sizes of the integrated intervention (II) on self-reported and biochemically validated quit rates will also be calculated. METHODS: The study will be a three-arm randomized controlled trial in a convenience sample of 150 smokers aged 18-25 years with alcohol drinking. Participants will be randomized into a standard treatment (ST), II, or control arm. The ST group will receive a brief smoking cessation intervention based on the 5A (Ask, Assess, Advice, Assist, Arrange) and 5R (Relevance, Risks, Rewards, Roadblocks, Repetition) models. The II group will receive brief advice on alcohol use based on the FRAMES (Feedback, Responsibility, Advice, Menu, Empathy, Efficacy) model in addition to the brief smoking cessation intervention. Both the ST and II groups will receive booster interventions at 1-week, 1-month, 3-month, and 6-month follow-up. The control group will receive leaflets on smoking cessation and alcohol reduction. Self-reported quitters at 6-month follow-up will be invited for biochemical validation. The primary outcomes are feasibility measures. The secondary outcomes are effect size of II on self-reported and biochemically validated quit rates at 6 months relative to control and ST. Outcomes will be assessed at baseline and at 1-week, 1-month, 3-month, and 6-month follow-ups. ANALYSIS: Descriptive statistics will be used to calculate the feasibility measures. The three arms will be compared using analysis of variance for continuous variables and chi-square test for categorical variables. Effect sizes of II for self-reported and biochemically validated quit rates at 6 months will be determined using the generalized estimating equation model.

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice.

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements typically characterized by repeated units of 1-6 bp. We leveraged whole-genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family of mice to map loci that modulate genome-wide patterns of new mutations arising during parent-to-offspring transmission at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and performed quantitative trait locus (QTL) analyses for each of these phenotypes. We identified a locus on Chromosome 13 at which strains inheriting the C57BL/6J (B) haplotype have a higher rate of STR expansions than those inheriting the DBA/2J (D) haplotype. The strongest candidate gene in this locus is Msh3, a known modifier of STR stability in cancer and at pathogenic repeat expansions in mice and humans, as well as a current drug target against Huntington's disease. The D haplotype at this locus harbors a cluster of variants near the 5' end of Msh3, including multiple missense variants near the DNA mismatch recognition domain. In contrast, the B haplotype contains a unique retrotransposon insertion. The rate of expansion covaries positively with Msh3 expression-with higher expression from the B haplotype. Finally, detailed analysis of mutation patterns showed that strains carrying the B allele have higher expansion rates, but slightly lower overall total mutation rates, compared with those with the D allele, particularly at tetranucleotide repeats. Our results suggest an important role for inherited variants in Msh3 in modulating genome-wide patterns of germline mutations at STRs.

Magnitude and determinants of alcohol use disorder among adult population in East Asian countries: A systematic review and meta-analysis.

Introduction: Alcohol use disorder is a medical condition characterized by an impaired ability to control or stop alcohol use despite adverse health outcomes. Despite several studies that have analyzed the prevalence and determinants, their results have been equivocal, and the reasons for the differences in prevalence rates and determinants of AUD across nationalities are unknown. Hence, this study estimated the pooled prevalence of alcohol use disorder and its determinant among adults in East Asian countries. Methods: Articles were searched from PubMed, Web of Science, EMBASE, PsycINFO, and Scopus. All observational study designs that fulfilled the predefined criteria were included in the study. The findings were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The quality and heterogeneity of articles were assessed using the new castle-Ottawa scale (NOS) and I2, respectively. Additionally, publication bias was checked through funnel plot and Egger's regression test. Results: A total of 14 articles with 93, 161 study participants were considered in the study. Of which 9 studies were included in the meta-analysis of the 1-year prevalence of alcohol use disorder, 6 in the lifetime, 9 in alcohol abuse, and 8 in alcohol dependency. Consequently, the overall pooled prevalence of one-year alcohol use disorder was 8.88% (95% CI: 6.32, 11.44), lifetime 13.41% (95%CI: 8.48, 18.34), alcohol abuse 5.4% (95% CI: 2.66, 8.13), and alcohol dependency 4.47% (95% CI: 2.66, 6.27). In the subgroup analysis by country, the highest 1-year and lifetime pooled prevalence of alcohol use disorder was observed in Korea at 9.78% (95% CI:4.40, 15.15) and 16.73% (95% CI: 15.31, 18.16), respectively. Besides, smoking (OR: 3.99; 95% CI: 1.65, 6.33) and male gender (OR: 5.9; 95% CI: 3.3, 8.51) were significant determinants of alcohol use disorder. Conclusions: The magnitude of alcohol use disorder was high among adults in East Asian countries. Smoking and male gender were the key determinants of alcohol use disorders.

