Non-Medical Determinants of Access and Quality of Maternal Health Services in India-Protocol for a Scoping Review.

Introduction: The Maternal Mortality Rate (MMR) is one of the most important health indicators of a country. In India, MMR has decline from 130 to 113 per 100,000 live births between 2014 and 2018, however, there are wide disparities in utilization of maternal health services (MHS) among different states and across different socioeconomic groups within the states. Although the government is providing MHS through various health programs in India, there are several non medical factors leading to the underutilization of MHS services. Objective: To map and summarise the non-medical determinants of access and quality of MHS in India. Methods: We are conducting a scoping review of the published literature from 2000 till date in databases such as PubMed, Cochrane, Science Direct and CINAHL by including eligible qualitative as well as quantitative studies conducted in India. Data extraction and analysis will be conducted through a narrative integrative synthesis approach to summarize the non-medical determinants of access and quality of MHS in India and understand their mechanisms of influence.At the third SPINE20 summit 2022 which took place in Bali, Indonesia, in August 2022, 17 associations endorsed its recommendations. Results: We will summarise the non-medical determinants that influence the access and quality of MHS. Conclusion: This scoping review would help to understand and summarise the existing non-medical determinants of access and quality of MHS, highlight the research gaps and suggest potential modalities for improvement of access and quality of MHS.

Systematic review on efficacy and safety of empirical versus pre-emptive antifungal therapy among children with febrile neutropenia reveals paucity of data.

BACKGROUND: Two approaches are used to manage invasive fungal disease (IFD) in febrile neutropenic patients viz. empirical therapy (without attempting to confirm the diagnosis), or pre-emptive therapy (after screening tests for IFD). OBJECTIVE: This systematic review was undertaken to compare these approaches in children. METHODS: We searched PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, Clinical Trial Registries and grey literature, for randomized controlled trials (RCT) comparing empirical versus pre-emptive antifungal therapy in children with FN suspected to have IFD. We used the Cochrane Risk of bias 2 tool for quality assessment, and evaluated the certainty of evidence using the GRADE approach. RESULTS: We identified 7989 citations. Stepwise screening identified only one relevant RCT that administered empirical (n = 73) or pre-emptive (n = 76) antifungal therapy. There were no significant differences in all-cause mortality (RR 1.56, 95% CI: 0.46, 5.31), IFD mortality (RR 1.04, 95% CI:0.15, 7.20) and other clinically important outcomes such as duration of fever, duration of hospitalization and proportion requiring ICU admission. There were no safety data reported. The number of days of antifungal therapy was significantly lower in the pre-emptive therapy arm. The certainty of evidence for all outcomes was 'moderate'. CONCLUSIONS: This systematic review highlighted the paucity of data, comparing empirical versus pre-emptive antifungal therapy in children with febrile neutropenia having suspected invasive fungal disease. Data from a single included trial suggests that both approaches may be comparable in research settings. Robust trials are warranted to address the gap in existing knowledge about the optimal approach in clinical practice.

Clinical criteria accurately diagnose severe but not moderate alcohol-associated hepatitis: A systematic review and meta-analysis.

BACKGROUND: The precision of clinical criteria and the utility of liver biopsy for diagnosis or prognosis remain unclear in patients with alcohol-associated hepatitis (AH). We systematically reviewed the literature to answer these questions. METHODS: Four databases were searched for studies describing the precision of clinical criteria (National Institute on Alcohol Abuse and Alcoholism, European Association for Study of Liver, or classical) and the role of histology in AH. The precision(positive predictive value) of criteria was pooled through random-effects meta-analysis, and its variation was investigated through subgroups and meta-regression of study-level factors with their percent contribution to variation (R2). The risk of bias among studies was evaluated through the QUADAS2 tool (PROSPERO-ID-CRD4203457250). RESULTS: Of 4320 studies, 18 in the systematic review and 15 (10/5: low/high risk of bias, N=1639) were included in the meta-analysis. The pooled precision of clinical criteria was 80.2% (95% CI: 69.7-89.7, I2:93%, p < 0.01), higher in studies with severe AH (mean-Model for End-Stage Liver Disease > 20) versus moderate AH (mean-Model for End-Stage Liver Disease < 20): 92% versus 67.1%, p < 0.01, and in studies with serum bilirubin cutoff 5 versus 3 mg/dL (88.5% vs.78.8%, p = 0.01). The factors contributing to variation in precision were Model for End-Stage Liver Disease (R2:72.7%), upper gastrointestinal bleed (R2:56.3%), aspartate aminotransferase:aspartate aminotransferase ratio (R2:100%), clinical criteria (R2:40.9%), bilirubin (R2:22.5%), and Mallory body on histology (R2:19.1%).The net inter-pathologist agreement for histologic findings of AH was variable (0.33-0.97), best among 2 studies describing AH through simple and uniform criteria, including steatosis, ballooning, and neutrophilic inflammation. Few studies reported the utility of histology in estimating steroid responsiveness (N = 1) and patient prognosis (N = 4); however, very broad septa, pericellular fibrosis, and cholestasis were associated with mortality. Bilirubinostasis was associated with infection in 1 study. CONCLUSIONS: Clinical criteria are reasonably precise for diagnosing severe AH, while there is an unmet need for better criteria for diagnosing moderate AH. Histologic diagnosis of AH should be simple and uniform.

