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Dr Anjali Kusumbe has been awarded an MRC Career Development Award to support her research examining how blood vessels support bone growth and repair.
Does This Infant Have a Dislocated Hip?: The Rational Clinical Examination Systematic Review.
IMPORTANCE: Delayed diagnosis of a dislocated hip in infants can lead to complex childhood surgery, interruption to family life, and premature osteoarthritis. OBJECTIVE: To evaluate the diagnostic accuracy of clinical examination in identifying dislocated hips in infants. DATA SOURCES: Systematic search of CINAHL, Embase, MEDLINE, and the Cochrane Library from the inception of each database until October 31, 2023. STUDY SELECTION: The 9 included studies reported the diagnostic accuracy of the clinical examination (index test) in infants aged 3 months or younger and a diagnostic hip ultrasound (reference test). The Graf method of ultrasound assessment was used to classify hip abnormalities. DATA EXTRACTION AND SYNTHESIS: The Rational Clinical Examination scale was used to assign levels of evidence and the Quality Assessment of Diagnostic Accuracy Studies tool was used to assess bias. Data were extracted using the individual hip as the unit of analysis; the data were pooled when the clinical examinations were evaluated by 3 or more of the included studies. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and likelihood ratios (LRs) of identifying a dislocated hip were calculated. RESULTS: Among infants screened with a clinical examination and a diagnostic ultrasound in 5 studies, the prevalence of a dislocated hip (n = 37 859 hips) was 0.94% (95% CI, 0.28%-2.0%). There were 8 studies (n = 44 827 hips) that evaluated use of the Barlow maneuver and the Ortolani maneuver (dislocate and relocate an unstable hip); the maneuvers had a sensitivity of 46% (95% CI, 26%-67%), a specificity of 99.1% (95% CI, 97.9%-99.6%), a positive LR of 52 (95% CI, 21-127), and a negative LR of 0.55 (95% CI, 0.37-0.82). There were 3 studies (n = 22 472 hips) that evaluated limited hip abduction and had a sensitivity of 13% (95% CI, 3.3%-37%), a specificity of 97% (95% CI, 87%-99%), a positive LR of 3.6 (95% CI, 0.72-18), and a negative LR of 0.91 (95% CI, 0.76-1.1). One study (n = 13 096 hips) evaluated a clicking sound and had a sensitivity of 13% (95% CI, 6.4%-21%), a specificity of 92% (95% CI, 92%-93%), a positive LR of 1.6 (95% CI, 0.91-2.8), and a negative LR of 0.95 (95% CI, 0.88-1.0). CONCLUSIONS AND RELEVANCE: In studies in which all infant hips were screened for developmental dysplasia of the hip, the prevalence of a dislocated hip was 0.94%. A positive LR for the Barlow and Ortolani maneuvers was the finding most associated with an increased likelihood of a dislocated hip. Limited hip abduction or a clicking sound had no clear diagnostic utility.
Persistence and Variation of the Indirect Effects of COVID-19 Restrictions on the Spectrum of Notifiable Infectious Diseases in China: Analysis of National Surveillance Among Children and Adolescents From 2018 to 2021.
BACKGROUND: Beyond the direct effect of COVID-19 infection on young people, the wider impact of the pandemic on other infectious diseases remains unknown. OBJECTIVE: This study aims to assess changes in the incidence and mortality of 42 notifiable infectious diseases during the pandemic among children and adolescents in China, compared with prepandemic levels. METHODS: The Notifiable Infectious Disease Surveillance System of China was used to detect new cases and fatalities among individuals aged 5-22 years across 42 notifiable infectious diseases spanning from 2018 to 2021. These infectious diseases were categorized into 5 groups: respiratory, gastrointestinal and enterovirus, sexually transmitted and blood-borne, zoonotic, and vector-borne diseases. Each year (2018-2021) was segmented into 4 phases: phase 1 (January 1-22), phase 2 (January 23-April 7), phase 3 (April 8-August 31), and phase 4 (September 1-December 31) according to the varying intensities of pandemic restrictive measures in 2020. Generalized linear models were applied to assess the change in the incidence and mortality within each disease category, using 2018 and 2019 as the reference. RESULTS: A total of 4,898,260 incident cases and 3701 deaths were included. The overall incidence of notifiable infectious diseases decreased sharply during the first year of the COVID-19 pandemic (2020) compared with prepandemic levels (2018 and 2019), and then rebounded in 2021, particularly in South China. Across the past 4 years, the number of deaths steadily decreased. The incidence of diseases rebounded