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A peer-support lifestyle intervention for preventing type 2 diabetes in India: A cluster-randomized controlled trial of the Kerala Diabetes Prevention Program

Me, 06/06/2018 - 23:00

by Kavumpurathu R. Thankappan, Thirunavukkarasu Sathish, Robyn J. Tapp, Jonathan E. Shaw, Mojtaba Lotfaliany, Rory Wolfe, Pilvikki Absetz, Elezebeth Mathews, Zahra Aziz, Emily D. Williams, Edwin B. Fisher, Paul Z. Zimmet, Ajay Mahal, Sajitha Balachandran, Fabrizio D'Esposito, Priyanka Sajeev, Emma Thomas, Brian Oldenburg

Background

The major efficacy trials on diabetes prevention have used resource-intensive approaches to identify high-risk individuals and deliver lifestyle interventions. Such strategies are not feasible for wider implementation in low- and middle-income countries (LMICs). We aimed to evaluate the effectiveness of a peer-support lifestyle intervention in preventing type 2 diabetes among high-risk individuals identified on the basis of a simple diabetes risk score.

Methods and findings

The Kerala Diabetes Prevention Program was a cluster-randomized controlled trial conducted in 60 polling areas (clusters) of Neyyattinkara taluk (subdistrict) in Trivandrum district, Kerala state, India. Participants (age 30–60 years) were those with an Indian Diabetes Risk Score (IDRS) ≥60 and were free of diabetes on an oral glucose tolerance test (OGTT). A total of 1,007 participants (47.2% female) were enrolled (507 in the control group and 500 in the intervention group). Participants from intervention clusters participated in a 12-month community-based peer-support program comprising 15 group sessions (12 of which were led by trained lay peer leaders) and a range of community activities to support lifestyle change. Participants from control clusters received an education booklet with lifestyle change advice. The primary outcome was the incidence of diabetes at 24 months, diagnosed by an annual OGTT. Secondary outcomes were behavioral, clinical, and biochemical characteristics and health-related quality of life (HRQoL). A total of 964 (95.7%) participants were followed up at 24 months. Baseline characteristics of clusters and participants were similar between the study groups. After a median follow-up of 24 months, diabetes developed in 17.1% (79/463) of control participants and 14.9% (68/456) of intervention participants (relative risk [RR] 0.88, 95% CI 0.66–1.16, p = 0.36). At 24 months, compared with the control group, intervention participants had a greater reduction in IDRS score (mean difference: −1.50 points, p = 0.022) and alcohol use (RR 0.77, p = 0.018) and a greater increase in fruit and vegetable intake (≥5 servings/day) (RR 1.83, p = 0.008) and physical functioning score of the HRQoL scale (mean difference: 3.9 score, p = 0.016). The cost of delivering the peer-support intervention was US$22.5 per participant. There were no adverse events related to the intervention. We did not adjust for multiple comparisons, which may have increased the overall type I error rate.

Conclusions

A low-cost community-based peer-support lifestyle intervention resulted in a nonsignificant reduction in diabetes incidence in this high-risk population at 24 months. However, there were significant improvements in some cardiovascular risk factors and physical functioning score of the HRQoL scale.

Trial registration

Australia and New Zealand Clinical Trials Registry ACTRN12611000262909.

Estimating the real-world effects of expanding antiretroviral treatment eligibility: Evidence from a regression discontinuity analysis in Zambia

Ma, 05/06/2018 - 23:00

by Aaloke Mody, Izukanji Sikazwe, Nancy L. Czaicki, Mwanza Wa Mwanza, Theodora Savory, Kombatende Sikombe, Laura K. Beres, Paul Somwe, Monika Roy, Jake M. Pry, Nancy Padian, Carolyn Bolton-Moore, Charles B. Holmes, Elvin H. Geng

Background

Although randomized trials have established the clinical efficacy of treating all persons living with HIV (PLWHs), expanding treatment eligibility in the real world may have additional behavioral effects (e.g., changes in retention) or lead to unintended consequences (e.g., crowding out sicker patients owing to increased patient volume). Using a regression discontinuity design, we sought to assess the effects of a previous change to Zambia’s HIV treatment guidelines increasing the threshold for treatment eligibility from 350 to 500 cells/μL to anticipate effects of current global efforts to treat all PLWHs.

