Comparison of Cranial Cruciate Ligament Rupture Incidence among Parous and Nulliparous Rottweiler Bitches: Evidence from a Lifetime Cohort Study Supporting a Paradigm of Pregnancy-Associated Protection against Subsequent Non-Reproductive Disease Outcomes.

Emerging evidence in women supports the notion that pregnancy may reset disease resistance, thereby providing protection against subsequent adverse health outcomes, but this hypothesis has not been adequately explored in domestic dogs. Cranial cruciate ligament (CCL) rupture is a degenerative orthopedic disease that frequently affects pet dogs, and its risk has been associated with disruption of the reproductive hormone axis. Our research team is conducting a lifetime cohort study of purebred Rottweilers in North America that have lived 30% longer than breed-average. Detailed medical and reproductive histories of 33 nulliparous and 32 parous Rottweilers were generated from questionnaires and review of medical records. Interviews with owners of bitches in the nulliparous group served to limit selection bias, confirming that in no instance was the reason for nulliparity based upon the owner's suspicion that a bitch had a heightened risk for CCL rupture. The risk of CCL rupture associated with parity and other exposure variables was estimated using multivariate logistic regression. Overall, CCL rupture was diagnosed in 17 of 65 (26%) bitches. Median age at first litter and CCL rupture were 3.6 and 6.5 years, respectively. Compared to nulliparous, parous bitches had a significant 94% reduction in CCL rupture risk adjusted for duration of ovary exposure, overweight body condition, dietary pattern, habitual physical activity, and work/sport activity [ORadjusted (95% CI) = 0.06 (0.01-0.46); (p = 0.006)]. The observed parity-associated CCL rupture risk reduction remained robust in sensitivity analysis excluding six nulliparous bitches for which decision not to breed was based on diagnosis of hip or elbow dysplasia, conditions which may be genetically linked to CCL rupture [ORadjusted (95% CI) = 0.08 (0.01-0.58); (p = 0.01)]. This work sets the stage for replication studies in other canine populations that should begin to explore the mechanistic basis for parity-associated CCL rupture risk reduction and to pursue other non-reproductive health outcomes in bitches whose incidence or severity may be parity-sensitive.

Sudden cardiac death due to an obstructive large right atrial myxoma.

Sudden cardiac death is a phenomenon that affects more than 200,000 individuals annually in the United States. Among sudden cardiac deaths, only a fractionally small portion is thought to be attributable to intracardiac neoplasms. Though rarely implicated as the primary cause of death, cardiac myxomas are the most common benign neoplasms of the heart and have been known to cause death due to multifactorial embolic events, fatal arrhythmias, and frank obstructive events. In this case, a healthy, asymptomatic young male was found unresponsive in his residence. Examination of the heart at autopsy revealed dilation of the right atrium and a large, hemorrhagic, irregular, and obstructing mass arising from the right atrium, consistent with cardiac myxoma. When unusual cardiac findings are discovered at autopsy, a systematic investigation of the heart, including retaining the organ for cardiac pathology consultation, is mandatory to correctly identify the cause of death.

Sudden Death Due to Coronary Vasculitis: An Unexpected Autopsy Finding and Unusual Association With Thymic Hyperplasia.

A 43-year-old Asian woman was found unresponsive on the sidewalk, prompting a call to 911. Upon transportation to the hospital, no signs of trauma were evident, but her condition deteriorated, leading to her eventual passing. An autopsy revealed a complete occlusion of the right coronary artery due to segmental coronary artery vasculitis. Without details of the individual's social or medical history, the specific type of coronary vasculitis couldn't be determined. The internal examination also showed thymic hyperplasia of unknown origin. While there is no conclusive evidence, a potential link between thymic hyperplasia, immune dysregulation, and coronary artery vasculitis is discussed, considering the case and existing literature.

