Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer.

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression, and aberrant RBP-RNA interactions can promote cancer progression. Here, we interrogate the function of RBPs in cancer using pooled CRISPR-Cas9 screening and identify 57 RBP candidates with distinct roles in supporting MYC-driven oncogenic pathways. We find that disrupting YTHDF2-dependent mRNA degradation triggers apoptosis in triple-negative breast cancer (TNBC) cells and tumors. eCLIP and m6A sequencing reveal that YTHDF2 interacts with mRNAs encoding proteins in the MAPK pathway that, when stabilized, induce epithelial-to-mesenchymal transition and increase global translation rates. scRibo-STAMP profiling of translating mRNAs reveals unique alterations in the translatome of single cells within YTHDF2-depleted solid tumors, which selectively contribute to endoplasmic reticulum stress-induced apoptosis in TNBC cells. Thus, our work highlights the therapeutic potential of RBPs by uncovering a critical role for YTHDF2 in counteracting the global increase of mRNA synthesis in MYC-driven breast cancers.

Effect of oropharyngeal colostrum therapy on neonatal sepsis in preterm neonates: A systematic review and meta-analysis.

Various studies have shown that oropharyngeal colostrum application (OPCA) is beneficial to preterm neonates. We performed a systematic review and meta-analysis to assess whether OPCA reduces the incidence of culture-proven neonatal sepsis in preterm neonates. Randomized controlled trials comparing OPCA with placebo or standard care in preterm neonates were included. Medline, Embase, Web of Science, Cumulated Index to Nursing and Allied Health Literature, Scopus, and CENTRAL were searched for studies published up to June 15, 2023. We used the Cochrane Risk of Bias tool, version 2, for risk of bias assessment, the random-effects model (RevMan 5.4) for meta-analysis, and Gradepro software for assessing the certainty of evidence. Twenty-one studies involving 2393 participants were included in this meta-analysis. Four studies had a low risk of bias, whereas seven had a high risk. Oropharyngeal colostrum significantly reduced the incidence of culture-proven sepsis (18 studies, 1990 neonates, risk ratio [RR]: 0.78, 95% confidence interval [95% CI]: 0.65, 0.94), mortality (18 studies, 2117 neonates, RR: 0.73, 95% CI: 0.59, 0.90), necrotizing enterocolitis (NEC) (17 studies, 1692 neonates, RR: 0.59, 95% CI: 0.43, 0.82), feeding intolerance episodes (four studies, 445 neonates, RR: 0.59, 95% CI: 0.38, 0.92), and the time to full enteral feeding (19 studies, 2142 neonates, mean difference: -2 to 21 days, 95% CI: -3.44, -0.99 days). There was no reduction in intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, ventilator-associated pneumonia, neurodevelopmental abnormalities, hospital stay duration, time to full oral feeding, weight at discharge, pneumonia, and duration of antibiotic therapy. The certainty of the evidence was high for the outcomes of culture-positive sepsis and mortality, moderate for NEC, low for time to full enteral feeding, and very low for feeding intolerance. OPCA reduces culture-positive sepsis and mortality (high certainty), NEC (moderate certainty), and time to full enteral feeding (low certainty) in preterm neonates. However, scarcity of data from extremely premature infants limits the generalizability of these results to this population.

Evidence-based clinical practice guideline for management of urinary tract infection and primary vesicoureteric reflux.

We present updated, evidence-based clinical practice guidelines from the Indian Society of Pediatric Nephrology (ISPN) for the management of urinary tract infection (UTI) and primary vesicoureteric reflux (VUR) in children. These guidelines conform to international standards; Institute of Medicine and AGREE checklists were used to ensure transparency, rigor, and thoroughness in the guideline development. In view of the robust methodology, these guidelines are applicable globally for the management of UTI and VUR. Seventeen recommendations and 18 clinical practice points have been formulated. Some of the key recommendations and practice points are as follows. Urine culture with > 104 colony forming units/mL is considered significant for the diagnosis of UTI in an infant if the clinical suspicion is strong. Urine leukocyte esterase and nitrite can be used as an alternative screening test to urine microscopy in a child with suspected UTI. Acute pyelonephritis can be treated with oral antibiotics in a non-toxic infant for 7-10 days. An acute-phase DMSA scan is not recommended in the evaluation of UTI. Micturating cystourethrography (MCU) is indicated in children with recurrent UTI, abnormal kidney ultrasound, and in patients below 2 years of age with non-E. coli UTI. Dimercaptosuccinic acid scan (DMSA scan) is indicated only in children with recurrent UTI and high-grade (3-5) VUR. Antibiotic prophylaxis is not indicated in children with a normal urinary tract after UTI. Prophylaxis is recommended to prevent UTI in children with bladder bowel dysfunction (BBD) and those with high-grade VUR. In children with VUR, prophylaxis should be stopped if the child is toilet trained, free of BBD, and has not had a UTI in the last 1 year. Surgical intervention in high-grade VUR can be considered for parental preference over antibiotic prophylaxis or in children developing recurrent breakthrough febrile UTIs on antibiotic prophylaxis.

