Associations between arterial stiffening and brain structure,perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study

BackgroundAortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.Methods and findingsThe Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007–2009 (Phase 9) and at a 4-year follow-up in 2012–2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = −5.65, 95% CI −9.75, −1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = −1.12, 95% CI −1.95, −0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = −10.85, 95% CI −17.91, −3.79, p < 0.0125) and parietal lobes (B = −12.75, 95% CI −21.58, −3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = −0.47, 95% CI −0.76 to −0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = −0.36, 95% CI −0.60 to −0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort.ConclusionsOur findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03335696","term_id":"NCT03335696"}}NCT03335696

Sana Suri and colleagues investigate differences in brain structure and connectivity associated with aortic stiffening in older adults.     

Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression

BackgroundSodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).Methods and findingsWe searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = −0.766 [−1.276, −0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R² = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R² = 86%). The association of DKA with a BMI >27 kg/m² and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: −9.91, 95% CI: −16.26, −3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.ConclusionsIn T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.

Giovanni Musso and colleagues conduct a meta-analysis to identify risk factors of diabetic ketoacidosis in patients with Type 1 diabetes taking SGLT2 inhibitors.     

Impact of color-coded and warning nutrition labelling schemes: A systematic review and network meta-analysis

BackgroundSuboptimal diets are a leading risk factor for death and disability. Nutrition labelling is a potential method to encourage consumers to improve dietary behaviour. This systematic review and network meta-analysis (NMA) summarises evidence on the impact of colour-coded interpretive labels and warning labels on changing consumers’ purchasing behaviour.Methods and findingsWe conducted a literature review of peer-reviewed articles published between 1 January 1990 and 24 May 2021 in PubMed, Embase via Ovid, Cochrane Central Register of Controlled Trials, and SCOPUS. Randomised controlled trials (RCTs) and quasi-experimental studies were included for the primary outcomes (measures of changes in consumers’ purchasing and consuming behaviour). A frequentist NMA method was applied to pool the results. A total of 156 studies (including 101 RCTs and 55 non-RCTs) nested in 138 articles were incorporated into the systematic review, of which 134 studies in 120 articles were eligible for meta-analysis. We found that the traffic light labelling system (TLS), nutrient warning (NW), and health warning (HW) were associated with an increased probability of selecting more healthful products (odds ratios [ORs] and 95% confidence intervals [CIs]: TLS, 1.5 [1.2, 1.87]; NW, 3.61 [2.82, 4.63]; HW, 1.65 [1.32, 2.06]). Nutri-Score (NS) and warning labels appeared effective in reducing consumers’ probability of selecting less healthful products (NS, 0.66 [0.53, 0.82]; NW,0.65 [0.54, 0.77]; HW,0.64 [0.53, 0.76]). NS and NW were associated with an increased overall healthfulness (healthfulness ratings of products purchased using models such as FSAm-NPS/HCSP) by 7.9% and 26%, respectively. TLS, NS, and NW were associated with a reduced energy (total energy: TLS, −6.5%; NS, −6%; NW, −12.9%; energy per 100 g/ml: TLS, −3%; NS, −3.5%; NW, −3.8%), sodium (total sodium/salt: TLS, −6.4%; sodium/salt per 100 g/ml: NS: −7.8%), fat (total fat: NS, −15.7%; fat per 100 g/ml: TLS: −2.6%; NS: −3.2%), and total saturated fat (TLS, −12.9%; NS: −17.1%; NW: −16.3%) content of purchases. The impact of TLS, NS, and NW on purchasing behaviour could be explained by improved understanding of the nutrition information, which further elicits negative perception towards unhealthful products or positive attitudes towards healthful foods. Comparisons across label types suggested that colour-coded labels performed better in nudging consumers towards the purchase of more healthful products (NS versus NW: 1.51 [1.08, 2.11]), while warning labels have the advantage in discouraging unhealthful purchasing behaviour (NW versus TLS: 0.81 [0.67, 0.98]; HW versus TLS: 0.8 [0.63, 1]). Study limitations included high heterogeneity and inconsistency in the comparisons across different label types, limited number of real-world studies (95% were laboratory studies), and lack of long-term impact assessments.ConclusionsOur systematic review provided comprehensive evidence for the impact of colour-coded labels and warnings in nudging consumers’ purchasing behaviour towards more healthful products and the underlying psychological mechanism of behavioural change. Each type of label had different attributes, which should be taken into consideration when making front-of-package nutrition labelling (FOPL) policies according to local contexts. Our study supported mandatory front-of-pack labelling policies in directing consumers’ choice and encouraging the food industry to reformulate their products.Protocol registryPROSPERO (CRD42020161877).

Jing Song and co-workers report a systematic review and network meta-analysis assessing evidence on food labeling and purchasing decisions.     

Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomised trials

BackgroundThe risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject.Methods and findingsWe searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available.From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] −57/10,000 [95% CI −106/10,000 to −8/10,000], I² 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267).Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD −31/10,000, [95% CI −56/10,000 to −5/10,000], I² 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD −97/10,000 [95% CI −169/10,000 to −26/10,000], I² 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results.Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD −127/10,000, [95% CI −204/10,000 to −50/10,000], I² 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI −29/10,000 to 84/10,000], I² 55%).A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited.ConclusionsIn this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks.Study Registration: PROSPERO CRD42020163174

Mårten Alkmark and co-workers report on a meta-analysis of randomized trials of labour induction at 41 weeks'' gestation as compared with expectant management until 42 weeks.     

Postpartum depressive symptoms following implementation of the 10 steps to successful breastfeeding program in Kinshasa,Democratic Republic of Congo: A cohort study

BackgroundSocial support and relevant skills training can reduce the risk of postpartum depression (PPD) by reducing the impact of stressors. The 10-step program to encourage exclusive breastfeeding that forms the basis of the Baby-Friendly Hospital Initiative (BFHI) provides both, suggesting it may lessen depressive symptoms directly or by reducing difficulties associated with infant feeding. Our objective was to quantify the association of implementing Steps 1–9 or Steps 1–10 on postpartum depressive symptoms and test whether this association was mediated by breastfeeding difficulties.Methods and findingsWe used data from a breastfeeding promotion trial of all women who gave birth to a healthy singleton between May 24 and August 25, 2012 in 1 of the 6 facilities comparing different BFHI implementations (Steps 1–9, Steps 1–10) to the standard of care (SOC) randomized by facility in Kinshasa, Democratic Republic of Congo. Depressive symptoms, a non-registered trial outcome, was assessed at 14 weeks via the Edinburgh Postnatal Depression Scale (EPDS). Inverse probability weighting (IPW) was used to estimate the association of BFHI implementations on depressive symptoms and the controlled direct association through breastfeeding difficulties at 10 weeks postpartum.A total of 903 mother–infant pairs were included in the analysis. Most women enrolled had previously given birth (76%) and exclusively breastfed at 10 weeks (55%). The median age was 27 (interquartile range (IQR): 23, 32 years). The proportion of women reporting breastfeeding difficulties at week 10 was higher in both Steps 1–9 (75%) and Steps 1–10 (91%) relative to the SOC (67%). However, the number of reported difficulties was similar between Steps 1–9 (median: 2; IQR: 0, 3) and SOC (2; IQR: 0, 3), with slightly more in Steps 1–10 (2; IQR: 1, 3). The prevalence of symptoms consistent with probable depression (EPDS score >13) was 18% for SOC, 11% for Steps 1–9 (prevalence difference [PD] = −0.08; 95% confidence interval (CI): −0.14 to −0.01, p = 0.019), and 8% for Steps 1–10 (PD = −0.11, −0.16 to −0.05; p < 0.001). We found mediation by breastfeeding difficulties. In the presence of any difficulties, the PD was reduced for both Steps 1–9 (−0.15; 95% confidence level (CL): −0.25, −0.06; p < 0.01) and Steps 1–10 (−0.16; 95% CL: −0.25, −0.06; p < 0.01). If no breastfeeding difficulties occurred in the population, there was no difference in the prevalence of probable depression for Steps 1–9 (0.21; 95% CL: −0.24, 0.66; p = 0.365) and Steps 1–10 (−0.03; 95% CL: −0.19, 0.13; p = 0.735). However, a limitation of the study is that the results are based on 2 hospitals randomized to each group.ConclusionsIn conclusion, in this cohort, the implementation of the BFHI steps was associated with a reduction in depressive symptoms in the groups implementing BFHI Steps 1–9 or 1–10 relative to the SOC, with the implementation of Steps 1–10 associated with the largest decrease. Specifically, the reduction in depressive symptoms was observed for women reporting breastfeeding difficulties. PPD has a negative impact on the mother, her partner, and the baby, with long-lasting consequences. This additional benefit of BFHI steps suggests that renewed effort to scale its implementation globally may be beneficial to mitigate the negative impacts of PPD on the mother, her partner, and the baby.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01428232","term_id":"NCT01428232"}}NCT01428232

In a cohort study, Robert Agler and colleagues investigate the associations between postnatal depression symptoms and implementation of a Baby-Friendly Hospital Initiative in Kinshasa, Democratic Republic of Congo.     

Effects of Exercise Modalities on Arterial Stiffness and Wave Reflection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Objectives

Physical activity is associated with lower cardiovascular and all-cause mortality. However, the effects of different exercise modalities on arterial stiffness are currently unclear. Our objectives were to investigate the effects of exercise modalities (aerobic, resistance or combined) on pulse wave velocity (PWV) and augmentation index (AIx), and to determine whether the effects on these indices differed according to the participants'' or exercise characteristics.

Methods

We searched the Medline, Embase and Cochrane Library databases from inception until April 2014 for randomized controlled trials lasting ≥4 weeks investigating the effects of exercise modalities on PWV and AIx in adults aged ≥18 years.