Methods and findings

We analyzed antiretroviral therapy (ART)-naïve adults who newly enrolled in HIV care in a network of 64 clinics operated by the Zambian Ministry of Health and supported by the Centre for Infectious Disease Research in Zambia (CIDRZ). Patients were restricted to those enrolling in a narrow window around the April 1, 2014 change to Zambian HIV treatment guidelines that raised the CD4 threshold for treatment from 350 to 500 cells/μL (i.e., August 1, 2013, to November 1, 2014). Clinical and sociodemographic data were obtained from an electronic medical record system used in routine care. We used a regression discontinuity design to estimate the effects of this change in treatment eligibility on ART initiation within 3 months of enrollment, retention in care at 6 months (defined as clinic attendance between 3 and 9 months after enrollment), and a composite of both ART initiation by 3 months and retention in care at 6 months in all new enrollees. We also performed an instrumental variable (IV) analysis to quantify the effect of actually initiating ART because of this guideline change on retention. Overall, 34,857 ART-naïve patients (39.1% male, median age 34 years [IQR 28–41], median CD4 268 cells/μL [IQR 134–430]) newly enrolled in HIV care during this period; 23,036 were analyzed after excluding patients around the threshold to allow for clinic-to-clinic variations in actual guideline uptake. In all newly enrolling patients, expanding the CD4 threshold for treatment from 350 to 500 cells/μL was associated with a 13.6% absolute increase in ART initiation within 3 months of enrollment (95% CI, 11.1%–16.2%), a 4.1% absolute increase in retention at 6 months (95% CI, 1.6%–6.7%), and a 10.8% absolute increase in the percentage of patients who initiated ART by 3 months and were retained at six months (95% CI, 8.1%–13.5%). These effects were greatest in patients who would have become newly eligible for ART with the change in guidelines: a 43.7% increase in ART initiation by 3 months (95% CI, 37.5%–49.9%), 13.6% increase in retention at six months (95% CI, 7.3%–20.0%), and a 35.5% increase in the percentage of patients on ART at 3 months and still in care at 6 months [95% CI, 29.2%–41.9%). We did not observe decreases in ART initiation or retention in patients not directly targeted by the guideline change. An IV analysis found that initiating ART in response to the guideline change led to a 37.9% (95% CI, 28.8%–46.9%) absolute increase in retention in care. Limitations of this study include uncertain generalizability under newer models of care, lack of laboratory data (e.g., viral load), inability to account for earlier stages in the HIV care cascade (e.g., HIV testing and linkage), and potential for misclassification of eligibility status or outcome.

Conclusions

In this study, guidelines raising the CD4 threshold for treatment from 350 to 500 cells/μL were associated with a rapid rise in ART initiation as well as enhanced retention among newly treatment-eligible patients, without negatively impacting patients with lower CD4 levels. These data suggest that health systems in Zambia and other high-prevalence settings could substantially enhance engagement even among those with high CD4 levels (i.e., above 500 cells/μL) by expanding treatment without undermining existing care standards.

Establishing a research agenda for early-onset colorectal cancer

Ve, 01/06/2018 - 23:00

by Caitlin C. Murphy, Amit G. Singal

In this month's Editorial Caitlin C. Murphy and Amit Singal discuss the increasing incidence of early-onset colorectal cancer in patients under the age of 50.

Future cost-effectiveness and equity of the NHS Health Check cardiovascular disease prevention programme: Microsimulation modelling using data from Liverpool, UK

Ma, 29/05/2018 - 23:00

by Chris Kypridemos, Brendan Collins, Philip McHale, Helen Bromley, Paula Parvulescu, Simon Capewell, Martin O’Flaherty

Background

Aiming to contribute to prevention of cardiovascular disease (CVD), the National Health Service (NHS) Health Check programme has been implemented across England since 2009. The programme involves cardiovascular risk stratification—at 5-year intervals—of all adults between the ages of 40 and 74 years, excluding any with preexisting vascular conditions (including CVD, diabetes mellitus, and hypertension, among others), and offers treatment to those at high risk. However, the cost-effectiveness and equity of population CVD screening is contested. This study aimed to determine whether the NHS Health Check programme is cost-effective and equitable in a city with high levels of deprivation and CVD.