differentially by the pandemic phase. For instance, although seasonal influenza dominated respiratory diseases in 2019, it showed a substantial decline during the pandemic (percent change in phase 2 2020: 0.21, 95% CI 0.09-0.50), which persisted until 2021 (percent change in phase 4 2021: 1.02, 95% CI 0.74-1.41). The incidence of gastrointestinal and enterovirus diseases decreased by 33.6% during 2020 but rebounded by 56.9% in 2021, mainly driven by hand, foot, and mouth disease (percent change in phase 3 2021: 1.28, 95% CI 1.17-1.41) and infectious diarrhea (percent change in phase 3 2020: 1.22, 95% CI 1.17-1.28). Sexually transmitted and blood-borne diseases were restrained during the first year of 2021 but rebounded quickly in 2021, mainly driven by syphilis (percent change in phase 3 2020: 1.31, 95% CI 1.23-1.40) and gonorrhea (percent change in phase 3 2020: 1.10, 95% CI 1.05-1.16). Zoonotic diseases were not dampened by the pandemic but continued to increase across the study period, mainly due to brucellosis (percent change in phase 2 2020: 0.94, 95% CI 0.75-1.16). Vector-borne diseases showed a continuous decline during 2020, dominated by hemorrhagic fever (percent change in phase 2 2020: 0.68, 95% CI 0.53-0.87), but rebounded in 2021. CONCLUSIONS: The COVID-19 pandemic was associated with a marked decline in notifiable infectious diseases in Chinese children and adolescents. These effects were not sustained, with evidence of a rebound to prepandemic levels by late 2021. To effectively address the postpandemic resurgence of infectious diseases in children and adolescents, it will be essential to maintain disease surveillance and strengthen the implementation of various initiatives. These include extending immunization programs, prioritizing the management of sexually transmitted infections, continuing feasible nonpharmaceutical intervention projects, and effectively managing imported infections.
An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.
Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.
Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.
OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.
RIVA - a phase IIa study of rituximab and varlilumab in relapsed or refractory B-cell malignancies: study protocol for a randomized controlled trial.
BACKGROUND: Over 12,000 new cases of B-cell malignancies are diagnosed in the UK each year, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the most common subtypes. Standard frontline therapy consists of immunochemotherapy with a CD20 monoclonal antibody (mAb), such as rituximab, delivered in combination with multi-agent chemotherapy. Despite being considered a treatable and potentially curable cancer, approximately 30% of DLBCL cases will relapse after frontline therapy. Advanced stage FL is incurable and typically has a relapsing and remitting course with a frequent need for re-treatment. Based on supportive preclinical data, we hypothesised that the addition of varlilumab (an anti-CD27 mAb) to rituximab (an anti-CD20 mAb) can improve the rate, depth and duration of the response of rituximab monotherapy in patients with relapsed or refractory B-cell malignancies. METHODS/DESIGN: Combination treatment of varlilumab plus rituximab, in two different dosing regimens, is being tested in the RIVA trial. RIVA is a two-stage open-label randomised phase IIa design in up to 40 patients with low- or high-grade relapsed or refractory CD20+ B-cell lymphoma. The study is open to recruitment in the UK. Enrolled patients are randomised 1:1 to two different experimental varlilumab to rituximab combinations. The primary objective is to determine the safety and tolerability of the combination and the anti-tumour activity (response) in relapsed or refractory B-cell malignancies. Secondary objectives will include an evaluation of the duration of the response and overall survival. Tertiary translational objectives include assessment of B-cell depletion, changes in immune effector cell populations, expression of CD27 as a biomarker of response and pharmacokinetic properties. Analyses will not be powered for formal statistical comparisons between treatment arms. DISCUSSION: RIVA will determine whether the combination of rituximab and varlilumab in relapsed or refractory B-cell malignancies is active and safe prior to future phase II/III trials. TRIAL REGISTRATION: EudraCT, 2017-000302-37. Registered on 16 January 2017. ISRCTN, ISRCTN15025004 . Registered on 16 August 2017.
Anterior Cruciate Ligament Return to Sport after Injury Scale (ACL-RSI) Scores over Time After Anterior Cruciate Ligament Reconstruction: A Systematic Review with Meta-analysis.