Results

Forty-two studies (1627 participants) were included in this analysis. Aerobic exercise improved both PWV (WMD: −0.63 m/s, 95% CI: −0.90, −0.35) and AIx (WMD:−2.63%, 95% CI: −5.25 to −0.02) significantly. Aerobic exercise training showed significantly greater reduction in brachial-ankle (WMD: −1.01 m/s, 95% CI: −1.57, −0.44) than in carotid-femoral (WMD: -0.39 m/s, 95% CI: −0.52, −0.27) PWV. Higher aerobic exercise intensity was associated with larger reductions in AIx (β: −1.55%, CI −3.09, 0.0001). In addition, aerobic exercise had a significantly larger effect in reducing PWV (WMD:−1.0 m/s, 95% CI: −1.43, −0.57) in participants with stiffer arteries (PWV ≥8 m/s). Resistance exercise had no effect on PWV and AIx. There was no significant effect of combined exercise on PWV and AIx.

Conclusions

We conclude that aerobic exercise improved arterial stiffness significantly and that the effect was enhanced with higher aerobic exercise intensity and in participants with greater arterial stiffness at baseline.

Trial Registration PROSPERO

Database registration: CRD42014009744,.     

Parenting interventions to promote early child development in the first three years of life: A global systematic review and meta-analysis

BackgroundParents are the primary caregivers of young children. Responsive parent–child relationships and parental support for learning during the earliest years of life are crucial for promoting early child development (ECD). We conducted a global systematic review and meta-analysis to evaluate the effectiveness of parenting interventions on ECD and parenting outcomes.Methods and findingsWe searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Global Health Library for peer-reviewed, published articles from database inception until November 15, 2020. We included randomized controlled trials (RCTs) of parenting interventions delivered during the first 3 years of life that evaluated at least 1 ECD outcome. At least 2 reviewers independently screened, extracted data, and assessed study quality from eligible studies. ECD outcomes included cognitive, language, motor, and socioemotional development, behavior problems, and attachment. Parenting outcomes included parenting knowledge, parenting practices, parent–child interactions, and parental depressive symptoms. We calculated intervention effect sizes as the standardized mean difference (SMD) and estimated pooled effect sizes for each outcome separately using robust variance estimation meta-analytic approaches. We used random-effects meta-regression models to assess potential effect modification by country-income level, child age, intervention content, duration, delivery, setting, and study quality. This review was registered with PROSPERO (CRD42018092458 and CRD42018092461). Of the 11,920 articles identified, we included 111 articles representing 102 unique RCTs. Pooled effect sizes indicated positive benefits of parenting interventions on child cognitive development (SMD = 0.32, 95% CI [confidence interval]: 0.23, 0.40, P < 0.001), language development (SMD = 0.28, 95% CI: 0.18 to 0.37, P < 0.001), motor development (SMD = 0.24, 95% CI: 0.15 to 0.32, P < 0.001), socioemotional development (SMD = 0.19, 95% CI: 0.10 to 0.28, P < 0.001), and attachment (SMD = 0.29, 95% CI: 0.18 to 0.40, P < 0.001) and reductions in behavior problems (SMD = −0.13, 95% CI: −0.18 to −0.08, P < 0.001). Positive benefits were also found on parenting knowledge (SMD = 0.56, 95% CI: 0.33 to 0.79, P < 0.001), parenting practices (SMD = 0.33, 95% CI: 0.22 to 0.44, P < 0.001), and parent–child interactions (SMD = 0.39, 95% CI: 0.24 to 0.53, P < 0.001). However, there was no significant reduction in parental depressive symptoms (SMD = −0.07, 95% CI: −0.16 to 0.02, P = 0.08). Subgroup analyses revealed significantly greater effects on child cognitive, language, and motor development, and parenting practices in low- and middle-income countries compared to high-income countries; and significantly greater effects on child cognitive development, parenting knowledge, parenting practices, and parent–child interactions for programs that focused on responsive caregiving compared to those that did not. On the other hand, there was no clear evidence of effect modification by child age, intervention duration, delivery, setting, or study risk of bias. Study limitations include considerable unexplained heterogeneity, inadequate reporting of intervention content and implementation, and varying quality of evidence in terms of the conduct of trials and robustness of outcome measures used across studies.ConclusionsParenting interventions for children during the first 3 years of life are effective for improving ECD outcomes and enhancing parenting outcomes across low-, middle-, and high-income countries. Increasing implementation of effective and high-quality parenting interventions is needed globally and at scale in order to support parents and enable young children to achieve their full developmental potential.

In a systematic review and meta-analysis, Joshua Jeong and colleagues study the effectiveness of parenting interventions in children 3 years and younger in promoting early childhood development and parenting outcomes.     