Methods and findings

IMPACTNCD is a dynamic stochastic microsimulation policy model, calibrated to Liverpool demographics, risk factor exposure, and CVD epidemiology. Using local and national data, as well as drawing on health and social care disease costs and health-state utilities, we modelled 5 scenarios from 2017 to 2040: Scenario (A): continuing current implementation of NHS Health Check; Scenario (B): implementation ‘targeted’ toward areas in the most deprived quintile with increased coverage and uptake; Scenario (C): ‘optimal’ implementation assuming optimal coverage, uptake, treatment, and lifestyle change; Scenario (D): scenario A combined with structural population-wide interventions targeting unhealthy diet and smoking; Scenario (E): scenario B combined with the structural interventions as above. We compared all scenarios with a counterfactual of no-NHS Health Check.Compared with no-NHS Health Check, the model estimated cumulative incremental cost-effectiveness ratio (ICER) (discounted £/quality-adjusted life year [QALY]) to be 11,000 (95% uncertainty interval [UI] −270,000 to 320,000) for scenario A, 1,500 (−91,000 to 100,000) for scenario B, −2,400 (−6,500 to 5,700) for scenario C, −5,100 (−7,400 to −3,200) for scenario D, and −5,000 (−7,400 to −3,100) for scenario E. Overall, scenario A is unlikely to become cost-effective or equitable, and scenario B is likely to become cost-effective by 2040 and equitable by 2039. Scenario C is likely to become cost-effective by 2030 and cost-saving by 2040. Scenarios D and E are likely to be cost-saving by 2021 and 2023, respectively, and equitable by 2025. The main limitation of the analysis is that we explicitly modelled CVD and diabetes mellitus only.

Conclusions

According to our analysis of the situation in Liverpool, current NHS Health Check implementation appears neither equitable nor cost-effective. Optimal implementation is likely to be cost-saving but not equitable, while targeted implementation is likely to be both. Adding structural policies targeting cardiovascular risk factors could substantially improve equity and generate cost savings.

Correction: Multimorbidity in patients with heart failure from 11 Asian regions: A prospective cohort study using the ASIAN-HF registry

Ve, 25/05/2018 - 23:00

by Jasper Tromp, Wan Ting Tay, Wouter Ouwerkerk, Tiew-Hwa Katherine Teng, Jonathan Yap, Michael R. MacDonald, Kirsten Leineweber, John J. V. McMurray, Michael R. Zile, Inder S. Anand, A. Mark Richards, Carolyn S. P. Lam, ASIAN-HF authors

Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis

Ve, 25/05/2018 - 23:00

by Antoine Bouquegneau, Charlotte Loheac, Olivier Aubert, Yassine Bouatou, Denis Viglietti, Jean–Philippe Empana, Camilo Ulloa, Mohammad Hassan Murad, Christophe Legendre, Denis Glotz, Annette M. Jackson, Adriana Zeevi, Stephan Schaub, Jean–Luc Taupin, Elaine F. Reed, John J. Friedewald, Dolly B. Tyan, Caner Süsal, Ron Shapiro, E. Steve Woodle, Luis G. Hidalgo, Jacqueline O’Leary, Robert A. Montgomery, Jon Kobashigawa, Xavier Jouven, Patricia Jabre, Carmen Lefaucheur, Alexandre Loupy

Background

Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients’ access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations.

Methods and findings

To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus).A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55–3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05–6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection.

Conclusions

In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification.

Trial registration

National Clinical Trial protocol ID: NCT03438058.

Child morbidity and mortality associated with alternative policy responses to the economic crisis in Brazil: A nationwide microsimulation study

Ma, 22/05/2018 - 23:00

by Davide Rasella, Sanjay Basu, Thomas Hone, Romulo Paes-Sousa, Carlos Octávio Ocké-Reis, Christopher Millett

Background

Since 2015, a major economic crisis in Brazil has led to increasing poverty and the implementation of long-term fiscal austerity measures that will substantially reduce expenditure on social welfare programmes as a percentage of the country’s GDP over the next 20 years. The Bolsa Família Programme (BFP)—one of the largest conditional cash transfer programmes in the world—and the nationwide primary healthcare strategy (Estratégia Saúde da Família [ESF]) are affected by fiscal austerity, despite being among the policy interventions with the strongest estimated impact on child mortality in the country. We investigated how reduced coverage of the BFP and ESF—compared to an alternative scenario where the level of social protection under these programmes is maintained—may affect the under-five mortality rate (U5MR) and socioeconomic inequalities in child health in the country until 2030, the end date of the Sustainable Development Goals.

