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Middle-income countries graduating from health aid: Transforming daunting challenges into smooth transitions

Ma, 25/06/2019 - 23:00

by Gavin Yamey, Osondu Ogbuoji, Justice Nonvignon

Gavin Yamey and co-authors discuss approaches to providing support for middle-income countries transitioning away from health aid.

Effect of pedometer-based walking interventions on long-term health outcomes: Prospective 4-year follow-up of two randomised controlled trials using routine primary care data

Ma, 25/06/2019 - 23:00

by Tess Harris, Elizabeth S. Limb, Fay Hosking, Iain Carey, Steve DeWilde, Cheryl Furness, Charlotte Wahlich, Shaleen Ahmad, Sally Kerry, Peter Whincup, Christina Victor, Michael Ussher, Steve Iliffe, Ulf Ekelund, Julia Fox-Rushby, Judith Ibison, Derek G. Cook

Background

Data are lacking from physical activity (PA) trials with long-term follow-up of both objectively measured PA levels and robust health outcomes. Two primary care 12-week pedometer-based walking interventions in adults and older adults (PACE-UP and PACE-Lift) found sustained objectively measured PA increases at 3 and 4 years, respectively. We aimed to evaluate trial intervention effects on long-term health outcomes relevant to walking interventions, using routine primary care data.

Methods and findings

Randomisation was from October 2012 to November 2013 for PACE-UP participants from seven general (family) practices and October 2011 to October 2012 for PACE-Lift participants from three practices. We downloaded primary care data, masked to intervention or control status, for 1,001 PACE-UP participants aged 45–75 years, 36% (361) male, and 296 PACE-Lift participants, aged 60–75 years, 46% (138) male, who gave written informed consent, for 4-year periods following randomisation. The following new events were counted for all participants, including those with preexisting diseases (apart from diabetes, for which existing cases were excluded): nonfatal cardiovascular, total cardiovascular (including fatal), incident diabetes, depression, fractures, and falls. Intervention effects on time to first event post-randomisation were modelled using Cox regression for all outcomes, except for falls, which used negative binomial regression to allow for multiple events, adjusting for age, sex, and study. Absolute risk reductions (ARRs) and numbers needed to treat (NNTs) were estimated. Data were downloaded for 1,297 (98%) of 1,321 trial participants. Event rates were low (<20 per group) for outcomes, apart from fractures and falls. Cox hazard ratios for time to first event post-randomisation for interventions versus controls were nonfatal cardiovascular 0.24 (95% confidence interval [CI] 0.07–0.77, p = 0.02), total cardiovascular 0.34 (95% CI 0.12–0.91, p = 0.03), diabetes 0.75 (95% CI 0.42–1.36, p = 0.34), depression 0.98 (95% CI 0.46–2.07, p = 0.96), and fractures 0.56 (95% CI 0.35–0.90, p = 0.02). Negative binomial incident rate ratio for falls was 1.07 (95% CI 0.78–1.46, p = 0.67). ARR and NNT for cardiovascular events were nonfatal 1.7% (95% CI 0.5%–2.1%), NNT = 59 (95% CI 48–194); total 1.6% (95% CI 0.2%–2.2%), NNT = 61 (95% CI 46–472); and for fractures 3.6% (95% CI 0.8%–5.4%), NNT = 28 (95% CI 19–125). Main limitations were that event rates were low and only events recorded in primary care records were counted; however, any underrecording would not have differed by intervention status and so should not have led to bias.

Conclusions

Routine primary care data used to assess long-term trial outcomes demonstrated significantly fewer new cardiovascular events and fractures in intervention participants at 4 years. No statistically significant differences between intervention and control groups were demonstrated for other events. Short-term primary care pedometer-based walking interventions can produce long-term health benefits and should be more widely used to help address the public health inactivity challenge.

Trial registrations

PACE-UP isrctn.com ISRCTN98538934; PACE-Lift isrctn.com ISRCTN42122561.

Biannual mass azithromycin distributions and malaria parasitemia in pre-school children in Niger: A cluster-randomized, placebo-controlled trial

Ma, 25/06/2019 - 23:00

by Ahmed M. Arzika, Ramatou Maliki, Nameywa Boubacar, Salissou Kane, Sun Y. Cotter, Elodie Lebas, Catherine Cook, Robin L. Bailey, Sheila K. West, Philip J. Rosenthal, Travis C. Porco, Thomas M. Lietman, Jeremy D. Keenan, for the MORDOR Study Group

Background

Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria.

Methods and findings

In a cluster-randomized trial conducted from 23 November 2014 until 31 July 2017, 30 rural communities in Niger were randomized to 2 years of biannual mass distributions of either azithromycin (20 mg/kg oral suspension) or placebo to children aged 1 to 59 months. Participants, field staff, and investigators were masked to treatment allocation. The primary malaria outcome was the community prevalence of parasitemia on thick blood smear, assessed in a random sample of children from each community at study visits 12 and 24 months after randomization. Analyses were performed in an intention-to-treat fashion. At the baseline visit, a total of 1,695 children were enumerated in the 15 azithromycin communities, and 3,029 children were enumerated in the 15 placebo communities. No communities were lost to follow-up. The mean prevalence of malaria parasitemia at baseline was 8.9% (95% CI 5.1%–15.7%; 52 of 552 children across all communities) in the azithromycin-treated group and 6.7% (95% CI 4.0%–12.6%; 36 of 542 children across all communities) in the placebo-treated group. In the prespecified primary analysis, parasitemia was lower in the azithromycin-treated group at month 12 (mean prevalence 8.8%, 95% CI 5.1%–14.3%; 51 of 551 children across all communities) and month 24 (mean 3.5%, 95% CI 1.9%–5.5%; 21 of 567 children across all communities) than it was in the placebo-treated group at month 12 (mean 15.3%, 95% CI 10.8%–20.6%; 81 of 548 children across all communities) and month 24 (mean 4.8%, 95% CI 3.3%–6.4%; 28 of 592 children across all communities) (P = 0.02). Communities treated with azithromycin had approximately half the odds of parasitemia compared to those treated with placebo (odds ratio [OR] 0.54, 95% CI 0.30 to 0.97). Parasite density was lower in the azithromycin group than the placebo group at 12 and 24 months (square root–transformed outcome; density estimates were 7,540 parasites/μl lower [95% CI −350 to −12,550 parasites/μl; P = 0.02] at a mean parasite density of 17,000, as was observed in the placebo arm). No significant difference in hemoglobin was observed between the 2 treatment groups at 12 and 24 months (mean 0.34 g/dL higher in the azithromycin arm, 95% CI −0.06 to 0.75 g/dL; P = 0.10). No serious adverse events were reported in either group, and among children aged 1 to 5 months, the most commonly reported nonserious adverse events (i.e., diarrhea, vomiting, and rash) were less common in the azithromycin-treated communities. Limitations of the trial include the timing of the treatments and monitoring visits, both of which took place before the peak malaria season, as well as the uncertain generalizability to areas with different malaria transmission dynamics.