Low-Dose Colchicine in Patients With Type 2 Diabetes and Recent Myocardial Infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

OBJECTIVE: The cardiovascular benefits of low-dose colchicine have been demonstrated in patients with coronary disease. Its effects were evaluated in this prespecified analysis in patients with type 2 diabetes (T2D) from the Colchicine Cardiovascular Outcomes Trial (COLCOT). RESEARCH DESIGN AND METHODS: COLCOT was a randomized, double-blinded trial of colchicine, 0.5 mg daily, versus placebo initiated within 30 days after a myocardial infarction. RESULTS: There were 959 patients with T2D enrolled and monitored for a median of 22.6 months. A primary end point event occurred in 8.7% of patients in the colchicine group and in 13.1% in the placebo group (hazard ratio 0.65; 95% CI 0.44-0.96; P = 0.03). Nausea was reported in 2.7% and 0.8% in the study groups (P = 0.03), and pneumonia occurred in 2.4% and 0.4% (P = 0.008). CONCLUSIONS: Among patients with T2D and a recent myocardial infarction, colchicine, 0.5 mg daily, leads to a large reduction of cardiovascular events. These results support the conduct of the COLCOT-T2D trial in primary prevention.

The impact of COVID-19 and the COVID-19 pandemic on hospitalized patients with STEMI in the United States: insights from the National Inpatient Sample.

BACKGROUND: It is unclear how COVID-19 pandemic affected care and outcomes among patients who are diagnosed with ST-elevation myocardial infarction (STEMI) in the USA. METHODS: We analyzed the data from National Inpatient Sample from 2016 to 2020 and assessed the impact of COVID-19 infection and the COVID-19 pandemic (year 2020) on in-hospital mortality, length of stay (LOS) and hospitalization costs.P. RESULTS: There were 1 050 905 hospitalizations with STEMI, and there was an 8.2% reduction in admissions in 2020. Patients with COVID-19 versus those without had significantly greater in-hospital mortality (45.2% vs. 10.7%; P < 0.001). In 2020, 3.0% of hospitalizations had a diagnosis of COVID-19, and the mortality was 11.5% compared to 10.7% for patients admitted in 2016-2019 period. There was a significantly increased mortality (OR 6.25, 95% CI 5.42-7.21, P < 0.001), LOS (coefficient 3.47, 95% CI 3.10-3.84, P < 0.001) and cost (coefficient 10.69, 95% CI 8.4-12.55, P < 0.001) with COVID-19 infection compared with no infection. There was a borderline difference in mortality (OR 1.04, 95% CI 1.00- 1.09, P = 0.050) but LOS (coefficient -0.21, 95% CI-0.28 to -0.14, P < 0.001) and costs (3.14, 95% CI 2.79 to 3.49, P < 0.001) were reduced in 2020 compared to 2016-2019 period. CONCLUSIONS: In conclusion, in patients hospitalized with STEMI, COVID-19 infection was associated with increased mortality, LOS, and cost but during the pandemic year of 2020 there was a small trend for increased mortality for patients with a diagnosis of STEMI.

Gastrointestinal bleeding in chronic kidney disease patients: a systematic review and meta-analysis.

Gastrointestinal bleeding (GIB) is a major cause of mortality in patients with renal failure. We conducted a systematic review of the literature to evaluate the rates, predictors, and outcomes of GIB in patients with chronic kidney disease (CKD). A search of MEDLINE and EMBASE databases was performed, and data were extracted from relevant studies. Statistical pooling was performed to determine the rate of GIB in patients with CKD, and a random-effect meta-analysis was performed to determine the predictors of GIB and mortality in patients with GIB. Twenty-two studies were included in this review, with 7,810,273 patients with CKD included in the analysis. The pooled results of five studies suggested that the rate of GIB in patients with CKD was 2.2%, and among the studies in which patients with CKD underwent endoscopy, the pooled results for GIB were 35.8%. Receipt of dialysis (OR 14.48, 95%CI 4.96-42.32), older age (OR 1.03, 95%CI 1.02-1.05), diabetes mellitus (OR 1.30, 95%CI 1.22-1.39), history of ulcers (OR 1.53, 95%CI 1.03-2.26), and cirrhosis (OR 1.73, 95%CI 1.41-2.12) were significantly associated with GIB. The pooled results suggest a twofold increase in the odds of mortality with GIB, with significant heterogeneity (OR 2.12, 95%CI 1.45-3.10, I2 = 93%). GIB in patients with CKD affects 2% of patients but can be greater in the group of patients who underwent endoscopy. Receipt of dialysis is a strong predictor of GIB, and sustained GIB is associated with a twofold increase in the odds of mortality compared to patients without GIB.