Methods and findings

We developed and validated a microsimulation model, creating a synthetic cohort of all 5,507 Brazilian municipalities for the period 2017–2030. This model was based on the longitudinal dataset and effect estimates from a previously published study that evaluated the effects of poverty, the BFP, and the ESF on child health. We forecast the economic crisis and the effect of reductions in BFP and ESF coverage due to current fiscal austerity on the U5MR, and compared this scenario with a scenario where these programmes maintain the levels of social protection by increasing or decreasing with the size of Brazil’s vulnerable populations (policy response scenarios). We used fixed effects multivariate regression models including BFP and ESF coverage and accounting for secular trends, demographic and socioeconomic changes, and programme duration effects. With the maintenance of the levels of social protection provided by the BFP and ESF, in the most likely economic crisis scenario the U5MR is expected to be 8.57% (95% CI: 6.88%–10.24%) lower in 2030 than under fiscal austerity—a cumulative 19,732 (95% CI: 10,207–29,285) averted under-five deaths between 2017 and 2030. U5MRs from diarrhoea, malnutrition, and lower respiratory tract infections are projected to be 39.3% (95% CI: 36.9%–41.8%), 35.8% (95% CI: 31.5%–39.9%), and 8.5% (95% CI: 4.1%–12.0%) lower, respectively, in 2030 under the maintenance of BFP and ESF coverage, with 123,549 fewer under-five hospitalisations from all causes over the study period. Reduced coverage of the BFP and ESF will also disproportionately affect U5MR in the most vulnerable areas, with the U5MR in the poorest quintile of municipalities expected to be 11.0% (95% CI: 8.0%–13.8%) lower in 2030 under the maintenance of BFP and ESF levels of social protection than under fiscal austerity, compared to no difference in the richest quintile. Declines in health inequalities over the last decade will also stop under a fiscal austerity scenario: the U5MR concentration index is expected to remain stable over the period 2017–2030, compared to a 13.3% (95% CI: 5.6%–21.8%) reduction under the maintenance of BFP and ESF levels of protection. Limitations of our analysis are the ecological nature of the study, uncertainty around future macroeconomic scenarios, and potential changes in other factors affecting child health. A wide range of sensitivity analyses were conducted to minimise these limitations.

Conclusions

The implementation of fiscal austerity measures in Brazil can be responsible for substantively higher childhood morbidity and mortality than expected under maintenance of social protection—threatening attainment of Sustainable Development Goals for child health and reducing inequality.

Clinical, socioeconomic, and behavioural factors at age 50 years and risk of cardiometabolic multimorbidity and mortality: A cohort study

Lu, 21/05/2018 - 23:00

by Archana Singh-Manoux, Aurore Fayosse, Séverine Sabia, Adam Tabak, Martin Shipley, Aline Dugravot, Mika Kivimäki

Background

Multimorbidity is increasingly common and is associated with adverse health outcomes, highlighting the need to broaden the single-disease framework that dominates medical research. We examined the role of midlife clinical characteristics, socioeconomic position, and behavioural factors in the development of cardiometabolic multimorbidity (at least 2 of diabetes, coronary heart disease, and stroke), along with how these factors modify risk of mortality.

Methods and findings

Data on 8,270 men and women were drawn from the Whitehall II cohort study, with mean follow-up of 23.7 years (1985 to 2017). Three sets of risk factors were assessed at age 50 years, each on a 5-point scale: clinical profile (hypertension, hypercholesterolemia, overweight/obesity, family history of cardiometabolic disease), occupational position, and behavioural factors (smoking, alcohol consumption, diet, physical activity). The outcomes examined were cardiometabolic disease (diabetes, coronary heart disease, stroke), cardiometabolic multimorbidity, and mortality. We used multi-state models to examine the role of risk factors in 5 components of the cardiometabolic disease trajectory: from healthy state to first cardiometabolic disease, from first cardiometabolic disease to cardiometabolic multimorbidity, from healthy state to death, from first cardiometabolic disease to death, and from cardiometabolic multimorbidity to death. A total of 2,501 participants developed 1 of the 3 cardiometabolic diseases, 511 developed cardiometabolic multimorbidity, and 1,406 died. When behavioural and clinical risk factors were considered individually, only smoking was associated with all five transitions. In a model containing all 3 risk factor scales, midlife clinical profile was the strongest predictor of first cardiometabolic disease (hazard ratio for the least versus most favourable profile: 3.74; 95% CI: 3.14–4.45) among disease-free participants. Among participants with 1 cardiometabolic disease, adverse midlife socioeconomic (1.54; 95% CI: 1.10–2.15) and behavioural factors (2.00; 95% CI: 1.40–2.85), but not clinical characteristics, were associated with progression to cardiometabolic multimorbidity. Only midlife behavioural factors predicted mortality among participants with cardiometabolic disease (2.12; 95% CI: 1.41–3.18) or cardiometabolic multimorbidity (3.47; 95% CI: 1.81–6.66). A limitation is that the study was not large enough to estimate transitions between each disease and subsequent outcomes and between all possible pairs of diseases.

