PLoS Medicine

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Measles vaccination: A matter of confidence and commitment

Ma, 26/03/2019 - 23:00

by Richard Turner, on behalf of the PLOS Medicine Editors

The PLOS Medicine Editors discuss issues of vaccination uptake in the context of recent and ongoing measles outbreaks.

Advances in clinical trial design for development of new TB treatments: A call for innovation

Ve, 22/03/2019 - 23:00

by Christian Lienhardt, Payam Nahid

Christian Lienhardt and Payam Nahid launch the Collection on Advances in Clinical Trial Design for Development of New Tuberculosis Treatments.

Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape

Ve, 22/03/2019 - 23:00

by Patrick P. J. Phillips, Carole D. Mitnick, James D. Neaton, Payam Nahid, Christian Lienhardt, Andrew J. Nunn

In a Collection Review, Patrick Phillips and colleagues discuss developments in clinical trial design for the evaluation of TB therapeutics.

Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial

Gi, 21/03/2019 - 23:00

by Melissa J. Gladstone, Jaya Chandna, Gwendoline Kandawasvika, Robert Ntozini, Florence D. Majo, Naume V. Tavengwa, Mduduzi N. N. Mbuya, Goldberg T. Mangwadu, Ancikaria Chigumira, Cynthia M. Chasokela, Lawrence H. Moulton, Rebecca J. Stoltzfus, Jean H. Humphrey, Andrew J. Prendergast, for the SHINE Trial Team

Background

Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.

Methods and findings

SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1–4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102–112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur–Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (−0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI −1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled.

Conclusions

We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children.

Trial registration

ClinicalTrials.gov NCT01824940

Cost-effectiveness of financial incentives for improving diet and health through Medicare and Medicaid: A microsimulation study

Ma, 19/03/2019 - 23:00

by Yujin Lee, Dariush Mozaffarian, Stephen Sy, Yue Huang, Junxiu Liu, Parke E. Wilde, Shafika Abrahams-Gessel, Thiago de Souza Veiga Jardim, Thomas A. Gaziano, Renata Micha

Background

Economic incentives through health insurance may promote healthier behaviors. Little is known about health and economic impacts of incentivizing diet, a leading risk factor for diabetes and cardiovascular disease (CVD), through Medicare and Medicaid.

Methods and findings

A validated microsimulation model (CVD-PREDICT) estimated CVD and diabetes cases prevented, quality-adjusted life years (QALYs), health-related costs (formal healthcare, informal healthcare, and lost-productivity costs), and incremental cost-effectiveness ratios (ICERs) of two policy scenarios for adults within Medicare and Medicaid, compared to a base case of no new intervention: (1) 30% subsidy on fruits and vegetables (“F&V incentive”) and (2) 30% subsidy on broader healthful foods including F&V, whole grains, nuts/seeds, seafood, and plant oils (“healthy food incentive”). Inputs included national demographic and dietary data from the National Health and Nutrition Examination Survey (NHANES) 2009–2014, policy effects and diet-disease effects from meta-analyses, and policy and health-related costs from established sources. Overall, 82 million adults (35–80 years old) were on Medicare and/or Medicaid. The mean (SD) age was 68.1 (11.4) years, 56.2% were female, and 25.5% were non-whites. Health and cost impacts were simulated over the lifetime of current Medicare and Medicaid participants (average simulated years = 18.3 years). The F&V incentive was estimated to prevent 1.93 million CVD events, gain 4.64 million QALYs, and save $39.7 billion in formal healthcare costs. For the healthy food incentive, corresponding gains were 3.28 million CVD and 0.12 million diabetes cases prevented, 8.40 million QALYs gained, and $100.2 billion in formal healthcare costs saved, respectively. From a healthcare perspective, both scenarios were cost-effective at 5 years and beyond, with lifetime ICERs of $18,184/QALY (F&V incentive) and $13,194/QALY (healthy food incentive). From a societal perspective including informal healthcare costs and lost productivity, respective ICERs were $14,576/QALY and $9,497/QALY. Results were robust in probabilistic sensitivity analyses and a range of one-way sensitivity and subgroup analyses, including by different durations of the intervention (5, 10, and 20 years and lifetime), food subsidy levels (20%, 50%), insurance groups (Medicare, Medicaid, and dual-eligible), and beneficiary characteristics within each insurance group (age, race/ethnicity, education, income, and Supplemental Nutrition Assistant Program [SNAP] status). Simulation studies such as this one provide quantitative estimates of benefits and uncertainty but cannot directly prove health and economic impacts.

