Maternal and congenital syphilis attributable to ethnoracial inequalities: a national record-linkage longitudinal study of 15 million births in Brazil.

BACKGROUND: This study estimated ethnoracial inequalities in maternal and congenital syphilis in Brazil, understanding race as a relational category product of a sociopolitical construct that functions as an essential tool of racism and its manifestations. METHODS: We linked routinely collected data from Jan 1, 2012 to Dec 31, 2017 to conduct a population-based study in Brazil. We estimated the attributable fraction of race (skin colour) for the entire population and specific subgroups compared with White women using adjusted logistic regression. We also obtained the attributable fraction of the intersection between two social markers (race and education) and compared it with White women with more than 12 years of education as the baseline. FINDINGS: Of 15 810 488 birth records, 144 564 women had maternal syphilis and 79 580 had congenital syphilis. If all women had the same baseline risk as White women, 35% (95% CI 34·89-36·10) of all maternal syphilis and 41% (40·49-42·09) of all congenital syphilis would have been prevented. Compared with other ethnoracial categories, these percentages were higher among Parda/Brown women (46% [45·74-47·20] of maternal syphilis and 52% [51·09-52·93] of congenital syphilis would have been prevented) and Black women (61% [60·25-61·75] of maternal syphilis and 67% [65·87-67·60] of congenital syphilis would have been prevented). If all ethnoracial groups had the same risk as White women with more than 12 years of education, 87% of all maternal syphilis and 89% of all congenital syphilis would have been prevented. INTERPRETATION: Only through effective control of maternal syphilis among populations at higher risk (eg, Black and Parda/Brown women with lower educational levels) can WHO's global health initiative to eliminate mother-to-child transmission of syphilis be made feasible. Recognising that racism and other intersecting forms of oppression affect the lives of minoritised groups and advocating for actions through the lens of intersectionality is imperative for attaining and guaranteeing health equity. Achieving health equality needs to be addressed to achieve syphilis control. Given the scale and complexity of the problem (which is unlikely to be unique to Brazil), structural issues and social markers of oppression, such as race and education, must be considered to prevent maternal and congenital syphilis and improve maternal and child outcomes globally. FUNDING: Wellcome Trust, CNPq-Brazil. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Mortality among over 6 million internal and international migrants in Brazil: a study using the 100 Million Brazilian Cohort.

Background: To understand if migrants living in poverty in low and middle-income countries (LMICs) have mortality advantages over the non-migrant population, we investigated mortality risk patterns among internal and international migrants in Brazil over their life course. Methods: We linked socio-economic and mortality data from 1st January 2011 to 31st December 2018 in the 100 Million Brazilian Cohort and calculated all-cause and cause-specific age-standardised mortality rates according to individuals' migration status for men and women. Using Cox regression models, we estimated the age- and sex-adjusted mortality hazard ratios (HR) for internal migrants (i.e., Brazilian-born individuals living in a different Brazilian state than their birth) compared to Brazilian-born non-migrants; and for international migrants (i.e., people born in another country) compared to Brazilian-born individuals. Findings: The study followed up 45,051,476 individuals, of whom 6,057,814 were internal migrants, and 277,230 were international migrants. Internal migrants had similar all-cause mortality compared to Brazilian non-migrants (aHR = 0.99, 95% CI = 0.98-0.99), marginally higher mortality for ischaemic heart diseases (aHR = 1.04, 95% CI = 1.03-1.05) and higher for stroke (aHR = 1.11, 95% CI = 1.09-1.13). Compared to Brazilian-born individuals, international migrants had 18% lower all-cause mortality (aHR = 0.82, 95% CI = 0.80-0.84), with up to 50% lower mortality from interpersonal violence among men (aHR = 0.50, 95% CI = 0.40-0.64), but higher mortality from avoidable causes related to maternal health (aHR = 2.17, 95% CI = 1.17-4.05). Interpretation: Although internal migrants had similar all-cause mortality, international migrants had lower all-cause mortality compared to non-migrants. Further investigations using intersectional approaches are warranted to understand the marked variations by migration status, age, and sex for specific causes of death, such as elevated maternal mortality and male lower interpersonal violence-related mortality among international migrants. Funding: The Wellcome Trust.