Conclusions

The importance of specific midlife factors in disease progression, from disease-free state to single disease, multimorbidity, and death, varies depending on the disease stage. While clinical risk factors at age 50 determine the risk of incident cardiometabolic disease in a disease-free population, midlife socioeconomic and behavioural factors are stronger predictors of progression to multimorbidity and mortality in people with cardiometabolic disease.

Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—A double-blind, randomized non-inferiority trial

Ma, 15/05/2018 - 23:00

by Ingvild Vik, Marianne Bollestad, Nils Grude, Anders Bærheim, Eivind Damsgaard, Thomas Neumark, Lars Bjerrum, Gloria Cordoba, Inge Christoffer Olsen, Morten Lindbæk

Background

Although uncomplicated urinary tract infections (UTIs) are often self-limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%.

Methods and findings

This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18–60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of pivmecillinam. After 4 weeks’ follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable.

Conclusions

Ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs.

Trial registration

ClinicalTrials.gov NCT01849926EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14

Injury and death during the ISIS occupation of Mosul and its liberation: Results from a 40-cluster household survey

Ma, 15/05/2018 - 23:00

by Riyadh Lafta, Maha A. Al-Nuaimi, Gilbert Burnham

Background

Measurement of mortality and injury in conflict situations presents many challenges compared with stable situations. However, providing information is important to assess the impact of conflict on populations and to estimate humanitarian needs, both in the immediate and longer term. Mosul, Iraq’s second largest city, was overrun by fighters of the Islamic State of Iraq and Syria (ISIS) on June 4, 2014. In this study, we conducted household surveys to measure reported deaths, injuries, and kidnappings in Mosul, Iraq, both during the occupation of the city by fighters of ISIS and the months of Iraqi military action known as the liberation.

Methods and findings

Mosul was overrun by ISIS forces on June 4, 2014, and was under exclusive ISIS control for 29 months. The military offensive by Iraqi forces, supported by coalition artillery and airstrikes, began on October 17, 2016, in east Mosul and concluded in west Mosul with the defeat of ISIS on June 29, 2017. We conducted a 40-cluster population-based survey as soon as the security forces permitted access for the survey team. The objective of the survey was to measure reported deaths, injuries, and kidnappings in Mosul households during 29 months of ISIS-exclusive control (June 2014–October 2016) and the nine months of Iraqi military action known as the liberation (October 2016–June 2017). In east Mosul, the survey was conducted from March 23 to March 31, 2017, and in west Mosul from July 18 to July 31, 2017. Sampling was based on pre-ISIS population distribution, with revisions made following the extensive destruction in west Mosul. The 1,202 sampled households included 7,559 persons: 4,867 in east Mosul and 2,692 in west Mosul. No households declined to participate. During the time from June 4, 2014, to the time of the survey, there were 628 deaths reported from the sampled households, of which 505 were due to intentional violence, a mortality rate of 2.09 deaths per 1,000 person-months. Over the entire time period, the group with the highest mortality rates from intentional violence was adults aged 20 to 39: 1.69 deaths per 1,000 person-months among women and 3.55 among men. In the 29 months of ISIS-exclusive control, mortality rates among all males were 0.71 reported deaths per 1,000 person-months and for all females were 0.50 deaths per 1,000 person-months. During the nine months of the military liberation, the mortality rates jumped to 13.36 deaths per 1,000 person-months for males and 8.33 for females. The increase was particularly dramatic in west Mosul. The leading cause of reported deaths from intentional violence was airstrikes—accounting for 201 civilian deaths—followed by 172 deaths from explosions. Reported deaths from airstrikes were most common in west Mosul, while reported deaths from explosions were similar on both sides of Mosul. Gunshots accounted for 86 cases, predominantly in west Mosul where ISIS snipers were particularly active. There were 35 persons who were reported to have been kidnapped, almost entirely prior to the military offensive. By the time of the survey, 20 had been released, 8 were dead, and 7 still missing, according to household reports. Almost all of the 223 injuries reported were due to intentional violence. Limitations to population-based surveys include a probable large survivor bias, the reliance on preconflict population distribution figures for sampling, and potential recall bias among respondents.