Conclusions

Economic incentives for healthier foods through Medicare and Medicaid could generate substantial health gains and be highly cost-effective.

Correction: The effect of a programme to improve men's sedentary time and physical activity: The European Fans in Training (EuroFIT) randomised controlled trial

Gi, 14/03/2019 - 23:00

by Sally Wyke, Christopher Bunn, Eivind Andersen, Marlene N. Silva, Femke van Nassau, Paula McSkimming, Spyros Kolovos, Jason M. R. Gill, Cindy M. Gray, Kate Hunt, Annie S. Anderson, Judith Bosmans, Judith G. M. Jelsma, Sharon Kean, Nicolas Lemyre, David W. Loudon, Lisa Macaulay, Douglas J. Maxwell, Alex McConnachie, Nanette Mutrie, Maria Nijhuis-van der Sanden, Hugo V. Pereira, Matthew Philpott, Glyn C. Roberts, John Rooksby, Øystein B. Røynesdal, Naveed Sattar, Marit Sørensen, Pedro J. Teixeira, Shaun Treweek, Theo van Achterberg, Irene van de Glind, Willem van Mechelen, Hidde P. van der Ploeg

Comparative effectiveness of generic and brand-name medication use: A database study of US health insurance claims

Me, 13/03/2019 - 23:00

by Rishi J. Desai, Ameet Sarpatwari, Sara Dejene, Nazleen F. Khan, Joyce Lii, James R. Rogers, Sarah K. Dutcher, Saeid Raofi, Justin Bohn, John G. Connolly, Michael A. Fischer, Aaron S. Kesselheim, Joshua J. Gagne

Background

To the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications.

Methods and findings

For commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004–2013) and (2) Truven MarketScan (years: 2003–2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88–0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84–0.99] and 0.84 [0.76–0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01–1.10] and 1.07 [1.01–1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98–1.13] and 1.11 [1.05–1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by either residual confounding or generic perception bias. Limitations of this study include potential residual confounding due to the unavailability of certain clinical parameters in administrative claims data and the inability to evaluate surrogate outcomes, such as immediate changes in blood pressure, upon switching from brand products to generics.

Conclusions

In this study, we observed that use of generics was associated with comparable clinical outcomes to use of brand-name products. These results could help in promoting educational interventions aimed at increasing patient and provider confidence in the ability of generic medicines to manage chronic diseases.

Seasonal malaria chemoprevention combined with community case management of malaria in children under 10 years of age, over 5 months, in south-east Senegal: A cluster-randomised trial

Me, 13/03/2019 - 23:00

by Jean Louis A. Ndiaye, Youssoupha Ndiaye, Mamadou S. Ba, Babacar Faye, Maguette Ndiaye, Amadou Seck, Roger Tine, Pape Moussa Thior, Sharanjeet Atwal, Khalid Beshir, Colin Sutherland, Oumar Gaye, Paul Milligan

Background

Seasonal malaria chemoprevention (SMC) is recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year. It may be appropriate to include older children, and to provide protection for more than 4 months. We evaluated the effectiveness of SMC using sulfadoxine-pyrimethamine plus amodiaquine given over 5 months to children under 10 years of age in Saraya district in south-east Senegal in 2011.