Increased acute care utilisation, comorbidities and mortality in adults with haemophilia: A population-based cohort study from 2012 to 2019.

INTRODUCTION: Improvements in treatment strategies have led to increased life expectancy of persons with haemophilia (PWH). Consequently, age-related comorbidities become increasingly relevant. AIM: To evaluate the prevalence of age-related comorbidities, mortality, health service utilisation and predictors of hospitalisation in PWH compared to the general population. METHODS: We conducted a population-based retrospective cohort study using linked administrative data. Men with haemophilia were identified in Alberta, Canada (2012-2019) with a validated case definition and were age-matched with male population controls. We calculated the prevalence of major comorbidities, all-cause mortality, and examined health service utilisation including Emergency Department visits and hospitalisations. Logistic regression was applied to identify predictors of hospitalisation. RESULTS: We identified 198 and 329 persons with moderately severe haemophilia and mild/moderate, respectively. Moderately severe haemophilia had a higher risk of death (standardised mortality ratio 3.2, 95% confidence interval [CI] 1.4-6.3) compared to the general population. PWH had a significantly higher prevalence of hypertension, liver diseases and malignancies than controls. Moderately severe haemophilia was associated with significantly higher rates of hospitalisations (52.5% vs. 14.5%), Emergency Department visits (89.1% vs. 62.7%) and intensive care admissions (8.9% vs. 2.3%). Age > 65 years (adjusted odds ratio [aOR] 6.8) and presence of multiple comorbidities (aOR 3.9) were significant predictors of hospitalisations among PWH. CONCLUSION: Despite advanced care, haemophilia is associated with higher acute care utilisation than the general population, highlighting the substantial burden of illness on patients and the health care system.

INTERBLEED: Design of an International Study of Risk Factors for Gastrointestinal Bleeding and Cardiovascular Events After Gastrointestinal Bleeding.

Background: Bleeding is the most common adverse event in those with cardiovascular (CV) disease receiving antithrombotic therapy, and it most commonly occurs in the gastrointestinal (GI) tract. Clinicians often dismiss bleeding as an adverse event that is reversible with effective antithrombotic therapy, but bleeding is associated with substantial morbidity and mortality, most likely mediated through an increased risk of CV events. Reducing the burden of bleeding requires knowledge of the potentially modifiable risk factors for bleeding and the potentially modifiable risk factors for adverse outcomes after bleeding. Methods: INTERBLEED is an international, multicentre, 2-component, observational study, with an incident case-control study examining the risk factors for GI bleeding, and a prospective cohort study of risk factors for CV events after GI bleeding. Cases either have CV disease and present to the hospital with GI bleeding or develop GI bleeding during hospitalization. Controls have CV disease, but no history of GI bleeding. We use a questionnaire to obtain detailed information on known and potential risk factors for GI bleeding and for CV events and outcomes after bleeding. We obtain CV and anthropometric measurements, perform functional and cognitive assessments, and follow participants at 3 months and 12 months. Results: As of April 1, 2022, the study is ongoing in 10 countries at 31 centres and has recruited 2407 cases and 1478 controls. Conclusions: Knowledge of risk factors for bleeding, and risk factors for CV events and functional decline after bleeding, will help develop strategies to prevent bleeding and subsequent complications.