Cost analysis of telemedicine use in paediatric nephrology-the LMIC perspective.

BACKGROUND: The overall cost of managing chronic diseases is a significant barrier to accessing complete and timely healthcare, especially in rural and geographically isolated areas. This cost disparity becomes more pronounced in the case of children and more so in under-resourced regions of the world. In the era of COVID-19, as the need for physical distancing increased, there was a transition in approach to healthcare provision to telemedicine consultations. This study evaluates the cost saving using teleconsultations in a paediatric nephrology clinic. METHODS: This prospective cohort study was conducted at AIIMS Jodhpur, a tertiary care centre in western Rajasthan from March 2021 to October 2022. All consecutive paediatric (29 days-18 years) patients attending telemedicine services for kidney-related illness were enrolled. Basic demographic details were collected. Cost analysis was done after 6 months, regarding perceived cost savings for the patient and family by using telehealth for follow-up during 6 months starting from enrolment. RESULTS: A total of 112 patients were enrolled; 266 teleconsultations attended; 109 patients who could be followed up saved INR 457,900 during 6 months of follow-up. The average cost saving was INR - 1577/patient/visit. Patients saved 4.99% of the family income (median 2.16% (IQR 0.66-5.5)). The highest expenditure per visit was incurred for food and transport. The median distance from the residence to the clinic was 122.5 km (IQR 30-250). Over the 6-month study period, patients saved a travel distance of 83,274 km (743 km/patient). CONCLUSIONS: The use of telemedicine as a follow-up method helps save significant costs and distances travelled by patients. A higher-resolution version of the Graphical abstract is available as Supplementary information.

Imparting child nutritional assessment skills among medical students using hybrid problem-based learning approach in a community setting.

Background: Malnutrition affects up to a third of children in India, with severe and acute malnutrition prevalent among under five children. Nutritional assessment skills for detecting malnutrition in children in primary care settings are vital. Hybrid problem-based learning (HPBL) is an innovative, collaborative, and adaptable instructional learning strategy that can be used to teach medical students clinical skills in a community setting. Methods: A two-month quasi-experimental study was undertaken in a rural setting with third-year medical students. Faculty members were sensitized and subject experts developed a training module addressing the knowledge, attitude, communication, and practice domains. The students underwent a 3-week training module where pre-testing, case presentation, and group formation in first week, an anchoring lecture, tutorial and self-directed learning and role-play by students in subsequent week, and in last week, case discussion, post-testing, and feedback rounds were done. Results: In all domains, knowledge (3.8, 0.01), practice (4.3, 0.01), attitude and communication (3.7, 0.01), and proportional satisfactory responses, the HPBL approach resulted in a significant improvement in nutritional assessment competency. Teachers preferred the practical and engaging character of the approach, stating that doubts and questions were better addressed and that they would use it to teach similar topics. Conclusion: HPBL is an excellent teaching method for clinical skills, like nutritional assessment in simulated/field settings. The novel teaching-learning approach was well received by students and faculty members. Learning outcomes and satisfaction rates enhanced in students and faculty were encouraged to apply the approach to other topics.

Biomarkers for prediction of acute kidney injury in pediatric patients: a systematic review and meta-analysis of diagnostic test accuracy studies.

