PLoS Medicine

Condividi contenuti PLOS Medicine: New Articles
A Peer-Reviewed Open-Access Journal
Aggiornato: 13 ore 32 min fa

Performance of the Access Bio/CareStart rapid diagnostic test for the detection of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis

Ve, 13/12/2019 - 23:00

by Benedikt Ley, Ari Winasti Satyagraha, Hisni Rahmat, Michael E. von Fricken, Nicholas M. Douglas, Daniel A. Pfeffer, Fe Espino, Lorenz von Seidlein, Gisela Henriques, Nwe Nwe Oo, Didier Menard, Sunil Parikh, Germana Bancone, Amalia Karahalios, Ric N. Price

Background

To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994).

Methods and findings

Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR−) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model.Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90–0.99) and a specificity of 0.95 (95% CI 0.92–0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94–1.00), with an LR+ and an LR− of 18.23 (95% CI 13.04–25.48) and 0.05 (95% CI 0.02–0.12), respectively.Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings.

Conclusions

The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR− render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings.

The projected impact of geographic targeting of oral cholera vaccination in sub-Saharan Africa: A modeling study

Me, 11/12/2019 - 23:00

by Elizabeth C. Lee, Andrew S. Azman, Joshua Kaminsky, Sean M. Moore, Heather S. McKay, Justin Lessler

Background

Cholera causes an estimated 100,000 deaths annually worldwide, with the majority of burden reported in sub-Saharan Africa. In May 2018, the World Health Assembly committed to reducing worldwide cholera deaths by 90% by 2030. Oral cholera vaccine (OCV) plays a key role in reducing the near-term risk of cholera, although global supplies are limited. Characterizing the potential impact and cost-effectiveness of mass OCV deployment strategies is critical for setting expectations and developing cholera control plans that maximize the chances of success.

Methods and findings

We compared the projected impacts of vaccination campaigns across sub-Saharan Africa from 2018 through 2030 when targeting geographically according to historical cholera burden and risk factors. We assessed the number of averted cases, deaths, and disability-adjusted life years and the cost-effectiveness of these campaigns with models that accounted for direct and indirect vaccine effects and population projections over time. Under current vaccine supply projections, an approach optimized to targeting by historical burden is projected to avert 828,971 (95% CI 803,370–859,980) cases (equivalent to 34.0% of projected cases; 95% CI 33.2%–34.8%). An approach that balances logistical feasibility with targeting historical burden is projected to avert 617,424 (95% CI 599,150–643,891) cases. In contrast, approaches optimized for targeting locations with limited access to water and sanitation are projected to avert 273,939 (95% CI 270,319–277,002) and 109,817 (95% CI 103,735–114,110) cases, respectively. We find that the most logistically feasible targeting strategy costs US$1,843 (95% CI 1,328–14,312) per DALY averted during this period and that effective geographic targeting of OCV campaigns can have a greater impact on cost-effectiveness than improvements to vaccine efficacy and moderate increases in coverage. Although our modeling approach does not project annual changes in baseline cholera risk or directly incorporate immunity from natural cholera infection, our estimates of the relative performance of different vaccination strategies should be robust to these factors.

Conclusions

Our study suggests that geographic targeting substantially improves the cost-effectiveness and impact of oral cholera vaccination campaigns. Districts with the poorest access to improved water and sanitation are not the same as districts with the greatest historical cholera incidence. While OCV campaigns can improve cholera control in the near term, without rapid progress in developing water and sanitation services or dramatic increases in OCV supply, our results suggest that vaccine use alone is unlikely to allow us to achieve the 2030 goal.

Incidence of maternal peripartum infection: A systematic review and meta-analysis

Ma, 10/12/2019 - 23:00

by Susannah L. Woodd, Ana Montoya, Maria Barreix, Li Pi, Clara Calvert, Andrea M. Rehman, Doris Chou, Oona M. R. Campbell

Background

Infection is an important, preventable cause of maternal morbidity, and pregnancy-related sepsis accounts for 11% of maternal deaths. However, frequency of maternal infection is poorly described, and, to our knowledge, it remains the one major cause of maternal mortality without a systematic review of incidence. Our objective was to estimate the average global incidence of maternal peripartum infection.