Conclusions

Mass azithromycin distributions were associated with a reduced prevalence of malaria parasitemia in this trial, suggesting one possible mechanism for the mortality benefit observed with this intervention.

Trial registration

The trial was registered on ClinicalTrials.gov (NCT02048007).

Educational attainment and cardiovascular disease in the United States: A quasi-experimental instrumental variables analysis

Ma, 25/06/2019 - 23:00

by Rita Hamad, Thu T. Nguyen, Jay Bhattacharya, M. Maria Glymour, David H. Rehkopf

Background

There is ongoing debate about whether education or socioeconomic status (SES) should be inputs into cardiovascular disease (CVD) prediction algorithms and clinical risk adjustment models. It is also unclear whether intervening on education will affect CVD, in part because there is controversy regarding whether education is a determinant of CVD or merely correlated due to confounding or reverse causation. We took advantage of a natural experiment to estimate the population-level effects of educational attainment on CVD and related risk factors.

Methods and findings

We took advantage of variation in United States state-level compulsory schooling laws (CSLs), a natural experiment that was associated with geographic and temporal differences in the minimum number of years that children were required to attend school. We linked census data on educational attainment (N = approximately 5.4 million) during childhood with outcomes in adulthood, using cohort data from the 1992–2012 waves of the Health and Retirement Study (HRS; N = 30,853) and serial cross-sectional data from 1971–2012 waves of the National Health and Nutrition Examination Survey (NHANES; N = 44,732). We examined self-reported CVD outcomes and related risk factors, as well as relevant serum biomarkers. Using instrumental variables (IV) analysis, we found that increased educational attainment was associated with reduced smoking (HRS β −0.036, 95%CI: −0.06, −0.02, p < 0.01; NHANES β −0.032, 95%CI: −0.05, −0.02, p < 0.01), depression (HRS β −0.049, 95%CI: −0.07, −0.03, p < 0.01), triglycerides (NHANES β −0.039, 95%CI: −0.06, −0.01, p < 0.01), and heart disease (HRS β −0.025, 95%CI: −0.04, −0.002, p = 0.01), and improvements in high-density lipoprotein (HDL) cholesterol (HRS β 1.50, 95%CI: 0.34, 2.49, p < 0.01; NHANES β 0.86, 95%CI: 0.32, 1.48, p < 0.01), but increased BMI (HRS β 0.20, 95%CI: 0.002, 0.40, p = 0.05; NHANES β 0.13, 95%CI: 0.01, 0.32, p = 0.05) and total cholesterol (HRS β 2.73, 95%CI: 0.09, 4.97, p = 0.03). While most findings were cross-validated across both data sets, they were not robust to the inclusion of state fixed effects. Limitations included residual confounding, use of self-reported outcomes for some analyses, and possibly limited generalizability to more recent cohorts.

Conclusions

This study provides rigorous population-level estimates of the association of educational attainment with CVD. These findings may guide future implementation of interventions to address the social determinants of CVD and strengthen the argument for including educational attainment in prediction algorithms and primary prevention guidelines for CVD.

The Flooring for Injury Prevention (FLIP) Study of compliant flooring for the prevention of fall-related injuries in long-term care: A randomized trial

Lu, 24/06/2019 - 23:00

by Dawn C. Mackey, Chantelle C. Lachance, Peiwei T. Wang, Fabio Feldman, Andrew C. Laing, Pet M. Leung, X. Joan Hu, Stephen N. Robinovitch

Background

Fall-related injuries exert an enormous health burden on older adults in long-term care (LTC). Softer landing surfaces, such as those provided by low-stiffness “compliant” flooring, may prevent fall-related injuries by decreasing the forces applied to the body during fall impact. Our primary objective was to assess the clinical effectiveness of compliant flooring at preventing serious fall-related injuries among LTC residents.

