Marginal structural models for repeated measures where intercept and slope are correlated: An application exploring the benefit of nutritional supplements on weight gain in HIV-infected children initiating antiretroviral therapy

BackgroundThe impact of nutritional supplements on weight gain in HIV-infected children on antiretroviral treatment (ART) remains uncertain. Starting supplements depends upon current weight-for-age or other acute malnutrition indicators, producing time-dependent confounding. However, weight-for-age at ART initiation may affect subsequent weight gain, independent of supplement use. Implications for marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) are unclear.MethodsIn the ARROW trial, non-randomised supplement use and weight-for-age were recorded monthly from ART initiation. The effect of supplements on weight-for-age over the first year was estimated using generalised estimating equation MSMs with IPTW, both with and without interaction terms between baseline weight-for-age and time. Separately, data were simulated assuming no supplement effect, with use depending on current weight-for-age, and weight-for-age trajectory depending on baseline weight-for-age to investigate potential bias associated with different MSM specifications.ResultsIn simulations, despite correctly specifying IPTW, omitting an interaction in the MSM between baseline weight-for-age and time produced increasingly biased estimates as associations between baseline weight-for-age and subsequent weight trajectory increased. Estimates were unbiased when the interaction between baseline weight-for-age and time was included, even if the data were simulated with no such interaction. In ARROW, without an interaction the estimated effect was +0.09 (95%CI +0.02,+0.16) greater weight-for-age gain per month's supplement use; this reduced to +0.03 (-0.04,+0.10) including the interaction.DiscussionThis study highlights a specific situation in which MSM model misspecification can occur and impact the resulting estimate. Since an interaction in the MSM (outcome) model does not bias the estimate of effect if the interaction does not exist, it may be advisable to include such a term when fitting MSMs for repeated measures

Wildfire impact : natural experiment reveals differential short-term changes in soil microbial communities

A wildfire which overran a sensor network site provided an opportunity (a natural experiment) to monitor short-term post-fire impacts (immediate and up to three months post-fire) in remnant eucalypt woodland and managed pasture plots. The magnitude of fire-induced changes in soil properties and soil microbial communities was determined by comparing (1) variation in fire-adapted eucalypt woodland vs. pasture grassland at the burnt site; (2) variation at the burnt woodland-pasture sites with variation at two unburnt woodland-pasture sites in the same locality; and (3) temporal variation pre- and post-fire. In the eucalypt woodland, soil ammonium, pH and ROC content increased post-fire, while in the pasture soil, soil nitrate increased post-fire and became the dominant soluble N pool. However, apart from distinct changes in N pools, the magnitude of change in most soil properties was small when compared to the unburnt sites. At the burnt site, bacterial and fungal community structure showed significant temporal shifts between pre- and post-fire periods which were associated with changes in soil nutrients, especially N pools. In contrast, microbial communities at the unburnt sites showed little temporal change over the same period. Bacterial community composition at the burnt site also changed dramatically post-fire in terms of abundance and diversity, with positive impacts on abundance of phyla such as Actinobacteria, Proteobacteria and Firmicutes. Large and rapid changes in soil bacterial community composition occurred in the fire-adapted woodland plot compared to the pasture soil, which may be a reflection of differences in vegetation composition and fuel loading. Given the rapid yet differential response in contrasting land uses, identification of key soil bacterial groups may be useful in assessing recovery of fire-adapted ecosystems, especially as wildfire frequency is predicted to increase with global climate change

Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature

Defects in cerebrospinal fluid (CSF) flow may contribute to idiopathic scoliosis. However, the mechanisms underlying detection of CSF flow in the central canal of the spinal cord are unknown. Here we demonstrate that CSF flows bidirectionally along the antero-posterior axis in the central canal of zebrafish embryos. In the cfap298tm304 mutant, reduction of cilia motility slows transport posteriorly down the central canal and abolishes spontaneous activity of CSF-contacting neurons (CSF-cNs). Loss of the sensory Pkd2l1 channel nearly abolishes CSF-cN calcium activity and single channel opening. Recording from isolated CSFcNs in vitro, we show that CSF-cNs are mechanosensory and require Pkd2l1 to respond to pressure. Additionally, adult pkd2l1 mutant zebrafish develop an exaggerated spine curvature, reminiscent of kyphosis in humans. These results indicate that CSF-cNs are mechanosensory cells whose Pkd2l1-driven spontaneous activity reflects CSF flow in vivo. Furthermore, Pkd2l1 in CSF-cNs contributes to maintenance of natural curvature of the spine