Methods and findings

We searched Medline, EMBASE, Global Health, and five other databases from January 2005 to June 2016 (PROSPERO: CRD42017074591). Specific outcomes comprised chorioamnionitis in labour, puerperal endometritis, wound infection following cesarean section or perineal trauma, and sepsis occurring from onset of labour until 42 days postpartum. We assessed studies irrespective of language or study design. We excluded conference abstracts, studies of high-risk women, and data collected before 1990. Three reviewers independently selected studies, extracted data, and appraised quality. Quality criteria for incidence/prevalence studies were adapted from the Joanna Briggs Institute. We used random-effects models to obtain weighted pooled estimates of incidence risk for each outcome and metaregression to identify study-level characteristics affecting incidence. From 31,528 potentially relevant articles, we included 111 studies of infection in women in labour or postpartum from 46 countries. Four studies were randomised controlled trials, two were before–after intervention studies, and the remainder were observational cohort or cross-sectional studies. The pooled incidence in high-quality studies was 3.9% (95% Confidence Interval [CI] 1.8%–6.8%) for chorioamnionitis, 1.6% (95% CI 0.9%–2.5%) for endometritis, 1.2% (95% CI 1.0%–1.5%) for wound infection, 0.05% (95% CI 0.03%–0.07%) for sepsis, and 1.1% (95% CI 0.3%–2.4%) for maternal peripartum infection. 19% of studies met all quality criteria. There were few data from developing countries and marked heterogeneity in study designs and infection definitions, limiting the interpretation of these estimates as measures of global infection incidence. A limitation of this review is the inclusion of studies that were facility-based or restricted to low-risk groups of women.

Conclusions

In this study, we observed pooled infection estimates of almost 4% in labour and between 1%–2% of each infection outcome postpartum. This indicates maternal peripartum infection is an important complication of childbirth and that preventive efforts should be increased in light of antimicrobial resistance. Incidence risk appears lower than modelled global estimates, although differences in definitions limit comparability. Better-quality research, using standard definitions, is required to improve comparability between study settings and to demonstrate the influence of risk factors and protective interventions.

Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

Ma, 10/12/2019 - 23:00

by Michael Wainberg, Anubha Mahajan, Anshul Kundaje, Mark I. McCarthy, Erik Ingelsson, Nasa Sinnott-Armstrong, Manuel A. Rivas

Background

Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk.

Methods and findings

We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m2 BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m2 BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12–1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m2) without a family history of diabetes, similar to that in obese individuals (BMI ≥ 30 kg/m2) with a family history (1.21-fold reduction, 95% CI 1.13–1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual’s entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life.

Conclusions

In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk.

The importance of adherence in tuberculosis treatment clinical trials and its relevance in explanatory and pragmatic trials

Ma, 10/12/2019 - 23:00

by Andrew Vernon, Katherine Fielding, Rada Savic, Lori Dodd, Payam Nahid

Andrew Vernon and co-authors discuss adherence to therapy and its measurement in tuberculosis treatment trials.

Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis

Lu, 09/12/2019 - 23:00

by Jan Menne, Eva Dumann, Hermann Haller, Bernhard M. W. Schmidt

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI).

Methods and findings

We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53–0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66–0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10–1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33–0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I–III).

Conclusions

SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.

Executive task-based brain function in children with type 1 diabetes: An observational study

Lu, 09/12/2019 - 23:00

by Lara C. Foland-Ross, Bruce Buckingam, Nelly Mauras, Ana Maria Arbelaez, William V. Tamborlane, Eva Tsalikian, Allison Cato, Gabby Tong, Kimberly Englert, Paul K. Mazaika, Allan L. Reiss, for the Diabetes Research in Children Network (DirecNet)

Background

Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood.

Methods and findings

Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 ± 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 ± 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of “no-go > go” were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct “go” trials; r = −0.36, 95% CI −0.53 to −0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < −0.29, 95% CIs −0.47 to −0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = −0.22, 95% CI −0.41 to −0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI −0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown.

Conclusions

These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.

Elective and nonelective cesarean section and obesity among young adult male offspring: A Swedish population–based cohort study

Ve, 06/12/2019 - 23:00

by Viktor H. Ahlqvist, Margareta Persson, Cecilia Magnusson, Daniel Berglind

Background

Previous studies have suggested that cesarean section (CS) is associated with offspring overweight and obesity. However, few studies have been able to differentiate between elective and nonelective CS, which may differ in their maternal risk profile and biological pathway. Therefore, we aimed to examine the association between differentiated forms of delivery with CS and risk of obesity in young adulthood.

