Environmental enteric dysfunction (EED) is an acquired enteropathy of the small intestine, characterized by enteric inflammation, villus blunting and decreased crypt-to-villus ratio. EED has been ...associated with poor outcomes, including chronic malnutrition (stunting), wasting and reduced vaccine efficacy among children living in low-resource settings. As a result, EED may be a valuable interventional target for programs aiming to reduce childhood morbidity in low and middle-income countries.
Several highly plausible mechanisms link the proposed pathophysiology underlying EED to adverse outcomes, but causal attribution of these pathways has proved challenging. We provide an overview of recent studies evaluating the causes and consequences of EED. These include studies of the role of subclinical enteric infection as a primary cause of EED, and efforts to understand how EED-associated systemic inflammation and malabsorption may result in long-term morbidity. Finally, we outline recently completed and upcoming clinical trials that test novel interventions to prevent or treat this highly prevalent condition.
Significant strides have been made in linking environmental exposure to enteric pathogens and toxins with EED, and in understanding the multifactorial mechanisms underlying this complex condition. Further insights may come from several ongoing and upcoming interventional studies trialing a variety of novel management strategies.
Future weak lensing surveys potentially hold the highest statistical power for constraining cosmological parameters compared to other cosmological probes. The statistical power of a weak lensing ...survey is determined by the sky coverage, the inverse of the noise in shear measurements and the galaxy number density. The combination of the latter two factors is often expressed in terms of n
eff - the 'effective number density of galaxies used for weak lensing measurements'. In this work, we estimate n
eff for the Large Synoptic Survey Telescope (LSST) project, the most powerful ground-based lensing survey planned for the next two decades. We investigate how the following factors affect the resulting n
eff of the survey with detailed simulations: (1) survey time, (2) shear measurement algorithm, (3) algorithm for combining multiple exposures, (4) inclusion of data from multiple filter bands, (5) redshift distribution of the galaxies and (6) masking and blending. For the first time, we quantify in a general weak lensing analysis pipeline the sensitivity of n
eff to the above factors.
We find that with current weak lensing algorithms, expected distributions of observing parameters, and all lensing data (r and i band, covering 18 000 degree2 of sky) for LSST, n
eff 37 arcmin−2 before considering blending and masking, n
eff 31 arcmin−2 when rejecting seriously blended galaxies and n
eff 26 arcmin−2 when considering an additional 15 per cent loss of galaxies due to masking. With future improvements in weak lensing algorithms, these values could be expected to increase by up to 20 per cent. Throughout the paper, we also stress the ways in which n
eff depends on our ability to understand and control systematic effects in the measurements.
To understand how the World Health Organization's (WHO's) guidelines on the inpatient care of children with complicated severe acute malnutrition may be strengthened to improve outcomes.
In December ...2015, we searched Google scholar and WHO's website for WHO recommendations on severe acute malnutrition management and evaluated the history and cited evidence behind these recommendations. We systematically searched WHO International Clinical Trials Registry Platform, clinicaltrials.gov and the Controlled Trials metaRegister until 10 August 2015 for recently completed, ongoing, or pending trials.
WHO's guidelines provide 33 recommendations on the topic. However, 16 (48.5%) of these recommendations were based solely on expert opinion - unsupported by published evidence. Another 11 (33.3%) of the recommendations were supported by the results of directly relevant research - i.e. either randomized trials (8) or observational studies (3). The other six recommendations (18.2%) were based on studies that were not conducted among children with complicated severe malnutrition or studies of treatment that were not identical to the recommended intervention. Trials registries included 20 studies related to the topic, including nine trials of alternative feeding regimens. Acute medical management and follow-up care studies were minimally represented.
WHO's guidelines on the topic have a weak evidence base and have undergone limited substantive adjustments over the past decades. More trials are needed to make that evidence base more robust. If the mortality associated with severe malnutrition is to be reduced, inpatient and post-discharge management trials, supported by studies on the causes of mortality, are needed.