Protocol for an OpenSAFELY cohort study collecting patient-reported outcome measures using the TPP Airmid smartphone application and linked big data to quantify the health and economic costs of long COVID (OpenPROMPT).

INTRODUCTION: The impact of long COVID on health-related quality of-life (HRQoL) and productivity is not currently known. It is important to understand who is worst affected by long COVID and the cost to the National Health Service (NHS) and society, so that strategies like booster vaccines can be prioritised to the right people. OpenPROMPT aims to understand the impact of long COVID on HRQoL in adults attending English primary care. METHODS AND ANALYSIS: We will ask people to participate in this cohort study through a smartphone app (Airmid), and completing a series of questionnaires held within the app. Questionnaires will ask about HRQoL, productivity and symptoms of long COVID. Participants will be asked to fill in the questionnaires once a month, for 90 days. Questionnaire responses will be linked, where possible, to participants' existing health records from primary care, secondary care, and COVID testing and vaccination data. Analysis will take place using the OpenSAFELY data platform and will estimate the impact of long COVID on HRQoL, productivity and cost to the NHS. ETHICS AND DISSEMINATION: The Proportionate Review Sub-Committee of the South Central-Berkshire B Research Ethics Committee has reviewed and approved the study and have agreed that we can ask people to take part (22/SC/0198). Our results will provide information to support long-term care, and make recommendations for prevention of long COVID in the future. TRIAL REGISTRATION NUMBER: NCT05552612.

OpenSAFELY: impact of national guidance on switching anticoagulant therapy during COVID-19 pandemic.

BACKGROUND: Early in the COVID-19 pandemic, the National Health Service (NHS) recommended that appropriate patients anticoagulated with warfarin should be switched to direct-acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately coprescribed two anticoagulants following a medication change and associated monitoring. OBJECTIVE: To describe which people were switched from warfarin to DOACs; identify potentially unsafe coprescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic. METHODS: With the approval of NHS England, we conducted a cohort study using routine clinical data from 24 million NHS patients in England. RESULTS: 20 000 of 164 000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in coprescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. International normalised ratio (INR) testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420). CONCLUSIONS: Increased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people coprescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.

Estimating underreporting of leprosy in Brazil using a Bayesian approach.

BACKGROUND: Leprosy remains concentrated among the poorest communities in low-and middle-income countries and it is one of the primary infectious causes of disability. Although there have been increasing advances in leprosy surveillance worldwide, leprosy underreporting is still common and can hinder decision-making regarding the distribution of financial and health resources and thereby limit the effectiveness of interventions. In this study, we estimated the proportion of unreported cases of leprosy in Brazilian microregions. METHODOLOGY/PRINCIPAL FINDINGS: Using data collected between 2007 to 2015 from each of the 557 Brazilian microregions, we applied a Bayesian hierarchical model that used the presence of grade 2 leprosy-related physical disabilities as a direct indicator of delayed diagnosis and a proxy for the effectiveness of local leprosy surveillance program. We also analyzed some relevant factors that influence spatial variability in the observed mean incidence rate in the Brazilian microregions, highlighting the importance of socioeconomic factors and how they affect the levels of underreporting. We corrected leprosy incidence rates for each Brazilian microregion and estimated that, on average, 33,252 (9.6%) new leprosy cases went unreported in the country between 2007 to 2015, with this proportion varying from 8.4% to 14.1% across the Brazilian States. CONCLUSIONS/SIGNIFICANCE: The magnitude and distribution of leprosy underreporting were adequately explained by a model using Grade 2 disability as a marker for the ability of the system to detect new missing cases. The percentage of missed cases was significant, and efforts are warranted to improve leprosy case detection. Our estimates in Brazilian microregions can be used to guide effective interventions, efficient resource allocation, and target actions to mitigate transmission.

Using the Robson classification to assess caesarean section rates in Brazil: an observational study of more than 24 million births from 2011 to 2017.