Methods and findings

Using Swedish population registers, a cohort of 97,291 males born between 1982 and 1987 were followed from birth until conscription (median 18 years of age) if they conscripted before 2006. At conscription, weight and height were measured and transformed to World Health Organization categories of body mass index (BMI). Maternal and infant data were obtained from the Medical Birth Register. Associations were evaluated using multinomial and linear regressions. Furthermore, a series of sensitivity analyses were conducted, including fixed-effects regressions to account for confounders shared between full brothers. The mothers of the conscripts were on average 28.5 (standard deviation 4.9) years old at delivery and had a prepregnancy BMI of 21.9 (standard deviation 3.0), and 41.5% of the conscripts had at least one parent with university-level education.Out of the 97,291 conscripts we observed, 4.9% were obese (BMI ≥ 30) at conscription. The prevalence of obesity varied slightly between vaginal delivery, elective CS, and nonelective CS (4.9%, 5.5%, and 5.6%, respectively), whereas BMI seemed to be consistent across modes of delivery. We found no evidence of an association between nonelective or elective CS and young adulthood obesity (relative risk ratio 0.96, confidence interval 95% 0.83–1.10, p = 0.532 and relative risk ratio 1.02, confidence interval 95% 0.88–1.18, p = 0.826, respectively) as compared with vaginal delivery after accounting for prepregnancy maternal BMI, maternal diabetes at delivery, maternal hypertension at delivery, maternal smoking, parity, parental education, maternal age at delivery, gestational age, birth weight standardized according to gestational age, and preeclampsia. We found no evidence of an association between any form of CS and overweight (BMI ≥ 25) as compared with vaginal delivery. Sibling analysis and several sensitivity analyses did not alter our findings. The main limitations of our study were that not all conscripts had available measures of anthropometry and/or important confounders (42% retained) and that our cohort only included a male population.

Conclusions

We found no evidence of an association between elective or nonelective CS and young adulthood obesity in young male conscripts when accounting for maternal and prenatal factors. This suggests that there is no clinically relevant association between CS and the development of obesity. Further large-scale studies are warranted to examine the association between differentiated forms of CS and obesity in young adult offspring.

Trial registration

Registered as observational study at ClinicalTrials.gov Identifier: NCT03918044.

Antenatal magnesium sulphate and adverse neonatal outcomes: A systematic review and meta-analysis

Ve, 06/12/2019 - 23:00

by Emily Shepherd, Rehana A. Salam, Deepak Manhas, Anne Synnes, Philippa Middleton, Maria Makrides, Caroline A. Crowther

Background

There is widespread, increasing use of magnesium sulphate in obstetric practice for pre-eclampsia, eclampsia, and preterm fetal neuroprotection; benefit for preventing preterm labour and birth (tocolysis) is unproven. We conducted a systematic review and meta-analysis to assess whether antenatal magnesium sulphate is associated with unintended adverse neonatal outcomes.

Methods and findings

CINAHL, Cochrane Library, LILACS, MEDLINE, Embase, TOXLINE, and Web of Science, were searched (inceptions to 3 September 2019). Randomised, quasi-randomised, and non-randomised trials, cohort and case–control studies, and case reports assessing antenatal magnesium sulphate for pre-eclampsia, eclampsia, fetal neuroprotection, or tocolysis, compared with placebo/no treatment or a different magnesium sulphate regimen, were included. The primary outcome was perinatal death. Secondary outcomes included pre-specified and non-pre-specified adverse neonatal outcomes. Two reviewers screened 5,890 articles, extracted data, and assessed risk of bias following Cochrane Handbook and RTI Item Bank guidance. For randomised trials, pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), were calculated using fixed- or random-effects meta-analysis. Non-randomised data were tabulated and narratively summarised. We included 197 studies (40 randomised trials, 138 non-randomised studies, and 19 case reports), of mixed quality. The 40 trials (randomising 19,265 women and their babies) were conducted from 1987 to 2018 across high- (16 trials) and low/middle-income countries (23 trials) (1 mixed). Indications included pre-eclampsia/eclampsia (24 trials), fetal neuroprotection (7 trials), and tocolysis (9 trials); 18 trials compared magnesium sulphate with placebo/no treatment, and 22 compared different regimens. For perinatal death, no clear difference in randomised trials was observed between magnesium sulphate and placebo/no treatment (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654 babies), nor between regimens. Eleven of 138 non-randomised studies reported on perinatal death. Only 1 cohort (127 babies; moderate to high risk of bias) observed an increased risk of perinatal death with >48 versus ≤48 grams magnesium sulphate exposure for tocolysis. No clear secondary adverse neonatal outcomes were observed in randomised trials, and a very limited number of possible adverse outcomes warranting further consideration were identified in non-randomised studies. Where non-randomised studies observed possible harms, often no or few confounders were controlled for (moderate to high risk of bias), samples were small (200 babies or fewer), and/or results were from subgroup analyses. Limitations include missing data for important outcomes across most studies, heterogeneity of included studies, and inclusion of published data only.