BACKGROUND: Severity of acute kidney injury (AKI) confers higher odds of mortality. Timely recognition and early initiation of preventive measures may help mitigate the injury further. Novel biomarkers may aid in the early detection of AKI. The utility of these biomarkers across various clinical settings in children has not been evaluated systematically. OBJECTIVE: To synthesize the currently available evidence on different novel biomarkers for the early diagnosis of AKI in pediatric patients. DATA SOURCES: We searched four electronic databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies published between 2004 and May 2022. STUDY ELIGIBILITY CRITERIA: Cohort and cross-sectional studies evaluating the diagnostic performance of biomarkers in predicting AKI in children were included. PARTICIPANTS AND INTERVENTIONS: Participants in the study included children (aged less than 18 years) at risk of AKI. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the QUADAS-2 tool for the quality assessment of the included studies. The area under the receiver operating characteristics (AUROC) was meta-analyzed using the random-effect inverse-variance method. Pooled sensitivity and specificity were generated using the hierarchical summary receiver operating characteristic (HSROC) model. RESULTS: We included 92 studies evaluating 13,097 participants. Urinary NGAL and serum cystatin C were the two most studied biomarkers, with summary AUROC of 0.82 (0.77-0.86) and 0.80 (0.76-0.85), respectively. Among others, urine TIMP-2*IGFBP7, L-FABP, and IL-18 showed fair to good predicting ability for AKI. We observed good diagnostic performance for predicting severe AKI by urine L-FABP, NGAL, and serum cystatin C. LIMITATIONS: Limitations were significant heterogeneity and lack of well-defined cutoff value for various biomarkers. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Urine NGAL, L-FABP, TIMP-2*IGFBP7, and cystatin C showed satisfactory diagnostic accuracy in the early prediction of AKI. To further improve the performance of biomarkers, they need to be integrated with other risk stratification models. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42021222698). A higher resolution version of the Graphical abstract is available as "Supplementary information".

Incidence, predictors, and short-term outcomes of acute kidney injury in children with diabetic ketoacidosis: a systematic review.

BACKGROUND: One-third of children with type 1 diabetes mellitus manifest with diabetic ketoacidosis (DKA). Most children presenting with DKA are in a volume-depleted state, leading to acute kidney injury (AKI). Besides volume depletion, hyperglycemia can induce tubular injury and kidney inflammation. Therefore, a thorough knowledge of incidence of AKI, risk factors, and outcomes in pediatric DKA is desirable to improve its management and outcomes. OBJECTIVE: To synthesize currently available evidence on the incidence, risk factors, and outcomes of AKI in children with DKA. DATA SOURCES: We searched three electronic databases (EMBASE, PubMed, and Web of Science) from inception to September 2022 for original studies reporting AKI in children with DKA. Search strategies for the individual databases were drafted using free text words and MeSH incorporating "acute kidney injury" and "diabetic ketoacidosis." STUDY ELIGIBILITY CRITERIA: Cohort and cross-sectional studies reporting AKI in children with type 1 DM and DKA were included. PARTICIPANTS AND INTERVENTIONS: Children (aged less than 18 years) with type 1 DM and DKA. STUDY APPRAISAL AND SYNTHESIS METHODS: The critical appraisal tool of NHLBI for cohort studies was used to assess the quality of the studies. We estimated the pooled incidence of AKI with 95% CI in children with DKA using a random effects model. The primary outcome was the pooled incidence of AKI during the DKA episodes. RESULTS: Twenty-one studies assessing 4087 children (4500 DKA episodes) reported AKI during DKA episodes. The pooled incidence of any stage of AKI during the DKA episode was 47% (95% CI: 40 to 55). Severe AKI was observed in 28% (21 to 35) of DKA episodes; however, only 4% (1 to 11%) of children with AKI received dialysis. Low serum bicarbonate, low corrected sodium, higher blood sugar, and high blood urea nitrogen at presentation have been reported to be associated with the development of AKI. CONCLUSION: AKI developed in almost half of the DKA episodes, and every fourth DKA episode was associated with severe AKI. The recovery rate from DKA-associated AKI appears to be high; however, further studies are needed to assess the exact impact of AKI on long-term outcomes. REGISTRATION: PROSPERO (CRD42022303200). A higher resolution version of the Graphical abstract is available as Supplementary information.

To feed or not to feed during therapeutic hypothermia in asphyxiated neonates: a systematic review and meta-analysis.