BACKGROUND: Applying the Robson classification to all births in Brazil, the objectives of our study were to estimate the rates of caesarean section delivery, assess the extent to which caesarean sections were clinically indicated, and identify variation across socioeconomic groups. METHODS: We conducted a population-based study using routine records of the Live Births Information System in Brazil from January 1, 2011, to December 31, 2017. We calculated the relative size of each Robson group; the caesarean section rate; and the contribution to the overall caesarean section rate. We categorised Brazilian municipalities using the Human Development Index to explore caesarean section rates further. We estimated the time trend in caesarean section rates. RESULTS: The rate of caesarean sections was higher in older and more educated women. Prelabour caesarean sections accounted for more than 54 % of all caesarean deliveries. Women with a previous caesarean section (Group 5) made up the largest group (21.7 %). Groups 6-9, for whom caesarean sections would be indicated in most cases, all had caesarean section rates above 82 %, as did Group 5. The caesarean section rates were higher in municipalities with a higher HDI. The general Brazilian caesarean section rate remained stable during the study period. CONCLUSIONS: Brazil is a country with one of the world's highest caesarean section rates. This nationwide population-based study provides the evidence needed to inform efforts to improve the provision of clinically indicated caesarean sections. Our results showed that caesarean section rates were lower among lower socioeconomic groups even when clinically indicated, suggesting sub-optimal access to surgical care.

Medications for chronic obstructive pulmonary disease: a historical non-interventional cohort study with validation against RCT results.

BACKGROUND: Chronic obstructive pulmonary disease treatment is informed by randomised controlled trial results, but it is unclear if these findings apply to people excluded from these trials. We used data from the TORCH (TOwards a Revolution in COPD Health) randomised controlled trial to validate non-interventional methods for assessing the clinical effectiveness of chronic obstructive pulmonary disease treatment in the UK Clinical Practice Research Datalink, before applying these methods to the analysis of people who would have been excluded from TORCH. OBJECTIVES: To validate the use of non-interventional Clinical Practice Research Datalink data and methods for estimating chronic obstructive pulmonary disease treatment effects against trial results, and, using validated methods, to determine treatment effects in people who would have been excluded from the TORCH trial. DESIGN: A historical non-interventional cohort design, including validation against randomised controlled trial results. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: People aged ≥ 18 years with chronic obstructive pulmonary disease registered in Clinical Practice Research Datalink GOLD between January 2000 and January 2017. For objective 1, we prepared a cohort that was analogous to the TORCH trial cohort by applying TORCH trial inclusion/exclusion criteria followed by individual matching to TORCH trial participants. For objectives 2 and 3, we prepared cohorts that were analogous to the TORCH trial that, nevertheless, would not have been eligible for the TORCH trial because of age, asthma, comorbidity or mild disease. INTERVENTIONS: The long-acting beta-2 agonist and inhaled corticosteroid combination product Seretide (GlaxoSmithKline plc) [i.e. fluticasone propionate plus salmeterol (FP-SAL)] compared with (1) no FP-SAL exposure or (2) exposure to salmeterol (i.e. the long-acting beta-2 agonist) only. MAIN OUTCOME MEASURES: Exacerbations, mortality, pneumonia and time to treatment change. RESULTS: For objective 1, the exacerbation rate ratio was comparable to that in the TORCH trial for FP-SAL compared with salmeterol (0.85, 95% confidence interval 0.74 to 0.97, vs. TORCH trial 0.88, 95% confidence interval 0.81 to 0.95), but not for FP-SAL compared with no FP-SAL (1.30, 95% confidence interval 1.19 to 1.42, vs. TORCH trial 0.75, 95% confidence interval 0.69 to 0.81). Active comparator results were also consistent with the TORCH trial for mortality (hazard ratio 0.93, 95% confidence interval 0.65 to 1.32, vs. TORCH trial hazard ratio 0.93, 95% confidence interval 0.77 to 1.13) and pneumonia (risk ratio 1.39, 95% confidence interval 1.04 to 1.87, vs. TORCH trial risk ratio 1.47, 95% confidence interval 1.25 to 1.73). For objectives 2 and 3, active comparator results were consistent with the TORCH trial for exacerbations, with the exception of people with milder chronic obstructive pulmonary disease, in whom we observed a stronger protective association (risk ratio 0.56, 95% confidence interval 0.46 to 0.70, vs. TORCH trial risk ratio 0.85, 95% confidence interval 0.74 to 0.97). For the analysis of mortality, we saw a lack of association with being prescribed FP-SAL (vs. being prescribed salmeterol), with the exception of those with prior asthma, for whom we observed an increase in mortality (hazard ratio 1.49, 95% confidence interval 1.21 to 1.85, vs. TORCH trial-analogous HR 0.93, 95% confidence interval 0.64 to 1.32). CONCLUSIONS: Routinely collected electronic health record data can be used to successfully measure chronic obstructive pulmonary disease treatment effects when comparing two treatments, but not for comparisons between active treatment and no treatment. Analyses involving patients who would have been excluded from trials mostly suggests that treatment effects for FP-SAL are similar to trial effects, although further work is needed to characterise a small increased risk of death in those with concomitant asthma. LIMITATIONS: Some of our analyses had small numbers. FUTURE WORK: The differences in treatment effects that we found should be investigated further in other data sets. Currently recommended chronic obstructive pulmonary disease inhaled combination therapy (other than FP-SAL) should also be investigated using these methods. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 51. See the NIHR Journals Library website for further project information.