Conclusions

Death and injuries during the military offensive to liberate Mosul considerably exceeded those during ISIS occupation. Airstrikes were the major reported cause of deaths, with the majority occurring in west Mosul. The extensive use of airstrikes and heavy artillery risks an extensive loss of life in densely populated urban areas. The high probability of survivor bias in this survey suggests that the actual number of injuries, kidnappings, and deaths in the neighborhoods sampled is likely to be higher than we report here.

Distributional change of women’s adult height in low- and middle-income countries over the past half century: An observational study using cross-sectional survey data

Ve, 11/05/2018 - 23:00

by Jewel Gausman, Ivan Meija Guevara, S. V. Subramanian, Fahad Razak

Background

Adult height reflects childhood circumstances and is associated with health, longevity, and maternal–fetal outcomes. Mean height is an important population metric, and declines in height have occurred in several low- and middle-income countries, especially in Africa, over the last several decades. This study examines changes at the population level in the distribution of height over time across a broad range of low- and middle-income countries during the past half century.

Methods and findings

The study population comprised 1,122,845 women aged 25–49 years from 59 countries with women’s height measures available from four 10-year birth cohorts from 1950 to 1989 using data from the Demographic and Health Surveys (DHS) collected between 1993 and 2013. Multilevel regression models were used to examine the association between (1) mean height and standard deviation (SD) of height (a population-level measure of inequality) and (2) median height and the 5th and 95th percentiles of height. Mean-difference plots were used to conduct a graphical analysis of shifts in the distribution within countries over time. Overall, 26 countries experienced a significant increase, 26 experienced no significant change, and 7 experienced a significant decline in mean height between the first and last birth cohorts. Rwanda experienced the greatest loss in height (−1.4 cm, 95% CI: −1.84 cm, −0.96 cm) while Colombia experienced the greatest gain in height (2.6 cm, 95% CI: 2.36 cm, 2.84 cm). Between 1950 and 1989, 24 out of 59 countries experienced a significant change in the SD of women’s height, with increased SD in 7 countries—all of which are located in sub-Saharan Africa. The distribution of women’s height has not stayed constant across successive birth cohorts, and regression models suggest there is no evidence of a significant relationship between mean height and the SD of height (β = 0.015 cm, 95% CI: −0.032 cm, 0.061 cm), while there is evidence for a positive association between median height and the 5th percentile (β = 0.915 cm, 95% CI: 0.820 cm, 1.002 cm) and 95th percentile (β = 0.995 cm, 95% CI: 0.925 cm, 1.066 cm) of height. Benin experienced the largest relative expansion in the distribution of height. In Benin, the ratio of variance between the latest and earliest cohort is estimated as 1.5 (95% CI: 1.4, 1.6), while Lesotho and Uganda experienced the greatest relative contraction of the distribution, with the ratio of variance between the latest and earliest cohort estimated as 0.8 (95% CI: 0.7, 0.9) in both countries. Limitations of the study include the representativeness of DHS surveys over time, age-related height loss, and consistency in the measurement of height between surveys.

Conclusions

The findings of this study indicate that the population-level distribution of women’s height does not stay constant in relation to mean changes. Because using mean height as a summary population measure does not capture broader distributional changes, overreliance on the mean may lead investigators to underestimate disparities in the distribution of environmental and nutritional determinants of health.

The next forum for unraveling FDA off-label marketing rules: State and federal legislatures

Ma, 08/05/2018 - 23:00

by Michael S. Sinha, Aaron S. Kesselheim

In a Guest Editorial, Aaron S. Kesselheim and Michael S. Sinha show how federal and state legislation to allow promotion of drugs for non-approved uses threatens to undermine the FDA's public health mission.

Access to antiretroviral therapy in HIV-infected children aged 0–19 years in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium, 2004–2015: A prospective cohort study

Ve, 04/05/2018 - 23:00

by Sophie Desmonde, Franck Tanser, Rachel Vreeman, Elom Takassi, Andrew Edmonds, Pagakrong Lumbiganon, Jorge Pinto, Karen Malateste, Catherine McGowan, Azar Kariminia, Marcel Yotebieng, Fatoumata Dicko, Constantin Yiannoutsos, Mwangelwa Mubiana-Mbewe, Kara Wools-Kaloustian, Mary-Ann Davies, Valériane Leroy, for the International Epidemiology Databases to Evaluate AIDS (IeDEA) Pediatric Working Group

Introduction

Access to antiretroviral therapy (ART) is a global priority. However, the attrition across the continuum of care for HIV-infected children between their HIV diagnosis and ART initiation is not well known. We analyzed the time from enrollment into HIV care to ART initiation in HIV-infected children within the International Epidemiology Databases to Evaluate AIDS (IeDEA) Global Cohort Consortium.