Methods and findings

The Flooring for Injury Prevention (FLIP) Study was a 4-year, randomized superiority trial in 150 single-occupancy resident rooms at a single Canadian LTC site. In April 2013, resident rooms were block randomized (1:1) to installation of intervention compliant flooring (2.54 cm SmartCells) or rigid control flooring (2.54 cm plywood) covered with identical hospital-grade vinyl. The primary outcome was serious fall-related injury over 4 years that required an emergency department visit or hospital admission and a treatment procedure or diagnostic evaluation in hospital. Secondary outcomes included minor fall-related injury, any fall-related injury, falls, and fracture. Outcomes were ascertained by blinded assessors between September 1, 2013 and August 31, 2017 and analyzed by intention to treat. Adverse outcomes were not assessed. During follow-up, 184 residents occupied 74 intervention rooms, and 173 residents occupied 76 control rooms. Residents were 64.3% female with mean (SD) baseline age 81.7 (9.5) years (range 51.1 to 104.6 years), body mass index 25.9 (7.7) kg/m2, and follow-up 1.64 (1.39) years. 1,907 falls were reported; 23 intervention residents experienced 38 serious injuries (from 29 falls in 22 rooms), while 23 control residents experienced 47 serious injuries (from 34 falls in 23 rooms). Compliant flooring did not affect odds of ≥1 serious fall-related injury (12.5% intervention versus 13.3% control, odds ratio [OR]: 0.98, 95% CI: 0.52 to 1.84, p = 0.950) or ≥2 serious fall-related injuries (5.4% versus 7.5%, OR: 0.74, 95% CI: 0.31 to 1.75, p = 0.500). Compliant flooring did not affect rate of serious fall-related injuries (0.362 versus 0.422 per 1,000 bed nights, rate ratio [RR]: 1.04, 95% CI: 0.45 to 2.39, p = 0.925; 0.038 versus 0.053 per fall, RR: 0.81, 95% CI: 0.38 to 1.71, p = 0.560), rate of falls with ≥1 serious fall-related injury (0.276 versus 0.303 per 1,000 bed nights, RR: 0.97, 95% CI: 0.52 to 1.79, p = 0.920), or time to first serious fall-related injury (0.237 versus 0.257, hazard ratio [HR]: 0.92, 95% CI: 0.52 to 1.62, p = 0.760). Compliant flooring did not affect any secondary outcome in this study. Study limitations included the following: findings were specific to 2.54 cm SmartCells compliant flooring installed in LTC resident rooms, standard fall and injury prevention interventions were in use throughout the study and may have influenced the observed effect of compliant flooring, and challenges with concussion detection in LTC residents may have prevented estimation of the effect of compliant flooring on fall-related concussions.

Conclusions

In contrast to results from previous retrospective and nonrandomized studies, this study found that compliant flooring underneath hospital-grade vinyl was not effective at preventing serious fall-related injuries in LTC. Future studies are needed to identify effective methods for preventing fall-related injuries in LTC.

Trial registration

ClinicalTrials.gov: NCT01618786

The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study

Lu, 24/06/2019 - 23:00

by Gary J. Weil, Joshua Bogus, Michael Christian, Christine Dubray, Yenny Djuardi, Peter U. Fischer, Charles W. Goss, Myra Hardy, Purushothaman Jambulingam, Christopher L. King, Vijesh Sridhar Kuttiat, Kaliannagounder Krishnamoorthy, Moses Laman, Jean Frantz Lemoine, Katiuscia K. O’Brian, Leanne J. Robinson, Josaia Samuela, Kenneth B. Schechtman, Anita Sircar, Adinarayanan Srividya, Andrew C. Steer, Taniawati Supali, Swaminathan Subramanian, the DOLF IDA Safety Study Group

Background

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings.

Methods and findings

Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87–1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%–0.1%) and 0.01% (95% CI 0.00%–0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites.

Conclusions

In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA.

Trial registration

Clinicaltrials.gov registration number: NCT02899936

Provision of family planning vouchers and early initiation of postpartum contraceptive use among women living with HIV in southwestern Uganda: A randomized controlled trial

Ve, 21/06/2019 - 23:00

by Esther C. Atukunda, Godfrey R. Mugyenyi, Celestino Obua, Elly B. Atuhumuza, Edward J. Lukyamuzi, Angela Kaida, Amon G. Agaba, Lynn T. Matthews

Background

Unwanted pregnancies remain a burden for women living with HIV (WLWH). Family planning prevents unplanned pregnancies while promoting longer birth intervals, key strategies to eliminate perinatal transmission of HIV and promote maternal and child health. We evaluated the effect of a family planning voucher, inclusive of immediate postpartum counseling, on uptake, early initiation, and continuation of modern contraceptive methods among recently postpartum WLWH delivering at a publicly funded regional referral hospital in rural, southwestern Uganda.

Methods and findings

We performed a randomized controlled trial between October, 2016 and June, 2018 at a referral hospital in southwestern Uganda. This interim analysis includes adult WLWH randomized and enrolled equally to receive a family planning voucher or standard of care (control). Enrolled postpartum WLWH completed an interviewer-administered questionnaire at enrollment and 6 months postpartum. Our primary outcome of interest for this analysis is initiation of a modern family planning method within 8 weeks postpartum. Secondary outcomes included family planning initiation at 12, 14, 16, and 20 weeks postpartum, family planning discontinuation and/or change, pregnancy incidence, and mean time without contraception. The trial was registered with clinicaltrials.gov (NCT02964169). At enrollment, half of the women in both the voucher (N = 87, 55%) and control (N = 86, 54%) groups wanted to have a child in 2 years postpartum. Over 80% of referent pregnancies in the voucher (N = 136, 86%) and control (N = 128, 81%) groups were planned. All women were accessing ART. The mean CD4 count was 396 cells/mm3 (SD = 61) for those enrolled in the control group versus 393 cells/mm3 (SD = 64) in the family planning voucher group. By 8 weeks postpartum, family planning was initiated in 144 (91%) participants in the voucher group and 83 (52%) participants in the control group (odds ratio [OR] 9.42; CI 4.67–13.97, P < 0.001). We also found high family planning uptake rates for both groups, with higher rates among the intervention group at 12 weeks (OR 5.66; CI 2.65–12.12, P < 0.001), 14 weeks (OR 2.51; CI 1.31–4.79, P < 0.001), 16 weeks (OR 4.02; CI 1.66–9.77, P = 0.001), and 20 weeks (OR 3.65; CI 1.40–9.47, P = 0.004) postpartum. The average time to family planning initiation was reduced to 5.9 weeks (SD = 2.4) for those in the voucher group compared to 9.3 weeks (SD = 5) in the control (P < 0.001). One pregnancy was recorded in the group receiving standard of care; none were reported in the voucher group. Method mix did not differ by group: injectables were selected by most women (N = 150, 50%), and 52% of this proportion were in the experimental arm, with <10% in each arm selecting condoms, oral contraception, or intrauterine devices (IUDs). Similar proportions of women changed contraceptive methods over the 6-month follow-up in the voucher and control groups (N = 8, 5% versus N = 5, 4%; P = 0.467). More women in the control group discontinued contraception for 1 to 2 weeks (N = 19, 13% versus N = 7, 5%; P = 0.008) or more than 4 weeks (N = 15, 10% versus N = 3, 2%; P = 0.002) compared to those given a family planning voucher. The main limitation of this study is that its findings may not be generalized to settings without improved availability of contraceptives in publicly funded facilities.