Effect of Hydroxychloroquine and Azithromycin Combination Use in COVID-19 Patients - An Umbrella Review.

Background: Hydroxychloroquine and Azithromycin combination was used rampantly in management of COVID-19 patients in different countries. Present review was conducted to evaluate the efficacy of Hydroxychloroquine and Azithromycin combination compared to the control (standard care) and any adverse effect following this combination use in COVID-19 patients if any. Material and Methods: We included all the systematic review with or without meta-analysis reporting the effect of Hydroxychloroquine (HCQ) and Azithromycin (AZM) combination use in COVID-19 patient using three databases namely PubMed, medline, CINHAL, Web of Science from July 2020 till Jan 2022. Results: The systematic search strategy has identified 104 studies in total, after removal of duplicates only 4 systematic reviews were included in the qualitative synthesis. The various tools for assessing and reporting the data in the reviews were PRISMA, ROBINS-I, Robs2, AMSTAR, MASTER checklists. Mortality among the hydroxychloroquine with azithromycin combination group was significantly higher than among the Standard Care group. The duration of hospital stay in days was shorter in the Standard Care group in comparison with the hydroxychloroquine group or the hydroxychloroquine and azithromycin combination group. Of the 4 systematic reviews included, 3 had low risk of bias and one had unclear risk of bias using the ROBIS tool. Chloroquine or Hydroxychloroquine combination did not shorten the duration of hospital stay. Conclusion: Rampant use of Chloroquine or Hydroxychloroquine alone or with Azithromycin combination caused adverse effects like QT prolongation. Finally, there is no evidence to support use of either Hydroxychloroquine with or without Azithromycin, for the treatment of COVID-19.

Otitis Media Prevalence in Children Below 18 Years of Age of India and the Associated Risk Factors: A Systematic Review and Meta-Analysis.

Ear ailments in children are a major public health problem in India. This systematic review and meta-analysis aim to quantitatively pool the epidemiologic evidence on the prevalence of all forms of otitis media in children of India. In this review PRISMA guidelines (preferred reporting items for systematic reviews and meta-analysis) were followed. We did extensive literature search in PubMed, Embase, Cinahl and Web of Science to identify relevant community based cross sectional studies that investigated the prevalence of otitis media in children of India. We used STATA version 16.0 software to perform meta-analysis. Six studies reporting the prevalence of otitis media in children were included in the final analysis. Based on the results of the random-effects sub-group meta-analysis model, the pooled estimated prevalence of Chronic suppurative otitis media in children of India was 3.78% (95% CI 2.72-4.84), Otitis media with effusion was found to be 2.68% (95% CI 1.80, 3.55) and Acute suppurative otitis media to be 0.55 (95% CI 0.32, 0.78). This review suggests substantial otitis media related disease burden in children of India. But due to lack of epidemiological studies, the actual disease burden remains concealed. It is imperative to promote more epidemiological studies that will aid policy makers in recommendation of preventive, diagnostic and treatment strategies for this disease.

Is Neck Pain Related to Sagittal Head and Neck Posture?: A Systematic Review and Meta-analysis.