Key pointsThe rate of gastrointestinal bleeding (GIB) in patients with chronic kidney disease (CKD) was 2.2%.The rate of GIB in patients with CKD is higher in those who undergo endoscopy.Dialysis, older age, diabetes mellitus, history of ulcers, and cirrhosis were significantly associated with GIB in CKD.GIB in patients with CKD was associated with a twofold increase in the odds of mortality.

Correlates of estimated lifetime cruciate ligament survival inform potential rupture risk reduction strategies: findings from the Exceptional Aging in Rottweilers Study.

Cranial cruciate ligament (CCL) rupture is one of the most commonly diagnosed orthopedic conditions of pet dogs, making estimated lifetime cruciate ligament survival an attractive endpoint for studies attempting to define clinical and genetic correlates of rupture risk reduction. Early life experiences contribute significantly to the origins of adult health outcomes, yet our current understanding of modifiable susceptibility factors that drive the high frequency of CCL rupture remains limited. We reasoned that combining lifetime medical history with standardized late-life assessment of lifetime cruciate ligament survival and detailed phenotyping of each dog for selected risk variables would provide a sensitive approach to identify factors that would differentiate between lifelong avoidance versus susceptibility to ligament rupture. Here, we report results of Kaplan-Meier analysis of estimated lifetime cruciate ligament survival and Cox proportional hazards modeling to assess risk variables in a lifetime cohort study of 123 purebred Rottweilers, a breed at high risk for veterinarian-diagnosed CCL rupture. We show that gonad removal during the 24-month developmental period is adversely associated with three measures of susceptibility-increased incidence of CCL rupture, multiplicity (bilateral rupture), and accelerated time to initial CCL failure. Our analysis reveals two other phenotypes-short adult height and the production of offspring (in females)-are associated with significant CCL rupture risk reduction. Together, the results provide clues to an early endocrine influence on lifetime cruciate ligament survival. Further, we identify two distinct clinical syndromes of CCL failure, providing a disease subtyping framework to advance future progress in genetic epidemiology, pathogenesis, and prediction. By conducting an evaluation of estimated lifetime CCL survival in dogs, we show that cruciate ligament survival may be jeopardized by gonad removal during the developmental period. Avoidance of such early environmental adversity may represent an actionable method for the control of canine CCL disease in certain breeds.

Results of an international survey on the status of prehospital care.

BACKGROUND: Prehospital care including recognition of stroke symptoms by the public and professionals combined with an efficient and effective emergency medical service (EMS) is essential to increase access to effective acute stroke care. We undertook a survey to document the status of stroke prehospital care globally. METHODS: A survey was distributed via email to the World Stroke Organization (WSO) members. Information was sought on the current status of stroke prehospital delay globally, including (1) ambulance availability and whether payment for use is required, (2) ambulance response times and the proportion of patients arriving at hospital by ambulance, (3) the proportion of patients arriving within 3 h and more than 24 h after symptom, (4) whether stroke care training of paramedics, call handlers, and primary care staff, (5) availability of specialist centers, and (6) the proportion of patients taken to specialist centers. Respondents were also asked to identify the top three changes in prehospital care that would benefit their population. Data were analyzed descriptively at both country and continent level. RESULTS: Responses were received from 116 individuals in 43 countries, with a response rate of 4.7%. Most respondents (90%) reported access to ambulances, but 40% of respondents reported payment was required by the patient. Where an ambulance service was available (105 respondents) 37% of respondents reported that less than 50% of patients used an ambulance and 12% less than 20% of patients used an ambulance. Large variations in ambulance response times were reported both within and between countries. Most of the participating high-income countries (HIC) offered a service used by patients, but this was rarely the case for the low- and middle-income countries (LMIC). Time to admission was often much longer in LMIC, and there was less access to stroke training for EMS and primary care staff. CONCLUSIONS: Significant deficiencies in stroke prehospital care exist globally especially in LMIC. In all countries, there are opportunities to improve the quality of the service in ways that would likely result in improved outcomes after acute stroke.

Quantitative systematic review of the transformational leadership style as a driver of nurses' organisational commitment.