Chronic obstructive pulmonary disease affects 3 million people in the UK and is characterised by breathing difficulties that get worse over time, with sudden acute symptoms (exacerbations), possibly requiring hospitalisation. The evidence for use of medicines for treating chronic obstructive pulmonary disease comes from randomised controlled trial results. Randomised controlled trials generally include younger people with severe disease who do not have any other illnesses apart from chronic obstructive pulmonary disease, meaning that the effectiveness of these trials in all people with chronic obstructive pulmonary disease is unknown. Very large databases of anonymous electronic health records captured during NHS consultations can be used to study patients excluded from trials. However, confidence in results from studies using these data can be low because of fears of unaccounted bias, as patients are not randomised to treatment. In this project, we selected a group of patients from a very large electronic health record database called the Clinical Practice Research Datalink who were very similar to participants in a well-known large chronic obstructive pulmonary disease randomised controlled trial [the TORCH (TOwards a Revolution in COPD Health) trial]. When we analysed data from these patients, we found very similar results to the TORCH trial in relation to the reduction of exacerbations, development of pneumonia and time until death, when comparing one chronic obstructive pulmonary disease treatment with another. Having shown that our methods could be trusted to produce valid results when comparing one chronic obstructive pulmonary disease treatment with another, we then went on to analyse patients in the Clinical Practice Research Datalink who would have been excluded from the TORCH trial for the following reasons: aged > 80 years, having asthma as well as chronic obstructive pulmonary disease, or having only mild chronic obstructive pulmonary disease. For exacerbations, we found that, for people with milder chronic obstructive pulmonary disease, one of the treatments we studied seemed to work better than in the trial. For the analysis of mortality, we found that, for people with asthma as well as chronic obstructive pulmonary disease, one of the treatments seemed not to work so well, with more people dying. Future studies are needed in different populations (such as in a database from another country) to confirm these results.

Assessment of common infections and incident dementia using UK primary and secondary care data: a historical cohort study.

BACKGROUND: Common infections have been associated with dementia risk; however, evidence is scarce. We aimed to investigate the association between common infections and dementia in adults (≥65 years) in a UK population-based cohort study. METHODS: We did a historical cohort study of individuals who were 65 years and older with no history of dementia or cognitive impairment using the Clinical Practice Research Datalink linked to Hospital Episode Statistics between Jan 1, 2004, and Dec 31, 2018. Multivariable Cox proportional hazard regression models were used to estimate the association between time-updated previous common infections (sepsis, pneumonia, other lower respiratory tract infections, urinary tract infections, and skin and soft tissue infections) and incident dementia diagnosis. We also tested for effect modification by diabetes since it is an independent risk factor for dementia and co-occurs with infection. FINDINGS: Between Jan 1, 2004, and Dec 31, 2018, our study included 989 800 individuals (median age 68·6 years [IQR 65·0-77·0]; 537 602 [54·3%] women) of whom 402 204 (40·6%) were diagnosed with at least one infection and 56 802 (5·7%) had incident dementia during a median follow-up of 5·2 years (IQR 2·3-9·0). Dementia risk increased in those with any infection (adjusted hazard ratio [HR] 1·53 [95% CI 1·50-1·55]) compared with those without infection. HRs were highest for sepsis (HR 2·08 [1·89-2·29]) and pneumonia (HR 1·88 [1·77-1·99]) and for infections leading to hospital admission (1·99 [1·94-2·04]). HRs were also higher in individuals with diabetes compared with those without diabetes. INTERPRETATION: Common infections, particularly those resulting in hospitalisation, were associated with an increased risk of dementia persisting over the long term. Whether reducing infections lowers the risk of subsequent dementia warrants evaluation. FUNDING: Alzheimer's Society, Wellcome Trust, and the Royal Society.