Contexte: L'hémorragie est l'effet indésirable le plus fréquent chez les patients atteints de maladies cardiovasculaires (CV) qui reçoivent un traitement antithrombotique, et elle survient le plus souvent dans le tractus gastro-intestinal (GI). Les cliniciens considèrent souvent l'hémorragie comme une simple manifestation indésirable réversible par un traitement antithrombotique efficace, mais une morbidité et une mortalité considérables y sont associées, probablement en raison d'un risque accru d'événements CV. Une réduction du fardeau de l'hémorragie nécessite une connaissance des facteurs de risque potentiellement modifiables tant de l'hémorragie que des événements indésirables qui surviennent après l'hémorragie. Méthodologie: INTERBLEED est une étude internationale, observationnelle et multicentrique à deux volets; le premier volet est une étude cas-témoins incidents visant à examiner les facteurs de risque d'hémorragie GI, alors que le second volet est une étude de cohorte prospective visant à examiner les facteurs de risque d'événements CV après une hémorragie GI. Les cas sont des patients atteints de maladies CV qui consultent les services hospitaliers pour une hémorragie GI ou qui présentent une hémorragie GI en cours d'hospitalisation. Les témoins sont des patients atteints de maladies CV, mais sans antécédents d'hémorragie GI. Un questionnaire est utilisé pour obtenir des renseignements détaillés au sujet de facteurs de risque connus et potentiels d'hémorragie GI et d'événements CV et d'autres résultats de santé après une hémorragie. Des mesures cardiovasculaires et anthropométriques ainsi que des évaluations fonctionnelles et cognitives sont réalisées, et les participants sont revus après trois mois et 12 mois. Résultats: En date du 1er avril 2022, l'étude est en cours dans 10 pays et 31 établissements de santé; 2 407 cas et 1 478 témoins ont été recrutés. Conclusions: La connaissance des facteurs de risque d'hémorragie, ainsi que des facteurs de risque d'événements CV et de déclin fonctionnel à la suite d'une hémorragie, aidera à mettre en place des stratégies pour prévenir les hémorragies et les complications qui peuvent en découler.

Development of a Community-Based Network to Promote Anti-Drug Messaging and Identify Hidden Drug Abusers in Hong Kong.

Developing a community-based network by training peers as anti-drug ambassadors (ADAs) is a feasible strategy to identify hidden drug abusers. The Ask, Warn, Advise, Refer and Do-it-again (AWARD) model of smoking cessation is useful for enhancing people's confidence in making referrals to anti-drug services. This study evaluated the effectiveness of such a network by examining the change in knowledge, attitudes and practices (KAP) of 198 ADAs aged 13-18 before and after six months of our training. A one-group pre-test and repeated post-test design was used. One-way repeated-measures analysis of variance was applied to assess the changes in KAP, with p-values adjusted by Bonferroni correction. The results showed that the ADAs statistically significantly improved their KAP regarding drug abuse at the six-month follow-up compared to baseline. All ADAs who knew drug abusers (n = 3) had referred them to services based on the AWARD model. A total of 154 anti-drug abuse activities were conducted, reaching 4561 people. Based on the results, we concluded that the community-based network was effective in improving the KAP of ADAs regarding drug abuse, as well as referring hidden drug abusers. Future studies should consider implementing the network on a larger scale, thus maximizing its anti-drug capacity.

Use of a positive psychology intervention (PPI) to promote the psychological well-being of children living in poverty: study protocol for a feasibility randomised controlled trial.

INTRODUCTION: Poverty has a detrimental influence on psychological well-being of children. Existing evidence shows that positive psychology interventions are possible to mitigate such impact. Despite criticisms that positive psychology resembles a scientific Pollyannaism that promotes overly positivity, positive psychology is not the scientific Pollyannaism that denies the difficulties and emotions that people may experience. Whereas, positive psychology acknowledges the difficulties and emotions, alongside with building up human resilience, strength and growth to face adversity. This study examined the feasibility of implementing a positive psychology intervention among Hong Kong Chinese children living in poverty. METHODS: A feasibility randomised controlled trial will be conducted. A convenience sample of 120 children aged 13-17 years will be recruited from a community centre in Kwai Tsing district. Participants who are randomised into the experimental group will join a 1.5-hour workshop covering four positive psychology techniques: (1) gratitude visits/letters, (2) three good things, (3) you at your best and (4) using signature strengths. A booster intervention will be provided at 1 week. Control group participants will not receive any intervention. Assessments will be conducted at baseline and at 1-week, 1-month, 3-month and 6-month follow-ups. ANALYSIS: Descriptive statistics will be used to calculate the feasibility measures. Effect sizes on psychological outcomes (ie, self-esteem, depressive symptoms and quality of life) will be estimated by mixed between-within subjects analysis of variance using partial eta squared with poverty (yes, no) entering into the model as a factor. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Hong Kong Polytechnic University Institutional Review Broad. We will obtain parental consent as our subjects are below 18 years old. Findings from this study will be disseminated via international publications and conferences. TRIAL REGISTRATION NUMBER: NCT04875507.