Conclusions

Our findings do not support clear associations between antenatal magnesium sulphate for beneficial indications and adverse neonatal outcomes. Further large, high-quality studies (prospective cohorts or individual participant data meta-analyses) assessing specific outcomes, or the impact of regimen, pregnancy, or birth characteristics on these outcomes, would further inform safety recommendations. PROSPERO: CRD42013004451.

Pubertal timing and adult fracture risk in men: A population-based cohort study

Lu, 02/12/2019 - 23:00

by Liesbeth Vandenput, Jenny M. Kindblom, Maria Bygdell, Maria Nethander, Claes Ohlsson

Background

Puberty is a critical period for bone mass accrual, and late puberty in boys is associated with reduced bone mass in adult men. The role of variations in pubertal timing within the normal range for adult fracture risk in men is, however, unknown. We, therefore, assessed the association between age at peak height velocity (PHV), an objective measure of pubertal timing, and fracture risk in adult men.

Methods and findings

In the BMI Epidemiology Study Gothenburg, 31,971 Swedish men born between January 1, 1945, and December 31, 1961, with detailed growth data (height and weight) available from centrally archived school healthcare records and the conscription register were followed until December 31, 2016. Age at PHV was calculated according to a modified infancy–childhood–puberty model, and fracture information was retrieved from the Swedish National Patient Register. The mean ± SD age at PHV was 14.1 ± 1.1 years. In total, 5,872 men (18.4%) sustained at least 1 fracture after 20 years of age and 5,731 men (17.9%) sustained a non-vertebral fracture after 20 years of age during a mean ± SD follow-up of 37.3 ± 11.7 years. Cox proportional hazards models adjusted for birth year and country of origin revealed that age at PHV was associated with the risk of any fracture and non-vertebral fracture. Participants with age at PHV in the highest tertile (after 14.5 years of age) were at greater risk of any fracture (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.08–1.22, P < 0.001) and non-vertebral fracture (HR 1.16, 95% CI 1.09–1.24, P < 0.001) compared with those with age at PHV in the lowest tertile (at 13.6 years of age or younger). Additional adjustments for birthweight, childhood BMI, adult educational level, and young adult height did not attenuate the associations between age at PHV and adult fracture risk. Limitations of this study include the inability to adjust for important risk factors for fracture, inadequate power to assess the relation between pubertal timing and specific fracture types, and the limited generalizability to other populations.

Conclusions

In this study, we observed that late pubertal timing was associated with increased adult fracture risk in men. These findings suggest that information on pubertal timing might aid in the identification of those men at greatest risk of fracture.

Maternal prescribed opioid analgesic use during pregnancy and associations with adverse birth outcomes: A population-based study

Lu, 02/12/2019 - 23:00

by Ayesha C. Sujan, Patrick D. Quinn, Martin E. Rickert, Kelsey K. Wiggs, Paul Lichtenstein, Henrik Larsson, Catarina Almqvist, A. Sara Öberg, Brian M. D’Onofrio

Background

Published research on prescribed opioid analgesic (POA) use during pregnancy and birth outcomes is limited in scope and has not adequately adjusted for potential confounding factors. To help address these gaps, we estimated associations between maternal POAs during pregnancy and two adverse birth outcomes using a large population-based dataset, multiple definitions of POA exposure, and several methods to evaluate the influence of both measured and unmeasured confounding factors.