The practice of withholding feed during therapeutic hypothermia (TH) in neonates with hypoxemic ischemic encephalopathy (HIE) is based on conventions rather than evidence. Recent studies suggest that enteral feeding might be safe during TH. We systematically compared the benefits and harms of enteral feeding in infants undergoing TH for HIE. We searched electronic databases and trial registries (MEDLINE, CINAHL, Embase, Web of Science, and CENTRAL) until December 15, 2022, for studies comparing enteral feeding and non-feeding strategies. We performed a random-effects meta-analysis using RevMan 5.4 software. The primary outcome was the incidence of stage II/III necrotizing enterocolitis (NEC). Other outcomes included the incidence of any stage NEC, mortality, sepsis, feed intolerance, time to full enteral feeds, and hospital stay. Six studies ((two randomized controlled trials (RCTs) and four nonrandomized studies of intervention (NRSIs)) enrolling 3693 participants were included. The overall incidence of stage II/III NEC was very low (0.6%). There was no significant difference in the incidence of stage II/III NEC in RCTs (2 trials, 192 participants; RR, 1.20; 95% CI: 0.53 to 2.71, I2, 0%) and NRSIs (3 studies, no events in either group). In the NRSIs, infants in the enteral feeding group had significantly lower sepsis rates (four studies, 3500 participants, RR, 0.59; 95% CI: 0.51 to 0.67, I2-0%) and lower all-cause mortality (three studies, 3465 participants, RR: 0.43; 95% CI: 0.33 to 0.57, I2-0%) than the infants in the "no feeding" group. However, no significant difference in mortality was observed in RCTs (RR: 0.70; 95% CI: 0.28 to 1.74, I2-0%). Infants in the enteral feeding group achieved full enteral feeding earlier, had higher breastfeeding rates at discharge, received parenteral nutrition for a shorter duration, and had shorter hospital stays than the control group.  Conclusion: In late preterm and term infants with HIE, enteral feeding appears safe and feasible during the cooling phase of TH. However, there is insufficient evidence to guide the timing of initiation, volume, and feed advancement. What is Known: • Many neonatal units withhold enteral feeding during therapeutic hypothermia, fearing an increased risk of complications (feed intolerance and necrotizing enterocolitis). • The overall risk of necrotizing enterocolitis in late-preterm and term infants is extremely low (< 1%). What is New: • Enteral feeding during therapeutic hypothermia is safe and does not increase the risk of necrotizing enterocolitis, hypoglycemia, or feed intolerance. It may reduce the incidence of sepsis and all-cause mortality until discharge.

Prevalence and risk factors for functional iron deficiency in children with chronic kidney disease.

INTRODUCTION: Anemia in chronic kidney disease (CKD) is multifactorial. The presence of functional iron deficiency (FID), whereby, there is a block in the transport of iron from macrophage to erythroid marrow is one possible etiology. In this study, we aim to assess the prevalence and risk factors of FID in pediatric CKD. METHODS: A cross-sectional study was performed from March to December 2018, after obtaining Institute Ethical Clearance. Children aged ≤ 12 years with CKD, with or without iron supplementation who consented were enrolled. Patients on erythropoietin or on maintenance dialysis were excluded. Details of patients and diseases characteristics were recorded. Various laboratory parameters including complete blood count, red blood cell indices, hypochromic RBC, reticulocyte hemoglobin content, and serum ferritin were measured. Appropriate statistical tests were applied. RESULTS: Out of 174 children, 127 (73%) had structural kidney disease as an etiology of CKD, and 110 (63%) had anemia. Prevalence of anemia was 44%, 43%, 74%, 64% and 92% in CKD stage 1, 2, 3, 4 and 5, respectively. Absolute iron deficiency was found in 66 (38%) even when some children were already on iron supplementation. FID was seen in 44 (25%) and on multivariate analysis, lower estimated glomerular filtration rate and mineral bone disease are associated risk factors. CONCLUSION: FID is present in one-fourth of our CKD cohort. It should be considered when the response to adequate measures of improving hemoglobin level fails. More studies are required to know its impact on short-term and long-term patient-related outcomes such as quality of life and mortality.

Use of exemplars-based feedforward to improve the performance of medical students in constructed response assessment.

Background: Exemplars are the graded responses to theory questions from previous examinations and are considered as means to guide students about what is valued by assessors; hence giving feed forward to students before the exam and developing self-regulated learning among students. The present study was undertaken to compare the effect on performance of students between intervention (didactic lecture and exemplar) and control group (didactic lecture). Methods: This study was an interventional study conducted among 256 students of a medical college in Rajasthan, India. Participants were randomized to either the control group A or to the interventional group B. Outcomes included a post intervention test evaluating the knowledge gained after the session and students 'attitudes about the same. A focus group discussion was conducted investigating the perceptions. The feedback from faculty was also taken. Results: The mean post test score of intervention group was found to be 6.1 ± 1.74 and of the control group was 5.5 ± 1.6; significantly higher with p-value of 0.03. Out of 128 participants in group B, majority (n = 94,73%) believed that exemplars improve learning and created their interest in topic (n = 78, 60.9%). Most of students (66%) were of the opinion that exemplars should be regularly used with didactic lectures. Key themes identified from focus group were: advantages of the exemplars-based feedforward, challenges in implementation and ways to improve the method. Conclusion: Exemplars improved the performance of students. The faculty members and students agreed that they are an effective tool to enhance learning.