BACKGROUND: Psychological readiness is an important consideration for athletes and clinicians when making return to sport decisions following anterior cruciate ligament reconstruction (ACLR). To improve our understanding of the extent of deficits in psychological readiness, a systematic review is necessary. OBJECTIVE: To investigate psychological readiness (measured via the Anterior Cruciate Ligament-Return to Sport after Injury scale (ACL-RSI)) over time after ACL tear and understand if time between injury and surgery, age, and sex are associated with ACL-RSI scores. METHODS: Seven databases were searched from the earliest date available to March 22, 2022. Articles reporting ACL-RSI scores after ACL tear were included. Risk of bias was assessed using the ROBINS-I, RoB-2, and RoBANS tools based on the study design. Evidence certainty was assessed for each analysis. Random-effects meta-analyses pooled ACL-RSI scores, stratified by time post-injury and based on treatment approach (i.e., early ACLR, delayed ACLR, and unclear approach). RESULTS: A total of 83 studies were included in this review (78% high risk of bias). Evidence certainty was 'weak' or 'limited' for all analyses. Overall, ACL-RSI scores were higher at 3 to 6 months post-ACLR (mean = 61.5 [95% confidence interval (CI) 58.6, 64.4], I2 = 94%) compared to pre-ACLR (mean = 44.4 [95% CI 38.2, 50.7], I2 = 98%), remained relatively stable, until they reached the highest point 2 to 5 years after ACLR (mean = 70.7 [95% CI 63.0, 78.5], I2 = 98%). Meta-regression suggests shorter time from injury to surgery, male sex, and older age were associated with higher ACL-RSI scores only 3 to 6 months post-ACLR (heterogeneity explained R2 = 47.6%), and this reduced 1-2 years after ACLR (heterogeneity explained R2 = 27.0%). CONCLUSION: Psychological readiness to return to sport appears to improve early after ACL injury, with little subsequent improvement until ≥ 2-years after ACLR. Longer time from injury to surgery, female sex and older age might be negatively related to ACL-RSI scores 12-24 months after ACLR. Due to the weak evidence quality rating and the considerable importance of psychological readiness for long-term outcomes after ACL injury, there is an urgent need for well-designed studies that maximize internal validity and identify additional prognostic factors for psychological readiness at times critical for return to sport decisions. REGISTRATION: Open Science Framework (OSF), https://osf.io/2tezs/ .
The post-authorisation safety of COVID-19 vaccines: real-world evidence
Vaccines against COVID-19 were developed, approved, and distributed at an unprecedented speed during the coronavirus disease pandemic. These vaccines have shown high efficacy in preventing severe COVID-19 and acceptable safety profiles in clinical trials. However, potential rare adverse events related to these new vaccines have been reported, and continuous vaccine safety surveillance is needed as mass immunisation against COVID-19 continues. With the ability of capturing information from larger and more diverse populations, routinely collected health data, also known as 'real-world data', can provide valuable real-world insights in post-marketing surveillance, complementing the knowledge gained from clinical trials. This thesis aims to assess the post-authorisation safety of COVID-19 vaccines by applying epidemiological and statistical methods using real-world data. I began with a literature review of real-world studies examining the safety of COVID-19 vaccines. I then introduced the methods and different data sources being used in the thesis. Three analytical studies were conducted using multiple electronic health records and claims datasets. In the first study, I characterised the background incidence rates of 15 pre-specified adverse events of special interest associated with COVID-19 vaccines. I observed considerable variability in the rates with respect to age and sex, emphasising the need for standardisation or stratification of the background rates used for vaccine surveillance. This study also found substantial heterogeneity in the estimated rates across databases, suggesting that observed rates among COVID-19 vaccine recipients should be compared with background rates obtained from the same database where possible. I then assessed the association between COVID-19 vaccines, SARS-CoV-2 infection, and the risk of immune-mediated neurological events. I applied the observed-to-expected analysis and the self-controlled case series methods using primary care records from the UK and Catalonia, Spain. This study found no increased risk of the included immune-mediated neurological events after COVID-19 vaccination, but increased risk after SARS-CoV-2 infection. These findings reaffirmed the safety of the studied COVID-19 vaccines, underscoring the importance of vaccination. Finally, I examined the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with COVID-19 vaccines using datasets from Europe and the US. I compared adenovirus-based COVID-19 vaccines with mRNA-based COVID-19 vaccines, and the secondary analysis compared two brands of mRNA vaccines. This study found an increased risk of thrombocytopenia after the first dose of ChAdOx1 (Oxford-AstraZeneca) compared with BNT162b2 (Pfizer-BioNTech). While the studied events were rare, these observed risks after adenovirus-based vaccines should be considered in planning future immunisation campaigns and vaccine development. In these analyses, I have demonstrated that real-world data can generate timely and reliable evidence on post-authorisation vaccine safety. These findings have important implications for clinical practice, health policy, and future research. Above all, in light of the well-established benefits of the COVID-19 vaccination, my findings should encourage continued confidence in vaccination.
Single nucleus and spatial transcriptomic profiling of healthy human hamstring tendon.