Methods and findings

Twenty-four villages, including 2,301 children aged 3–59 months and 2,245 aged 5–9 years, were randomised to receive SMC with community case management (CCM) (SMC villages) or CCM alone (control villages). In all villages, community health workers (CHWs) were trained to treat malaria cases with artemisinin combination therapy after testing with a rapid diagnostic test (RDT). In SMC villages, CHWs administered SMC to children aged 3 months to 9 years once a month for 5 months. The study was conducted from 27 July to 31 December 2011. The primary outcome was malaria (fever or history of fever with a positive RDT). The prevalence of anaemia and parasitaemia was measured in a survey at the end of the transmission season. Molecular markers associated with resistance to SMC drugs were analysed in samples from incident malaria cases and from children with parasitaemia in the survey. SMC was well tolerated with no serious adverse reactions. There were 1,472 RDT-confirmed malaria cases in the control villages and 270 in the SMC villages. Among children under 5 years of age, the rate difference was 110.8/1,000/month (95% CI 64.7, 156.8; p < 0.001) and among children 5–9 years of age, 101.3/1,000/month (95% CI 66.7, 136.0; p < 0.001). The mean haemoglobin concentration at the end of the transmission season was higher in SMC than control villages, by 6.5 g/l (95% CI 2.0, 11; p = 0.007) among children under 5 years of age, and by 5.2 g/l (95% CI 0.4, 9.9; p = 0.035) among children 5–9 years of age. The prevalence of parasitaemia was 18% in children under 5 years of age and 25% in children 5–9 years of age in the control villages, and 5.7% and 5.8%, respectively, in these 2 age groups in the SMC villages, with prevalence differences of 12.5% (95% CI 6.8%, 18.2%; p < 0.001) in children under 5 years of age and 19.3% (95% CI 8.3%, 30.2%; p < 0.001) in children 5–9 years of age. The pfdhps-540E mutation associated with clinical resistance to sulfadoxine-pyrimethamine was found in 0.8% of samples from malaria cases but not in the final survey. Twelve children died in the control group and 14 in the SMC group, a rate difference of 0.096/1,000 child-months (95% CI 0.99, 1.18; p = 0.895). Limitations of this study include that we were not able to obtain blood smears for microscopy for all suspected malaria cases, such that we had to rely on RDTs for confirmation, which may have included false positives.

Conclusions

In this study SMC for children under 10 years of age given over 5 months was feasible, well tolerated, and effective in preventing malaria episodes, and reduced the prevalence of parasitaemia and anaemia. SMC with CCM achieved high coverage and ensured children with malaria were promptly treated with artemether-lumefantrine.

Trial registration

www.clinicaltrials.gov NCT01449045.

Individual prognosis at diagnosis in nonmetastatic prostate cancer: Development and external validation of the PREDICT <i>Prostate</i> multivariable model

Ma, 12/03/2019 - 23:00

by David R. Thurtle, David C. Greenberg, Lui S. Lee, Hong H. Huang, Paul D. Pharoah, Vincent J. Gnanapragasam

Background

Prognostic stratification is the cornerstone of management in nonmetastatic prostate cancer (PCa). However, existing prognostic models are inadequate—often using treatment outcomes rather than survival, stratifying by broad heterogeneous groups and using heavily treated cohorts. To address this unmet need, we developed an individualised prognostic model that contextualises PCa-specific mortality (PCSM) against other cause mortality, and estimates the impact of treatment on survival.

Methods and findings

Using records from the United Kingdom National Cancer Registration and Analysis Service (NCRAS), data were collated for 10,089 men diagnosed with nonmetastatic PCa between 2000 and 2010 in Eastern England. Median follow-up was 9.8 years with 3,829 deaths (1,202 PCa specific). Totals of 19.8%, 14.1%, 34.6%, and 31.5% of men underwent conservative management, prostatectomy, radiotherapy (RT), and androgen deprivation monotherapy, respectively. A total of 2,546 men diagnosed in Singapore over a similar time period represented an external validation cohort. Data were randomly split 70:30 into model development and validation cohorts. Fifteen-year PCSM and non-PCa mortality (NPCM) were explored using separate multivariable Cox models within a competing risks framework. Fractional polynomials (FPs) were utilised to fit continuous variables and baseline hazards. Model accuracy was assessed by discrimination and calibration using the Harrell C-index and chi-squared goodness of fit, respectively, within both validation cohorts. A multivariable model estimating individualised 10- and 15-year survival outcomes was constructed combining age, prostate-specific antigen (PSA), histological grade, biopsy core involvement, stage, and primary treatment, which were each independent prognostic factors for PCSM, and age and comorbidity, which were prognostic for NPCM. The model demonstrated good discrimination, with a C-index of 0.84 (95% CI: 0.82–0.86) and 0.84 (95% CI: 0.80–0.87) for 15-year PCSM in the UK and Singapore validation cohorts, respectively, comparing favourably to international risk-stratification criteria. Discrimination was maintained for overall mortality, with C-index 0.77 (95% CI: 0.75–0.78) and 0.76 (95% CI: 0.73–0.78). The model was well calibrated with no significant difference between predicted and observed PCa-specific (p = 0.19) or overall deaths (p = 0.43) in the UK cohort. Key study limitations were a relatively small external validation cohort, an inability to account for delayed changes to treatment beyond 12 months, and an absence of tumour-stage subclassifications.