Ethnic differences in guideline-indicated statin initiation for people with type 2 diabetes in UK primary care, 2006-2019: A cohort study.

BACKGROUND: Type 2 diabetes is 2-3 times more prevalent in people of South Asian and African/African Caribbean ethnicity than people of European ethnicity living in the UK. The former 2 groups also experience excess atherosclerotic cardiovascular disease (ASCVD) complications of diabetes. We aimed to study ethnic differences in statin initiation, a cornerstone of ASCVD primary prevention, for people with type 2 diabetes. METHODS AND FINDINGS: Observational cohort study of UK primary care records, from 1 January 2006 to 30 June 2019. Data were studied from 27,511 (88%) people of European ethnicity, 2,386 (8%) people of South Asian ethnicity, and 1,142 (4%) people of African/African Caribbean ethnicity with incident type 2 diabetes, no previous ASCVD, and statin use indicated by guidelines. Statin initiation rates were contrasted by ethnicity, and the number of ASCVD events that could be prevented by equalising prescribing rates across ethnic groups was estimated. Median time to statin initiation was 79, 109, and 84 days for people of European, South Asian, and African/African Caribbean ethnicity, respectively. People of African/African Caribbean ethnicity were a third less likely to receive guideline-indicated statins than European people (n/N [%]: 605/1,142 [53%] and 18,803/27,511 [68%], respectively; age- and gender-adjusted HR 0.67 [95% CI 0.60 to 0.76], p < 0.001). The HR attenuated marginally in a model adjusting for total cholesterol/high-density lipoprotein cholesterol ratio (0.77 [95% CI 0.69 to 0.85], p < 0.001), with no further diminution when deprivation, ASCVD risk factors, comorbidity, polypharmacy, and healthcare usage were accounted for (fully adjusted HR 0.76 [95% CI 0.68, 0.85], p < 0.001). People of South Asian ethnicity were 10% less likely to receive a statin than European people (1,489/2,386 [62%] and 18,803/27,511 [68%], respectively; fully adjusted HR 0.91 [95% CI 0.85 to 0.98], p = 0.008, adjusting for all covariates). We estimated that up to 12,600 ASCVD events could be prevented over the lifetimes of people currently affected by type 2 diabetes in the UK by equalising statin prescribing across ethnic groups. Limitations included incompleteness of recording of routinely collected data. CONCLUSIONS: In this study we observed that people of African/African Caribbean ethnicity with type 2 diabetes were substantially less likely, and people of South Asian ethnicity marginally less likely, to receive guideline-indicated statins than people of European ethnicity, even after accounting for sociodemographics, healthcare usage, ASCVD risk factors, and comorbidity. Underuse of statins in people of African/African Caribbean or South Asian ethnicity with type 2 diabetes is a missed opportunity to prevent cardiovascular events.

Ethnic differences in the incidence of clinically diagnosed influenza: an England population-based cohort study 2008-2018.