Background: Neck pain (NP) is common in all age groups and adversely affects the patients' entire lifestyle. There exists inconclusive evidence relating faulty craniocervical posture with pain-related disability. This review aims to determine whether sagittal head and neck posture differs in NP and pain-free subjects, to critically appraise the correlation of posture with NP. Methods: Of 3796 articles identified at primary search from CINAHL, PubMed, Google Scholar, EMBASE, 26 were included based on eligibility criteria. Mean pooled difference (MPD) and effect size (ES) were calculated to establish relationship among studies, to assess postural correlation with NP measures [Visual Analogue Scale (VAS), Numeric Pain Rating Scale (NPRS), neck disability index (NDI), Northwick Park NP Questionnaire (NPQ)] and for age- and gender-wise variation. Risk of bias was assessed using Newcastle-Ottawa Quality Assessment Scale. Results: Craniovertebral angle (CVA) had a significant MPD of - 2.93(95% CI - 4.95 to - 0.91). Sagittal head angle (SHA) and forward head posture (FHP) had an insignificant MPD of 1.15 (95% CI - 1.16 to 3.46) and - 0.26 (95% CI - 1.89 to 1.36), respectively. Age- and gender-wise CVA difference was found to be 2.36° and 2.57°, respectively. ES was significant for correlation between CVA and pain intensity [NPRS: - 0.44 (95% CI - 0.61 to - 0.26); VAS: - 0.31 (95% CI - 0.46 to - 0.16)], and between CVA and disability [NDI: - 0.18 (95% CI - 0.31 to - 0.05); NPQ: - 0.47 (95% CI - 0.61 to - 0.320)]. Conclusion: CVA differs for age, gender, and pain vs pain-free subjects, and correlates negatively with NP measures. Other surrogate measures (SHA, cranial and cervical angles, FHP) warrant further research. PROSPERO Registration: PROSPERO 2021 CRD42021275485.

Effectiveness-of Calcium Phosphate derivative agents on the prevention and remineralization of caries among children- A systematic review & meta-analysis of randomized controlled trials.

OBJECTIVES: Dental caries among children is a highly prevalent yet easily preventable oral health issue among children. Various calcium phosphate (CaP) derivatives are implicated to exhibit caries preventive potential; however, no study has summarized the anti-caries effectiveness of these agents. This systematic review and meta-analysis sought to assess the caries-preventive and tooth-remineralizing effect of various (CaP) derivative agents compared to no-intervention/placebo or Fluoride (F) use alone among children. MATERIALS AND METHODS: EMBASE, Ovid, PubMed, Scopus, Web of Science, Cochrane central register of controlled trials (CENTRAL), and grey literature were searched for relevant articles up to April 2021. Only English-language articles were included. Total 2636 articles were searched through different databases; out of the 2161 articles were screened after duplicate removal. 26 studies fulfilling the eligibility criteria were included in this systematic review. Methodological quality assessment and quantitative analysis were done using RevMan. GRADE was used to evaluate the certainty of evidence. RESULTS: A total of 26 trials fulfilling the eligibility criteria were included. The meta-analysis of 10 studies revealed that complete white spot lesions (WSLs) regression (RR=1.56; 95% CI, 1.27 to 1.91; P < .0001, I2=0%), post intervention active WSLs (RR=0.80; 95% CI, 0.70 to 0.90; P = .0004, I2=0%) and post intervention Salivary S. mutans count (RR= 0.69; 95% CI, 0.48 to 0.99; P = .47, I2=0%) significantly favored the CaP+F combined therapy as compared to F alone. No significant differences in the lesion area, Delta F, and DIAGNOdent values were observed between the 2 groups. Low certainty of the evidence was found in the present systematic review due to the high/unclear risk of bias, imprecision, and indirectness of included trials. CONCLUSIONS: Topical treatment using CaP+F group showed superior remineralization potential as well as the antibacterial effect on dental caries among children as compared to no intervention and/or placebo or F alone. Apart from CPP-ACP, other CaP derivatives like TCP and fTCP seem to have promising effects in remineralizing early lesions, however, very few trials exist on these potential agents. To provide definitive recommendations in this area, more clinical trials on caries preventive effectiveness of various CaP agents are warranted.

Multisystem Inflammatory Syndrome Associated With COVID-19 in Children (MIS-C): A Systematic Review of Studies From India.

BACKGROUND: With wide clinical spectrum, multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) in children (MIS-C) is a relatively novel condition occurring weeks to months' post SARS-CoV-2 infection. The aim was to systematically review data on clinical features, laboratory parameters and therapeutics of MIS-C from India. Methods: This systematic review was done as per the PRISMA guidelines, and quality assessment was done using NIH tool for case-series. A systematic search through databases yielded studies whose data was pooled to calculate the mean frequencies with standard deviation using GraphPad software. RESULTS: Screening of 2548 articles published till December, 2021, yielded 11 case-series. World Health Organization case definition was used widely. There was a slight preponderance of males (57%), median (IQR) age was 7 (6,7) years, 63% (n=305) required intensive care unit admissions, and mortality rate was 10% (n=261). Clinical features included fever, mucocutaneous features (72%), and gastrointestinal problems (62%) in majority. Widely used treatment was corticosteroids (76%) and intravenous immunoglobulin (62%) with other options depending on patient's state. An increased level of inflammatory markers and derangement in other parameters corroborated with disease status. Kawasaki disease like features, not reported in many studies, ranged from 4-76% of patients. CONCLUSION: MIS-C presents with a wide spectrum clinical features, increased inflammatory markers and managed as per the disease course and presentation. Future studies monitoring the long-term effects of MIS-C are recommended.