The molecular and cellular basis of health in human tendons remains poorly understood. Among human tendons, hamstring tendon has markedly low pathology and can provide a prototypic healthy tendon reference. The aim of this study was to determine the transcriptomes and location of all cell types in healthy hamstring tendon. Using single nucleus RNA sequencing, we profiled the transcriptomes of 10 533 nuclei from four healthy donors and identified 12 distinct cell types. We confirmed the presence of two fibroblast cell types, endothelial cells, mural cells, and immune cells, and identified cell types previously unreported in tendons, including different skeletal muscle cell types, satellite cells, adipocytes, and undefined nervous system cells. The location of these cell types within tendon was defined using spatial transcriptomics and imaging, and potential transcriptional networks and cell-cell interactions were analyzed. We demonstrate that fibroblasts have the highest number of potential cell-cell interactions in our dataset, are present throughout the tendon, and play an important role in the production and organization of extracellular matrix, thus confirming their role as key regulators of hamstring tendon homeostasis. Overall, our findings underscore the complexity of the cellular networks that underpin healthy human tendon function and the central role of fibroblasts as key regulators of hamstring tendon tissue homeostasis.
Impact of public release of performance data on the behaviour of healthcare consumers and providers.
BACKGROUND: It is becoming increasingly common to publish information about the quality and performance of healthcare organisations and individual professionals. However, we do not know how this information is used, or the extent to which such reporting leads to quality improvement by changing the behaviour of healthcare consumers, providers, and purchasers. OBJECTIVES: To estimate the effects of public release of performance data, from any source, on changing the healthcare utilisation behaviour of healthcare consumers, providers (professionals and organisations), and purchasers of care. In addition, we sought to estimate the effects on healthcare provider performance, patient outcomes, and staff morale. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers on 26 June 2017. We checked reference lists of all included studies to identify additional studies. SELECTION CRITERIA: We searched for randomised or non-randomised trials, interrupted time series, and controlled before-after studies of the effects of publicly releasing data regarding any aspect of the performance of healthcare organisations or professionals. Each study had to report at least one main outcome related to selecting or changing care. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for eligibility and extracted data. For each study, we extracted data about the target groups (healthcare consumers, healthcare providers, and healthcare purchasers), performance data, main outcomes (choice of healthcare provider, and improvement by means of changes in care), and other outcomes (awareness, attitude, knowledge of performance data, and costs). Given the substantial degree of clinical and methodological heterogeneity between the studies, we presented the findings for each policy in a structured format, but did not undertake a meta-analysis. MAIN RESULTS: We included 12 studies that analysed data from more than 7570 providers (e.g. professionals and organisations), and a further 3,333,386 clinical encounters (e.g. patient referrals, prescriptions). We included four cluster-randomised trials, one cluster-non-randomised trial, six interrupted time series studies, and one controlled before-after study. Eight studies were undertaken in the USA, and one each in Canada, Korea, China, and The Netherlands. Four studies examined the effect of public release of performance data on consumer healthcare choices, and four on improving quality.There was low-certainty evidence that public release of performance data may make little or no difference to long-term healthcare utilisation by healthcare consumers (3 studies; 18,294 insurance plan beneficiaries), or providers (4 studies; 3,000,000 births, and 67 healthcare providers), or to provider performance (1 study; 82 providers). However, there was also low-certainty evidence to suggest that public release of performance data may slightly improve some patient outcomes (5 studies, 315,092 hospitalisations, and 7502 providers). There was low-certainty evidence from a single study to suggest that public release of performance data may have differential effects on disadvantaged populations. There was no evidence about effects on healthcare utilisation decisions by purchasers, or adverse effects. AUTHORS' CONCLUSIONS: The existing evidence base is inadequate to directly inform policy and practice. Further studies should consider whether public release of performance data can improve patient outcomes, as well as healthcare processes.
Algebraic representation of Gaussian Markov combinations
Markov combinations for structural meta-analysis problems provide a way of constructing a statistical model that takes into account two or more marginal distributions by imposing conditional independence constraints between the variables that are not jointly observed. This paper considers Gaussian distributions and discusses how the covariance and concentration matrices of the different combinations can be found via matrix operations. In essence all these Markov combinations correspond to finding a positive definite completion of the covariance matrix over the set of random variables of interest and respecting the constraints imposed by each Markov combination. The paper further shows the potential of investigating the properties of the combinations via algebraic statistics tools. An illustrative application will motivate the importance of solving problems of this type.
On the importance of cognitive profiling: A graphical modelling analysis of domain-specific and domain-general deficits after stroke.