Exploring Contributing Factors of Solitary Drinking among Hong Kong Chinese Adolescents and Young Adults: A Descriptive Phenomenology.

Adolescents and young adults mostly drink alcohol because of social activities. However, some drink outside of normative social contexts, exhibiting a behaviour pattern known as solitary drinking. Increasing evidence indicates that solitary drinking is strongly associated with problematic drinking in adolescents and young adults. However, it remains unclear why individuals initiate and maintain this drinking habit. To address this gap in the existing literature, the current study explored the factors contributing to solitary drinking in this population. Descriptive phenomenology was used. A convenience sample of 44 solitary drinkers aged between 10 and 24 were invited to undergo individual semi-structured interviews. All interviews were audio-recorded and transcribed verbatim. The data were analysed by two researchers separately using Colaizzi's method. Using qualitative descriptions, the following factors were identified as explaining the initiation and continuation of solitary drinking among adolescents and young adults: (1) enhancement and coping drinking motives, (2) social discomfort, (3) reduced self-control, (4) automatic mental process, and (5) a desperate response to stressors. Since reduced self-control plays an important role in long-term addiction, future studies should be conducted to determine potential applications of mindfulness-based interventions to improve self-control, which may prevent the progression from solitary drinking to alcohol use disorder.

A novel qualitative approach for identifying effective communication for recruitment of minority women to a breast cancer prevention study.

Ensuring that racial and ethnic minority women are involved in breast cancer research is important to address well-documented current disparities in cancer incidence, stages of diagnosis, and mortality rates. This study used a novel interactive focus group method to identify innovative communication strategies for recruiting women from two minority groups-Latinas and Asian Americans-into the Komen Tissue Bank, a specific breast cancer biobank clinical trial. Through activities that employed visual interactive tools to facilitate group discussion and self-reflection, the authors examined perspectives and motivations for Asian American women (N = 17) and Latinas (N = 14) toward donating their healthy breast tissue. Findings included three themes that, while common to both groups, were unique in how they were expressed: lack of knowledge concerning breast cancer risks and participation in clinical research, cultural influences in BC risk thinking, and how altruism relates to perceived personal connection to breast cancer. More significantly, this study illuminated the importance of using innovative methods to encourage deeper, more enlightened participation among underrepresented populations that may not arise in a traditional focus group format. The findings from this study will inform future health communication efforts to recruit women from these groups into clinical research projects like the Komen Tissue Bank.

Exploring Factors Contributing to the Smoking Behaviour among Hong Kong Chinese Young Smokers during COVID-19 Pandemic: A Qualitative Study.

COVID-19 has significant impacts on young smokers in their smoking behaviors. This qualitative study summarises the lived experience of young smokers during COVID-19. Moreover, through their lived experience, we aim to understand how the COVID-19 pandemic influence tobacco use behaviours in this population. A purposive sampling of 48 smokers aged between 17-25 years old is individually interviewed for 30 to 45 min. All interviews are transcribed in verbatim and analysed by two researchers separately using Colaizzi's method of descriptive phenomenology. The results reveal the following six important themes, which could explain the mixed pattern of smoking behaviour changes in young smokers: (1) perceptions of COVID-19 and its association with smoking, (2) more time at home, (3) taking masks off to smoke, (4) the effects of COVID-19 on smokers' financial status and academic performance, (5) reduced social gatherings, and (6) restricted access to tobacco products. To conclude, this pandemic and the anti-pandemic measures, i.e., mask mandates, stay-at-home and work-from-home orders, and class suspension, result in both new obstacles and new advantages for smoking cessation among young people. More studies should be performed to monitor any transition of tobacco products and the trajectory of use in this population during this pandemic, thus informing public health policy making.