Cirrhosis and fungal infections-a cocktail for catastrophe: A systematic review and meta-analysis with machine learning.

OBJECTIVES: We evaluated the magnitude and factors contributing to poor outcomes among cirrhosis patients with fungal infections (FIs). METHODS: We searched PubMed, Embase, Ovid and WOS and included articles reporting mortality in cirrhosis with FIs. We pooled the point and relative-risk (RR) estimates of mortality on random-effects meta-analysis and explored their heterogeneity (I 2 ) on subgroups, meta-regression and machine learning (ML). We assessed the study quality through New-Castle-Ottawa Scale and estimate-asymmetry through Eggers regression. (CRD42019142782). RESULTS: Of 4345, 34 studies (2134 patients) were included (good/fair/poor quality: 12/21/1). Pooled mortality of FIs was 64.1% (95% CI: 55.4-72.0, I 2 : 87%, p < .01), which was 2.1 times higher than controls (95% CI: 1.8-2.5, I 2 :89%, p < .01). Higher CTP (MD: +0.52, 95% CI: 0.27-0.77), MELD (MD: +2.75, 95% CI: 1.21-4.28), organ failures and increased hospital stay (30 vs. 19 days) were reported among cases with FIs. Patients with ACLF (76.6%, RR: 2.3) and ICU-admission (70.4%, RR: 1.6) had the highest mortality. The risk was maximum for pulmonary FIs (79.4%, RR: 1.8), followed by peritoneal FIs (68.3%, RR: 1.7) and fungemia (55%, RR: 1.7). The mortality was higher in FIs than in bacterial (RR: 1.7) or no infections (RR: 2.9). Estimate asymmetry was evident (p < 0.05). Up to 8 clusters and 5 outlier studies were identified on ML, and the estimate-heterogeneity was eliminated by excluding such studies. CONCLUSIONS: A substantially worse prognosis, poorer than bacterial infections in cirrhosis patients with FIs, indicates an unmet need for improving fungal diagnostics and therapeutics in this population. ACLF and ICU admission should be included in the host criteria for defining IFIs.

Immune-mediated liver injury following COVID-19 vaccination: A systematic review.

Immune-mediated liver injury (ILI) following coronavirus disease 2019 (COVID-19) vaccination is not well-characterized. Therefore, we systematically reviewed the literature on ILI after COVID-19 vaccination. We searched PubMed, Cochrane, Ovid, Embase, and gray literature to include articles describing ILI following COVID-19 vaccination. Reports without confirmatory evidence from liver biopsy were excluded. Descriptive analysis, and study quality were reported as appropriate. Of the 1,048 articles found, 13 (good/fair quality; 23 patients) were included. Studies were primarily from Europe (n = 8), America (n = 2), Asia (n = 2), or Australia (n = 1). Patients were predominantly females (62.5%) of age 55.3 years (49.1-61.4), with an antecedent exposure to Moderna messenger RNA (mRNA)-1273 (47.8%), Pfizer-BioNTech BNT162b2 mRNA (39.2%), or ChAdOx1 nCoV-19 vaccine (13%). Pre-existing comorbidities (69.6%) were common, including liver disease in 26.1% and thyroid disorders in 13% of patients. About two-thirds of the patients were on concurrent medications (paracetamol, levothyroxine, statins, and non-steroidal anti-inflammatory drugs). Jaundice was the most common symptom (78.3%). Peak bilirubin, alanine aminotransferase, and alkaline phosphatase levels were 10.8 (6.8-14.8) mg/dl, 1,106.5 (757.0-1,702.5) U/L, and 229 (174.6-259.6) U/L, respectively. Histological findings were intense portal lymphoplasmacytic infiltrate with interface hepatitis. Steroids were used in 86.9% of patients, and complete response, recovering course, and death were reported in 56.5%, 39.1%, and 4.3% of patients, respectively. ILI following COVID-19 vaccination is rare. The diagnosis is established on temporal correlation, biochemical findings, and histopathology. Prognosis is excellent with corticosteroids. Causality establishment remains a challenge.