Conclusion

These findings indicate that a well-structured, time-bound family planning voucher program appeared to increase early postpartum contraceptive uptake and continuation in a setting in which users are faced with financial, knowledge, and structural barriers to contraceptive services. Further work should clarify the role of vouchers in empowering WLWH to avoid unintended pregnancies over time.

Trial registration

ClinicalTrials.gov NCT02964169.

Associations of genetically determined iron status across the phenome: A mendelian randomization study

Gi, 20/06/2019 - 23:00

by Dipender Gill, Beben Benyamin, Luke S. P. Moore, Grace Monori, Ang Zhou, Fotios Koskeridis, Evangelos Evangelou, Mike Laffan, Ann P. Walker, Konstantinos K. Tsilidis, Abbas Dehghan, Paul Elliott, Elina Hyppönen, Ioanna Tzoulaki

Background

Iron is integral to many physiological processes, and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status.

Methods and findings

Genome-wide association study (GWAS) summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify 3 genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene [HFE] and rs855791 in the transmembrane protease serine 6 gene [TMPRSS6]) that associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 424,439 European individuals (54% female) in the UK Biobank who were aged 40–69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics (HES) from April, 1995 to March, 2016. Two-sample summary data mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR–PheWAS analysis for the 3 iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate (FDR) threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR–PheWAS analyses. After correcting for multiple testing, the 3 genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation [SD] increase in genetically determined serum iron levels 0.72, 95% confidence interval [CI] 0.64–0.81, P = 4 × 10−8) and hypercholesterolemia (hypercholesterolemia: OR 0.88, 95% CI 0.83–0.93, P = 2 × 10−5) and increasing risk of traits related to infection of the skin and related structures (cellulitis and abscess of the leg: OR 1.25, 95% CI 1.10–1.42, P = 6 × 10−4). The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and misclassification of diagnoses in the HES data. Furthermore, this work only investigated participants with European ancestry, and the findings may not be applicable to other ethnic groups.

Conclusions

Our findings offer novel, to our knowledge, insight into previously unreported effects of iron status, highlighting a potential protective effect of higher iron status on hypercholesterolemia and a detrimental role on risk of skin and skin structure infections. Given the modifiable and variable nature of iron status, these findings warrant further investigation.

Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis

Ma, 18/06/2019 - 23:00

by William D. Thompson, Jessica Tyrrell, Maria-Carolina Borges, Robin N. Beaumont, Bridget A. Knight, Andrew R. Wood, Susan M. Ring, Andrew T. Hattersley, Rachel M. Freathy, Debbie A. Lawlor

Background

Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.

Methods and findings

We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother–child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, ‘leave-one-out’, and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight −0.03 g [95% CI −2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15–9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (−20 g [95% CI −44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121–236 g, p = 1.43 × 10−9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.

Conclusions

Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.

Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: Evidence from the Health and Retirement Study

Ma, 18/06/2019 - 23:00

by Zuyun Liu, Xi Chen, Thomas M. Gill, Chao Ma, Eileen M. Crimmins, Morgan E. Levine

Background

An individual’s rate of aging directly influences his/her susceptibility to morbidity and mortality. Thus, quantifying aging and disentangling how various factors coalesce to produce between-person differences in the rate of aging, have important implications for potential interventions. We recently developed and validated a novel multi-system-based aging measure, Phenotypic Age (PhenoAge), which has been shown to capture mortality and morbidity risk in the full US population and diverse subpopulations. The aim of this study was to evaluate associations between PhenoAge and a comprehensive set of factors, including genetic scores, childhood and adulthood circumstances, and health behaviors, to determine the relative contributions of these factors to variance in this aging measure.

Methods and findings

Based on data from 2,339 adults (aged 51+ years, mean age 69.4 years, 56% female, and 93.9% non-Hispanic white) from the US Health and Retirement Study, we calculated PhenoAge and evaluated the multivariable associations for a comprehensive set of factors using 2 innovative approaches—Shapley value decomposition (the Shapley approach hereafter) and hierarchical clustering. The Shapley approach revealed that together all 11 study domains (4 childhood and adulthood circumstances domains, 5 polygenic score [PGS] domains, and 1 behavior domain, and 1 demographic domain) accounted for 29.2% (bootstrap standard error = 0.003) of variance in PhenoAge after adjustment for chronological age. Behaviors exhibited the greatest contribution to PhenoAge (9.2%), closely followed by adulthood adversity, which was suggested to contribute 9.0% of the variance in PhenoAge. Collectively, the PGSs contributed 3.8% of the variance in PhenoAge (after accounting for chronological age). Next, using hierarchical clustering, we identified 6 distinct subpopulations based on the 4 childhood and adulthood circumstances domains. Two of these subpopulations stood out as disadvantaged, exhibiting significantly higher PhenoAges on average. Finally, we observed a significant gene-by-environment interaction between a previously validated PGS for coronary artery disease and the seemingly most disadvantaged subpopulation, suggesting a multiplicative effect of adverse life course circumstances coupled with genetic risk on phenotypic aging. The main limitations of this study were the retrospective nature of self-reported circumstances, leading to possible recall biases, and the unrepresentative racial/ethnic makeup of the population.