Efficacy of live attenuated and inactivated influenza vaccines among children in rural India: A 2-year,randomized, triple-blind,placebo-controlled trial

BackgroundInfluenza is a cause of febrile acute respiratory infection (FARI) in India; however, few influenza vaccine trials have been conducted in India. We assessed absolute and relative efficacy of live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) among children aged 2 to 10 years in rural India through a randomized, triple-blind, placebo-controlled trial conducted over 2 years.Methods and findingsIn June 2015, children were randomly allocated to LAIV, IIV, intranasal placebo, or inactivated polio vaccine (IPV) in a 2:2:1:1 ratio. In June 2016, vaccination was repeated per original allocation. Overall, 3,041 children received LAIV (n = 1,015), IIV (n = 1,010), nasal placebo (n = 507), or IPV (n = 509). Mean age of children was 6.5 years with 20% aged 9 to 10 years.Through weekly home visits, nasal and throat swabs were collected from children with FARI and tested for influenza virus by polymerase chain reaction. The primary outcome was laboratory-confirmed influenza-associated FARI; vaccine efficacy (VE) was calculated using modified intention-to-treat (mITT) analysis by Cox proportional hazards model (PH) for each year.In Year 1, VE was 40.0% (95% confidence interval (CI) 25.2 to 51.9) for LAIV and 59.0% (95% CI 47.8 to 67.9) for IIV compared with controls; relative efficacy of LAIV compared with IIV was −46.2% (95% CI −88.9 to −13.1). In Year 2, VE was 51.9% (95% CI 42.0 to 60.1) for LAIV and 49.9% (95% CI 39.2 to 58.7) for IIV; relative efficacy of LAIV compared with IIV was 4.2% (95% CI −19.9 to 23.5). No serious adverse vaccine-attributable events were reported. Study limitations include differing dosage requirements for children between nasal and injectable vaccines (single dose of LAIV versus 2 doses of IIV) in Year 1 and the fact that immunogenicity studies were not conducted.ConclusionsIn this study, we found that LAIV and IIV vaccines were safe and moderately efficacious against influenza virus infection among Indian children.Trial registrationClinical Trials Registry of India CTRI/2015/06/005902.

Anand Krishnan and co-workers study the efficacy and safety of influenza vaccines for children in India.     

Interpersonal psychotherapy delivered by nonspecialists for depression and posttraumatic stress disorder among Kenyan HIV–positive women affected by gender-based violence: Randomized controlled trial

BackgroundHIV–positive women suffer a high burden of mental disorders due in part to gender-based violence (GBV). Comorbid depression and posttraumatic stress disorder (PTSD) are typical psychiatric consequences of GBV. Despite attention to the HIV-GBV syndemic, few HIV clinics offer formal mental healthcare. This problem is acute in sub-Saharan Africa, where the world’s majority of HIV–positive women live and prevalence of GBV is high.Methods and findingsWe conducted a randomized controlled trial at an HIV clinic in Kisumu, Kenya. GBV-affected HIV–positive women with both major depressive disorder (MDD) and PTSD were randomized to 12 sessions of interpersonal psychotherapy (IPT) plus treatment as usual (TAU) or Wait List+TAU. Nonspecialists were trained to deliver IPT inside the clinic. After 3 months, participants were reassessed, and those assigned to Wait List+TAU were given IPT. The primary outcomes were diagnosis of MDD and PTSD (Mini International Neuropsychiatric Interview) at 3 months. Secondary outcomes included symptom measures of depression and PTSD, intimate partner violence (IPV), and disability. A total of 256 participants enrolled between May 2015 and July 2016. At baseline, the mean age of the women in this study was 37 years; 61% reported physical IPV in the past week; 91% reported 2 or more lifetime traumatic events and monthly income was 18USD. Multilevel mixed-effects logistic regression showed that participants randomized to IPT+TAU had lower odds of MDD (odds ratio [OR] 0.26, 95% CI [0.11 to 0.60], p = 0.002) and lower odds of PTSD (OR 0.35, [0.14 to 0.86], p = 0.02) than controls. IPT+TAU participants had lower odds of MDD-PTSD comorbidity than controls (OR 0.36, 95% CI [0.15 to 0.90], p = 0.03). Linear mixed models were used to assess secondary outcomes: IPT+TAU participants had reduced disability (−6.9 [−12.2, −1.5], p = 0.01), and nonsignificantly reduced work absenteeism (−3.35 [−6.83, 0.14], p = 0.06); partnered IPT+TAU participants had a reduction of IPV (−2.79 [−5.42, −0.16], p = 0.04). Gains were maintained across 6-month follow-up. Treatment group differences were observed only at month 3, the time point at which the groups differed in IPT status (before cross over). Study limitations included 35% attrition inclusive of follow-up assessments, generalizability to populations not in HIV care, and data not collected on TAU resources accessed.ConclusionsIPT for MDD and PTSD delivered by nonspecialists in the context of HIV care yielded significant improvements in HIV–positive women’s mental health, functioning, and GBV (IPV) exposure, compared to controls.Trial registrationClinical Trials Identifier {"type":"clinical-trial","attrs":{"text":"NCT02320799","term_id":"NCT02320799"}}NCT02320799.