Background: People of non-White ethnicity have a higher risk of severe outcomes following influenza infection. It is unclear whether this is driven by an increased risk of infection or complications. We therefore aimed to investigate the incidence of clinically diagnosed influenza/influenza-like illness (ILI) by ethnicity in England from 2008-2018. Methods: We used linked primary and secondary healthcare data (from the Clinical Practice Research Datalink [CPRD] GOLD and Aurum databases and Hospital Episodes Statistics Admitted Patient Care [HES APC]). We included patients with recorded ethnicity who were aged 40-64 years and did not have a chronic health condition that would render them eligible for influenza vaccination. ILI infection was identified from diagnostic codes in CPRD and HES APC. We calculated crude annual infection incidence rates by ethnic group. Multivariable Poisson regression models with random effects were used to estimate any ethnic disparities in infection risk. Our main analysis adjusted for age, sex, and influenza year. Results: A total of 3,735,308 adults aged 40-64 years were included in the study; 87.6% White, 5.2% South Asian, 4.2% Black, 1.9% Other, and 1.1% Mixed. We identified 102,316 ILI episodes recorded among 94,623 patients. The rate of ILI was highest in the South Asian (9.6 per 1,000 person-years), Black (8.4 per 1,000 person-years) and Mixed (6.9 per 1,000 person-years) ethnic groups. The ILI rate in the White ethnic group was 5.7 per 1,000 person-years. After adjustment for age sex and influenza year, higher incidence rate ratios (IRR) for ILI were seen for South Asian (1.70, 95% CI 1.66-1.75), Black (1.48, 1.44-1.53) and Mixed (1.22, 1.15-1.30) groups compared to White ethnicity. Conclusions: Our results suggest that influenza infection risk differs between White and non-White groups who are not eligible for routine influenza vaccination.

The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs.

BACKGROUND: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. OBJECTIVES: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. DESIGN: A series of 200 double-blinded N-of-1 trials. SETTING: Participants were recruited from 50 general practices in England and Wales. PARTICIPANTS: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. INTERVENTIONS: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. MAIN OUTCOME MEASURES: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful. RESULTS: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. CONCLUSIONS: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. FUTURE WORK: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. LIMITATIONS: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

Statins are one of the most commonly prescribed drugs in the UK. There is strong evidence that they are effective in safely reducing heart disease; however, there is some doubt about whether or not statins cause muscle pain, stiffness or weakness. This research has been carried out to understand the effect of statins on muscle symptoms. To answer our question, we asked 200 volunteers from across England and Wales to participate in the study. Patients who joined the study either had recently stopped taking statins because of muscle symptoms or were considering stopping because of muscle symptoms. Patients who participated were randomly assigned to a sequence of six 2-month treatment periods during which they received either statins or a placebo. Neither patients nor their general practitioner knew which tablet they were receiving. This helped to reduce bias in the data. At the end of each treatment period, patients were asked to report any muscle symptoms, or any other symptoms, that they experienced. The key result of this work is that patients reported no difference, on average, in their muscle symptoms between periods of taking a statin and periods of taking a placebo. We also assessed the impact on the patient's quality of life by looking at how statins affected the following areas: general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. As with muscle symptoms, there was no evidence of a difference between statin and placebo periods. The majority of patients who finished the trial decided to continue using statins after the trial. Future research should be carried out to assess different statin doses, as higher doses are often used following a heart attack. In addition, further work is needed to see how the approach we used could be adopted into everyday clinical care.

Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts.

OBJECTIVES: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. METHODS: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region. RESULTS: In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. CONCLUSIONS: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.

A comprehensive high cost drugs dataset from the NHS in England - An OpenSAFELY-TPP Short Data Report.

Background: At the outset of the COVID-19 pandemic, there was no routine comprehensive hospital medicines data from the UK available to researchers. These records can be important for many analyses including the effect of certain medicines on the risk of severe COVID-19 outcomes. With the approval of NHS England, we set out to obtain data on one specific group of medicines, "high-cost drugs" (HCD) which are typically specialist medicines for the management of long-term conditions, prescribed by hospitals to patients. Additionally, we aimed to make these data available to all approved researchers in OpenSAFELY-TPP. This report is intended to support all studies carried out in OpenSAFELY-TPP, and those elsewhere, working with this dataset or similar data. Methods: Working with the North East Commissioning Support Unit and NHS Digital, we arranged for collation of a single national HCD dataset to help inform responses to the COVID-19 pandemic. The dataset was developed from payment submissions from hospitals to commissioners. Results: In the financial year (FY) 2018/19 there were 2.8 million submissions for 1.1 million unique patient IDs recorded in the HCD. The average number of submissions per patient over the year was 2.6. In FY 2019/20 there were 4.0 million submissions for 1.3 million unique patient IDs. The average number of submissions per patient over the year was 3.1. Of the 21 variables in the dataset, three are now available for analysis in OpenSafely-TPP: Financial year and month of drug being dispensed; drug name; and a description of the drug dispensed. Conclusions: We have described the process for sourcing a national HCD dataset, making these data available for COVID-19-related analysis through OpenSAFELY-TPP and provided information on the variables included in the dataset, data coverage and an initial descriptive analysis.