Effect of Probiotics on the Frequency of CD4+ T-Cells in HIV-Infected Children and Adolescents: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Depletion of CD4+ T-cells in the gut-associated lymphoid tissue is the hallmark of HIV infection, with only partial restoration by potent antiretroviral therapy (ART). Gut dysbiosis, together with disruption of mucosal integrity contributes to chronic immune activation that further exacerbates the disease. Data from randomized controlled trials in pediatric HIV patients have indicated potential of probiotics in complementing routine ART in managing HIV-associated gastrointestinal complications. We have systematically extracted data from these trials and performed meta-analysis to quantify the effect of probiotics on CD4+ T-cell counts and any adverse events associated with their supplementation. METHODS: A systematic search through multiple databases yielded three studies that were pooled using fixed-effect model. Risk of bias assessment was done by the Cochrane risk of bias tool and publication bias was assessed by Egger's test. RESULTS: Included studies had moderate risk of bias and Egger's statistics revealed no publication bias (p > 0.05). Pooled analysis showed significant improvement in CD4+ T-cell counts, with mean difference, 123.92 (95% CI: 104.36-143.48), p < 0.0001, no heterogeneity (I2=0) among the included trials. Subgroup analysis also depicted improvement in CD4+ T-cell counts irrespective of treatment duration, in both ART naïve and treated patients. No adverse effects with probiotic consumption were reported. CONCLUSIONS: Probiotics supplementation led to an improvement in CD4+ T-cell counts among HIV-infected children with no observed adverse effects. Despite the inherent limitations of included studies, our systematic review would justify more well-designed, large-scale trials in children, which may guide pediatricians on whether to incorporate probiotics as an adjunct therapy to routine ART.

HIV infection is associated with a progressive decline of CD4+ T-cell numbers and increase in viral load. To keep the virus replication in check, patients need to take the antiretroviral therapy life-long, which is not without gastrointestinal discomfort. Probiotics have already shown multiple benefits ranging from reduction in diarrhea, nausea and bloating besides replenishment of CD4+ T-cells numbers. Based on this background information, we have compiled the data on probiotics among HIV-infected children. A pooled analysis from randomized clinical trials revealed significant improvement in CD4+ T-cell counts in HIV-infected children without any adverse effects. However, we recommend large and well-designed trials in future that would help in forming a concrete and high quality evidence in this context.

Burden of Attention Deficit Hyperactivity Disorder (ADHD) in Indian Children: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the pooled prevalence of attention deficit hyperactivity disorder (ADHD) in Indian children. METHODS: The searching of published literature was conducted in different databases (PubMed, Ovid SP, and EMBASE). The authors also tried to acquire information from the unpublished literature about the prevalence of ADHD. A screening was done to include eligible original studies, community or school-based, cross-sectional or cohort, reporting the prevalence of ADHD in children aged ≤ 18 y in India. Retrieved data were analyzed using STATA MP12 (Texas College station). RESULTS: Of 729 studies retrieved by searching different databases, 183 studies were removed as duplicates, and 546 titles and abstracts were screened. After screening, 19 studies were included for quantitative analysis. Subgroup analysis was conducted with respect to their setting (school-based/community-based). Fifteen studies performed in a school-based setting showed 75.1 (95% CI 56.0-94.1) pooled prevalence of ADHD per 1000 children of 4-19 y of age. In community-based settings, the pooled prevalence per 1000 children surveyed was 18.6 (95% CI 8.8-28.4). The overall pooled prevalence of ADHD was observed as 63.2 (95% CI 49.2-77.1) in 1000 children surveyed. Significant heterogeneity was observed in the systemic review. CONCLUSIONS: ADHD accounts for a significant health burden, and understanding its burden is crucial for effective health policy-making for educational intervention and rehabilitation.

Role of environmental lead in the occurrence of anemia in Indian children: a systematic review and meta-analysis.

Exposure to lead among children, as well as adults, is a major global health issue. With diverse routes of exposure (e.g., food, air, and water) either environmentally or occupationally, lead among children can cause mild, moderate, to severe health complications in the later stages of life. The average blood lead level reported by CDC in 2021 is 3.5 µg/dL, and the level of blood lead toxicity is ≥ 10 µg/dL. In this study, we planned to systematically analyze the association between blood lead levels (BLLs) (≥ 10 µg/dL and < 10 µg/dL) and the risk of anemia (hemoglobin level < 11 g/dL) among Indian children aged between ≥ 1 and ≤ 18 years. An online literature search of 5 databases, PubMed, Ovid, EMBASE, Web of Science, and Google Scholar was accomplished with a search updated until 8th March 2021. Study designs included cohort, cross-sectional, and case-control studies that have evaluated the association of lead toxicity or exposure with anemia (Hb < 11 g/dL) reported in urban and/or rural Indian children. Meta-analysis was performed among a total of 864 children from 4 cross-sectional studies. The association between lead toxicity (BLLs ≥ 10 µg/dL) and the risk of being anemic was not statistically significant (RR = 1.15 (95% CI: 0.86-1.55, I2 = 77%). The risks of bias in all included studies were low according to the Newcastle Ottawa Scale. Increased blood lead levels did not appear to be the major contributor to anemia in Indian Children. We need to focus primarily on improving the nutritional quality, fortified food supplements, and a balanced diet for children to reduce the anemia burden in India. Lead toxicity should be sought as an etiological factor only in areas of high environmental risk factors which were leaded paints, leaded batteries, a house near major road/traffic areas, and pesticide exposure.