AIMS: To explore the association between nurses' perceptions of their nurse manager's transformational leadership style and nurses' organisational commitment. DESIGN: Narrative systematic review. DATA SOURCES: The CINAHL Complete, MEDLINE, PubMed, Business Source Complete, Cochrane Library, along with OpenGrey t were systematically searched for observational studies written in English, between January 2009 and December 2020. REVIEW METHODS: This systematic review is based on the guidelines of the Cochrane Handbook, and PRISMA-P. Two reviewers independently selected studies. The quality of evidence was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Cross-Sectional Studies. RESULTS: Seven cross-sectional studies with 2885 participants were included. Six studies reported that the transformational leadership style was positively related to nurses' organisational commitment, and the remaining study reported a negative association. CONCLUSIONS: Six studies were found that the transformational leadership style is a driver of nurses' organisational commitment. Only one study reported that transformational leadership style negatively associated with acute care nurses' organisational commitment. However, the negative finding is less valid, as the study data indicates that the nurse managers' ineffective transformational leadership style in the acute care unit or the culture influence, which may have influenced the results. IMPACTS: It provides the guideline, recommendation, and important evidence to support nursing managers adopting the transformational leadership style to promote nurse retention helping to alleviate the nursing shortage. This is beneficial to the well-being of the nurse. Meanwhile, this can help the health organisation reducing the cost of nurses' turnover and recruiting new nurses. It is also good for address future ageing population healthcare problem in the long term.

The effectiveness of pressure support ventilation and T-piece in differing duration among weaning patients: A systematic review and network meta-analysis.

BACKGROUND: A spontaneous breathing trial (SBT) is recommended to help patients to liberate themselves from mechanical ventilation as soon as possible in the ICU. The respiratory workload in SBT, which depends on being with or without respiratory support and a specific time, is more accurate to reflect how much support the weaning patients need compared with only considering SBT technologies. AIM: To compare and rank the effectiveness of different respiratory workloads during SBT via differing technologies (Pressure Support Ventilation and T-piece) and differing duration (30 and 120 min) in SBTs. STUDY DESIGN: A comprehensive literature search was performed in six English electronic databases to identify eligible randomized controlled trials (RCTs) published before September 2020. The pooled risk ratio (RR) with 95% confidence interval (CI) was calculated by Markov chain Monte Carlo methods. A Bayesian network meta-analysis was conducted using "gemtc" version 0.8.2 of R software. Each intervention's ranking possibilities were calculated using the surface under the cumulative ranking analysis (SUCRA). RESULTS: A total of nine RCTs including 3115 participants were eligible for this network meta-analysis involving four different commonly used SBT strategies and four outcomes. The only statistically significant difference was between Pressure Support Ventilation (PSV) 30 min and T-piece 120 min in the outcome of the rate of success in SBTs (RR = 0.91; 95% CI, 0.84-0.98). The cumulative rank probability showed that the rate of success in SBT from best to worst was PSV 30 min, PSV 120 min, T-piece 30 min and T-piece 120 min. PSV 30 min and PSV 120 min are more likely to have a higher rate of extubation (SUCRA values of 82.5% for 30 min PSV, 70.7% for 120 min PSV, 36.4% for T-piece 30 min, 10.4% for T-piece 120). Meanwhile, T-piece 120 min (SUCRA, 62.9%) and PSV 120 min (SUCRA, 60.9%) may result in lower reintubation rates, followed by T-piece 30 min (SUCRA, 41.8%) and PSV 30 min (SUCRA, 34.4%). CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: In comprehensive consideration of four outcomes, regarding SBT strategies, 30-min PSV was superior in simple-to-wean patients. Besides, 120-min T-piece and 120-min PSV are more likely to achieve a lower reintubation rate. Thus, the impact of duration is more significant among patients who have a high risk of reintubation. It is still unclear whether the SBTs affect the outcome of mortality; further studies may need to explore the underlying mechanism.

Should Audits Consider the Care Pathway Model? A New Approach to Benchmarking Real-World Activities.

Clinical audit is a method to assess the quality of healthcare services based on whether standards are met or not met. This approach is limited because it fails to recognize how decisions that take place over time and the natural progression of disease has an impact on what happens to patients and the care they receive. The aim of this paper is to introduce the concept of care pathway and explain how care pathways can be audited to better understand care. The care pathway is defined by clinically relevant events that take place within one or more healthcare institutions. The process begins with defining an ideal care pathway which is created by considering local expertise and guidelines. It is then possible to audit against the extent to which this ideal care pathway is achieved. This care pathway audit can enable identification of patterns in real-world care which can help with the of design interventions to help shift patients from the less to more desirable pathways. We conclude that through the process of the care pathway audit cycle, it is possible to learn about real-world activities, better utilize resources, promote safer care, improve quality of care, and help develop more effective interventions.