Susan Meffert and co-workers evaluate interpersonal psychotherapy for treatment of psychiatric disorders in women with HIV infection in Kenya.     

Impact of decreasing the proportion of higher energy foods and reducing portion sizes on food purchased in worksite cafeterias: A stepped-wedge randomised controlled trial

BackgroundOverconsumption of energy from food is a major contributor to the high rates of overweight and obesity in many populations. There is growing evidence that interventions that target the food environment may be effective at reducing energy intake. The current study aimed to estimate the effect of decreasing the proportion of higher energy (kcal) foods, with and without reducing portion size, on energy purchased in worksite cafeterias.Methods and findingsThis stepped-wedge randomised controlled trial (RCT) evaluated 2 interventions: (i) availability: replacing higher energy products with lower energy products; and (ii) size: reducing the portion size of higher energy products. A total of 19 cafeterias were randomised to the order in which they introduced the 2 interventions. Availability was implemented first and maintained. Size was added to the availability intervention. Intervention categories included main meals, sides, cold drinks, snacks, and desserts. The study setting was worksite cafeterias located in distribution centres for a major United Kingdom supermarket and lasted for 25 weeks (May to November 2019). These cafeterias were used by 20,327 employees, mainly (96%) in manual occupations. The primary outcome was total energy (kcal) purchased from intervention categories per day. The secondary outcomes were energy (kcal) purchased from nonintervention categories per day, total energy purchased per day, and revenue. Regression models showed an overall reduction in energy purchased from intervention categories of −4.8% (95% CI −7.0% to −2.7%), p < 0.001 during the availability intervention period and a reduction of −11.5% (95% CI −13.7% to −9.3%), p < 0.001 during the availability plus size intervention period, relative to the baseline. There was a reduction in energy purchased of −6.6% (95% CI −7.9% to −5.4%), p < 0.001 during the availability plus size period, relative to availability alone. Study limitations include using energy purchased as the primary outcome (and not energy consumed) and the availability only of transaction-level sales data per site (and not individual-level data).ConclusionsDecreasing the proportion of higher energy foods in cafeterias reduced the energy purchased. Decreasing portion sizes reduced this further. These interventions, particularly in combination, may be effective as part of broader strategies to reduce overconsumption of energy from food in out-of-home settings.Trial registrationISRCTN registry ISRCTN87225572.

James Reynolds and co-workers investigate the provision of smaller food portions and substitution of less calorific foods in workplace cafeterias.     

Ddhd1 knockout mouse as a model of locomotive and physiological abnormality in familial spastic paraplegia

We have previously reported a novel homozygous 4-bp deletion in DDHD1 as the responsible variant for spastic paraplegia type 28 (SPG28; OMIM#609340). The variant causes a frameshift, resulting in a functionally null allele in the patient. DDHD1 encodes phospholipase A₁ (PLA₁) catalyzing phosphatidylinositol to lysophosphatidylinositol (LPI). To clarify the pathogenic mechanism of SPG28, we established Ddhd1 knockout mice (Ddhd1[−/−]) carrying a 5-bp deletion in Ddhd1, resulting in a premature termination of translation at a position similar to that of the patient. We observed a significant decrease in foot–base angle (FBA) in aged Ddhd1(−/−) (24 months of age) and a significant decrease in LPI 20:4 (sn-2) in Ddhd1(−/−) cerebra (26 months of age). These changes in FBA were not observed in 14 months of age. We also observed significant changes of expression levels of 22 genes in the Ddhd1(−/−) cerebra (26 months of age). Gene Ontology (GO) terms relating to the nervous system and cell–cell communications were significantly enriched. We conclude that the reduced signaling of LPI 20:4 (sn-2) by PLA₁ dysfunction is responsible for the locomotive abnormality in SPG28, further suggesting that the reduction of downstream signaling such as GPR55 which is agonized by LPI is involved in the pathogenesis of SPG28.     

Effectiveness of Group Problem Management Plus,a brief psychological intervention for adults affected by humanitarian disasters in Nepal: A cluster randomized controlled trial