Conclusions

In a sample of US older adults, genetic, behavioral, and socioenvironmental circumstances during childhood and adulthood account for about 30% of differences in phenotypic aging. Our results also suggest that the detrimental effects of disadvantaged life course circumstances for health and aging may be further exacerbated among persons with genetic predisposition to coronary artery disease. Finally, our finding that behaviors had the largest contribution to PhenoAge highlights a potential policy target. Nevertheless, further validation of these findings and identification of causal links are greatly needed.

College affirmative action bans and smoking and alcohol use among underrepresented minority adolescents in the United States: A difference-in-differences study

Ma, 18/06/2019 - 23:00

by Atheendar S. Venkataramani, Erin Cook, Rourke L. O’Brien, Ichiro Kawachi, Anupam B. Jena, Alexander C. Tsai

Background

College affirmative action programs seek to expand socioeconomic opportunities for underrepresented minorities. Between 1996 and 2013, 9 US states—including California, Texas, and Michigan—banned race-based affirmative action in college admissions. Because economic opportunity is known to motivate health behavior, banning affirmative action policies may have important adverse spillover effects on health risk behaviors. We used a quasi-experimental research design to evaluate the association between college affirmative action bans and health risk behaviors among underrepresented minority (Black, Hispanic, and Native American) adolescents.

Methods and findings

We conducted a difference-in-differences analysis using data from the 1991–2015 US national Youth Risk Behavior Survey (YRBS). We compared changes in self-reported cigarette smoking and alcohol use in the 30 days prior to survey among underrepresented minority 11th and 12th graders in states implementing college affirmative action bans (Arizona, California, Florida, Michigan, Nebraska, New Hampshire, Oklahoma, Texas, and Washington) versus outcomes among those residing in states not implementing bans (n = 35 control states). We also assessed whether underrepresented minority adults surveyed in the 1992–2015 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) who were exposed to affirmative action bans during their late high school years continued to smoke cigarettes between the ages of 19 and 30 years. Models adjusted for individual demographic characteristics, state and year fixed effects, and state-specific secular trends. In the YRBS (n = 34,988 to 36,268, depending on the outcome), cigarette smoking in the past 30 days among underrepresented minority 11th–12th graders increased by 3.8 percentage points after exposure to an affirmative action ban (95% CI: 2.0, 5.7; p < 0.001). In addition, there were also apparent increases in past-30-day alcohol use, by 5.9 percentage points (95% CI: 0.3, 12.2; p = 0.041), and past-30-day binge drinking, by 3.5 percentage points (95% CI: −0.1, 7.2, p = 0.058), among underrepresented minority 11th–12th graders, though in both cases adjustment for multiple comparisons resulted in failure to reject the null hypothesis (adjusted p = 0.083 for both outcomes). Underrepresented minority adults in the TUS-CPS (n = 71,575) exposed to bans during their late high school years were also 1.8 percentage points more likely to report current smoking (95% CI: 0.1, 3.6; p = 0.037). Event study analyses revealed a discrete break for all health behaviors timed with policy discussion and implementation. No substantive or statistically significant effects were found for non-Hispanic White adolescents, and the findings were robust to a number of additional specification checks. The limitations of the study include the continued potential for residual confounding from unmeasured time-varying factors and the potential for recall bias due to the self-reported nature of the health risk behavior outcomes.

Conclusions

In this study, we found evidence that some health risk behaviors increased among underrepresented minority adolescents after exposure to state-level college affirmative action bans. These findings suggest that social policies that shift socioeconomic opportunities could have meaningful population health consequences.

Mediating roles of preterm birth and restricted fetal growth in the relationship between maternal education and infant mortality: A Danish population-based cohort study

Ve, 14/06/2019 - 23:00

by Yongfu Yu, Zeyan Liew, Aolin Wang, Onyebuchi A. Arah, Jialiang Li, Jørn Olsen, Sven Cnattingius, Guoyou Qin, Carsten Obel, Bo Fu, Jiong Li

Background

Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality.

Methods and findings

We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981–2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0–27 days) and postneonatal (28–364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48–1.80, P < 0.001) and 1.19 (95% CI 1.08–1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15–1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01–1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%–81%) than with postneonatal mortality (proportion eliminated: 21%–23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare.

Conclusions

PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors.

Evaluating the impact of community health volunteer home visits on child diarrhea and fever in the Volta Region, Ghana: A cluster-randomized controlled trial

Ve, 14/06/2019 - 23:00

by Yeunji Ma, Christopher R. Sudfeld, Heunghee Kim, Jaeeun Lee, Yinseo Cho, John Koku Awoonor-Williams, Joseph Kwami Degley, Seungman Cha

Background

Although there is mounting evidence demonstrating beneficial effects of community health workers (CHWs), few studies have examined the impact of CHW programs focused on preventing infectious diseases in children through behavior changes. We assessed the preventive effects of community health volunteers (CHVs), who receive no financial incentive, on child diarrhea and fever prevalence in Ghana.