Correction: Geographic and socioeconomic factors associated with leprosy treatment default: An analysis from the 100 Million Brazilian Cohort.

[This corrects the article DOI: 10.1371/journal.pntd.0007714.].

Conditional Cash Transfer Program and Leprosy Incidence: Analysis of 12.9 Million Families From the 100 Million Brazilian Cohort.

Leprosy is a neglected tropical disease predominately affecting poor and marginalized populations. To test the hypothesis that poverty-alleviating policies might be associated with reduced leprosy incidence, we evaluated the association between the Brazilian Bolsa Familia (BFP) conditional cash transfer program and new leprosy case detection using linked records from 12,949,730 families in the 100 Million Brazilian Cohort (2007-2014). After propensity score matching BFP beneficiary to nonbeneficiary families, we used Mantel-Haenszel tests and Poisson regressions to estimate incidence rate ratios for new leprosy case detection and secondary endpoints related to operational classification and leprosy-associated disabilities at diagnosis. Overall, cumulative leprosy incidence was 17.4/100,000 person-years at risk (95% CI: 17.1, 17.7) and markedly higher in "priority" (high-burden) versus "nonpriority" (low-burden) municipalities (22.8/100,000 person-years at risk, 95% confidence interval (CI): 22.2, 23.3, compared with 14.3/100,000 person-years at risk, 95% CI: 14.0, 14.7). After matching, BFP participation was not associated with leprosy incidence overall (incidence rate ratio (IRR)Poisson = 0.97, 95% CI: 0.90, 1.04) but was associated with lower leprosy incidence when restricted to families living in high-burden municipalities (IRRPoisson = 0.86, 95% CI: 0.77, 0.96). In high-burden municipalities, the association was particularly pronounced for paucibacillary cases (IRRPoisson = 0.82, 95% CI: 0.68, 0.98) and cases with leprosy-associated disabilities (IRRPoisson = 0.79, 95% CI: 0.65, 0.97). These findings provide policy-relevant evidence that social policies might contribute to ongoing leprosy control efforts in high-burden communities.

Incidence of and Factors Associated With Leprosy Among Household Contacts of Patients With Leprosy in Brazil.

Importance: Despite progress toward reducing global incidence, leprosy control remains a challenge in low- and middle-income countries. Objective: To estimate new case detection rates of leprosy among household contacts of patients with previously diagnosed leprosy and to investigate its associated risk factors. Design, Setting, and Participants: This population-based cohort study included families registered in the 100 Million Brazilian Cohort linked with nationwide registries of leprosy; data were collected from January 1, 2007, through December 31, 2014. Household contacts of patients with a previous diagnosis of leprosy from each household unit were followed up from the time of detection of the primary case to the time of detection of a subsequent case or until December 31, 2014. Data analysis was performed from May to December 2018. Exposures: Clinical characteristics of the primary case and sociodemographic factors of the household contact. Main Outcomes and Measures: Incidence of leprosy, estimated as the new case detection rate of leprosy per 100 000 household contacts at risk (person-years at risk). The association between occurrence of a subsequent leprosy case and the exposure risk factors was assessed using multilevel mixed-effects logistic regressions allowing for state- and household-specific random effects. Results: Among 42 725 household contacts (22 449 [52.5%] female; mean [SD] age, 22.4 [18.5] years) of 17 876 patients detected with leprosy, the new case detection rate of leprosy was 636.3 (95% CI, 594.4-681.1) per 100 000 person-years at risk overall and 521.9 (95% CI, 466.3-584.1) per 100 000 person-years at risk among children younger than 15 years. Household contacts of patients with multibacillary leprosy had higher odds of developing leprosy (adjusted odds ratio [OR], 1.48; 95% CI, 1.17-1.88), and the odds increased among contacts aged 50 years or older (adjusted OR, 3.11; 95% CI, 2.03-4.76). Leprosy detection was negatively associated with illiterate or preschool educational level (adjusted OR, 0.59; 95% CI, 0.38-0.92). For children, the odds were increased among boys (adjusted OR, 1.70; 95% CI, 1.20-2.42). Conclusions and Relevance: The findings in this Brazilian population-based cohort study suggest that the household contacts of patients with leprosy may have increased risk of leprosy, especially in households with existing multibacillary cases and older contacts. Public health interventions, such as contact screening, that specifically target this population appear to be needed.