Methods and findings

We obtained data by linking information from several Swedish registers and conducted a retrospective cohort study on a population-based sample of 620,458 Swedish births occurring between 2007 and 2013 (48.6% female; 44.4% firstborn). We evaluated associations between prenatal POA exposure and risk for preterm birth (PTB; <37 gestational weeks) and small for gestational age (SGA; birth weight 2 standard deviations below the expected weight for gestational age or lower). We evaluated the influence of confounding by adjusting for a wide range of measured covariates while comparing exposed and unexposed infants. Additionally, we adjusted for unmeasured confounding factors by using several advanced epidemiological designs. Infants exposed to POAs anytime during pregnancy were at increased risk for PTB compared with unexposed infants (6.4% exposed versus 4.4% unexposed; adjusted odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.31–1.45, p < 0.001). This association was attenuated when we compared POA-exposed infants with acetaminophen-exposed infants (OR = 1.18, 95% CI 1.07–1.30, p < 0.001), infants born to women who used POAs before pregnancy only (OR = 1.05, 95% CI 0.96–1.14, p = 0.27), and unexposed siblings (OR = 0.99, 95% CI 0.85–1.14, p = 0.92). We also evaluated associations with short-term versus persistent POA use during pregnancy and observed a similar pattern of results, although the magnitudes of associations with persistent exposure were larger than associations with any use or short-term use. Although short-term use was not associated with SGA (adjusted ORsingle-trimester = 0.95, 95% CI 0.87–1.04, p = 0.29), persistent use was associated with increased risk for SGA (adjusted ORmultiple-trimester = 1.40, 95% CI 1.17–1.67, p < 0.001) compared with unexposed infants. The association with persistent exposure was attenuated when we used alternative comparison groups (e.g., sibling comparison OR = 1.22, 95% CI 0.60–2.48, p = 0.58). Of note, our study had limitations, including potential bias from exposure misclassification, an inability to adjust for all sources of confounding, and uncertainty regarding generalizability to countries outside of Sweden.

Conclusions

Our results suggested that observed associations between POA use during pregnancy and risk of PTB and SGA were largely due to unmeasured confounding factors, although we could not rule out small independent associations, particularly for persistent POA use during pregnancy.

The overweight and obesity transition from the wealthy to the poor in low- and middle-income countries: A survey of household data from 103 countries

Me, 27/11/2019 - 23:00

by Tara Templin, Tiago Cravo Oliveira Hashiguchi, Blake Thomson, Joseph Dieleman, Eran Bendavid

Background

In high-income countries, obesity prevalence (body mass index greater than or equal to 30 kg/m2) is highest among the poor, while overweight (body mass index greater than or equal to 25 kg/m2) is prevalent across all wealth groups. In contrast, in low-income countries, the prevalence of overweight and obesity is higher among wealthier individuals than among poorer individuals. We characterize the transition of overweight and obesity from wealthier to poorer populations as countries develop, and project the burden of overweight and obesity among the poor for 103 countries.

Methods and findings

Our sample used 182 Demographic and Health Surveys and World Health Surveys (n = 2.24 million respondents) from 1995 to 2016. We created a standard wealth index using household assets common among all surveys and linked national wealth by country and year identifiers. We then estimated the changing probability of overweight and obesity across every wealth decile as countries’ per capita gross domestic product (GDP) rises using logistic and linear fixed-effect regression models. We found that obesity rates among the wealthiest decile were relatively stable with increasing national wealth, and the changing gradient was largely due to increasing obesity prevalence among poorer populations (3.5% [95% uncertainty interval: 0.0%–8.3%] to 14.3% [9.7%–19.0%]). Overweight prevalence among the richest (45.0% [35.6%–54.4%]) and the poorest (45.5% [35.9%–55.0%]) were roughly equal in high-income settings. At $8,000 GDP per capita, the adjusted probability of being obese was no longer highest in the richest decile, and the same was true of overweight at $10,000. Above $25,000, individuals in the richest decile were less likely than those in the poorest decile to be obese, and the same was true of overweight at $50,000. We then projected overweight and obesity rates by wealth decile to 2040 for all countries to quantify the expected rise in prevalence in the relatively poor. Our projections indicated that, if past trends continued, the number of people who are poor and overweight will increase in our study countries by a median 84.4% (range 3.54%–383.4%), most prominently in low-income countries. The main limitations of this study included the inclusion of cross-sectional, self-reported data, possible reverse causality of overweight and obesity on wealth, and the lack of physical activity and food price data.

Conclusions

Our findings indicate that as countries develop economically, overweight prevalence increased substantially among the poorest and stayed mostly unchanged among the wealthiest. The relative poor in upper- and lower-middle income countries may have the greatest burden, indicating important planning and targeting needs for national health programs.

Joint statement on EPA proposed rule and public availability of data (2019)

Ma, 26/11/2019 - 23:00

by H. Holden Thorp, Magdalena Skipper, Veronique Kiermer, May Berenbaum, Deborah Sweet, Richard Horton

Addressing the context and consequences of substance use, misuse, and dependence: A global imperative

Ma, 26/11/2019 - 23:00

by Alexander C. Tsai, Margarita Alegría, Steffanie A. Strathdee

In an Editorial, Guest Editors Alexander Tsai, Margarita Alegria and Steffanie Strathdee discuss the accompanying Special Issue on Substance Use, Misuse and Dependence.