Methods and findings

We conducted a cluster-randomized controlled trial in 40 communities in the Volta Region, Ghana. Twenty communities were randomly allocated to the intervention arm, and 20 to the control arm, using a computer-generated block randomization list. In the intervention arm, CHVs were deployed in their own community with the key task of conducting home visits for health education and community mobilization. The primary outcomes of the trial were diarrhea and fever prevalence at 6 and 12 months among under-5 children based on caregivers’ recall. Secondary outcomes included oral rehydration treatment and rapid diagnostic testing for malaria among under-5 children, and family planning practices of caregivers. Generalized estimating equations (GEEs) with a log link and exchangeable correlation matrix were used to determine the relative risk (RR) and 95% confidence intervals (CIs) for diarrhea, fever, and secondary outcomes adjusted for clustering and stratification. Between April 18 and May 4, 2015, 1,956 children were recruited and followed up until September 20, 2016. At 6 and 12 months post-randomization, 1,660 (85%) and 1,609 (82%) participants, respectively, had outcomes assessed. CHVs’ home visits had no statistically significant effect on diarrhea or fever prevalence at either time point. After a follow-up of 12 months, the prevalence of diarrhea and fever was 7.0% (55/784) and 18.4% (144/784), respectively, in the control communities and 4.5% (37/825) and 14.7% (121/825), respectively, in the intervention communities (12-month RR adjusted for clustering and stratification: diarrhea, RR 0.73, 95% CI 0.37–1.45, p = 0.37; fever, RR 0.76, 95% CI 0.51–1.14, p = 0.20). However, the following were observed: improved hand hygiene practices, increased utilization of insecticide-treated bed nets, and greater participation in community outreach programs (p-values < 0.05) in the intervention group. In a post hoc subgroup analysis, the prevalence of diarrhea and fever at 6 months was 3.2% (2/62) and 17.7% (11/62), respectively, in the intervention communities with ≥70% coverage and a ≥30-minute visit duration, and 14.4% (116/806) and 30.2% (243/806) in the control communities (RR adjusted for clustering, stratification, baseline prevalence, and covariates: diarrhea, RR 0.23, 95% CI 0.09–0.60, p = 0.003; fever, RR 0.69, 95% CI 0.52–0.92, p = 0.01). The main limitations were the following: We were unable to investigate the longer-term effects of CHVs; the trial may have been underpowered to detect small to moderate effects due to the large decline in diarrheal and fever prevalence in both the intervention and control group; and caregivers’ practices were based on self-report, and the possibility of caregivers providing socially desirable responses cannot be excluded.

Conclusions

We found no effect of CHVs’ home visits on the prevalence of child diarrhea or fever. However, CHV programs with high community coverage and regular household contacts of effective duration may reduce childhood infectious disease prevalence.

Trial registration

International Standard Randomised Controlled Trial Registry, ISRCTN49236178.

Government policy interventions to reduce human antimicrobial use: A systematic review and evidence map

Ma, 11/06/2019 - 23:00

by Susan Rogers Van Katwyk, Jeremy M. Grimshaw, Miriam Nkangu, Ranjana Nagi, Marc Mendelson, Monica Taljaard, Steven J. Hoffman

Background

Growing political attention to antimicrobial resistance (AMR) offers a rare opportunity for achieving meaningful action. Many governments have developed national AMR action plans, but most have not yet implemented policy interventions to reduce antimicrobial overuse. A systematic evidence map can support governments in making evidence-informed decisions about implementing programs to reduce AMR, by identifying, describing, and assessing the full range of evaluated government policy options to reduce antimicrobial use in humans.

Methods and findings

Seven databases were searched from inception to January 28, 2019, (MEDLINE, CINAHL, EMBASE, PAIS Index, Cochrane Central Register of Controlled Trials, Web of Science, and PubMed). We identified studies that (1) clearly described a government policy intervention aimed at reducing human antimicrobial use, and (2) applied a quantitative design to measure the impact. We found 69 unique evaluations of government policy interventions carried out across 4 of the 6 WHO regions. These evaluations included randomized controlled trials (n = 4), non-randomized controlled trials (n = 3), controlled before-and-after designs (n = 7), interrupted time series designs (n = 25), uncontrolled before-and-after designs (n = 18), descriptive designs (n = 10), and cohort designs (n = 2). From these we identified 17 unique policy options for governments to reduce the human use of antimicrobials. Many studies evaluated public awareness campaigns (n = 17) and antimicrobial guidelines (n = 13); however, others offered different policy options such as professional regulation, restricted reimbursement, pay for performance, and prescription requirements. Identifying these policies can inform the development of future policies and evaluations in different contexts and health systems. Limitations of our study include the possible omission of unpublished initiatives, and that policies not evaluated with respect to antimicrobial use have not been captured in this review.

Conclusions

To our knowledge this is the first study to provide policy makers with synthesized evidence on specific government policy interventions addressing AMR. In the future, governments should ensure that AMR policy interventions are evaluated using rigorous study designs and that study results are published.

Protocol registration

PROSPERO CRD42017067514.

The association between maternal body mass index and child obesity: A systematic review and meta-analysis

Ma, 11/06/2019 - 23:00

by Nicola Heslehurst, Rute Vieira, Zainab Akhter, Hayley Bailey, Emma Slack, Lem Ngongalah, Augustina Pemu, Judith Rankin

Background

There is a global obesity crisis, particularly among women and disadvantaged populations. Early-life intervention to prevent childhood obesity is a priority for public health, global health, and clinical practice. Understanding the association between childhood obesity and maternal pre-pregnancy weight status would inform policy and practice by allowing one to estimate the potential for offspring health gain through channelling resources into intervention. This systematic review and meta-analysis aimed to examine the dose–response association between maternal body mass index (BMI) and childhood obesity in the offspring.

Methods and findings

Searches in MEDLINE, Child Development & Adolescent Studies, CINAHL, Embase, and PsycInfo were carried out in August 2017 and updated in March 2019. Supplementary searches included hand-searching reference lists, performing citation searching, and contacting authors. Two researchers carried out independent screening, data extraction, and quality assessment. Observational studies published in English and reporting associations between continuous and/or categorical maternal and child BMI or z-score were included. Categorical outcomes were child obesity (≥95th percentile, primary outcome), overweight/obesity (≥85th percentile), and overweight (85th to 95th percentile). Linear and nonlinear dose–response meta-analyses were conducted using random effects models. Studies that could not be included in meta-analyses were summarised narratively. Seventy-nine of 41,301 studies identified met the inclusion criteria (n = 59 cohorts). Meta-analyses of child obesity included 20 studies (n = 88,872); child overweight/obesity, 22 studies (n = 181,800); and overweight, 10 studies (n = 53,238). Associations were nonlinear and there were significantly increased odds of child obesity with maternal obesity (odds ratio [OR] 3.64, 95% CI 2.68–4.95) and maternal overweight (OR 1.89, 95% CI 1.62–2.19). Significantly increased odds were observed for child overweight/obesity (OR 2.69, 95% CI 2.10–3.46) and for child overweight (OR 1.80, 95% CI 1.25, 2.59) with maternal obesity. A limitation of this research is that the included studies did not always report the data in a format that enabled inclusion in this complex meta-analysis.

