Type 2 cytokines sensitize human sensory neurons to itch-associated stimuli.

Introduction: Chronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Methods: We measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing. Results: Type 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and non-type 2 inflammatory stimuli. Discussion: This study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons.

Routine antibiotics for infants less than 6 months of age with growth failure/faltering: a systematic review.

OBJECTIVE: This systematic review commissioned by WHO aimed to synthesise evidence from current literature on the effects of systematically given, routine use of antibiotics for infants under 6 months of age with growth failure/faltering. SETTINGS: Low-income and middle-income countries. PARTICIPANTS: The study population was infants less than 6 months of age with growth failure/faltering. INTERVENTION: The intervention group was infants who received no antibiotics or antibiotics other than those recommended in 2013 guidelines by WHO to treat childhood severe acute malnutrition. The comparison group was infants who received antibiotics according to the aforementioned guidelines. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was all-cause mortality, and secondary outcomes: clinical deterioration, antimicrobial resistance, recovery from comorbidity, adverse events, markers of intestinal inflammation, markers of systemic inflammation, hospital-acquired infections and non-response. The Grading of Recommendations Assessment, Development and Evaluation approach was considered to report the overall evidence quality for an outcome. RESULTS: We screened 5137 titles and abstracts and reviewed the full text of 157 studies. None of the studies from the literature search qualified to answer the question for this systematic review. CONCLUSIONS: There is a paucity of evidence on the routine use of antibiotics for the treatment of malnutrition in infants less than 6 months of age. Future studies with adequate sample sizes are needed to assess the potential risks and benefits of antibiotics in malnourished infants under 6 months of age. PROSPERO REGISTRATION NUMBER: CRD42021277073.

Protocol for a systematic review on routine use of antibiotics for infants less than 6 months of age with growth failure/faltering.

INTRODUCTION: Antibiotics have been used as an adjunct in treating children with severe acute malnutrition 6-59 months of age; however, the data for infants less than 6 months are scarce. The WHO recently started guideline development for preventing and treating wasting, including growth failure/faltering in infants less than 6 months. This systematic review commissioned by WHO aims to synthesise evidence from current literature on the effectiveness of antibiotics for infants less than 6 months of age with growth failure/faltering. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis for studies that assessed the effect of antibiotics in the treatment of infants with growth faltering. We will search multiple electronic databases. We will include randomised control trials and non-randomised studies with a control arm. The study population is infants less than 6 months of age with growth failure. The intervention group will be infants who received no antibiotics or antibiotics other than recommended in 2013 guidelines by WHO to treat severe acute malnutrition in children. The comparison group will be infants who received antibiotics according to the 2013 guideline by WHO. We will consider the following outcomes: mortality, clinical deterioration, antimicrobial resistance, recovery from comorbidity, adverse events, markers of intestinal inflammation, markers of systemic inflammation, hospital-acquired infections, non-response. We will use the meta-analysis to pool the studies where applicable. We will use the Grading of Recommendations Assessment, Development, and Evaluation approach to reporting the overall evidence quality for an outcome. ETHICS AND DISSEMINATION: This is a systematic review and will not involve contact with a human subject. The findings of this review will be published in a peer-review journal and will guide the WHO's recommendation for the use of antibiotics in infants less than 6 months of age with growth failure. PROSPERO REGISTRATION NUMBER: CRD42021277073.

Optimal iron content in ready-to-use therapeutic foods for the treatment of severe acute malnutrition in the community settings: a protocol for the systematic review and meta-analysis.

INTRODUCTION: The current standard of care for children with severe acute malnutrition (SAM) involves using ready-to-use therapeutic food (RUTF) to promote growth; however, the precise formulation to achieve optimal recovery remains unclear. Emerging research suggests that alternative RUTF formulations may be more effective in correcting SAM-related complications such as anaemia and iron deficiency. This systematic review commissioned by the WHO aims to synthesise the most recent research on the iron content in RUTF and related products in the community-based treatment of uncomplicated severe malnutrition in children aged 6 months and older. METHODS AND ANALYSIS: We will search multiple electronic databases. We will include randomised controlled trials and non-randomised studies with a control arm. The intervention group will be infants who received RUTF treatments other than the current recommended guidelines set forth by the WHO. The comparison group is children receiving RUTF containing iron at the current WHO-recommended level of 1.9 mg/100 kcal (10-14 mg/100 g). The primary outcomes of interest include blood haemoglobin concentration, any anaemia, severe anaemia, iron-deficiency anaemia, recovery from SAM and any adverse outcomes. We will use meta-analysis to pool findings if sufficient homogeneity exists among included studies. The risk of bias in studies will be evaluated using the Cochrane risk of bias-2. We will use the Grading of Recommendations Assessment, Development, and Evaluation(GRADE) approach to examine the overall certainty of evidence. ETHICS AND DISSEMINATION: This is a systematic review and will not involve direct contact with human subjects. The findings of this review will be published in a peer-reviewed journal and will guide the WHO's recommendation on the optimal iron content in RUTFs for the treatment of SAM in children aged 6-59 months.