Conclusions

‘PREDICT Prostate’ is an individualised multivariable PCa prognostic model built from baseline diagnostic information and the first to our knowledge that models potential treatment benefits on overall survival. Prognostic power is high despite using only routinely collected clinicopathological information.

Age distribution, trends, and forecasts of under-5 mortality in 31 sub-Saharan African countries: A modeling study

Ma, 12/03/2019 - 23:00

by Iván Mejía-Guevara, Wenyun Zuo, Eran Bendavid, Nan Li, Shripad Tuljapurkar

Background

Despite the sharp decline in global under-5 deaths since 1990, uneven progress has been achieved across and within countries. In sub-Saharan Africa (SSA), the Millennium Development Goals (MDGs) for child mortality were met only by a few countries. Valid concerns exist as to whether the region would meet new Sustainable Development Goals (SDGs) for under-5 mortality. We therefore examine further sources of variation by assessing age patterns, trends, and forecasts of mortality rates.

Methods and findings

Data came from 106 nationally representative Demographic and Health Surveys (DHSs) with full birth histories from 31 SSA countries from 1990 to 2017 (a total of 524 country-years of data). We assessed the distribution of age at death through the following new demographic analyses. First, we used a direct method and full birth histories to estimate under-5 mortality rates (U5MRs) on a monthly basis. Second, we smoothed raw estimates of death rates by age and time by using a two-dimensional P-Spline approach. Third, a variant of the Lee–Carter (LC) model, designed for populations with limited data, was used to fit and forecast age profiles of mortality. We used mortality estimates from the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) to adjust, validate, and minimize the risk of bias in survival, truncation, and recall in mortality estimation. Our mortality model revealed substantive declines of death rates at every age in most countries but with notable differences in the age patterns over time. U5MRs declined from 3.3% (annual rate of reduction [ARR] 0.1%) in Lesotho to 76.4% (ARR 5.2%) in Malawi, and the pace of decline was faster on average (ARR 3.2%) than that observed for infant (IMRs) (ARR 2.7%) and neonatal (NMRs) (ARR 2.0%) mortality rates. We predict that 5 countries (Kenya, Rwanda, Senegal, Tanzania, and Uganda) are on track to achieve the under-5 sustainable development target by 2030 (25 deaths per 1,000 live births), but only Rwanda and Tanzania would meet both the neonatal (12 deaths per 1,000 live births) and under-5 targets simultaneously. Our predicted NMRs and U5MRs were in line with those estimated by the UN IGME by 2030 and 2050 (they overlapped in 27/31 countries for NMRs and 22 for U5MRs) and by the Institute for Health Metrics and Evaluation (IHME) by 2030 (26/31 and 23/31, respectively). This study has a number of limitations, including poor data quality issues that reflected bias in the report of births and deaths, preventing reliable estimates and predictions from a few countries.

Conclusions

To our knowledge, this study is the first to combine full birth histories and mortality estimates from external reliable sources to model age patterns of under-5 mortality across time in SSA. We demonstrate that countries with a rapid pace of mortality reduction (ARR ≥ 3.2%) across ages would be more likely to achieve the SDG mortality targets. However, the lower pace of neonatal mortality reduction would prevent most countries from achieving those targets: 2 countries would reach them by 2030, 13 between 2030 and 2050, and 13 after 2050.