Long-term mortality in mothers of infants with neonatal abstinence syndrome: A population-based parallel-cohort study in England and Ontario, Canada

Ma, 26/11/2019 - 23:00

by Astrid Guttmann, Ruth Blackburn, Abby Amartey, Limei Zhou, Linda Wijlaars, Natasha Saunders, Katie Harron, Maria Chiu, Ruth Gilbert

Background

Opioid addiction is a major public health threat to healthy life expectancy; however, little is known of long-term mortality for mothers with opioid use in pregnancy. Pregnancy and delivery care are opportunities to improve access to addiction and supportive services. Treating neonatal abstinence syndrome (NAS) as a marker of opioid use during pregnancy, this study reports long-term maternal mortality among mothers with a birth affected by NAS in relation to that of mothers without a NAS-affected birth in 2 high-prevalence jurisdictions, England and Ontario, Canada.

Methods and findings

We conducted a population-based study using linked administrative health data to develop parallel cohorts of mother–infant dyads in England and Ontario between 2002 and 2012. The study population comprised 13,577 and 4,966 mothers of infants with NAS and 4,205,675 and 929,985 control mothers in England and Ontario, respectively. Death records captured all-cause maternal mortality after delivery through March 31, 2016, and cause-specific maternal mortality to December 31, 2014. The primary exposure was a live birth of an infant with NAS, and the main outcome was all deaths among mothers following their date of delivery. We modelled the association between NAS and all-cause maternal mortality using Cox regression, and the cumulative incidence of cause-specific mortality within a competing risks framework. All-cause mortality rates, 10-year cumulative incidence risk of death, and crude and age-adjusted hazard ratios were calculated. Estimated crude 10-year mortality based on Kaplan–Meier curves in mothers of infants with NAS was 5.1% (95% CI 4.7%–5.6%) in England and 4.6% (95% CI 3.8%–5.5%) in Ontario versus 0.4% (95% CI 0.41%–0.42%) in England and 0.4% (95% CI 0.38%–0.41%) in Ontario for controls (p < 0.001 for all comparisons). Survival curves showed no clear inflection point or period of heightened risk. The crude hazard ratio for all-cause mortality was 12.1 (95% 11.1–13.2; p < 0.001) in England and 11.4 (9.7–13.4; p < 0.001) in Ontario; age adjustment did not reduce the hazard ratios. The cumulative incidence of death was higher among NAS mothers than controls for almost all causes of death. The majority of deaths were by avoidable causes, defined as those that are preventable, amenable to care, or both. Limitations included lack of direct measures of maternal opioid use, other substance misuse, and treatments or supports received.

Conclusions

In this study, we found that approximately 1 in 20 mothers of infants with NAS died within 10 years of delivery in both England and Canada—a mortality risk 11–12 times higher than for control mothers. Risk of death was not limited to the early postpartum period targeted by most public health programs. Policy responses to the current opioid epidemic require effective strategies for long-term support to improve the health and welfare of opioid-using mothers and their children.

Opioid agonist treatment scale-up and the initiation of injection drug use: A dynamic modeling analysis

Ma, 26/11/2019 - 23:00

by Charles Marks, Annick Borquez, Sonia Jain, Xiaoying Sun, Steffanie A. Strathdee, Richard S. Garfein, M-J Milloy, Kora DeBeck, Javier A. Cepeda, Dan Werb, Natasha K. Martin

Background

Injection drug use (IDU) is associated with multiple health harms. The vast majority of IDU initiation events (in which injection-naïve persons first adopt IDU) are assisted by a person who injects drugs (PWID), and as such, IDU could be considered as a dynamic behavioral transmission process. Data suggest that opioid agonist treatment (OAT) enrollment is associated with a reduced likelihood of assisting with IDU initiation. We assessed the association between recent OAT enrollment and assisting IDU initiation across several North American settings and used dynamic modeling to project the potential population-level impact of OAT scale-up within the PWID population on IDU initiation.