Global epidemiological burden of fungal infections in cirrhosis patients: A systematic review with meta-analysis.

BACKGROUND AND AIMS: Fungal infections (FIs) have serious implications, yet understated in cirrhosis. Therefore, we reviewed the epidemiology and trends of FIs among cirrhotics. METHODS: Four electronic databases were searched for full-text articles describing prevalence of FIs in cirrhosis. Studies from post-transplant, malignancy and classical-immuno-deficiency patients were excluded. A random-effects meta-analysis was done to pool estimates of FIs (overall, and by type and infection-site), and their variation(I2 ) was explored on moderator-analysis and meta-regression. Risk of bias and asymmetry in estimates was assessed by a checklist and Egger's regression, respectively.(CRD42019142782). RESULTS: Thirty-four low-risk and four moderate-risk studies (31 984 cirrhotics) were included. Pooled estimates of overall FIs (17 studies), invasive fungal infections (IFIs; 17 studies), invasive candidiasis (23 studies) and invasive aspergillosis (16 studies) in cirrhosis were 10.2%(6.0-16.9), 9.5%(5.4-16.2), 4.0%(2.0-8.0) and 2.8%(1.5-5.3), respectively (I2  > 90%;each). Site of FIs in decreasing order of pooled prevalence was pulmonary, urinary tract, bloodstream, peritoneal, oesophageal and cerebral. Geographic differences in these estimates were remarkable, with highest burden of overall FIs from Belgium, the United States and India. Non-albicans-Candida and Aspergillus infections have increased over the last decade in cirrhosis. Intensive-care-unit (ICU)-admitted and acute-on-chronic liver failure (ACLF) patients had the highest prevalence of IFIs. MELD score(cases), bias score and sample size across studies were the predictors of variance in overall FI estimates. Diabetes, steroid and broad-spectrum antibiotic-exposure, and multiple organ failures were the common predispositions reported in patients with FIs. CONCLUSIONS: FIs impose a substantial burden in cirrhosis. ACLF and ICU admission should be considered as a host factor for defining IFIs. Epidemiology of FIs can guide interpretation of biomarkers and antifungal treatment in cirrhosis.

Factors determining the mortality in cirrhosis patients with invasive candidiasis: A systematic review and meta-analysis.

The impact of invasive candidiasis (IC) on the outcomes in the non-conventional high-risk cirrhosis population is poorly characterized. Therefore, we reviewed the outcomes and their influencing factors in cirrhosis patients with IC. PubMed, Embase, Ovid, CINHAL, and Web of Science were searched for full-text observational studies describing mortality due to IC in cirrhosis. We did a systematic review and random-effects meta-analysis to pool the point-estimate and comparative-odds of mortality. The estimate's heterogeneity was explored on sub-groups, outliers-test, and meta-regression. We evaluated the asymmetry in estimates on funnel plot and Eggers regression. Quality of studies was assessed on the New-Castle Ottawa scale. Of 3143 articles, 13 studies (611 patients) were included (good/fair quality: 6/7). IC patients were sick with a high model for end-stage liver disease (MELD: 27.0) and long hospital stay (33.2 days). The pooled-mortality was 54.7% (95% CI: 41.3--67.5), I2: 80%, P < 0.01. Intensive care unit (ICU) admission (P < 0.001), site of infection; viz. peritonitis and candidemia (P = 0.014) and high MELD of cases (P = 0.029) were predictors of high mortality. The odds of mortality due to IC was 4.4 times higher than controls and was 8.5 and 3.3 times higher than non-infected, and bacterially-infected controls. Studies in ICU-admitted (OR: 5.0) or acute-on-chronic liver failure (ACLF, OR: 6.3) patients had numerically higher odds of mortality than all-hospitalized cirrhosis patients (OR: 4.0). In conclusion, substantially high mortality is reported in cirrhosis patients with IC. ICU admission, ACLF, high MELD, peritonitis, and candidemia are key factors determining high mortality in cirrhosis patients with IC. LAY SUMMARY: We report a high mortality rate of 55% in patients with liver cirrhosis and invasive candidiasis. Higher odds (4.4 times) of death, especially in patients with ACLF (6.3 times) or ICU admission (5.0 times) were seen. Candida peritonitis and candidemia are associated with high mortality in cirrhosis.