A modern pulse of ultrafast exhumation and diachronous crustal melting in the Nanga Parbat Massif.

We combine monazite petrochronology with thermal modeling to evaluate the relative roles of crustal melting, surface denudation, and tectonics in facilitating ultrafast exhumation of the Nanga Parbat Massif in the western Himalayan syntaxis. Our results reveal diachronous melting histories between samples and a pulse of ultrafast exhumation (9 to 13 mm/year) that began ~1 Ma and was preceded by several million years of slower, but still rapid, exhumation (2 to 5 mm/year). Recent studies show that an exhumation pulse of similar timing and magnitude occurred in the eastern Himalayan syntaxis. A synchronous exhumation pulse in both Himalayan syntaxes suggests that neither erosion by rivers and/or glaciers nor a pulse of crustal melting was a primary trigger for accelerated exhumation. Rather, our results, combined with those of recent studies in the eastern syntaxis, imply that larger-scale tectonic processes impose the dominant control on the current tempo of rapid exhumation in the Himalayan syntaxes.

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

Characteristics of Deaths With Evidence of Pathological Hoarding in Cook County 2017 to 2018.

ABSTRACT: Hoarding disorder was recently recognized as an independent diagnosis; it is characterized by the accumulation of objects causing a functional impairment and is commonly associated with increased risk of injury or death. Limited data exist about deaths of persons found in hoarding environments. This study investigated the characteristics and circumstances surrounding deaths found in "hoarding" environments. Using the electronic record management system, a search for the term "hoard" from 2017 to 2018 identified 138 cases. The mean age was 67 years, 56% were male, 76% were White, and 86% of decedents lived alone. Decomposition was noted in 61% of cases. A full autopsy was performed in 36 cases (26%); natural was the most common manner of death (80%), followed by accident (14%). Cases in which hoarding was thought to be contributory to the cause of death occurred in 5 cases. A qualitative hoard evaluation was done on 29 cases (21%) with available photographs. A hoarding level was assigned using the Clutter Hoarding Scale with an average of 3.39/5. Overall, the analysis showed deaths in pathological hoarding environments appeared to impact all socioeconomic groups and was associated with increased risk of accidental death and being found in a state of decomposition.

Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma.

INTRODUCTION: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype. METHODS: Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma. RESULTS: Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone (BiP, CANX, CALR), ER-associated protein degradation (EDEM1, DERL1) and ER stress-induced apoptosis (DDIT3, PPP1R15A) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs. CONCLUSION: Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma.

A Senescence Bystander Effect in Human Lung Fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the lungs of IPF patients compared with age-matched controls. The cause of this abnormal accumulation of senescent cells is unknown but evidence suggests that, once established, senescence can be transferred from senescent to non-senescent cells. In this study, we investigated whether senescent human lung fibroblasts (LFs) and alveolar epithelial cells (AECs) could induce a senescent-like phenotype in "naïve" non-senescent LFs in vitro. Primary cultures of LFs from adult control donors (Ctrl-LFs) with a low baseline of senescence were exposed to conditioned medium (CM) from: (i) Ctrl-LFs induced to become senescent using H2O2 or etoposide; (ii) LFs derived from IPF patients (IPF-LFs) with a high baseline of senescence; or (iii) senescence-induced A549 cells, an AEC line. Additionally, ratios of non-senescent Ctrl-LFs and senescence-induced Ctrl-LFs (100:0, 0:100, 50:50, 90:10, 99:1) were co-cultured and their effect on induction of senescence measured. We demonstrated that exposure of naïve non-senescent Ctrl-LFs to CM from senescence-induced Ctrl-LFs and AECs and IPF-LFs increased the markers of senescence including nuclear localisation of phosphorylated-H2A histone family member X (H2AXγ) and expression of p21, IL-6 and IL-8 in Ctrl-LFs. Additionally, co-cultures of non-senescent and senescence-induced Ctrl-LFs induced a senescent-like phenotype in the non-senescent cells. These data suggest that the phenomenon of "senescence-induced senescence" can occur in vitro in primary cultures of human LFs, and provides a possible explanation for the abnormal abundance of senescent cells in the lungs of IPF patients.

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.

BACKGROUND: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. METHODS: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FINDINGS: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). INTERPRETATION: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. FUNDING: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.