We report a detection of the baryon acoustic oscillation (BAO) feature in the three-dimensional correlation function of the transmitted flux fraction in the Lyα forest of high-redshift quasars. The ...study uses 48 640 quasars in the redshift range 2.1 ≤ z ≤ 3.5 from the Baryon Oscillation Spectroscopic Survey (BOSS) of the third generation of the Sloan Digital Sky Survey (SDSS-III). At a mean redshift z = 2.3, we measure the monopole and quadrupole components of the correlation function for separations in the range 20 h-1 Mpc < r < 200 h-1 Mpc. A peak in the correlation function is seen at a separation equal to (1.01 ± 0.03) times the distance expected for the BAO peak within a concordance ΛCDM cosmology. This first detection of the BAO peak at high redshift, when the universe was strongly matter dominated, results in constraints on the angular diameter distance DA and the expansion rate H at z = 2.3 that, combined with priors on H0 and the baryon density, require the existence of dark energy. Combined with constraints derived from cosmic microwave background observations, this result implies H(z = 2.3) = (224 ± 8) km s-1 Mpc-1, indicating that the time derivative of the cosmological scale parameter ȧ = H(z = 2.3)/(1 + z) is significantly greater than that measured with BAO at z ~ 0.5. This demonstrates that the expansion was decelerating in the range 0.7 < z < 2.3, as expected from the matter domination during this epoch. Combined with measurements of H0, one sees the pattern of deceleration followed by acceleration characteristic of a dark-energy dominated universe.
In this paper, we present results from the weak-lensing shape measurement GRavitational lEnsing Accuracy Testing 2010 (GREAT10) Galaxy Challenge. This marks an order of magnitude step change in the ...level of scrutiny employed in weak-lensing shape measurement analysis. We provide descriptions of each method tested and include 10 evaluation metrics over 24 simulation branches.
GREAT10 was the first shape measurement challenge to include variable fields; both the shear field and the point spread function (PSF) vary across the images in a realistic manner. The variable fields enable a variety of metrics that are inaccessible to constant shear simulations, including a direct measure of the impact of shape measurement inaccuracies, and the impact of PSF size and ellipticity, on the shear power spectrum. To assess the impact of shape measurement bias for cosmic shear, we present a general pseudo-C
ℓ formalism that propagates spatially varying systematics in cosmic shear through to power spectrum estimates. We also show how one-point estimators of bias can be extracted from variable shear simulations.
The GREAT10 Galaxy Challenge received 95 submissions and saw a factor of 3 improvement in the accuracy achieved by other shape measurement methods. The best methods achieve sub-per cent average biases. We find a strong dependence on accuracy as a function of signal-to-noise ratio, and indications of a weak dependence on galaxy type and size. Some requirements for the most ambitious cosmic shear experiments are met above a signal-to-noise ratio of 20. These results have the caveat that the simulated PSF was a ground-based PSF. Our results are a snapshot of the accuracy of current shape measurement methods and are a benchmark upon which improvement can be brought. This provides a foundation for a better understanding of the strengths and limitations of shape measurement methods.
Shigella infections are a leading cause of diarrhoeal death among children in low-income and middle-income countries. WHO guidelines reserve antibiotics for treating children with dysentery. Reliance ...on dysentery for identification and management of Shigella infection might miss an opportunity to reduce Shigella-associated morbidity and mortality. We aimed to systematically review and evaluate Shigella-associated and dysentery-associated mortality, the diagnostic value of dysentery for the identification of Shigella infection, and the efficacy of antibiotics for children with Shigella or dysentery, or both.
We did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery), and meta-analyses where appropriate, of studies in resource-limited settings. We searched MEDLINE, Embase, and LILACS database for studies published before Jan 1, 2017, in English, French, and Spanish. We included studies of human beings with diarrhoea and accepted all study-specific definitions of dysentery. For the mortality and diagnostic value searches, we excluded studies that did not include an effect estimate or data necessary to calculate this estimate. The search for treatment included only randomised controlled trials that were done after Jan 1, 1980, and assessed antibiotics in children (aged <18 years) with dysentery or laboratory-confirmed Shigella. We extracted or calculated odds ratios (ORs) and 95% CIs for relative mortality and did random-effects meta-analysis to arrive at pooled ORs. We calculated 95% CIs assuming a binomial distribution and did random-effects meta-regression of log-transformed sensitivity and specificity estimates for diagnostic value. We assessed the heterogeneity of papers included in these meta-analyses using the I2 statistic and evaluated publication bias using funnel plots. This review is registered with PROSPERO (CRD42017063896).