Blueprint designing and validation for competency-based curriculum for theory assessment in community medicine.

Background: Blueprint provides a base for assessment by assigning proportionate weightage to various content areas and helps the paper setter to construct a uniform and valid assessment. This study aimed to design and validate a blueprint for theory in Community Medicine as per the new curriculum for Medical Undergraduates in India. Methods: Blueprint in community medicine was designed by assigning impact score (I) and frequency score (F) for the competencies. Blueprint was validated using the Content Validity Index (CVI), and inter-rater agreement for subject experts using Fleiss' kappa statistics was calculated. Feedback from faculty and students was obtained afterward to assess the postimplementation response. Results: Blueprint was designed by an expert group where impact score and frequency score were assigned to 146 competencies in the theory of Community Medicine. In Delphi survey I, 63.2% of subject experts responded, while in Delphi survey II, a response rate of 58.3% was achieved. Value of the Fleiss' Kappa test for an inter-rater agreement was 0.68, i.e. "substantial agreement," while CVI among the raters came out to be 0.86, i.e. overall valid assessment. Feedback of faculty (n = 11) suggested that the blueprint was helpful and standardized the paper setting, whereas feedback from students (n = 138) depicted that it helped in preparing for exams, and they would recommend it to other students. Conclusion: Validated blueprint by consensus of subject experts has impact score and frequency score along with topic-wise distribution of marks for the convenience of faculty and its utility is well proven among learners too.

Diagnostic accuracy of renal angina index alone or in combination with biomarkers for predicting acute kidney injury in children.

Early recognition of patients at risk for severe acute kidney injury (AKI) by renal angina index (RAI) may help in the early institution of preventive measures. Objective was to evaluate performance of RAI alone or in combination with biomarkers in predicting severe AKI (KDIGO stage 2 and 3 or equivalent) and receipt of kidney replacement therapy (KRT) in critically ill children. We searched PubMed, EMBASE, Web of Sciences, and CENTRAL for studies published till May 2021. Search terms included acute kidney injury, pediatrics, adolescent, renal angina index, and biomarker. Proceedings of relevant conferences and references of included studies were also scrutinized. Two reviewers independently assessed the study eligibility. Cohort and cross-sectional studies evaluating the diagnostic performance of RAI in predicting AKI or receipt of KRT in children were included. Eligible participants were the children less than 18 years with RAI assessment on day 0 ofadmission. We followed PRISMA-DTA guidelines and used the QUADAS-2 tool for quality assessment. A bivariate model for meta-analysis was used to calculate the summary estimates of diagnostic parameters. Major outcomes were the diagnostic accuracy of RAI (≥ 8) alone or with biomarkers in predicting severe AKI and KRT receipt. Diagnostic accuracy was reported using summary sensitivity, specificity, and area under the curve (AUC). Overall, 22 studies (24 reports, 14,001 participants) were included. RAI ≥ 8 on day 0 has summary sensitivity, specificity, and AUC of 0.86 (95% CI, 0.77-0.92), 0.77 (0.68-0.83), and 0.88 (0.85-0.91) respectively for prediction of severe AKI on day 3. In comparison, a combination of RAI and urinary neutrophil gelatinase-associated lipocalin (NGAL) showed summary sensitivity, specificity, and AUC of 0.76 (0.62-0.85), 0.89 (0.74-0.96), and 0.87 (0.84-0.90) respectively for predicting severe AKI. The sensitivity, specificity, and AUC of RAI for predicting receipt of KRT were 0.82 (0.71-0.90), 0.74 (0.66-0.81), and 0.85 (0.81-0.88) respectively. In meta-regression, only the study setting (sepsis vs. heterogenous) was associated with heterogeneity. We observed substantial heterogeneity among eligible studies. Five studies had concerns in patient selection, and seven studies also had applicability concerns in patient selection for this review. Moderate certainty evidence showed that RAI ≥ 8 has good predicting ability in recognizing children at risk of severe AKI and receipt of KRT. The combination of urinary NGAL and RAI further improves the predicting ability (low-certainty evidence). Further studies are required on the context-driven assessment of novel biomarkers in the early prediction of AKI in RAI-positive children. Systematic review registration number: CRD4202122268. A higher resolution version of the Graphical abstract is available as Supplementary information.

Three-hourly versus two-hourly feeding interval in stable preterm infants: an updated systematic review and meta-analysis of randomized controlled trials.