BackgroundGlobally, 235 million people are impacted by humanitarian emergencies worldwide, presenting increased risk of experiencing a mental disorder. Our objective was to test the effectiveness of a brief group psychological treatment delivered by trained facilitators without prior professional mental health training in a disaster-prone setting.Methods and findingsWe conducted a cluster randomized controlled trial (cRCT) from November 25, 2018 through September 30, 2019. Participants in both arms were assessed at baseline, midline (7 weeks post-baseline, which was approximately 1 week after treatment in the experimental arm), and endline (20 weeks post-baseline, which was approximately 3 months posttreatment). The intervention was Group Problem Management Plus (PM+), a psychological treatment of 5 weekly sessions, which was compared with enhanced usual care (EUC) consisting of a family psychoeducation meeting with a referral option to primary care providers trained in mental healthcare. The setting was 72 wards (geographic unit of clustering) in eastern Nepal, with 1 PM+ group per ward in the treatment arm. Wards were eligible if they were in disaster-prone regions and residents spoke Nepali. Wards were assigned to study arms based on covariate constrained randomization. Eligible participants were adult women and men 18 years of age and older who met screening criteria for psychological distress and functional impairment. Outcomes were measured at the participant level, with assessors blinded to group assignment. The primary outcome was psychological distress assessed with the General Health Questionnaire (GHQ-12). Secondary outcomes included depression symptoms, posttraumatic stress disorder (PTSD) symptoms, “heart–mind” problems, social support, somatic symptoms, and functional impairment. The hypothesized mediator was skill use aligned with the treatment’s mechanisms of action. A total of 324 participants were enrolled in the control arm (36 wards) and 319 in the Group PM+ arm (36 wards). The overall sample (N = 611) had a median age of 45 years (range 18–91 years), 82% of participants were female, 50% had recently experienced a natural disaster, and 31% had a chronic physical illness. Endline assessments were completed by 302 participants in the control arm (36 wards) and 303 participants in the Group PM+ arm (36 wards). At the midline assessment (immediately after Group PM+ in the experimental arm), mean GHQ-12 total score was 2.7 units lower in Group PM+ compared to control (95% CI: 1.7, 3.7, p < 0.001), with standardized mean difference (SMD) of −0.4 (95% CI: −0.5, −0.2). At 3 months posttreatment (primary endpoint), mean GHQ-12 total score was 1.4 units lower in Group PM+ compared to control (95% CI: 0.3, 2.5, p = 0.014), with SMD of −0.2 (95% CI: −0.4, 0.0). Among the secondary outcomes, Group PM+ was associated with endline with a larger proportion attaining more than 50% reduction in depression symptoms (29.9% of Group PM+ arm versus 17.3% of control arm, risk ratio = 1.7, 95% CI: 1.2, 2.4, p = 0.002). Fewer participants in the Group PM+ arm continued to have “heart–mind” problems at endline (58.8%) compared to the control arm (69.4%), risk ratio = 0.8 (95% CI, 0.7, 1.0, p = 0.042). Group PM+ was not associated with lower PTSD symptoms or functional impairment. Use of psychosocial skills at midline was estimated to explain 31% of the PM+ effect on endline GHQ-12 scores. Adverse events in the control arm included 1 suicide death and 1 reportable incidence of domestic violence; in the Group PM+ arm, there was 1 death due to physical illness. Study limitations include lack of power to evaluate gender-specific effects, lack of long-term outcomes (e.g., 12 months posttreatment), and lack of cost-effectiveness information.ConclusionsIn this study, we found that a 5-session group psychological treatment delivered by nonspecialists modestly reduced psychological distress and depression symptoms in a setting prone to humanitarian emergencies. Benefits were partly explained by the degree of psychosocial skill use in daily life. To improve the treatment benefit, future implementation should focus on approaches to enhance skill use by PM+ participants.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03747055","term_id":"NCT03747055"}}NCT03747055.

Mark Jordans and co-workers evaluate a group therapy intervention in adults affected by psychological distress in Nepal.     

A Meta-Analysis of Core Stability Exercise versus General Exercise for Chronic Low Back Pain

Objective

To review the effects of core stability exercise or general exercise for patients with chronic low back pain (LBP).

Summary of Background Data

Exercise therapy appears to be effective at decreasing pain and improving function for patients with chronic LBP in practice guidelines. Core stability exercise is becoming increasingly popular for LBP. However, it is currently unknown whether core stability exercise produces more beneficial effects than general exercise in patients with chronic LBP.

Methods

Published articles from 1970 to October 2011 were identified using electronic searches. For this meta-analysis, two reviewers independently selected relevant randomized controlled trials (RCTs) investigating core stability exercise versus general exercise for the treatment of patients with chronic LBP. Data were extracted independently by the same two individuals who selected the studies.

Results

From the 28 potentially relevant trials, a total of 5 trials involving 414 participants were included in the current analysis. The pooling revealed that core stability exercise was better than general exercise for reducing pain [mean difference (−1.29); 95% confidence interval (−2.47, −0.11); P = 0.003] and disability [mean difference (−7.14); 95% confidence interval (−11.64, −2.65); P = 0.002] at the time of the short-term follow-up. However, no significant differences were observed between core stability exercise and general exercise in reducing pain at 6 months [mean difference (−0.50); 95% confidence interval (−1.36, 0.36); P = 0.26] and 12 months [mean difference (−0.32); 95% confidence interval (−0.87, 0.23); P = 0.25].

Conclusions

Compared to general exercise, core stability exercise is more effective in decreasing pain and may improve physical function in patients with chronic LBP in the short term. However, no significant long-term differences in pain severity were observed between patients who engaged in core stability exercise versus those who engaged in general exercise.