The Ayushman Bharat Pradhan Mantri Jan Arogya Yojana and the path to universal health coverage in India: Overcoming the challenges of stewardship and governance

Ve, 08/03/2019 - 00:00

by Blake J. Angell, Shankar Prinja, Anadi Gupt, Vivekanand Jha, Stephen Jan

In an Essay, Blake Angell and colleagues discuss ambitious reforms planned to expand coverage of the health system in India.

The association between Zika virus infection and microcephaly in Brazil 2015–2017: An observational analysis of over 4 million births

Me, 06/03/2019 - 00:00

by Oliver J. Brady, Aaron Osgood-Zimmerman, Nicholas J. Kassebaum, Sarah E. Ray, Valdelaine E. M. de Araújo, Aglaêr A. da Nóbrega, Livia C. V. Frutuoso, Roberto C. R. Lecca, Antony Stevens, Bruno Zoca de Oliveira, José M. de Lima Jr., Isaac I. Bogoch, Philippe Mayaud, Thomas Jaenisch, Ali H. Mokdad, Christopher J. L. Murray, Simon I. Hay, Robert C. Reiner Jr., Fatima Marinho

Background

In 2015, high rates of microcephaly were reported in Northeast Brazil following the first South American Zika virus (ZIKV) outbreak. Reported microcephaly rates in other Zika-affected areas were significantly lower, suggesting alternate causes or the involvement of arboviral cofactors in exacerbating microcephaly rates.

Methods and findings

We merged data from multiple national reporting databases in Brazil to estimate exposure to 9 known or hypothesized causes of microcephaly for every pregnancy nationwide since the beginning of the ZIKV outbreak; this generated between 3.6 and 5.4 million cases (depending on analysis) over the time period 1 January 2015–23 May 2017. The association between ZIKV and microcephaly was statistically tested against models with alternative causes or with effect modifiers. We found no evidence for alternative non-ZIKV causes of the 2015–2017 microcephaly outbreak, nor that concurrent exposure to arbovirus infection or vaccination modified risk. We estimate an absolute risk of microcephaly of 40.8 (95% CI 34.2–49.3) per 10,000 births and a relative risk of 16.8 (95% CI 3.2–369.1) given ZIKV infection in the first or second trimester of pregnancy; however, because ZIKV infection rates were highly variable, most pregnant women in Brazil during the ZIKV outbreak will have been subject to lower risk levels. Statistically significant associations of ZIKV with other birth defects were also detected, but at lower relative risks than that of microcephaly (relative risk < 1.5). Our analysis was limited by missing data prior to the establishment of nationwide ZIKV surveillance, and its findings may be affected by unmeasured confounding causes of microcephaly not available in routinely collected surveillance data.

Conclusions

This study strengthens the evidence that congenital ZIKV infection, particularly in the first 2 trimesters of pregnancy, is associated with microcephaly and less frequently with other birth defects. The finding of no alternative causes for geographic differences in microcephaly rate leads us to hypothesize that the Northeast region was disproportionately affected by this Zika outbreak, with 94% of an estimated 8.5 million total cases occurring in this region, suggesting a need for seroprevalence surveys to determine the underlying reason.

Potential effectiveness of prophylactic HPV immunization for men who have sex with men in the Netherlands: A multi-model approach

Ma, 05/03/2019 - 00:00

by Johannes A. Bogaards, Sofie H. Mooij, Maria Xiridou, Maarten F. Schim van der Loeff

Background

Men who have sex with men (MSM) are at high risk for anal cancer, primarily related to human papillomavirus genotype 16 (HPV16) infections. At 8.5 per 100,000 per year, the incidence rate of anal cancer among MSM is similar to that of cervical cancer among adult women in the Netherlands. However, MSM are not included in most HPV vaccination programs. We explored the potential effectiveness of prophylactic immunization in reducing anogenital HPV16 transmission among MSM in the Netherlands.