The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials

Objectives To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect.Design Systematic review and meta-analysis.Data sources Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science.Study selection Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention.Results Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. in random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions.Conclusion Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. the antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.Vanier Canada Graduate ScholarshipMcGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, CanadaZvitambo Inst Maternal Child Hlth Res, Harare, ZimbabweQueen Mary Univ London, Blizard Inst, Ctr Paediat, London, EnglandMRC, Clin Trials Unit, London, EnglandJohns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USACornell Univ, Div Nutr Sci, Program Int Nutr, Ithaca, NY 14853 USAWashington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USAUniv Malawi, Blantyre, MalawiUniv Cambridge, Dept Archaeol & Anthropol, Div Biol Anthropol, Cambridge CB2 1TN, EnglandUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilUniv British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, CanadaUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials

Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral Hhmorrhage

Objective: To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. Methods: We performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). Conclusions: We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up

SPACA3gene variants in a New Zealand cohort of infertile and fertile couples

SPRASA (also referred to as SLLP1) is a protein identified in the acrosome of human sperm and encoded by the gene SPACA3. SPRASA is associated with sperm-oocyte recognition and binding, and may play a role in fertility. In order to determine whether variants in the SPACA3 gene are associated with human infertility, we undertook a genetic analysis of 102 infertile and 104 fertile couples. Three gene variants were identified using PCR-based DNA sequencing; 1) an insertion of TGC within a quadruple tri-nucleotide (TGC) repeat region in the 5’ untranslated region (UTR) (g.–22TGC(4_5), 2) a guanine to adenosine transition at position 239 (c.239G> A) resulting in a non-synonymous amino acid substitution from cysteine to tyrosine (p.C80Y) at position 80 in the putative transmembrane region, and 3) a novel nucleotide variant (c.691G> C) located in the 3’UTR. A functional effect of the g.–22TGC (4_5) was confirmed by a luciferase expression assay, while the effects of the variants c.239G> A and c.691G> C were predicted using in silico analysis. Although the frequencies of these variants were not significantly different between the infertile and fertile populations, we present evidence that the variants could affect the expression levels or function of SPRASA, thereby affecting a couple's fertility. Larger populations, especially individuals/couples with unexplained infertility, need to be screened for these variants to validate a relationship with fertility

Why small-quantity lipid-based nutrient supplements should be integrated into comprehensive strategies to prevent child undernutrition in nutritionally vulnerable populations : response to Gupta et al.’s commentary

We write in response to the commentary by Gupta et al. (2023) on small-quantity lipid-based nutrient supplements (SQ-LNS) for infants and young children 6 to 24 months of age, which was prompted by the recent brief guidance note from UNICEF (2023) explaining when, why and how SQ-LNS are being prioritized as part of their package of preventive actions to combat early childhood malnutrition. The UNICEF document was disseminated shortly after publication of a correspondence in Nature Food (Aguayo et al. 2023), authored by nutrition leaders from several organizations, that summarized the evidence on the benefits of SQ-LNS and called for this intervention to be scaled up and integrated into programs for populations in which child undernutrition is prevalent and dietary quality is very poor. We agree with Gupta et al. that child malnutrition is the result of many factors and there is no single “quick fix” or “magic bullet”. In fact, the above-cited documents state clearly and frequently that provision of SQ-LNS is not a stand-alone intervention and must be integrated into comprehensive strategies to improve infant and young child feeding (IYCF), including the promotion of dietary diversity, as well as other actions needed to prevent malnutrition. SQ-LNS are intended for vulnerable populations who lack access to an affordable, nutritionally adequate complementary feeding diet and have high rates of stunting, wasting and mortality. In such populations, we agree with Gupta et al. that IYCF messages alone are not enough. This is precisely why SQ-LNS were originally developed

Ancient DNA and deep population structure in sub-Saharan African foragers

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa(1-4). Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations(3,5). Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch. DNA analysis of 6 individuals from eastern and south-central Africa spanning the past approximately 18,000 years, and of 28 previously published ancient individuals, provides genetic evidence supporting hypotheses of increasing regionalization at the end of the Pleistocene.info:eu-repo/semantics/publishedVersio