Fluid resuscitation in children with severe infection and septic shock: a systematic review and meta-analysis.

This study aimed to evaluate the current evidence on various aspects of fluid therapy such as type, volume, and timing of fluid bolus administration in children with septic shock. Systematic review and meta-analysis of clinical trials including children less than 18 years of age admitted to the pediatric emergency and intensive care unit with severe infection and shock requiring fluid resuscitation. The intervention included balanced crystalloids (BC) vs normal saline (NS), colloids vs NS, restricted vs liberal fluid bolus, and slow vs fast fluid bolus. The primary outcome was mortality rate. Of the 219 citations retrieved, 12 trials (3526 children with severe infection with or without malaria and shock) were included. The pooled results found no significant difference in the mortality rate between groups comparing balanced crystalloids (BC) vs normal saline (NS), colloids vs NS, restricted vs liberal fluid bolus, and slow vs fast fluid bolus. The risk of acute kidney injury (AKI) was significantly less in the BC group compared to the NS group. The certainty of evidence for mortality was of "moderate certainty" in the BC vs NS group, and was of "very low certainty" for the other two groups. CONCLUSIONS: The current meta-analysis found no significant difference in the mortality rate between the types of resuscitation fluid, and their speed or volume of administration. However, a significantly decreased risk of AKI was found in the BC group. More evidence is needed regarding the speed and volume of administration of fluid boluses in critically ill children.Prospero registration: CRD42020209066. WHAT IS KNOWN: • Balanced crystalloids (BC) may be better than normal saline (NS) for fluid resuscitation in critically ill children. WHAT IS NEW: • BC are better than NS for fluid resuscitation in critically ill children as they decrease AKI and hyperchloremia.

Microglial remodeling of actin network by Tau oligomers, via G protein-coupled purinergic receptor, P2Y12R-driven chemotaxis.

Alzheimer's disease (AD) is associated with age-related neurodegeneration, synaptic deformation and chronic inflammation mediated by microglia and infiltrated macrophages in the brain. Tau oligomers can be released from damaged neurons via various mechanisms such as exosomes, neurotransmitter, membrane leakage etc. Microglia sense the extracellular Tau through several cell-surface receptors and mediate chemotaxis and phagocytosis. The purinergic receptor P2Y12R recently gained interest in neurodegeneration for neuro-glial communication and microglial chemotaxis towards the site of plaque deposition. To understand the effect of extracellular Tau oligomers in microglial migration, the P2Y12R-mediated actin remodeling, reorientation of tubulin network and rate of migration were studied in the presence of ATP. The extracellular Tau species directly interacted with P2Y12R and also induced this purinoceptor expression in microglia. Microglial P2Y12R colocalized with remodeled membrane-associated actin network as a component of migration in response to Tau oligomers. As an inducer of P2Y12R, ATP facilitated the localization of P2Y12R in lamellipodia and filopodia during accelerated microglial migration. The direct interaction of extracellular Tau oligomers with microglial P2Y12R would facilitate the signal transduction in both way, directional chemotaxis and receptor-mediated phagocytosis. These unprecedented findings emphasize that microglia can modulate the membrane-associated actin structure and incorporate P2Y12R to perceive the axis and rate of chemotaxis in Tauopathy.

Multiple Electrolytes Solution Versus Saline as Bolus Fluid for Resuscitation in Pediatric Septic Shock: A Multicenter Randomized Clinical Trial.

OBJECTIVE: To determine if initial fluid resuscitation with balanced crystalloid (e.g., multiple electrolytes solution [MES]) or 0.9% saline adversely affects kidney function in children with septic shock. DESIGN: Parallel-group, blinded multicenter trial. SETTING: PICUs of four tertiary care centers in India from 2017 to 2020. PATIENTS: Children up to 15 years of age with septic shock. METHODS: Children were randomized to receive fluid boluses of either MES (PlasmaLyte A) or 0.9% saline at the time of identification of shock. All children were managed as per standard protocols and monitored until discharge/death. The primary outcome was new and/or progressive acute kidney injury (AKI), at any time within the first 7 days of fluid resuscitation. Key secondary outcomes included hyperchloremia, any adverse event (AE), at 24, 48, and 72 hours, and all-cause ICU mortality. INTERVENTIONS: MES solution ( n = 351) versus 0.9% saline ( n = 357) for bolus fluid resuscitation during the first 7 days. MEASUREMENTS AND MAIN RESULTS: The median age was 5 years (interquartile range, 1.3-9); 302 (43%) were girls. The relative risk (RR) for meeting the criteria for new and/or progressive AKI was 0.62 (95% CI, 0.49-0.80; p < 0.001), favoring the MES (21%) versus the saline (33%) group. The proportions of children with hyperchloremia were lower in the MES versus the saline group at 24, 48, and 72 hours. There was no difference in the ICU mortality (33% in the MES vs 34% in the saline group). There was no difference with regard to infusion-related AEs such as fever, thrombophlebitis, or fluid overload between the groups. CONCLUSIONS: Among children presenting with septic shock, fluid resuscitation with MES (balanced crystalloid) as compared with 0.9% saline resulted in a significantly lower incidence of new and/or progressive AKI during the first 7 days of hospitalization.