Increased vs. Standard Dose of Iron in Ready-to-Use Therapeutic Foods for the Treatment of Severe Acute Malnutrition in a Community Setting: A Systematic Review and Meta-Analysis.

The optimal dose of iron in ready-to-use therapeutic foods (RUTF) used to treat uncomplicated severe acute malnutrition (SAM) in community settings is not well established. The objective of this systematic review was to assess if an increased iron dose in RUTF, compared with the standard iron dose in the World Health Organization (WHO)-recommended peanut-based RUTF, improved outcomes in children aged six months or older. We searched multiple electronic databases and only included randomized controlled trials. We pooled the data in a meta-analysis to obtain relative risk (RR) and reported it with a 95% confidence interval (CI). Three studies, one each from Zambia, the Democratic Republic of Congo, and Malawi, were included. In all studies, the RUTF used in the intervention group was milk-free soya-maize-sorghum-based RUTF. The pooled results showed that, compared to the control group, a high iron content in RUTF may lead to increase in hemoglobin concentration (mean difference 0.33 g/dL, 95% CI: 0.02, 0.64, two studies, certainty of evidence: low) and a decrease in any anemia (RR 0.66, 95% CI: 0.48, 0.91, two studies, certainty of evidence: low), but also decrease recovery rates (RR 0.91, 95% CI: 0.84, 0.99, three studies, certainty of evidence: low) and increase mortality (RR 1.30, 95% CI: 0.87, 1.95, three studies, certainty of evidence: moderate). However, the CIs were imprecise for the latter outcome. Future studies with large sample sizes are needed to confirm the beneficial versus harmful effects of high iron content in RUTF in treating uncomplicated SAM in children aged 6-59 months in community settings.

SUBSTANTIAL EXTERNAL DOSE RATE VARIABILITY OBSERVED IN A COHORT OF LU-177 PATIENTS INDEPENDENT OF BMI AND SEX.

External dose rates were measured 1 m away from 230 Lu-177 patients to characterise the variability in normalised dose rates as a function of administered activity, body mass index (BMI) and sex. The largest dose rate observed was 0.07 mSv/h associated with an administered activity of 7.2 GBq. Substantial variability was found in the distribution of the normalised dose rate associated that had an average of 0.0037 mSv/h per GBq and a 95% confidence interval of 0.0024-0.0058 mSv/h per GBq. Based on this study, estimating the patient dose rate based on the Lu-177 gamma exposure factor overestimates the dose rate by a factor of 2. A statistically significant inverse relationship was found between the patient dose rate and patient BMI and an empirically derived equation relating these two quantities was reported. On average, male patient dose rates were 3.5% lower than female dose rates, which may be attributed to the larger average BMI of the male patient group.

Peritoneal Effluent Cell-Free DNA Sequencing in Peritoneal Dialysis Patients With and Without Peritonitis.

RATIONALE & OBJECTIVE: Conventional culture can be insensitive for the detection of rare infections and for the detection of common infections in the setting of recent antibiotic usage. Patients receiving peritoneal dialysis (PD) with suspected peritonitis have a significant proportion of negative conventional cultures. This study examines the utility of metagenomic sequencing of peritoneal effluent cell-free DNA (cfDNA) for evaluating the peritoneal effluent in PD patients with and without peritonitis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We prospectively characterized cfDNA in 68 peritoneal effluent samples obtained from 33 patients receiving PD at a single center from September 2016 to July 2018. OUTCOMES: Peritoneal effluent, microbial, and human cfDNA characteristics were evaluated in culture-confirmed peritonitis and culture-negative peritonitis. ANALYTICAL APPROACH: Descriptive statistics were analyzed and microbial cfDNA was detected in culture-confirmed peritonitis and culture-negative peritonitis. RESULTS: Metagenomic sequencing of cfDNA was able to detect and identify bacterial, viral, and eukaryotic pathogens in the peritoneal effluent from PD patients with culture-confirmed peritonitis, as well as patients with recent antibiotic usage and in cases of culture-negative peritonitis. LIMITATIONS: Parallel cultures were not obtained in all the peritoneal effluent specimens. CONCLUSIONS: Metagenomic cfDNA sequencing of the peritoneal effluent can identify pathogens in PD patients with peritonitis, including culture-negative peritonitis.

Urinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract.

Urinary tract infections are one of the most common infections in humans. Here we tested the utility of urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections. We isolated cfDNA from 141 urine samples from a cohort of 82 kidney transplant recipients and performed next-generation sequencing. We found that urinary cfDNA is highly informative about bacterial and viral composition of the microbiome, antimicrobial susceptibility, bacterial growth dynamics, kidney allograft injury, and host response to infection. These different layers of information are accessible from a single assay and individually agree with corresponding clinical tests based on quantitative PCR, conventional bacterial culture, and urinalysis. In addition, cfDNA reveals the frequent occurrence of pathologies that remain undiagnosed with conventional diagnostic protocols. Our work identifies urinary cfDNA as a highly versatile analyte to monitor infections of the urinary tract.