3649 papers were identified and 60 studies were included for analyses: 13 for mortality, 27 for diagnostic value, and 20 for treatment. Shigella infection was associated with mortality (pooled OR 2·8, 95% CI 1·6–4·8; p=0·000) whereas dysentery was not associated with mortality (1·3, 0·7–2·3; p=0·37). Between 1977 and 2016, dysentery identified 1·9–85·9% of confirmed Shigella infections, with sensitivity decreasing over time (p=0·04). Ten (50%) of 20 included antibiotic trials were among children with dysentery, none were placebo-controlled, and two (10%) evaluated antibiotics no longer recommended for acute infectious diarrhoea. Ciprofloxacin showed superior microbiological, but not clinical, effectiveness compared with pivmecillinam, and no superior microbiological and clinical effectiveness compared with gatifloxacin. Substantial heterogeneity was reported for meta-analyses of the Shigella-associated mortality studies (I2=78·3%) and dysentery-associated mortality studies (I2=73·2%). Too few mortality studies were identified to meaningfully test for publication bias. No evidence of publication bias was found in this analysis of studies of diagnostic value.
Current WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection.
Bill & Melinda Gates Foundation and the Center for AIDS Research International Core.
Interventions to reduce childhood stunting burden require clinical trials with a primary outcome of linear growth. When growth is measured longitudinally, there are several options for including ...baseline measurements in the analysis. This study compares the performance of several methods. Randomized controlled trials evaluating a hypothetical intervention to improve length-for-age z-score (LAZ) from birth through 24 months of age were simulated. The intervention effect was evaluated using linear regression and five methods for handling baseline measurements: comparing final measurements only (FINAL), comparing final measurement adjusted for baseline (ADJUST), comparing the change in the measurement over time (DELTA), adjusting for baseline when comparing the changes over time (DELTA+ADJUST) and adjusting for baseline in two-step residuals approach (RESIDUALS). We calculated bias, precision and power of each method for scenarios with and without a baseline imbalance in LAZ. Using a 0.15 effect size at 18 months, FINAL and DELTA required 1200 and 1500 enroled participants, respectively, to reach 80% power, whereas ADJUST, DELTA+ADJUST and RESIDUALS only required 900 participants. The adjusted models also produced unbiased estimates when there was a baseline imbalance, whereas the FINAL and DELTA methods produced biased estimates, as large as 0.07 lower and higher, respectively, than the true effect. Adjusted methods required smaller sample size and produced more precise results than both DELTA and FINAL methods in all test scenarios. If randomization fails, and there is an imbalance in LAZ at baseline, DELTA and FINAL methods can produce biased estimates, but adjusted models remain unbiased. These results warn against using the FINAL or DELTA methods.
The emergence and spread of β-lactamase-producing Klebsiella spp. has been associated with a substantial healthcare burden resulting in therapeutic failures. We sought to describe the proportion of ...phenotypic resistance to commonly used antibiotics, characterize β-lactamase genes among isolates with antimicrobial resistance (AMR), and assess the correlates of phenotypic AMR in Klebsiella spp. isolated from stool or rectal swab samples collected from children being discharged from hospital.
We conducted a cross-sectional study involving 245 children aged 1-59 months who were being discharged from hospitals in western Kenya between June 2016 and November 2019. Whole stool or rectal swab samples were collected and Klebsiella spp. isolated by standard microbiological culture. β-lactamase genes were detected by PCR whilst phenotypic antimicrobial susceptibility was determined using the disc diffusion technique following standard microbiology protocols. Descriptive analyses were used to characterize phenotypic AMR and carriage of β-lactamase-producing genes. The modified Poisson regression models were used to assess correlates of phenotypic beta-lactam resistance.
The prevalence of β-lactamase carriage among Klebsiella spp. isolates at hospital discharge was 62.9% (154/245). Antibiotic use during hospitalization (adjusted prevalence ratio aPR = 4.51; 95%CI: 1.79-11.4, p < 0.001), longer duration of hospitalization (aPR = 1.42; 95%CI: 1.14-1.77, p < 0.002), and access to treated water (aPR = 1.38; 95%CI: 1.12-1.71, p < 0.003), were significant predictors of phenotypically determined β-lactamase. All the 154 β-lactamase-producing Klebsiella spp. isolates had at least one genetic marker of β-lactam/third-generation cephalosporin resistance. The most prevalent genes were bla
142/154 (92.2%,) and bla
142/154 (92.2%,) followed by bla
88/154 (57.1%,) and bla
48/154 (31.2%,) respectively.