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Treatment Algorithm in Cancer-Associated Thrombosis: Updated Canadian Expert Consensus.

Patients with cancer-associated thrombosis (CAT) are at high risk of recurrent venous thromboembolism (VTE) and major bleeding complications. Risks vary significantly between individuals based on cancer status, treatment, and other characteristics. To facilitate the evidence-based management of anticoagulant therapy in this patient population, a committee of 11 Canadian clinical experts updated a consensus-based algorithm for the acute and extended treatment of symptomatic and incidental CAT that was developed in 2018. Following a systematic review of the literature, updates to the algorithm were discussed during an online teleconference, and the algorithm was subsequently refined based on feedback from committee members. Clinicians using this treatment algorithm should consider bleeding risk, type of cancer, and drug-drug interactions, as well as patient and clinician preferences, in tailoring anticoagulation for patients with CAT. Anticoagulant therapy should be adapted as the patient's cancer status and management change over time.

Effects of the School-Based Integrated Health Promotion Program With Hydroponic Planting on Green Space Use and Satisfaction, Dietary Habits, and Mental Health in Early Adolescent Students: A Feasibility Quasi-Experiment.

Background: School-based green space activities have been found to be beneficial to the physical activity level and lifestyle habits of adolescent students. However, their effects on green space use and satisfaction, mental health, and dietary behaviors required further investigation. This study aimed to investigate the effects of school-based hydroponic planting integrated with health promotion activities in improving green space use, competence and satisfaction, healthy lifestyle, mental health, and health-related quality of life (QoL) among early adolescent students in secondary schools. Methods: This study adopted a three-group comparison design (one control and two intervention groups). Secondary school students (N = 553) of grades 7-9 participated in either (1) hydroponic planting (two times per week for 8 months) integrated with health promotion activities; (2) only health promotion activities (one time per week for 6 weeks); or (3) control group. Outcomes assessed by questionnaire included green space use and satisfaction, life happiness, lifestyle, depressive symptoms, and health-related QoL. Results: After adjusting for sex and school grade, the scores in "green space distance and use" and "green space activity and competence" were significantly better in the intervention groups than in the control group. Hydroponic planting integrated with health promotion activities was also associated with better scores in dietary habits and resistance to substance use. Intervention groups had a higher score in "Green space sense and satisfaction" and life happiness when compared with the control group. Conclusions: Our study shows that the school-based hydroponic planting integrated with health promotion activities were feasible and, to a certain extent, useful to improve green space use and competence, dietary habits, and resistance to substance use among early adolescent students in secondary schools in urban areas. Future studies should address the limitations identified, for example, designing a randomized controlled trial that could fit school schedules to generate new evidence for physical and mental health in adolescent communities.

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

All-cause mortality and causes of death in persons with haemophilia: A systematic review and meta-analysis.

INTRODUCTION: Improvements in haemophilia treatment over the last decades resulted in increased life expectancy in persons with haemophilia (PWH). AIM: We conducted a systematic review and meta-analysis to examine all-cause mortality and causes of death among PWH. METHODS: We systematically searched EMBASE, MEDLINE, Web of Science, CINAHL and Cochrane central register of controlled trials from inception through March 15, 2021. Studies that reported a mortality estimate of PWH compared with the general population and/or reported causes of death were included. Random-effects meta-analysis with inverse variance method was used to obtain pooled estimates. We stratified the analysis by the year of cohort entry (before 2000 vs after 2000). RESULT: Of the 4769 studies identified, 52 met the eligibility criteria. The pooled all-cause standardized mortality ratio (SMR) from 9 studies in PWH was 1.93 (95% CI 1.38-2.70; I2 = 97%). The pooled SMRs before and after the year 2000 were 2.40 (95% CI 1.92-3.00; I2 = 87%) and 1.20 (95% CI 1.03-1.40; I2 = 62%), respectively. Before the year 2000, 31.2% deaths occurred due to HIV followed by haemorrhage (26.0%), cardiovascular disease (18.2%), liver disease (9.0%), and cancer (8.9%). Fewer (13.9%) deaths were attributable to HIV after the year 2000 with the proportion of deaths due to haemorrhage remaining unchanged. CONCLUSION: With treatment advances, mortality in PWH has declined over the last few decades approaching that of the general population. However, haemorrhage remains a leading cause of death requiring further attention.