Cognitive problems following stroke are typically analysed using either short but relatively uninformative general tests or through detailed but time consuming tests of domain specific deficits (e.g., in language, memory, praxis). Here we present an analysis of neuropsychological deficits detected using a screen designed to fall between other screens by being 'broad' (testing multiple cognitive abilities) but 'shallow' (sampling the abilities briefly, to be time efficient) - the BCoS. Assessment using the Birmingham Cognitive Screen (BCoS) enables the relations between 'domain specific' and 'domain general' cognitive deficits to be evaluated as the test generates an overall cognitive profile for individual patients. We analysed data from 287 patients tested at a sub-acute stage of stroke (<3 months). Graphical modelling techniques were used to investigate the associative structure and conditional independence between deficits within and across the domains sampled by BCoS (attention and executive functions, language, memory, praxis and number processing). The patterns of deficit within each domain conformed to existing cognitive models. However, these within-domain patterns underwent substantial change when the whole dataset was modelled, indicating that domain-specific deficits can only be understood in relation to linked changes in domain-general processes. The data point to the importance of using over-arching cognitive screens, measuring domain-general as well as domain-specific processes, in order to account for neuropsychological deficits after stroke. The paper also highlights the utility of using graphical modelling to understand the relations between cognitive components in complex datasets.
Graphical modeling for gene set analysis: A critical appraisal.
Current demand for understanding the behavior of groups of related genes, combined with the greater availability of data, has led to an increased focus on statistical methods in gene set analysis. In this paper, we aim to perform a critical appraisal of the methodology based on graphical models developed in Massa et al. (2010) that uses pathway signaling networks as a starting point to develop statistically sound procedures for gene set analysis. We pay attention to the potential of the methodology with respect to the organizational aspects of dealing with such complex but highly informative starting structures, that is pathways. We focus on three themes: the translation of a biological pathway into a graph suitable for modeling, the role of shrinkage when more genes than samples are obtained, the evaluation of respondence of the statistical models to the biological expectations. To study the impact of shrinkage, two simulation studies will be run. To evaluate the biological expectation we will use data from a network with known behavior that offer the possibility of carrying out a realistic check of respondence of the model to changes in the experimental conditions.
Alcohol consumption and cause-specific mortality in Cuba: prospective study of 120 623 adults.
BACKGROUND: The associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba. METHODS: In 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35-79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08. FINDINGS: After exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (<1 bottle/week), but this association was almost completely attenuated on exclusion of early follow-up. INTERPRETATION: In this large prospective study in Cuba, weekly alcohol consumption was continuously related to premature mortality. Reverse causality is likely to account for much of the apparent excess risk among non-drinkers. The findings support limits to alcohol consumption that are lower than present recommendations in Cuba. FUNDING: Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen).
Development and Internal Validation of a Risk Score to Detect Asymptomatic Carotid Stenosis.
OBJECTIVE: Asymptomatic carotid stenosis (ACS) is associated with an increased risk of ischaemic stroke and myocardial infarction. Risk scores have been developed to detect individuals at high risk of ACS, thereby enabling targeted screening, but previous external validation showed scope for refinement of prediction by adding additional predictors. The aim of this study was to develop a novel risk score in a large contemporary screened population. METHODS: A prediction model was developed for moderate (≥50%) and severe (≥70%) ACS using data from 596 469 individuals who attended screening clinics. Variables that predicted the presence of ≥50% and ≥70% ACS independently were determined using multivariable logistic regression. Internal validation was performed using bootstrapping techniques. Discrimination was assessed using area under the receiver operating characteristic curves (AUROCs) and agreement between predicted and observed cases using calibration plots. RESULTS: Predictors of ≥50% and ≥70% ACS were age, sex, current smoking, diabetes mellitus, prior stroke/transient ischaemic attack, coronary artery disease, peripheral arterial disease, blood pressure, and blood lipids. Models discriminated between participants with and without ACS reliably, with an AUROC of 0.78 (95% confidence interval [CI] 0.77-0.78) for ≥ 50% ACS and 0.82 (95% CI 0.81-0.82) for ≥ 70% ACS. The number needed to screen in the highest decile of predicted risk to detect one case with ≥50% ACS was 13 and that of ≥70% ACS was 58. Targeted screening of the highest decile identified 41% of cases with ≥50% ACS and 51% with ≥70% ACS. CONCLUSION: The novel risk model predicted the prevalence of ACS reliably and performed better than previous models. Targeted screening among the highest decile of predicted risk identified around 40% of all cases with ≥50% ACS. Initiation or intensification of cardiovascular risk management in detected cases might help to reduce both carotid related ischaemic strokes and myocardial infarctions.