Conclusions

This research has identified a 264% increase in the odds of child obesity when mothers have obesity before conception. This study provides substantial evidence for the need to develop interventions that commence prior to conception, to support women of childbearing age with weight management in order to halt intergenerational obesity.

Changes in rapid HIV treatment initiation after national “treat all” policy adoption in 6 sub-Saharan African countries: Regression discontinuity analysis

Lu, 10/06/2019 - 23:00

by Olga Tymejczyk, Ellen Brazier, Constantin T. Yiannoutsos, Michael Vinikoor, Monique van Lettow, Fred Nalugoda, Mark Urassa, Jean d’Amour Sinayobye, Peter F. Rebeiro, Kara Wools-Kaloustian, Mary-Ann Davies, Elizabeth Zaniewski, Nanina Anderegg, Grace Liu, Nathan Ford, Denis Nash, on behalf of the IeDEA consortium

Background

Most countries have formally adopted the World Health Organization’s 2015 recommendation of universal HIV treatment (“treat all”). However, there are few rigorous assessments of the real-world impact of treat all policies on antiretroviral treatment (ART) uptake across different contexts.

Methods and findings

We used longitudinal data for 814,603 patients enrolling in HIV care between 1 January 2004 and 10 July 2018 in 6 countries participating in the global International epidemiology Databases to Evaluate AIDS (IeDEA) consortium: Burundi (N = 11,176), Kenya (N = 179,941), Malawi (N = 84,558), Rwanda (N = 17,396), Uganda (N = 96,286), and Zambia (N = 425,246). Using a quasi-experimental regression discontinuity design, we assessed the change in the proportion initiating ART within 30 days of enrollment in HIV care (rapid ART initiation) after country-level adoption of the treat all policy. A modified Poisson model was used to identify factors associated with failure to initiate ART rapidly under treat all. In each of the 6 countries, over 60% of included patients were female, and median age at enrollment ranged from 32 to 36 years. In all countries studied, national adoption of treat all was associated with large increases in rapid ART initiation. Significant increases in rapid ART initiation immediately after treat all policy adoption were observed in Rwanda, from 44.4% to 78.9% of patients (34.5 percentage points [pp], 95% CI 27.2 to 41.7; p < 0.001), Kenya (25.7 pp, 95% CI 21.8 to 29.5; p < 0.001), Burundi (17.7 pp, 95% CI 6.5 to 28.9; p = 0.002), and Malawi (12.5 pp, 95% CI 7.5 to 17.5; p < 0.001), while no immediate increase was observed in Zambia (0.4 pp, 95% CI −2.9 to 3.8; p = 0.804) and Uganda (−4.2 pp, 95% CI −9.0 to 0.7; p = 0.090). The rate of rapid ART initiation accelerated sharply following treat all policy adoption in Malawi, Uganda, and Zambia; slowed in Kenya; and did not change in Rwanda and Burundi. In post hoc analyses restricted to patients enrolling under treat all, young adults (16–24 years) and men were at increased risk of not rapidly initiating ART (compared to older patients and women, respectively). However, rapid ART initiation following enrollment increased for all groups as more time elapsed since treat all policy adoption. Study limitations include incomplete data on potential ART eligibility criteria, such as clinical status, pregnancy, and enrollment CD4 count, which precluded the assessment of rapid ART initiation specifically among patients known to be eligible for ART before treat all.

Conclusions

Our analysis indicates that adoption of treat all policies had a strong effect on increasing rates of rapid ART initiation, and that these increases followed different trajectories across the 6 countries. Young adults and men still require additional attention to further improve rapid ART initiation.

Changes in resistance among coliform bacteraemia associated with a primary care antimicrobial stewardship intervention: A population-based interrupted time series study

Ve, 07/06/2019 - 23:00

by Virginia Hernandez-Santiago, Peter G. Davey, Dilip Nathwani, Charis A. Marwick, Bruce Guthrie

Background

Primary care antimicrobial stewardship interventions can improve antimicrobial prescribing, but there is less evidence that they reduce rates of resistant infection. This study examined changes in broad-spectrum antimicrobial prescribing in the community and resistance in people admitted to hospital with community-associated coliform bacteraemia associated with a primary care stewardship intervention.

Methods and findings

Segmented regression analysis of data on all patients registered with a general practitioner in the National Health Service (NHS) Tayside region in the east of Scotland, UK, from 1 January 2005 to 31 December 2015 was performed, examining associations between a primary care antimicrobial stewardship intervention in 2009 and primary care prescribing of fluoroquinolones, cephalosporins, and co-amoxiclav and resistance to the same three antimicrobials/classes among community-associated coliform bacteraemia. Prescribing outcomes were the rate per 1,000 population prescribed each antimicrobial/class per quarter. Resistance outcomes were proportion of community-associated (first 2 days of hospital admission) coliform (Escherichia coli, Proteus spp., or Klebsiella spp.) bacteraemia among adult (18+ years) patients resistant to each antimicrobial/class. 11.4% of 3,442,205 oral antimicrobial prescriptions dispensed in primary care over the study period were for targeted antimicrobials. There were large, statistically significant reductions in prescribing at 1 year postintervention that were larger by 3 years postintervention when the relative reduction was −68.8% (95% CI −76.3 to −62.1) and the absolute reduction −6.3 (−7.6 to −5.2) people exposed per 1,000 population per quarter for fluoroquinolones; relative −74.0% (−80.3 to −67.9) and absolute reduction −6.1 (−7.2 to −5.2) for cephalosporins; and relative −62.3% (−66.9 to −58.1) and absolute reduction −6.8 (−7.7 to −6.0) for co-amoxiclav, all compared to their prior trends. There were 2,143 eligible bacteraemia episodes involving 2,004 patients over the study period (mean age 73.7 [SD 14.8] years; 51.4% women). There was no increase in community-associated coliform bacteraemia admissions associated with reduced community broad-spectrum antimicrobial use. Resistance to targeted antimicrobials reduced by 3.5 years postintervention compared to prior trends, but this was not statistically significant for co-amoxiclav. Relative and absolute changes were −34.7% (95% CI −52.3 to −10.6) and −63.5 (−131.8 to −12.8) resistant bacteraemia per 1,000 bacteraemia per quarter for fluoroquinolones; −48.3% (−62.7 to −32.3) and −153.1 (−255.7 to −77.0) for cephalosporins; and −17.8% (−47.1 to 20.8) and −63.6 (−206.4 to 42.4) for co-amoxiclav, respectively. Overall, there was reversal of a previously rising rate of fluoroquinolone resistance and flattening of previously rising rates of cephalosporin and co-amoxiclav resistance. The limitations of this study include that associations are not definitive evidence of causation and that potential effects of underlying secular trends in the postintervention period and/or of other interventions occurring simultaneously cannot be definitively excluded.