Methods and findings

We employed data from a prospective multicohort study of PWID in 3 settings (Vancouver, Canada [n = 1,737]; San Diego, United States [n = 346]; and Tijuana, Mexico [n = 532]) from 2014 to 2017. Site-specific modified Poisson regression models were constructed to assess the association between recent (past 6 month) OAT enrollment and history of ever having assisted an IDU initiation with recently assisting IDU initiation. Findings were then pooled using linear mixed-effects techniques. A dynamic transmission model of IDU among the general population was developed, stratified by known factors associated with assisting IDU initiation and relevant drug use behaviors. The model was parameterized to a generic North American setting (approximately 1% PWID) and used to estimate the impact of increasing OAT coverage among PWID from baseline (approximately 21%) to 40%, 50%, and 60% on annual IDU initiation incidence and corresponding PWID population size across a decade. From Vancouver, San Diego, and Tijuana, respectively, 4.5%, 5.2%, and 4.3% of participants reported recently assisting an IDU initiation, and 49.4%, 19.7%, and 2.1% reported recent enrollment in OAT. Recent OAT enrollment was significantly associated with a 45% lower likelihood of providing recent IDU initiation assistance among PWID (relative risk [RR] 0.55 [95% CI 0.36–0.84], p = 0.006) compared to those not recently on OAT. Our dynamic model predicts a baseline mean of 1,067 (2.5%–97.5% interval [95% I 490–2,082]) annual IDU initiations per 1,000,000 individuals, of which 886 (95% I 406–1,750) are assisted by PWID. Based on our observed statistical associations, our dynamic model predicts that increasing OAT coverage from approximately 21% to 40%, 50%, or 60% among PWID could reduce annual IDU initiations by 11.5% (95% I 2.4–21.7), 17.3% (95% I 5.6–29.4), and 22.8% (95% I 8.1–36.8) and reduce the PWID population size by 5.4% (95% I 0.1–12.0), 8.2% (95% I 2.2–16.9), and 10.9% (95% I 3.2–21.8) relative to baseline, respectively, in a decade. Less impact occurs when the protective effect of OAT is diminished, when a greater proportion of IDU initiations are unassisted by PWID, and when average IDU career length is longer. The study’s main limitations are uncertainty in the causal pathway between OAT enrollment and assisting with IDU initiation and the use of a simplified model of IDU initiation.

Conclusions

In addition to its known benefits on preventing HIV, hepatitis C virus (HCV), and overdose among PWID, our modeling suggests that OAT scale-up may also reduce the number of IDU initiations and PWID population size.

The CHIRPY DRAGON intervention in preventing obesity in Chinese primary-school--aged children: A cluster-randomised controlled trial

Ma, 26/11/2019 - 23:00

by Bai Li, Miranda Pallan, Wei Jia Liu, Karla Hemming, Emma Frew, Rong Lin, Wei Liu, James Martin, Mandana Zanganeh, Kiya Hurley, Kar Keung Cheng, Peymane Adab

Background

In countries undergoing rapid economic transition such as China, rates of increase in childhood obesity exceed that in the West. However, prevention trials in these countries are inadequate in both quantity and methodological quality. In high-income countries, recent reviews have demonstrated that school-based prevention interventions are moderately effective but have some methodological limitations. To address these issues, this study evaluated clinical- and cost- effectiveness of the Chinese Primary School Children Physical Activity and Dietary Behaviour Changes Intervention (CHIRPY DRAGON) developed using the United Kingdom Medical Research Council complex intervention framework to prevent obesity in Chinese primary-school–aged children.

Methods and findings

In this cluster-randomised controlled trial, we recruited 40 state-funded primary schools from urban districts of Guangzhou, China. A total of 1,641 year-one children with parent/guardian consent took part in baseline assessments prior to stratified randomisation of schools (intervention arm, 20 schools, n = 832, mean age = 6.15 years, 55.6% boys; control arm n = 809, mean age = 6.14 years, 53.3% boys). The 12-month intervention programme included 4 school- and family-based components delivered by 5 dedicated project staff. We promoted physical activity and healthy eating behaviours through educational and practical workshops, family activities, and supporting the school to improve physical activity and food provision. The primary outcome, assessed blind to allocation, was between-arm difference in body mass index (BMI) z score at completion of the intervention. A range of prespecified, secondary anthropometric, behavioural, and psychosocial outcomes were also measured. We estimated cost effectiveness based on quality-adjusted life years (QALYs), taking a public sector perspective. Attrition was low with 55 children lost to follow up (3.4%) and no school dropout. Implementation adherence was high. Using intention to treat analysis, the mean difference (MD) in BMI z scores (intervention − control) was −0.13 (−0.26 to 0.00, p = 0.048), with the effect being greater in girls (MD = −0.18, −0.32 to −0.05, p = 0.007, p for interaction = 0.015) and in children with overweight or obesity at baseline (MD = −0.49, −0.73 to −0.25, p < 0.001, p for interaction < 0.001). Significant beneficial intervention effects were also observed on consumption of fruit and vegetables, sugar-sweetened beverages and unhealthy snacks, screen-based sedentary behaviour, and physical activity in the intervention group. Cost effectiveness was estimated at £1,760 per QALY, with the probability of the intervention being cost effective compared with usual care being at least 95% at a willingness to pay threshold of £20,000 to 30,000 per QALY. There was no evidence of adverse effects or harms. The main limitations of this study were the use of dietary assessment tools not yet validated for Chinese children and the use of the UK value set to estimate QALYS.