Evidence from randomized controlled trials (RCTs) suggests that three-hourly feeding is safe and might help achieve full feeds earlier in preterm infants. We systematically compared the benefits and harms of three-hourly and two-hourly feeding schedules in preterm infants. We searched electronic databases (MEDLINE, CINAHL, Embase, Web of Science, and Scopus) and trial registries until November 16, 2021, for RCTs comparing the two feeding schedules. We did a random-effects meta-analysis using RevMan 5.4 software. The primary outcome was the incidence of stage II or III necrotizing enterocolitis (NEC). Other outcomes were the incidence of any stage NEC, mortality, time to full enteral feeds, and hospital stay. Six trials (872 participants) are included. There was no significant difference in the incidence of stage II/III NEC (3 trials; 530 participants; RR 1.39; 95% CI: 0.53, 3.65; I2 - 0%, low certainty), and any stage NEC (5 studies; 767 participants; RR 0.98; 95% CI: 0.53, 1.82; I2 -0%, very low certainty) between three and two-hourly feeding groups. There was no difference in achieving full feeds (5 trials; 755 participants; MD: - 0.0 days; 95% CI: - 0.32, 0.31, low certainty) or other outcomes. On subgroup analysis, neonates with birthweight < 1000 g and in the three-hourly feeding regime achieved full enteral feeds slower than those in the two-hourly feeding group (1 trial; 84 participants; MD: 2.9 days, 95% CI: 1.16, 4.64, low certainty). CONCLUSION: In stable preterm infants (1000-1500 g), three-hourly feeding can be followed safely. In infants < 1000 g, there is insufficient evidence to advise on an optimal feeding interval, although a 2-h interval might be preferable.Prospero Registration Number: CRD42021246568. WHAT IS KNOWN: • Most of the units follow two-hourly feeding schedules without any evidence. • Recent trials suggest that the three hourly feeding schedules can be safely followed in stable preterm infants. WHAT IS NEW: • Low certainty evidence suggests that three-hourly feeding is safe in stable preterm infants (1000-1500 grams). • In infants with birthweight <1000 grams, two-hourly feeding may be considered as it was associated with a shorter time to full feeds in subgroup analysis.

Non-antibiotic interventions for prevention of urinary tract infections in children: a systematic review and meta-analysis of randomized controlled trials.

A considerable proportion of children experience a recurrence of urinary tract infection (UTI) following the first episode. While low-dose antibiotic prophylaxis has been the mainstay for the prevention of UTI, recent evidence raised concerns over their efficacy and safety. Hence, we aim to systematically synthesize evidence on the efficacy and safety of non-antibiotic prophylactic interventions for UTI. Using keywords related to study population (children) and intervention (non-antibiotic), we searched CENTRAL, Embase, PubMed, and Web of Science for randomized controlled trials (RCTs) published until August 2020. RCTs comparing any non-antibiotic interventions with placebo/antibiotics for prevention of UTIs in children were considered eligible. We used a random-effect model to provide pooled estimates. Sixteen trials evaluating 1426 participants were included. Cranberry was as effective as antibiotic prophylaxis (RR: 0.92; 95% CI: 0.56-1.50) but better than placebo/no therapy (RR: 0.48; 95% CI: 0.28-0.80) in reducing UTI recurrence. Probiotic therapy was more effective in reducing UTI recurrence (RR: 0.52; 95% CI: 0.29-0.94) when compared with placebo. While probiotic therapy was not better than antibiotics prophylaxis in preventing UTI (RR: 0.82; 95% CI: 0.56-1.21), they have a lower risk of antibiotic resistance (RR: 0.38; 95% CI: 0.21-0.69).Conclusion: Cranberry products and probiotics are the two non-antibiotic interventions that have been chiefly evaluated, reduce the risk of UTI recurrence when compared with placebo in children with a normal urinary tract. The findings from this systematic review suggest that while cranberry and probiotics may be used, there is a definite need to identify better and more acceptable non-antibiotic interventions. What is Known: • Efficacy of the low-dose antibiotic is controversial in preventing UTI and it is associated with increase in the risk of antimicrobial resistance. • Non-antibiotic interventions such as cranberry products are effective in preventing UTI recurrence in adults. What is New: • Cranberry products are effective in reducing the recurrence of UTI in children with normal urinary tract. • Low-quality evidence suggests that probiotics can be a potential prophylactic measure to reduce recurrence of UTI in the pediatric population.

Routine prefeed gastric aspiration in preterm infants: a systematic review and meta-analysis.