Carriage of β-lactamase producing Klebsiella spp. in stool is common among children discharged from hospital in western Kenya and is associated with longer duration of hospitalization, antibiotic use, and access to treated water. The findings emphasize the need for continued monitoring of antimicrobial susceptibility patterns to inform the development and implementation of appropriate treatment guidelines. In addition, we recommend measures beyond antimicrobial stewardship and infection control within hospitals, improved sanitation, and access to safe drinking water to mitigate the spread of β-lactamase-producing Klebsiella pathogens in these and similar settings.
Children who have been discharged from hospital in sub-Saharan Africa remain at substantial risk of mortality in the post-discharge period. Antimicrobial resistance (AMR) may be an important factor. ...We sought to determine the prevalence and risk factors associated with AMR in commensal Escherichia coli (E. coli) from Kenyan children at the time of discharge.
Fecal samples were collected from 406 children aged 1-59 months in western Kenya at the time of discharge from hospital and cultured for E. coli. Susceptibility to ampicillin, ceftriaxone, cefotaxime, ceftazidime, cefoxitin, imipenem, ciprofloxacin, gentamicin, combined amoxicillin/clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin, and chloramphenicol was determined by disc diffusion according to guidelines from the Clinical and Laboratory Standards Institute (CLSI). Poisson regression was used to determine associations between participant characteristics and the presence of extended-spectrum beta-lactamases (ESBL) producing E. coli. Non-susceptibility to ampicillin (95%), gentamicin (44%), ceftriaxone (46%), and the presence of ESBL (44%) was high. Receipt of antibiotics during the hospitalization was associated with the presence of ESBL (aPR = 2.23; 95% CI: 1.29-3.83) as was being hospitalized within the prior year (aPR = 1.32 1.07-1.69). Open defecation (aPR = 2.02; 95% CI: 1.39-2.94), having a toilet shared with other households (aPR = 1.49; 95% CI: 1.17-1.89), and being female (aPR = 1.42; 95% CI: 1.15-1.76) were associated with carriage of ESBL E. coli.
AMR is common among isolates of E. coli from children at hospital discharge in Kenya, including nearly half having detectable ESBL.
The increasing spread of fluoroquinolone resistant enteric bacteria is a global public health concern. Children recently discharged from the hospital are at high risk of carriage of antimicrobial ...resistance (AMR) due to frequent exposure to antimicrobials during inpatient stays. This study aimed to determine the prevalence, correlates of ciprofloxacin (CIP) non-susceptibility, and distribution of plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coli (E. coli) and Klebsiella spp isolated from children under five years being discharged from two Kenyan Hospitals.
E. coli and Klebsiella spp were isolated from fecal samples from children discharged from hospital and subjected to antimicrobial susceptibility testing (AST) by disc diffusion and E-test. CIP non-susceptible isolates were screened for seven PMQR genes using multiplex polymerase chain reaction (PCR). Poisson regression was used to determine the association between the carriage of CIP non-susceptible isolates and patient characteristics.
Of the 280 CIP non-susceptible isolates: 188 E. coli and 92 Klebsiella spp isolates identified among 266 discharged children, 195 (68%) were CIP-non-susceptible with minimum inhibitory concentrations (MICs) of ≥ 1 µg/mL. Among these 195 isolates, 130 (67%) had high-level CIP MIC = ≥ 32 µg/mL). Over 80% of the isolates had at least one PMQR gene identified: aac(6')lb-cr (60%), qnrB (24%), oqxAB (22%), qnrS (16%), and qepA (6%), however, qnrA was not identified in any isolates tested. Co-carriage of qnrB with acc(6')-lb-cr was the most predominant accounting for 20% of all the isolates. Ceftriaxone use during hospital admission and the presence of extended spectrum beta-lactamase (ESBL) production were significantly associated with the carriage of CIP non-susceptible E. coli and Klebsiella spp.
CIP non-susceptibility is common among E. coli and Klebsiella spp isolated from hospital discharged children in Kenya. Carriage and co-carriage of PMQR, including the newly identified qepA gene, were frequently observed. These findings suggest that children leaving the hospital may serve as an important reservoir for transmission of resistant E. coli and Klebsiella spp to the community. Enhanced surveillance for AMR determinants is critical to inform interventions to control antimicrobial-resistant bacteria.
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