Vaccine-induced immune thrombotic thrombocytopenia presenting with normal platelet count.

Adenoviral-vector based vaccines for coronavirus disease 2019 (COVID-19) have been linked with a thrombotic syndrome, vaccine-induced thrombotic thrombocytopenia (VITT). A key clinical question is whether VITT can be reliably ruled out by the absence of thrombocytopenia. We report on three patients who presented to our institute with this syndrome. Noteworthy in our presentations are two patients who presented for medical assessment of thrombotic symptoms with a normal platelet count, one preceding and one following a period of thrombocytopenia. Prompt diagnosis of VITT is critical to prevent rapid patient decline. We provide herein a new diagnostic algorithm that we believe will help optimally capture case presentations of VITT. These cases broaden and refine our understanding of the disease process and highlight to practitioners that VITT cannot be adequately ruled out by thrombocytopenia alone.

Risk of arterial and venous thromboembolic events among patients with colorectal carcinoma: a real-world, population-based study.

Objective: To assess real-world patterns of arterial and venous thromboembolism among patients with colorectal carcinoma. Methods: The Alberta provincial cancer registry and other provincial medical records were used to identify patients with colorectal cancer (2004-2018) with no preceding or succeeding cancer diagnosis. The incidence of both arterial and venous thromboembolism in this patient population as well as factors associated with these thromboembolic events were examined through logistic regression analysis. Results: A total of 17,296 patients were found eligible and were included into the current study. We observed that 1564 patients (9%) experienced a thromboembolic event and 15,732 patients (91%) did not. The following factors were associated with any thromboembolic event: male sex (odds ratio [OR]: 1.20; 95% CI: 1.08-1.34), higher comorbidity (OR: 1.36; 95% CI: 1.31-1.41), metastatic disease (OR for nonmetastatic vs metastatic disease: 0.53; 95% CI: 0.47-0.60), living within North zone (OR for Edmonton zone vs North zone: 0.70; 95% CI: 0.59-0.84), treatment with fluoropyrimidines (OR for no fluoropyrimidines vs fluoropyrimidines: 0.53; 95% CI: 0.47-0.60) and treatment with bevacizumab (OR: for no bevacizumab vs bevacizumab: 0.53; 95% CI: 0.47-0.60). Factors associated with venous thromboembolism include, younger age (continuous OR with increasing age: 0.99; 95% CI: 0.98-0.99), higher comorbidity (OR: 1.10; 95% CI: 1.04-1.17), metastatic disease (OR for nonmetastatic disease vs metastatic disease: 0.40; 95% CI: 0.35-0.47), North zone (OR for Edmonton zone vs North zone: 0.70; 95% CI: 0.56-0.86), treatment with fluoropyrimidines (OR for no fluoropyrimidines vs fluoropyrimidines: 0.45; 95% CI: 0.39-0.53) and treatment with bevacizumab (OR for no bevacizumab vs bevacizumab: 0.73; 95% CI: 0.58-0.93). Conclusion: Thromboembolic events are not uncommon among colorectal cancer patients, and the risk is increased with male sex, higher comorbidity, presence of metastatic disease, living within the North zone of the province (where there is limited access to tertiary care centers) and treatment with fluoropyrimidines or bevacizumab.

Lay abstract In this analysis of patients who have been diagnosed of colon and rectal cancers in Alberta, Canada, development of blood clots was not uncommon. Certain patient and treatment risk factors seem to increase the risk of this phenomenon.

Heparin for Moderately Ill Patients with Covid-19.

BACKGROUND: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. METHODS: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat. RESULTS: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85). CONCLUSIONS: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.