Despite lack of evidence, the practice of routine prefeed gastric residue aspiration before the next feed is common. Recent studies suggest that this practice might be even harmful. Therefore, we aimed to evaluate the effect of avoiding routine prefeed gastric residue aspiration as compared to routine aspiration, on various clinical outcomes in preterm infants. We searched five different electronic databases (MEDLINE, EMBASE, Web of Science, CINAHL, and Cochrane Library) until March 8, 2021. Only randomized controlled trials comparing the practice of routine prefeed gastric aspiration with no routine aspiration in preterm infants were considered eligible. The random-effects meta-analysis was done using RevMan 5.3 software. Of the 894 unique records identified by our search, we included 6 studies (451 participants) in the review. There was no significant difference in the incidence of necrotizing enterocolitis (RR 0.80; 95% CI 0.31 to 2.08; 421 participants in 5 trials). Avoiding routine prefeed aspiration was associated with achieving full enteral feeds earlier (MD - 3.19 days, 95% CI - 4.22 to - 2.16), shorter duration of hospitalization (MD - 5.32 days; 95% CI - 10.25 to - 0.38), and lower incidence of late-onset sepsis (RR 0.77; 95% CI 0.60 to 0.99). Time to regain birth weight, days of total parenteral nutrition or central venous line usage, culture-positive sepsis, and all-cause mortality did not differ between the two groups.Conclusion: In the absence of other signs of feed intolerance, routine prefeed gastric residue aspiration should be avoided in preterm infants.Prospero registration number: CRD42020197657 What is Known: • Though, routine prefeed aspiration before next feed is a common practice in preterm gavage-fed infants. • Recent study suggests that the omission of routine gastric residual evaluation led to improved weight gain and earlier hospital discharge. What is New: • Low- to moderate-quality evidence suggest that avoiding routine prefeed gastric residue monitoring helps in the reduction of late-onset sepsis, achieving full enteral feeds earlier, and earlier discharge from the hospital. • Abandoning the practice of routine prefeed aspiration in absence of other signs of feed intolerance in preterm low birthweight neonates is safe.

Efficacy and safety of hydroxychloroquine/chloroquine against SARS-CoV-2 infection: A systematic review and meta-analysis.

INTRODUCTION: Hydroxychloroquine (HCQ)/Chloroquine (CQ) has been evaluated for treatment and prophylaxis against SARS-CoV-2 infection in various studies with conflicting results. We performed a systematic review to synthesize the currently available evidence over the efficacy and safety of HCQ/CQ therapy alone against SARS-CoV-2 infection. METHODS: We searched Embase, PubMed, Web of Science, and Cochrane central for randomized controlled trials (RCTs) and prospective cohort studies published until October 15, 2020 and assessing the efficacy of HCQ alone against SARS-CoV-2 infection. We included studies evaluating HCQ/CQ alone as intervention and placebo/standard care as a control group. Retrospective studies and studies using other drugs (namely azithromycin, corticosteroids, immunomodulators, etc.) we excluded. Thirteen RCTs and three prospective cohort studies were included in this review. We pooled data using a random-effect model. RESULTS: Pooled data from 12 studies (9917 participants) showed that HCQs increase mortality as compared to placebo/standard of care (RR 1.10; 95% CI:1.00-1.20). Hydroxychloroquine did not reduce the need for hospitalization in out-patients (RR 0.57; 95% CI 0.31-1.02). HCQ group has a significantly higher rate of any adverse event (RR 2.68; 95% CI 1.55-4.64), as compared to the control group. Also, using HCQ for prophylaxis against SARS-CoV-2 infection did not reduce the risk of acquiring SARS-CoV-2 infection (RR 1.04; 95% CI 0.58-1.88). CONCLUSIONS: HCQ therapy for COVID-19 is associated with an increase in mortality and other adverse events. The negative effects are more pronounced in hospitalized patients. Therefore, with the available evidence, HCQ should not be used in prophylaxis or treatment of patients with COVID-19.