Methods and findings

We developed a range of mathematical models for penile–anal HPV16 transmission, varying in sexual contact structure and natural history of infection, to provide robust and plausible predictions about the effectiveness of targeted vaccination. Models were informed by an observational cohort study among MSM in Amsterdam, 2010–2013. Parameters on sexual behavior and HPV16 infections were obtained by fitting the models to data from 461 HIV-negative study participants, considered representative of the local MSM population. We assumed 85% efficacy of vaccination against future HPV16 infections as reported for HIV-negative MSM, and age-specific uptake rates similar to those for hepatitis B vaccination among MSM in the Netherlands. Targeted vaccination was contrasted with vaccination of 12-year-old boys at 40% uptake in base-case scenarios, and we also considered the effectiveness of a combined strategy. Offering vaccine to MSM without age restrictions resulted in a model-averaged 27.3% reduction (90% prediction interval [PI] 11.9%–37.5%) in prevalence of anal HPV16 infections, assuming similar uptake among MSM as achieved for hepatitis B vaccination. The predicted reduction improved to 46.1% (90% PI 21.8%–62.4%) if uptake rates among MSM were doubled. The reductions in HPV16 infection prevalence were mostly achieved within 30 years of a targeted immunization campaign, during which they exceeded those induced by vaccinating 40% of preadolescent boys, if started simultaneously. The reduction in anal HPV16 prevalence amounted to 74.8% (90% PI 59.8%–93.0%) under a combined vaccination strategy. HPV16 prevalence reductions mostly exceeded vaccine coverage projections among MSM, illustrating the efficiency of prophylactic immunization even when the HPV vaccine is given after sexual debut. Mode of protection was identified as the key limitation to potential effectiveness of targeted vaccination, as the projected reductions were strongly reduced if we assumed no protection against future infections in recipients with prevalent infection or infection-derived immunity at the time of immunization. Unverified limitations of our study include the sparsity of data to inform the models, the omission of oral sex in transmission to the penile or anal site, and the restriction that our modeling results apply primarily to HIV-negative MSM.

Conclusions

Our findings suggest that targeted vaccination may generate considerable reductions in anogenital HPV16 infections among MSM, and has the potential to accelerate anal cancer prevention, especially when combined with sex-neutral vaccination in preadolescence.

Correction: Evaluating strategies for control of tuberculosis in prisons and prevention of spillover into communities: An observational and modeling study from Brazil

Sa, 02/03/2019 - 00:00

by Tarub S. Mabud, Maria de Lourdes Delgado Alves, Albert I. Ko, Sanjay Basu, Katharine S. Walter, Ted Cohen, Barun Mathema, Caroline Colijn, Everton Lemos, Julio Croda, Jason R. Andrews

Health system performance for people with diabetes in 28 low- and middle-income countries: A cross-sectional study of nationally representative surveys

Sa, 02/03/2019 - 00:00

by Jennifer Manne-Goehler, Pascal Geldsetzer, Kokou Agoudavi, Glennis Andall-Brereton, Krishna K. Aryal, Brice Wilfried Bicaba, Pascal Bovet, Garry Brian, Maria Dorobantu, Gladwell Gathecha, Mongal Singh Gurung, David Guwatudde, Mohamed Msaidie, Corine Houehanou, Dismand Houinato, Jutta Mari Adelin Jorgensen, Gibson B. Kagaruki, Khem B. Karki, Demetre Labadarios, Joao S. Martins, Mary T. Mayige, Roy Wong McClure, Omar Mwalim, Joseph Kibachio Mwangi, Bolormaa Norov, Sarah Quesnel-Crooks, Bahendeka K. Silver, Lela Sturua, Lindiwe Tsabedze, Chea Stanford Wesseh, Andrew Stokes, Maja Marcus, Cara Ebert, Justine I. Davies, Sebastian Vollmer, Rifat Atun, Till W. Bärnighausen, Lindsay M. Jaacks

Background

The prevalence of diabetes is increasing rapidly in low- and middle-income countries (LMICs), urgently requiring detailed evidence to guide the response of health systems to this epidemic. In an effort to understand at what step in the diabetes care continuum individuals are lost to care, and how this varies between countries and population groups, this study examined health system performance for diabetes among adults in 28 LMICs using a cascade of care approach.