Conclusions

This school- and family-based obesity prevention programme was effective and highly cost effective in reducing BMI z scores in primary-school–aged children in China. Future research should identify strategies to enhance beneficial effects among boys and investigate the transferability of the intervention to other provinces in China and countries that share the same language and cultures.

Trial registration

ISRCTN Identifier ISRCTN11867516.

Stigma as a fundamental hindrance to the United States opioid overdose crisis response

Ma, 26/11/2019 - 23:00

by Alexander C. Tsai, Mathew V. Kiang, Michael L. Barnett, Leo Beletsky, Katherine M. Keyes, Emma E. McGinty, Laramie R. Smith, Steffanie A. Strathdee, Sarah E. Wakeman, Atheendar S. Venkataramani

Alexander Tsai and co-authors discuss the role of stigma in responses to the US opioid crisis.

Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records

Ma, 26/11/2019 - 23:00

by John Macleod, Colin Steer, Kate Tilling, Rosie Cornish, John Marsden, Tim Millar, John Strang, Matthew Hickman

Background

Patients with opioid dependency prescribed opioid agonist treatment (OAT) may also be prescribed sedative drugs. This may increase mortality risk but may also increase treatment duration, with overall benefit. We hypothesised that prescription of benzodiazepines in patients receiving OAT would increase risk of mortality overall, irrespective of any increased treatment duration.

Methods and findings

Data on 12,118 patients aged 15–64 years prescribed OAT between 1998 and 2014 were extracted from the Clinical Practice Research Datalink. Data from the Office for National Statistics on whether patients had died and, if so, their cause of death were available for 7,016 of these patients. We identified episodes of prescription of benzodiazepines, z-drugs, and gabapentinoids and used linear regression and Cox proportional hazards models to assess the associations of co-prescription (prescribed during OAT and up to 12 months post-treatment) and concurrent prescription (prescribed during OAT) with treatment duration and mortality. We examined all-cause mortality (ACM), drug-related poisoning (DRP) mortality, and mortality not attributable to DRP (non-DRP). Models included potential confounding factors. In 36,126 person-years of follow-up there were 657 deaths and 29,540 OAT episodes, of which 42% involved benzodiazepine co-prescription and 29% concurrent prescription (for z-drugs these respective proportions were 20% and 11%, and for gabapentinoids 8% and 5%). Concurrent prescription of benzodiazepines was associated with increased duration of methadone treatment (adjusted mean duration of treatment episode 466 days [95% CI 450 to 483] compared to 286 days [95% CI 275 to 297]). Benzodiazepine co-prescription was associated with increased risk of DRP (adjusted HR 2.96 [95% CI 1.97 to 4.43], p < 0.001), with evidence of a dose–response effect, but showed little evidence of an association with non-DRP (adjusted HR 0.91 [95% CI 0.66 to 1.25], p = 0.549). Co-prescription of z-drugs showed evidence of an association with increased risk of DRP (adjusted HR 2.75 [95% CI 1.57 to 4.83], p < 0.001) but little evidence of an association with non-DRP (adjusted HR 0.79 [95% CI 0.49 to 1.28], p = 0.342). There was no evidence of an association of gabapentinoid co-prescription with DRP (HR 1.54 [95% CI 0.60 to 3.98], p = 0.373) but evidence of an association with increased non-DRP (HR 1.83 [95% CI 1.28 to 2.62], p = 0.001). Concurrent benzodiazepine prescription also increased mortality risk after consideration of duration of OAT (adjusted HR for DRP with benzodiazepine concurrent prescription 3.34 [95% CI 2.14 to 5.20], p < 0.001). The main limitation of this study is the possibility that unmeasured confounding factors led to an association between benzodiazepine prescription and DRP that is not causal.

Conclusions

In this study, co-prescription of benzodiazepine was specifically associated with increased risk of DRP in opioid-dependent individuals. Co-prescription of z-drugs and gabapentinoids was also associated with increased mortality risk; however, for z-drugs there was no evidence for a dose–response effect on DRP, and for gabapentinoids the increased mortality risk was not specific to DRP. Concurrent prescription of benzodiazepine was associated with longer treatment but still increased risk of death overall. Clinicians should be cautious about prescribing benzodiazepines to opioid-dependent individuals.