Comparison of oral triclofos and intranasal midazolam and dexmedetomidine for sedation in children undergoing magnetic resonance imaging (MRI): an open-label, three-arm, randomized trial.

The purpose of this study was to compare the efficacy of oral triclofos (TRI), intranasal midazolam (INM), and intranasal dexmedetomidine (IND) in achieving successful sedation in children undergoing MRI. This open-label, three-arm, randomized trial was conducted in a tertiary care teaching hospital over 18-month period. Children scheduled for MRI were enrolled. Rate of successful/adequate sedation was assessed using the Paediatric Sedation State Scale (PSSS). The primary outcome was the efficacy (successful sedation or sedation rate) of the three drugs. One-hundred and ninety-five children were included for the MRI procedure. IND was found to be superior in terms of achieving successful sedation. INM had a shorter onset and duration of sedation compared to IND and TRI, but with an increased failure rate (88.3%). Keeping INM as the reference group, it was found that the odds of sedation increased 4.1 times on changing from INM to IND (p < 0.01), and 2.26 times on changing from INM to TRI (p < 0.01). Adverse events included nasal discomfort (18.3%) in INM group; and self-limited tachycardia (4.6%) and hypotension (10.8%) in the IND group. CONCLUSION: IND was more efficacious than INM or TRI for procedural sedation in children undergoing MRI without any significant adverse events. CLINICAL TRIAL REGISTRATION: CTRI/2019/01/017257; date registered: 25/01/2019. WHAT IS KNOWN: • Oral triclofos (TRI) and intranasal midazolam (INM) have been used for procedural sedation in children undergoing MRI with variable success; but the experience with intranasal dexmedetomidine (IND) is limited. WHAT IS NEW: • IND provides more effective sedation compared to INM or TRI for procedural sedation in children undergoing MRI, without any significant adverse events.

Vitamin D as an adjunct to antibiotics for the treatment of acute childhood pneumonia.

BACKGROUND: Children with acute pneumonia may be vitamin D deficient. Clinical trials have found that prophylactic vitamin D supplementation decreases children's risk of developing pneumonia. Data on the therapeutic effects of vitamin D in acute childhood pneumonia are limited. This is an update of a Cochrane Review first published in 2018. OBJECTIVES: To evaluate the efficacy and safety of vitamin D supplementation as an adjunct to antibiotics for the treatment of acute childhood pneumonia. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries on 28 December 2021. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared vitamin D supplementation with placebo in children (aged one month to five years) hospitalised with acute community-acquired pneumonia, as defined by the World Health Organization (WHO) acute respiratory infection guidelines. For this update, we reappraised eligible trials according to research integrity criteria, excluding RCTs published from April 2018 that were not prospectively registered in a trials registry according to WHO or Clinical Trials Registry - India (CTRI) guidelines (it was not mandatory to register clinical trials in India before April 2018). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. For dichotomous data, we extracted the number of participants experiencing the outcome and the total number of participants in each treatment group. For continuous data, we used the arithmetic mean and standard deviation (SD) for each treatment group together with number of participants in each group. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: In this update, we included three new trials involving 468 children, bringing the total number of trials to seven, with 1601 children (631 with pneumonia and 970 with severe or very severe pneumonia). We categorised three previously included studies and three new studies as 'awaiting classification' based on the research integrity screen. Five trials used a single bolus dose of vitamin D (300,000 IU in one trial and 100,000 IU in four trials) at the onset of illness or within 24 hours of hospital admission; one used a daily dose of oral vitamin D (1000 IU for children aged up to one year and 2000 IU for children aged over one year) for five days; and one used variable doses (on day 1, 20,000 IU in children younger than six months, 50,000 IU in children aged six to 12 months, and 100,000 IU in children aged 13 to 59 months; followed by 10,000 IU/day for four days or until discharge). Three trials performed microbiological diagnosis of pneumonia, radiological diagnosis of pneumonia, or both. Vitamin D probably has little or no effect on the time to resolution of acute illness (mean difference (MD) -1.28 hours, 95% confidence interval (CI) -5.47 to 2.91; 5 trials, 1188 children; moderate-certainty evidence). We do not know if vitamin D has an effect on the duration of hospitalisation (MD 4.96 hours, 95% CI -8.28 to 18.21; 5 trials, 1023 children; very low-certainty evidence). We do not know if vitamin D has an effect on mortality rate (risk ratio (RR) 0.69, 95% CI 0.44 to 1.07; 3 trials, 584 children; low-certainty evidence). The trials reported no major adverse events. According to GRADE criteria, the evidence was of very low-to-moderate certainty for all outcomes, owing to serious trial limitations, inconsistency, indirectness, and imprecision. Three trials received funding: one from the New Zealand Aid Corporation, one from an institutional grant, and one from multigovernment organisations (Bangladesh, Sweden, and UK). The remaining four trials were unfunded. AUTHORS' CONCLUSIONS: Based on the available evidence, we are uncertain whether vitamin D supplementation has important effects on outcomes of acute pneumonia when used as an adjunct to antibiotics. The trials reported no major adverse events. Uncertainty in the evidence is due to imprecision, risk of bias, inconsistency, and indirectness.