Methods and findings

We pooled individual participant data from nationally representative surveys done between 2008 and 2016 in 28 LMICs. Diabetes was defined as fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl), random plasma glucose ≥ 11.1 mmol/l (200 mg/dl), HbA1c ≥ 6.5%, or reporting to be taking medication for diabetes. Stages of the care cascade were as follows: tested, diagnosed, lifestyle advice and/or medication given (“treated”), and controlled (HbA1c < 8.0% or equivalent). We stratified cascades of care by country, geographic region, World Bank income group, and individual-level characteristics (age, sex, educational attainment, household wealth quintile, and body mass index [BMI]). We then used logistic regression models with country-level fixed effects to evaluate predictors of (1) testing, (2) treatment, and (3) control. The final sample included 847,413 adults in 28 LMICs (8 low income, 9 lower-middle income, 11 upper-middle income). Survey sample size ranged from 824 in Guyana to 750,451 in India. The prevalence of diabetes was 8.8% (95% CI: 8.2%–9.5%), and the prevalence of undiagnosed diabetes was 4.8% (95% CI: 4.5%–5.2%). Health system performance for management of diabetes showed large losses to care at the stage of being tested, and low rates of diabetes control. Total unmet need for diabetes care (defined as the sum of those not tested, tested but undiagnosed, diagnosed but untreated, and treated but with diabetes not controlled) was 77.0% (95% CI: 74.9%–78.9%). Performance along the care cascade was significantly better in upper-middle income countries, but across all World Bank income groups, only half of participants with diabetes who were tested achieved diabetes control. Greater age, educational attainment, and BMI were associated with higher odds of being tested, being treated, and achieving control. The limitations of this study included the use of a single glucose measurement to assess diabetes, differences in the approach to wealth measurement across surveys, and variation in the date of the surveys.

Conclusions

The study uncovered poor management of diabetes along the care cascade, indicating large unmet need for diabetes care across 28 LMICs. Performance across the care cascade varied by World Bank income group and individual-level characteristics, particularly age, educational attainment, and BMI. This policy-relevant analysis can inform country-specific interventions and offers a baseline by which future progress can be measured.

<i>PLOS Medicine</i> 2018 Reviewer and Editorial Board Thank You

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PLOS and the PLOS Medicine team would like to express our appreciation to the Editorial Board members, guest editors, and reviewers who participated in the manuscript assessment process for the journal in 2018.

Constructing care cascades for active tuberculosis: A strategy for program monitoring and identifying gaps in quality of care

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by Ramnath Subbaraman, Ruvandhi R. Nathavitharana, Kenneth H. Mayer, Srinath Satyanarayana, Vineet K. Chadha, Nimalan Arinaminpathy, Madhukar Pai

The cascade of care is a model for evaluating patient retention across sequential stages of care required to achieve a successful treatment outcome. This approach was first used to evaluate HIV care and has since been applied to other diseases. The tuberculosis (TB) community has only recently started using care cascade analyses to quantify gaps in quality of care. In this article, we describe methods for estimating gaps (patient losses) and steps (patients retained) in the care cascade for active TB disease. We highlight approaches for overcoming challenges in constructing the TB care cascade, which include difficulties in estimating the population-level burden of disease and the diagnostic gap due to the limited sensitivity of TB diagnostic tests. We also describe potential uses of this model for evaluating the impact of interventions to improve case finding, diagnosis, linkage to care, retention in care, and post-treatment monitoring of TB patients.

The US Affordable Care Act: Reflections and directions at the close of a decade

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by Adrianna McIntyre, Zirui Song

In this month's Editorial, PLOS Medicine Academic Editor Zirui Song and his colleague Adrianna McIntyre discuss outcomes and possible futures for the United States Affordable Care Act as it nears the ten year mark.