Paracetamol exposure and asthma: What does the evidence say? An overview of systematic reviews.

OBJECTIVE: To conduct an umbrella review collating the existing evidence to determine whether there is an association between exposure of Paracetamol in-utero or in infancy and the development of childhood Asthma. METHODS: In this review, systematic reviews with or without meta-analysis that reported the association between paracetamol and asthma in children were included. To identify relevant reviews, a search was performed in the electronic databases PubMed, the Cochrane Library, and Ovid MEDLINE. The protocol was registered in PROSPERO CRD42020156023. A separate search was conducted for primary studies from the last 5 years not yet included in systematic reviews reporting the association from January 2016 to March 2021. RESULTS: The electronic searches identified 1966 review titles. After the removal of 493 duplicates, 1475 titles and abstracts were screened against the eligibility criteria. Full-text screening yielded six systematic reviews to be included in this review. The search for primary studies in the last 5 years yielded 1214 hits, out of which 5 studies were found suitable for inclusion. Three of them, that were not included in the systematic reviews, and have been summarised in this paper. The odds ratios (ORs) for the outcome of asthma in offspring of mothers with prenatal paracetamol consumption in any trimester were 1.28 (1.13-1.39) and 1.21 (1.02-1.44). For first trimester exposures, they were 1.12 (0.99-1.27), 1.39 (1.01-1.91), and 1.21 (1.14-1.28), for the second or third trimester, they were 1.49 (1.37-1.63) and 1.13 (1.04-1.23). For the third trimester only, the figure was 1.17 (1.04-1.31). Of the six reviews included, 1 had a low risk of bias, 2 had an unclear risk while 3 had a high risk of bias assessed using the ROBIS tool. There was no significant increased risk of asthma with early infancy exposure. The inter-study heterogeneity varied from I2 = 41% to I2 = 76% across reviews. In the primary studies, the OR for prenatal exposure ranged from 1.12 (0.25-4.98) to 4.66 (1.92-11.3) and for infancy exposure was 1.56 (1.06-2.30). All three included primary studies were adjudged to be of high quality using the Newcastle Ottawa scale. CONCLUSIONS: There is a modest association between paracetamol exposure in-utero and the future development of asthma. Exposure in infancy has a less consistant association. All the studies done thus far are observational in nature, with their inherent biases. Further research, preferably randomized controlled trials are recommended to answer this pertinent question.

Invasive aspergillosis is a critical determinant of mortality in cirrhosis: a systematic review with meta-analysis.

Invasive fungal infections pose a severe threat in unconventional immunocompromised hosts such as cirrhosis. Herein we review the impact of invasive aspergillosis (IA) on the prognosis of cirrhosis patients. An electronic search for full-text articles describing IA in cirrhosis was conducted and the disease outcomes and mortality (point-estimate and comparative risk) were pooled on random-effects meta-analysis. Of 4127 articles, 11 studies (9 with good/fair and 2 with poor quality) were included. IA was associated with high disease severity and multi-organ failures in cirrhosis. The pooled-mortality of IA was 81.8% (95% CI: 64.3-91.8, I2 = 59%, P < 0.01). Estimate's-heterogeneity (I2) was explored through sub-groups, meta-regression, and influential diagnostics. Mortality estimates were higher among subgroups of acute-on-chronic liver failure (ACLF, 86.4%) and intensive care unit (ICU)-admitted patients (84.0%). The odds of mortality related to IA were 8.9 times higher than controls and much higher in ACLF (OR: 22.5) and ICU-admitted patients (OR: 36.4). The odds of mortality in IA were 4.1, 12.9, and 48.6 times higher than bacterial, no-fungal infections, and no-infection controls. There was no asymmetry in mortality estimates or odds ratios and mortality in IA was high irrespective of country of origin, site of infection, proven or probable category, and quality of study. Thus, IA is associated with very high mortality in cirrhosis patients, especially in ACLF and ICU-admitted patients. Intensive research is needed for the rapid diagnosis and treatment of IA in cirrhosis. LAY SUMMARY: We report a high mortality rate of 81.8% in patients with liver cirrhosis and invasive aspergillosis. Higher odds (8.9 times) of death, especially in patients with ACLF or ICU admission were seen. Mortality was not affected by the country of study, site of infection, proven or probable nature of infection category, and quality of study.