Methods and findings

We included 135,479 HIV-1-infected children, aged 0–19 years and ART-naïve at enrollment, between 1 January 2004 and 31 December 2015, in IeDEA cohorts from Central Africa (3 countries; n = 4,948), East Africa (3 countries; n = 22,827), West Africa (7 countries; n = 7,372), Southern Africa (6 countries; n = 93,799), Asia-Pacific (6 countries; n = 4,045), and Latin America (7 countries; n = 2,488). Follow-up in these cohorts is typically every 3–6 months. We described time to ART initiation and missed opportunities (death or loss to follow-up [LTFU]: last clinical visit >6 months) since baseline (the date of HIV diagnosis or, if unavailable, date of enrollment). Cumulative incidence functions (CIFs) for and determinants of ART initiation were computed, with death and LTFU as competing risks. Among the 135,479 children included, 99,404 (73.4%) initiated ART, 1.9% died, 1.4% were transferred out, and 20.4% were lost to follow-up before ART initiation. The 24-month CIF for ART initiation was 68.2% (95% CI: 67.9%–68.4%); it was lower in sub-Saharan Africa—ranging from 49.8% (95% CI: 48.4%–51.2%) in Central Africa to 72.5% (95% CI: 71.5%–73.5%) in West Africa—compared to Latin America (71.0%, 95% CI: 69.1%–72.7%) and the Asia-Pacific (78.3%, 95% CI: 76.9%–79.6%). Adolescents aged 15–19 years and infants <1 year had the lowest cumulative incidence of ART initiation compared to other ages: 62.2% (95% CI: 61.6%–62.8%) and 66.4% (95% CI: 65.7%–67.0%), respectively. Overall, 49.1% were ART-eligible per local guidelines at baseline, of whom 80.6% initiated ART. The following children had lower cumulative incidence of ART initiation: female children (p < 0.01); those aged <1 year, 2–4 years, 5–9 years, and 15–19 years (versus those aged 10–14 years, p < 0.01); those who became eligible during follow-up (versus eligible at enrollment, p < 0.01); and those receiving care in low-income or lower-middle-income countries (p < 0.01). The main limitations of our study include left truncation and survivor bias, caused by deaths of children prior to enrollment, and use of enrollment date as a proxy for missing data on date of HIV diagnosis, which could have led to underestimation of the time between HIV diagnosis and ART initiation.

Conclusions

In this study, 68% of HIV-infected children initiated ART by 24 months. However, there was a substantial risk of LTFU before ART initiation, which may also represent undocumented mortality. In 2015, many obstacles to ART initiation remained, with substantial inequities. More effective and targeted interventions to improve access are needed to reach the target of treating 90% of HIV-infected children with ART.

All science should inform policy and regulation

Gi, 03/05/2018 - 23:00

by John P. A. Ioannidis

In the context of a recent proposal to exclude research from consideration at the Environmental Protection Agency, John Ioannidis points out that “perceived perfection is not a characteristic of science, but of dogma” and envisions how governments can promote a standard of openness in science.

Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults

Me, 02/05/2018 - 23:00

by Ling Lu, Derrick A. Bennett, Iona Y. Millwood, Sarah Parish, Mark I. McCarthy, Anubha Mahajan, Xu Lin, Fiona Bragg, Yu Guo, Michael V. Holmes, Shoaib Afzal, Børge G. Nordestgaard, Zheng Bian, Michael Hill, Robin G. Walters, Liming Li, Zhengming Chen, Robert Clarke

Background

Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations.

Methods and findings

Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%–18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%–23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: −1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data.

Conclusions

The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.

Public versus internal conceptions of addiction: An analysis of internal Philip Morris documents

Ma, 01/05/2018 - 23:00

by Jesse Elias, Yogi Hale Hendlin, Pamela M. Ling

Background

Tobacco addiction is a complex, multicomponent phenomenon stemming from nicotine’s pharmacology and the user’s biology, psychology, sociology, and environment. After decades of public denial, the tobacco industry now agrees with public health authorities that nicotine is addictive. In 2000, Philip Morris became the first major tobacco company to admit nicotine’s addictiveness. Evolving definitions of addiction have historically affected subsequent policymaking. This article examines how Philip Morris internally conceptualized addiction immediately before and after this announcement.