Patterns of joint involvement in juvenile idiopathic arthritis and prediction of disease course: A prospective study with multilayer non-negative matrix factorization

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by Simon W. M. Eng, Florence A. Aeschlimann, Mira van Veenendaal, Roberta A. Berard, Alan M. Rosenberg, Quaid Morris, Rae S. M. Yeung, on behalf of the ReACCh-Out Research Consortium

Background

Joint inflammation is the common feature underlying juvenile idiopathic arthritis (JIA). Clinicians recognize patterns of joint involvement currently not part of the International League of Associations for Rheumatology (ILAR) classification. Using unsupervised machine learning, we sought to uncover data-driven joint patterns that predict clinical phenotype and disease trajectories.

Methods and findings

We analyzed prospectively collected clinical data, including joint involvement using a standard 71-joint homunculus, for 640 discovery patients with newly diagnosed JIA enrolled in a Canada-wide study who were followed serially for five years, treatment-naïve except for nonsteroidal anti-inflammatory drugs (NSAIDs) and diagnosed within one year of symptom onset. Twenty-one patients had systemic arthritis, 300 oligoarthritis, 125 rheumatoid factor (RF)-negative polyarthritis, 16 RF-positive polyarthritis, 37 psoriatic arthritis, 78 enthesitis-related arthritis (ERA), and 63 undifferentiated arthritis. At diagnosis, we observed global hierarchical groups of co-involved joints.To characterize these patterns, we developed sparse multilayer non-negative matrix factorization (NMF). Model selection by internal bi-cross-validation identified seven joint patterns at presentation, to which all 640 discovery patients were assigned: pelvic girdle (57 patients), fingers (25), wrists (114), toes (48), ankles (106), knees (283), and indistinct (7). Patterns were distinct from clinical subtypes (P < 0.001 by χ2 test) and reproducible through external data set validation on a 119-patient, prospectively collected independent validation cohort (reconstruction accuracy Q2 = 0.55 for patterns; 0.35 for groups).Some patients matched multiple patterns. To determine whether their disease outcomes differed, we further subdivided the 640 discovery patients into three subgroups by degree of localization—the percentage of their active joints aligning with their assigned pattern: localized (≥90%; 359 patients), partially localized (60%–90%; 124), or extended (<60%; 157). Localized patients more often maintained their baseline patterns (P < 0.05 for five groups by permutation test) than nonlocalized patients (P < 0.05 for three groups by permutation test) over a five-year follow-up period.We modelled time to zero joints in the discovery cohort using a multivariate Cox proportional hazards model considering joint pattern, degree of localization, and ILAR subtype. Despite receiving more intense treatment, 50% of nonlocalized patients had zero joints at one year compared to six months for localized patients. Overall, localized patients required less time to reach zero joints (partial: P = 0.0018 versus localized by log-rank test; extended: P = 0.0057).Potential limitations include the requirement for patients to be treatment naïve (except NSAIDs), which may skew the patient cohorts towards milder disease, and the validation cohort size precluded multivariate analyses of disease trajectories.

Conclusions

Multilayer NMF identified patterns of joint involvement that predicted disease trajectory in children with arthritis. Our hierarchical unsupervised approach identified a new clinical feature, degree of localization, which predicted outcomes in both cohorts. Detailed assessment of every joint is already part of every musculoskeletal exam for children with arthritis. Our study supports both the continued collection of detailed joint involvement and the inclusion of patterns and degrees of localization to stratify patients and inform treatment decisions. This will advance pediatric rheumatology from counting joints to realizing the potential of using data available from uncovering patterns of joint involvement.

A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial

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by Robert H. J. Bandsma, Wieger Voskuijl, Emmanuel Chimwezi, Greg Fegan, André Briend, Johnstone Thitiri, Moses Ngari, Laura Mwalekwa, Victor Bandika, Rehema Ali, Fauzat Hamid, Betty Owor, Neema Mturi, Isabel Potani, Benjamin Allubha, Anneke C. Muller Kobold, Rosalie H. Bartels, Christian J. Versloot, Marjon Feenstra, Deborah A. van den Brink, Patrick F. van Rheenen, Marko Kerac, Celine Bourdon, James A. Berkley

Background

Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase.

Methods and findings

In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2–5 days), which was similar between randomized groups (0.23 [95% CI −0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite.

Conclusions

Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM.

Trial registration

ClinicalTrials.gov NCT02246296.