Computational tissue staining of non-linear multimodal imaging using supervised and unsupervised deep learning.

Hematoxylin and Eosin (H&E) staining is the 'gold-standard' method in histopathology. However, standard H&E staining of high-quality tissue sections requires long sample preparation times including sample embedding, which restricts its application for 'real-time' disease diagnosis. Due to this reason, a label-free alternative technique like non-linear multimodal (NLM) imaging, which is the combination of three non-linear optical modalities including coherent anti-Stokes Raman scattering, two-photon excitation fluorescence and second-harmonic generation, is proposed in this work. To correlate the information of the NLM images with H&E images, this work proposes computational staining of NLM images using deep learning models in a supervised and an unsupervised approach. In the supervised and the unsupervised approach, conditional generative adversarial networks (CGANs) and cycle conditional generative adversarial networks (cycle CGANs) are used, respectively. Both CGAN and cycle CGAN models generate pseudo H&E images, which are quantitatively analyzed based on mean squared error, structure similarity index and color shading similarity index. The mean of the three metrics calculated for the computationally generated H&E images indicate significant performance. Thus, utilizing CGAN and cycle CGAN models for computational staining is beneficial for diagnostic applications without performing a laboratory-based staining procedure. To the author's best knowledge, it is the first time that NLM images are computationally stained to H&E images using GANs in an unsupervised manner.

Comparative accuracy of 1,3 beta-D glucan and galactomannan for diagnosis of invasive fungal infections in pediatric patients: a systematic review with meta-analysis.

Invasive fungal infections (IFI) cause considerable morbidity and mortality in pediatric patients. Serum biomarkers such as 1,3-beta-D glucan (BDG) and galactomannan (GM) have been evaluated for the IFI diagnosis. However, most evidence regarding their utility is derived from studies in adult oncology patients. This systematic review aimed to compare the diagnostic accuracy of BDG and GM individually or in combination for diagnosing IFI in pediatric patients. PubMed, CINAHL, Embase, and Cochrane Library were searched until March 2019 for diagnostic studies evaluating both serum GM and BDG for diagnosing pediatric IFI. The pooled diagnostic odds ratio (DOR), specificity and sensitivity were computed. Receiver operating characteristics (ROC) curve and area under the curve (AUC) were used for summarizing overall assay performance. Six studies were included in the meta-analysis. The summary estimates of sensitivity, specificity, pooled DOR, AUC of the GM assay for proven or probable IFI were 0.74, 0.76, 13.25, and 0.845. The summary estimates of sensitivity, specificity, pooled DOR, AUC of the BDG assay were 0.70, 0.69, 4.3, and 0.722. The combined predictive ability of both tests was reported in two studies (sensitivity: 0.67, specificity: 0.877). Four studies were performed in hematology-oncology patients, while two were retrospective studies from pediatric intensive care units (ICUs). In the subgroup of hematology-oncology patients, DOR of BDG remained similar at 4.25 but increased to 40.28 for GM. We conclude that GM and BDG have a modest performance for identifying IFI in pediatric patients. GM has a better accuracy over BDG. Combining both improves the specificity at the cost of sensitivity.

Towards an Interpretable Classifier for Characterization of Endoscopic Mayo Scores in Ulcerative Colitis Using Raman Spectroscopy.

Ulcerative colitis (UC) is one of the main types of chronic inflammatory diseases that affect the bowel, but its pathogenesis is yet to be completely defined. Assessing the disease activity of UC is vital for developing a personalized treatment. Conventionally, the assessment of UC is performed by colonoscopy and histopathology. However, conventional methods fail to retain biomolecular information associated to the severity of UC and are solely based on morphological characteristics of the inflamed colon. Furthermore, assessing endoscopic disease severity is limited by the requirement for experienced human reviewers. Therefore, this work presents a nondestructive biospectroscopic technique, for example, Raman spectroscopy, for assessing endoscopic disease severity according to the four-level Mayo subscore. This contribution utilizes multidimensional Raman spectroscopic data to generate a predictive model for identifying colonic inflammation. The predictive modeling of the Raman spectroscopic data is performed using a one-dimensional deep convolutional neural network (1D-CNN). The classification results of 1D-CNN achieved a mean sensitivity of 78% and a mean specificity of 93% for the four Mayo endoscopic scores. Furthermore, the results of the 1D-CNN are interpreted by a first-order Taylor expansion, which extracts the Raman bands important for classification. Additionally, a regression model of the 1D-CNN model is constructed to study the extent of misclassification and border-line patients. The overall results of Raman spectroscopy with 1D-CNN as a classification and regression model show a good performance, and such a method can serve as a complementary method for UC analysis.