Administrative Data Linkage in Brazil: Potentials for Health Technology Assessment.

Health technology assessment (HTA) is the systematic evaluation of the properties and impacts of health technologies and interventions. In this article, we presented a discussion of HTA and its evolution in Brazil, as well as a description of secondary data sources available in Brazil with potential applications to generate evidence for HTA and policy decisions. Furthermore, we highlighted record linkage, ongoing record linkage initiatives in Brazil, and the main linkage tools developed and/or used in Brazilian data. Finally, we discussed the challenges and opportunities of using secondary data for research in the Brazilian context. In conclusion, we emphasized the availability of high quality data and an open, modern attitude toward the use of data for research and policy. This is supported by a rigorous but enabling legal framework that will allow the conduct of large-scale observational studies to evaluate clinical, economical, and social impacts of health technologies and social policies.

Propensity Score Methods in Health Technology Assessment: Principles, Extended Applications, and Recent Advances.

Randomized clinical trials (RCT) are accepted as the gold-standard approaches to measure effects of intervention or treatment on outcomes. They are also the designs of choice for health technology assessment (HTA). Randomization ensures comparability, in both measured and unmeasured pretreatment characteristics, of individuals assigned to treatment and control or comparator. However, even adequately powered RCTs are not always feasible for several reasons such as cost, time, practical and ethical constraints, and limited generalizability. RCTs rely on data collected on selected, homogeneous population under highly controlled conditions; hence, they provide evidence on efficacy of interventions rather than on effectiveness. Alternatively, observational studies can provide evidence on the relative effectiveness or safety of a health technology compared to one or more alternatives when provided under the setting of routine health care practice. In observational studies, however, treatment assignment is a non-random process based on an individual's baseline characteristics; hence, treatment groups may not be comparable in their pretreatment characteristics. As a result, direct comparison of outcomes between treatment groups might lead to biased estimate of the treatment effect. Propensity score approaches have been used to achieve balance or comparability of treatment groups in terms of their measured pretreatment covariates thereby controlling for confounding bias in estimating treatment effects. Despite the popularity of propensity scores methods and recent important methodological advances, misunderstandings on their applications and limitations are all too common. In this article, we present a review of the propensity scores methods, extended applications, recent advances, and their strengths and limitations.

Use of real-world evidence in postmarketing medicines regulation in the European Union: a systematic assessment of European Medicines Agency referrals 2013-2017.

OBJECTIVES: To assess the use, and evaluate the usefulness, of non-interventional studies and routinely collected healthcare data in postmarketing assessments conducted by the European Medicines Agency (EMA). DESIGN: We reviewed and systematically assessed all referrals to the EMA made due to safety or efficacy concerns that were evaluated between 1 January 2013 and 30 June 2017. We extracted information from the assessment report and the referral notification. Two reviewers independently assessed the contribution of non-interventional evidence to decision-making. RESULTS: The preliminary evidence leading to the assessment in 52 eligible referrals was mostly from spontaneous reports (cited in 26 of 52 referrals) and randomised trials (22/52). In contrast, many evidence types were used for the full assessment. Non-interventional studies were frequently used in the full assessment for the evaluation of product safety (31/52) and product efficacy (18/52). In particular, non-interventional studies were relied on for the evaluation of safety and efficacy in subgroups, the evaluation of safety relating to a rare adverse event, understanding product usage and misuse and for evaluation of the effectiveness of risk minimisation measures. The most common recommendations were changes to product information (43/52) and marketing authorisation withdrawal or suspension (12/52). In the majority of referrals, non-interventional evidence was judged to contribute to the decision made (30/52) and in three referrals it was the primary source of evidence. CONCLUSIONS: European regulatory decision-making relies on multiple evidence types, particularly randomised trials, spontaneous reports and non-interventional studies. Non-interventional studies had an important role particularly for the characterisation and quantification of adverse events, the evaluation of product usage and for evaluating the effectiveness of regulatory action to minimise risk.