Efficacy and Safety of Phenobarbitone as First-Line Treatment for Neonatal Seizure: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Phenobarbitone is used as a first-line drug for neonatal seizures. However, its poor short- and long-term safety profile is concerning. We aim to systematically synthesize the data on the efficacy and safety of phenobarbitone as a first-line agent and compare it against other anti-epileptic drugs (AEDs) in neonates. METHODS: Using keywords related to the study population (neonatal seizure) and intervention (phenobarbitone), we searched CENTRAL, Embase, PubMed and Web of Science until 15 December 2020. Randomized controlled trials (RCTs) comparing phenobarbitone with any other AED as first-line therapy for seizure control in the neonates were considered eligible. The random-effect meta-analysis was done using RevMan 5.3 software. RESULTS: We screened through 443 records and identified nine eligible studies (719 participants). Five RCTs comparing phenobarbitone with levetiracetam did not find any difference in seizure control with the first dose [risk ratio (RR) 1.43, 95% CI 0.79-2.57] or adverse effects (RR 4.66; 95% CI 0.33-65.83). Two trials comparing phenobarbitone and phenytoin also did not find any difference in seizure control with the first dose (RR 2.09; 95% CI 0.31-14.03) and other outcomes. Only one RCT compared phenobarbitone and lorazepam and found lorazepam to be more efficacious in seizure control with the first dose (RR 0.71; 95% CI 0.53-0.94). Three trials compared neurodevelopmental outcomes, in which levetiracetam was better in two, whereas one did not find any difference. CONCLUSION: Phenobarbitone is at least as efficacious and safe as other drugs like phenytoin and levetiracetam. The data over the long-term neurodevelopmental outcome are lacking. The existing evidence is insufficient to recommend other drugs over phenobarbitone.

Radiological Findings of COVID-19 in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: The majority of the children with SARS-CoV-2 infection present with respiratory symptoms, hence various chest imaging modalities have been used in the management. Knowledge about the radiological findings of coronavirus disease (COVID-19) in children is limited. Hence, we systematically synthesized the available data that will help in better management of COVID-19 in children. METHODS: Four different electronic databases (MEDLINE, EMBASE, Web of Science and CENTRAL) were searched for articles reporting radiological findings in children with COVID-19. Studies reporting thoracic radiological findings of COVID-19 in patients aged <19 years were included. A random-effect meta-analysis (wherever feasible) was performed to provide pooled estimates of various findings. RESULTS: A total of 1984 records were screened of which forty-six studies (923 patients) fulfilled the eligibility criteria and were included in this systematic review. A chest computed tomography (CT) scan was the most frequently used imaging modality. While one-third of the patients had normal scans, a significant proportion (19%) of clinically asymptomatic children had radiological abnormalities too. Unilateral lung involvement (55%) was frequent when compared with bilateral and ground-glass opacities were the most frequent (40%) definitive radiological findings. Other common radiological findings were non-specific patchy shadows (44%), consolidation (23%), halo sign (26%), pulmonary nodules and prominent bronchovascular marking. Interstitial infiltration being the most frequent lung ultrasound finding. CONCLUSION: CT scan is the most frequently used imaging modality for COVID-19 in children and can detect pneumonia before the appearance of clinical symptoms. Undefined patchy shadows, grand-glass opacities and consolidation are commonly observed imaging findings in COVID-19 pneumonia.

Clinical Features and Outcome of SARS-CoV-2 Infection in Neonates: A Systematic Review.

OBJECTIVE: The objective of this study is to systematically synthesize the currently available literature on various modes of transmission (congenital, intrapartum, and postpartum), clinical features and outcomes of SARS-CoV-2 infection in neonates. METHODS: We conducted a comprehensive literature search using PubMed, EMBASE, and Web of Science until 9 June 2020. A combination of keywords and MeSH terms, such as COVID-19, coronavirus, SARS-CoV-2, 2019-nCoV, severe acute respiratory syndrome coronavirus 2, neonates, newborn, infant, pregnancy, obstetrics, vertical transmission, maternal-foetal transmission and intrauterine transmission, were used in the search strategy. We included studies reporting neonatal outcomes of SARS-CoV-2 proven pregnancies or neonatal cases diagnosed with SARS-CoV-2 infection. RESULTS: Eighty-six publications (45 case series and 41 case reports) were included in this review. Forty-five case series reported 1992 pregnant women, of which 1125 (56.5%) gave birth to 1141 neonates. A total of 281 (25%) neonates were preterm, and caesarean section (66%) was the preferred mode of delivery. Forty-one case reports describe 43 mother-baby dyads of which 16 were preterm, 9 were low birth weight and 27 were born by caesarean section. Overall, 58 neonates were reported with SARS-CoV-2 infection (4 had a congenital infection), of which 29 (50%) were symptomatic (23 required ICU) with respiratory symptoms being the predominant manifestation (70%). No mortality was reported in SARS-CoV-2-positive neonates. CONCLUSION: The limited low-quality evidence suggests that the risk of SARS-CoV-2 infections in neonates is extremely low. Unlike children, most COVID-positive neonates were symptomatic and required intensive care. Postpartum acquisition was the commonest mode of infection in neonates, although a few cases of congenital infection have also been reported.