Systematic Review Registration

http://www.crd.york.ac.uk/PROSPERO PROSPERO registration number: CRD42011001717.     

Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis

BackgroundNumerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.Methods and findingsWe carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), itolizumab (OR 0.10, 95% CI 0.01 to 0.92, p = 0.042), sofosbuvir plus daclatasvir (OR 0.26, 95% CI 0.07 to 0.88, p = 0.030), anakinra (OR 0.30, 95% CI 0.11 to 0.82, p = 0.019), tocilizumab (OR 0.43, 95% CI 0.30 to 0.60, p < 0.001), and convalescent plasma (OR 0.48, 95% CI 0.24 to 0.96, p = 0.038) were associated with reduced mortality rate in non-ICU setting, while high-dose intravenous immunoglobulin (IVIG) (OR 0.13, 95% CI 0.03 to 0.49, p = 0.003), ivermectin (OR 0.15, 95% CI 0.04 to 0.57, p = 0.005), and tocilizumab (OR 0.62, 95% CI 0.42 to 0.90, p = 0.012) were associated with reduced mortality rate in critically ill patients. Convalescent plasma was the only treatment option that was associated with improved viral clearance rate at 2 weeks compared to standard care (OR 11.39, 95% CI 3.91 to 33.18, p < 0.001). The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal cardiac complications in cardiac-impaired populations (OR 2.23, 95% CI 1.24 to 4.00, p = 0.007). No drug was significantly associated with increased noncardiac serious adverse events compared to standard care. The quality of evidence of collective outcomes were estimated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The major limitation of the present study is the overall low level of evidence that reduces the certainty of recommendations. Besides, the risk of bias (RoB) measured by RoB2 and ROBINS-I framework for individual studies was generally low to moderate. The outcomes deducted from observational studies could not infer causality and can only imply associations. The study protocol is publicly available on PROSPERO (CRD42020186527).ConclusionsIn this NMA, we found that anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and IVIG), convalescent plasma, and remdesivir were associated with improved outcomes of hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin, especially in the vulnerable population. Only 29% of current evidence on pharmacological management of COVID-19 is supported by moderate or high certainty and can be translated to practice and policy; the remaining 71% are of low or very low certainty and warrant further studies to establish firm conclusions.

In this meta-analysis, Min Seo Kim and colleagues synthesise results from randomized trials and observational studies on COVID-19 treatments.     

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial

BackgroundAdherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted.Methods and findingsWe randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI −0.25 to 0.79, p = 0.302), systolic blood pressure (−3.9; 95% CI −9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI −0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports.ConclusionsIn this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02744963","term_id":"NCT02744963"}}NCT02744963.     

Effectiveness of a primary care-based integrated mobile health intervention for stroke management in rural China (SINEMA): A cluster-randomized controlled trial

BackgroundManaging noncommunicable diseases through primary healthcare has been identified as the key strategy to achieve universal health coverage but is challenging in most low- and middle-income countries. Stroke is the leading cause of death and disability in rural China. This study aims to determine whether a primary care-based integrated mobile health intervention (SINEMA intervention) could improve stroke management in rural China.Methods and findingsBased on extensive barrier analyses, contextual research, and feasibility studies, we conducted a community-based, two-arm cluster-randomized controlled trial with blinded outcome assessment in Hebei Province, rural Northern China including 1,299 stroke patients (mean age: 65.7 [SD:8.2], 42.6% females, 71.2% received education below primary school) recruited from 50 villages between June 23 and July 21, 2017. Villages were randomly assigned (1:1) to either the intervention or control arm (usual care). In the intervention arm, village doctors who were government-sponsored primary healthcare providers received training, conducted monthly follow-up visits supported by an Android-based mobile application, and received performance-based payments. Participants received monthly doctor visits and automatically dispatched daily voice messages. The primary outcome was the 12-month change in systolic blood pressure (BP). Secondary outcomes were predefined, including diastolic BP, health-related quality of life, physical activity level, self-reported medication adherence (antiplatelet, statin, and antihypertensive), and performance in “timed up and go” test. Analyses were conducted in the intention-to-treat framework at the individual level with clusters and stratified design accounted for by following the prepublished statistical analysis plan. All villages completed the 12-month follow-up, and 611 (intervention) and 615 (control) patients were successfully followed (3.4% lost to follow-up among survivors). The program was implemented with high fidelity, and the annual program delivery cost per capita was US$24.3. There was a significant reduction in systolic BP in the intervention as compared with the control group with an adjusted mean difference: −2.8 mm Hg (95% CI −4.8, −0.9; p = 0.005). The intervention was significantly associated with improvements in 6 out of 7 secondary outcomes in diastolic BP reduction (p < 0.001), health-related quality of life (p = 0.008), physical activity level (p < 0.001), adherence in statin (p = 0.003) and antihypertensive medicines (p = 0.039), and performance in “timed up and go” test (p = 0.022). We observed reductions in all exploratory outcomes, including stroke recurrence (4.4% versus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference [RD] = 4.9 percentage points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32, 0.62; RD = 4.9 pp), disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp), and death (1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp). Limitations include the relatively short study duration of only 1 year and the generalizability of our findings beyond the study setting.ConclusionsIn this study, a primary care-based mobile health intervention integrating provider-centered and patient-facing technology was effective in reducing BP and improving stroke secondary prevention in a resource-limited rural setting in China.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03185858","term_id":"NCT03185858"}}NCT03185858.