Conclusions

In this population-based study in Scotland, compared to prior trends, there were very large reductions in community broad-spectrum antimicrobial use associated with the stewardship intervention. In contrast, changes in resistance among coliform bacteraemia were more modest. Prevention of resistance through judicious use of new antimicrobials may be more effective than trying to reverse resistance that has become established.

Treatment of latent infection to achieve tuberculosis elimination in low-incidence countries

Gi, 06/06/2019 - 23:00

by Jonathon R. Campbell, David Dowdy, Kevin Schwartzman

In a Perspective for the Tuberculosis Special Issue, Kevin Schwartzman and colleagues discuss the choices and implications for personal versus public health benefits when pursuing tuberculosis elimination in low-incidence countries.

Iron deficiency, elevated erythropoietin, fibroblast growth factor 23, and mortality in the general population of the Netherlands: A cohort study

Gi, 06/06/2019 - 23:00

by Michele F. Eisenga, Maarten A. De Jong, Peter Van der Meer, David E. Leaf, Gerwin Huls, Ilja M. Nolte, Carlo A. J. M. Gaillard, Stephan J. L. Bakker, Martin H. De Borst

Background

Emerging data in chronic kidney disease (CKD) patients suggest that iron deficiency and higher circulating levels of erythropoietin (EPO) stimulate the expression and concomitant cleavage of the osteocyte-derived, phosphate-regulating hormone fibroblast growth factor 23 (FGF23), a risk factor for premature mortality. To date, clinical implications of iron deficiency and high EPO levels in the general population, and the potential downstream role of FGF23, are unclear. Therefore, we aimed to determine the associations between iron deficiency and higher EPO levels with mortality, and the potential mediating role of FGF23, in a cohort of community-dwelling subjects.

Methods and findings

We analyzed 6,544 community-dwelling subjects (age 53 ± 12 years; 50% males) who participated in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study—a prospective population-based cohort study, of which we used the second survey (2001–2003)—and follow-up was performed for a median of 8 years. We measured circulating parameters of iron status, EPO levels, and plasma total FGF23 levels. Our primary outcome was all-cause mortality. In multivariable linear regression analyses, ferritin (ß = –0.43), transferrin saturation (TSAT) (ß = −0.17), hepcidin (ß = −0.36), soluble transferrin receptor (sTfR; ß = 0.33), and EPO (ß = 0.28) were associated with FGF23 level, independent of potential confounders. During median (interquartile range [IQR]) follow-up of 8.2 (7.7–8.8) years, 379 (6%) subjects died. In multivariable Cox regression analyses, lower levels of TSAT (hazard ratio [HR] per 1 standard deviation [SD], 0.84; 95% confidence interval [CI], 0.75–0.95; P = 0.004) and higher levels of sTfR (HR, 1.15; 95% CI 1.03–1.28; P = 0.01), EPO (HR, 1.17; 95% CI 1.05–1.29; P = 0.004), and FGF23 (HR, 1.20; 95% CI 1.10–1.32; P < 0.001) were each significantly associated with an increased risk of death, independent of potential confounders. Adjustment for FGF23 levels markedly attenuated the associations of TSAT (HR, 0.89; 95% CI 0.78–1.01; P = 0.06), sTfR (HR, 1.08; 95% CI 0.96–1.20; P = 0.19), and EPO (HR, 1.10; 95% CI 0.99–1.22; P = 0.08) with mortality. FGF23 remained associated with mortality (HR, 1.15; 95% CI 1.04–1.27; P = 0.008) after adjustment for TSAT, sTfR, and EPO levels. Mediation analysis indicated that FGF23 explained 31% of the association between TSAT and mortality; similarly, FGF23 explained 32% of the association between sTfR and mortality and 48% of the association between EPO and mortality (indirect effect P < 0.05 for all analyses). The main limitations of this study were the observational study design and the absence of data on intact FGF23 (iFGF23), precluding us from discerning whether the current results are attributable to an increase in iFGF23 or in C-terminal FGF23 fragments.

Conclusions and relevance

In this study, we found that functional iron deficiency and higher EPO levels were each associated with an increased risk of death in the general population. Our findings suggest that FGF23 could be involved in the association between functional iron deficiency and increased EPO levels and death. Investigation of strategies aimed at correcting iron deficiency and reducing FGF23 levels is warranted.

Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study

Ma, 04/06/2019 - 23:00

by Yahia Al-Jebari, Ingrid Glimelius, Carina Berglund Nord, Gabriella Cohn-Cedermark, Olof Ståhl, Torgrim Tandstad, Allan Jensen, Hege Sagstuen Haugnes, Gedske Daugaard, Lars Rylander, Aleksander Giwercman

Background

Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk.

Methods and findings

In this nationwide register study, all singletons born in Sweden 1994–2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19–1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment–to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54–1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25–4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995–2000—both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited.

Conclusions

No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.