Methods and findings

We analyzed previously secret, internal Philip Morris documents made available as a result of litigation against the tobacco industry. We compared these documents to public company statements and found that Philip Morris’s move from public denial to public affirmation of nicotine’s addictiveness coincided with pressure on the industry from poor public approval ratings, the Master Settlement Agreement (MSA), the United States government’s filing of the Racketeer Influenced and Corrupt Organizations (RICO) suit, and the Institute of Medicine’s (IoM’s) endorsement of potentially reduced risk products. Philip Morris continued to research the causes of addiction through the 2000s in order to create successful potentially reduced exposure products (PREPs). While Philip Morris’s public statements reinforce the idea that nicotine’s pharmacology principally drives smoking addiction, company scientists framed addiction as the result of interconnected biological, social, psychological, and environmental determinants, with nicotine as but one component. Due to the fragmentary nature of the industry document database, we may have missed relevant information that could have affected our analysis.

Conclusions

Philip Morris’s research suggests that tobacco industry activity influences addiction treatment outcomes. Beyond nicotine’s pharmacology, the industry’s continued aggressive advertising, lobbying, and litigation against effective tobacco control policies promotes various nonpharmacological determinants of addiction. To help tobacco users quit, policy makers should increase attention on the social and environmental dimensions of addiction alongside traditional cessation efforts.

Health insurance coverage with or without a nurse-led task shifting strategy for hypertension control: A pragmatic cluster randomized trial in Ghana

Ma, 01/05/2018 - 23:00

by Gbenga Ogedegbe, Jacob Plange-Rhule, Joyce Gyamfi, William Chaplin, Michael Ntim, Kingsley Apusiga, Juliet Iwelunmor, Kwasi Yeboah Awudzi, Kofi Nana Quakyi, Jazmin Mogaverro, Kiran Khurshid, Bamidele Tayo, Richard Cooper

Background

Poor access to care and physician shortage are major barriers to hypertension control in sub-Saharan Africa. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. We conducted a study to evaluate the comparative effectiveness of provision of health insurance coverage (HIC) alone versus a nurse-led task shifting strategy for hypertension control (TASSH) plus HIC on systolic blood pressure (SBP) reduction among patients with uncontrolled hypertension in Ghana.

Methods and findings

Using a pragmatic cluster randomized trial, 32 community health centers within Ghana’s public healthcare system were randomly assigned to either HIC alone or TASSH + HIC. A total of 757 patients with uncontrolled hypertension were recruited between November 28, 2012, and June 11, 2014, and followed up to October 7, 2016. Both intervention groups received health insurance coverage plus scheduled nurse visits, while TASSH + HIC comprised cardiovascular risk assessment, lifestyle counseling, and initiation/titration of antihypertensive medications for 12 months, delivered by trained nurses within the healthcare system. The primary outcome was change in SBP from baseline to 12 months. Secondary outcomes included lifestyle behaviors and blood pressure control at 12 months and sustainability of SBP reduction at 24 months. Of the 757 patients (389 in the HIC group and 368 in the TASSH + HIC group), 85% had 12-month data available (60% women, mean BP 155.9/89.6 mm Hg). In intention-to-treat analyses adjusted for clustering, the TASSH + HIC group had a greater SBP reduction (−20.4 mm Hg; 95% CI −25.2 to −15.6) than the HIC group (−16.8 mm Hg; 95% CI −19.2 to −15.6), with a statistically significant between-group difference of −3.6 mm Hg (95% CI −6.1 to −0.5; p = 0.021). Blood pressure control improved significantly in both groups (55.2%, 95% CI 50.0% to 60.3%, for the TASSH + HIC group versus 49.9%, 95% CI 44.9% to 54.9%, for the HIC group), with a non-significant between-group difference of 5.2% (95% CI −1.8% to 12.4%; p = 0.29). Lifestyle behaviors did not change appreciably in either group. Twenty-one adverse events were reported (9 and 12 in the TASSH + HIC and HIC groups, respectively). The main study limitation is the lack of cost-effectiveness analysis to determine the additional costs and benefits, if any, of the TASSH + HIC group.

Conclusions

Provision of health insurance coverage plus a nurse-led task shifting strategy was associated with a greater reduction in SBP than provision of health insurance coverage alone, among patients with uncontrolled hypertension in Ghana. Future scale-up of these systems-level strategies for hypertension control in sub-Saharan Africa requires a cost–benefit analysis.

Trial registration

ClinicalTrials.gov NCT01802372