Lijing Yan and colleagues evaluate a mobile health intervention for secondary stroke prevention in China.     

A randomised controlled feasibility trial of a BabyWASH household playspace: The CAMPI study

BackgroundWater, sanitation and hygiene (WASH) interventions should support infant growth but trial results are inconsistent. Frequently, interventions do not consider behaviours or transmission pathways specific to age. A household playspace (HPS) is one intervention component which may block faecal-oral transmission. This study was a two-armed, parallel-group, randomised, controlled feasibility trial of a HPS in rural Ethiopia. It aimed to recommend proceeding to a definitive trial. Secondary outcomes included effects on infant health, injury prevention and women’s time.MethodsNovember 2019−January 2020 106 households were identified and assessed for eligibility. Recruited households (N = 100) were randomised (blinded prior to the trial start) to intervention or control (both n = 50). Outcomes included recruitment, attrition, adherence, and acceptability. Data were collected at baseline, two and four weeks.FindingsRecruitment met a priori criteria (≥80%). There was no loss to follow-up, and no non-use, meeting adherence criteria (both ≤10%). Further, 48.0% (95% CI 33.7−62.6; n = 24) of households appropriately used and 56.0% (41.3−70.0; n = 28) cleaned the HPS over four weeks, partly meeting adherence criteria (≥50%). For acceptability, 41.0% (31.3−51.3; n = 41) of infants were in the HPS during random visits, failing criteria (≥50%). Further, the proportion of HPS use decreased during some activities, failing criteria (no decrease in use). A modified Barrier Analysis described good acceptability and multiple secondary benefits, including on women’s time burden and infant injury prevention.InterpretationDespite failing some a priori criteria, the trial demonstrated mixed adherence and good acceptability among intervention households. A definitive trial to determine efficacy is warranted if recommended adjustments are made.FundingPeople In Need; Czech Development Agency.Trial registrationRIDIE-ID-5de0b6938afb8.     

Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study

BackgroundPlasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life.Methods and findingsTo identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: {"type":"clinical-trial","attrs":{"text":"NCT02867059","term_id":"NCT02867059"}}NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI −15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI −0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI −15.9% to +25.0%], P. falciparum: +3.2% [CI −3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI −8.7% to +21.1%], P. falciparum: −1.4% [CI −4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity.ConclusionsPET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.

John Woodford and co-authors use positron emission tomography/magnetic resonance imaging (PET/MRI) to describe unique splenic morphology and metabolism in early P. vivax infection.     

Fine Mapping of the Body Fat QTL on Human Chromosome 1q43

IntroductionEvidence for linkage and association of obesity-related quantitative traits to chromosome 1q43 has been reported in the Quebec Family Study (QFS) and in populations of Caribbean Hispanic ancestries yet no specific candidate locus has been replicated to date.MethodsUsing a set of 1,902 single nucleotide polymorphisms (SNPs) genotyped in 525 African American (AA) and 391 European American (EA) women enrolled in the NIEHS uterine fibroid study (NIEHS-UFS), we generated a fine association map for the body mass index (BMI) across a 2.3 megabase-long interval delimited by RGS7 (regulator of G-protein signaling 7) and PLD5 (Phospholipase D, member 5). Multivariable-adjusted linear regression models were fitted to the data to evaluate the association in race-stratified analyses and meta-analysis.ResultsThe strongest associations were observed in a recessive genetic model and peaked in the 3’ end of RGS7 at intronic rs261802 variant in the AA group (p = 1.0 x 10⁻⁴) and in meta-analysis of AA and EA samples (p = 9.0 x 10⁻⁵). In the EA group, moderate associations peaked at rs6429264 (p = 2.0 x 10⁻³) in the 2 Kb upstream sequence of RGS7. In the reference populations for the European ancestry in the 1,000 genomes project, rs6429264 occurs in strong linkage disequilibrium (D’ = 0.94) with rs1341467, the strongest candidate SNP for total body fat in QFS that failed genotyping in the present study. Additionally we report moderate associations at the 3’ end of PLD5 in meta-analysis (3.2 x 10⁻⁴ ≤ p ≤ 5.8 x 10⁻⁴).ConclusionWe report replication data suggesting that RGS7, a gene abundantly expressed in the brain, might be a putative body fat QTL on human chromosome 1q43. Future genetic and functional studies are required to substantiate our observations and to potentially link them to the neurobehavioral phenotypes associated with the RGS7 region.