Vascular dysfunction in juvenile idiopathic arthritis: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis of studies evaluating vascular function in patients with JIA. Relevant literature published from 1st January 1965 to 1st March 2022 was searched systematically utilizing PubMed, Web of Science, and Embase databases. Observational studies were included-patients with JIA (classified according to the International League of Associations for Rheumatology criteria) were included as cases (study population) and age/sex-matched healthy participants as controls (comparator group). Outcome measures were differences in non-invasive parameters of vascular function. Online Population, Intervention, Comparison, Outcomes Portal was used for deduplication of studies and data extraction. Review Manager, Comprehensive Meta-analysis, and Meta-Essential softwares were used for data synthesis/analysis (encompassing data pooling and evaluation of heterogeneity and publication bias). Newcastle-Ottawa Scale and GRADEpro GDT software were utilized to assess study quality and certainty of evidence, respectively. Of 338 citations, 17 observational studies with 1423 participants (cases = 757, controls = 666) were included. Carotid intima-media thickness (CIMT) was higher [mean difference (MD) 0.02 mm {95% confidence interval (CI) 0.01-0.04}, p = 0.0006, I2 = 69%] in patients with JIA. Besides, decreased flow-mediated dilatation (FMD) [MD - 2.18% {95%CI - 3.69- - 0.68}, p = 0.004, I2 = 73%] was also observed. Results of studies assessing pulse wave velocity or arterial stiffness could not be pooled due to significant methodological variations. A 'very low' certainty of evidence suggests the presence of vascular dysfunction in JIA. Future longitudinal studies are required to determine whether altered CIMT and FMD in patients with JIA translate to an enhanced risk of (adverse) clinical cardiovascular events. PROSPERO (CRD42022323752).

Long-term vascular dysfunction in Kawasaki disease: systematic review and meta-analyses.

BACKGROUND: Long-term physiological dysfunction in coronary/systemic vasculature may persist in individuals with Kawasaki disease even in the absence of coronary artery abnormalities. We perform a systematic review and meta-analyses of studies assessing long-term vascular function in Kawasaki disease. METHODS: PubMed, Embase, and Web of Science databases were searched for relevant literature published till May 2021. Patients with Kawasaki disease were included as cases and healthy age/sex-matched individuals as controls. Newcastle Ottawa Scale was used to assess the study quality. Outcome measures were differences in markers of vascular function 1 year after diagnosis of Kawasaki disease. Data were analysed using Review Manager software. Comprehensive meta-analysis software was used for meta-regression. To assess the certainty of evidence, GRADE Profiler software was utilised. RESULTS: Of 2280 citations, 49 case-control studies (comprising 2714 cases and 2118 controls) were included for data synthesis. Decreased flow-mediated dilatation [3.83, 95%CI 0.94-6.72] and increased pulse-wave velocity [39.34 cm/sec, 95%CI 20.86-57.83], arterial stiffness [0.35, 95%CI 0.11-0.59], and common carotid artery intima-media thickness were noted in patients with Kawasaki disease. No significant difference was observed for nitroglycerine-mediated dilatation and endothelial peripheral artery tonometry (endo-PAT). Significant inter-study heterogeneity was observed for flow-mediated dilatation, arterial stiffness, carotid artery intima-media thickness, and endo-PAT. The GRADE evidence was of 'very low quality' for all outcome measures except 'moderate quality' for pulse-wave velocity. CONCLUSIONS: Evidence suggests the presence of long-term endothelial dysfunction in patients with Kawasaki disease even in the absence of coronary artery abnormalities. Avoidance of development of other cardiovascular risk factors seems prudent in patients with Kawasaki disease.

Feasibility of establishing acute respiratory infection treatment units (ATU) for improvement of care of children with acute respiratory infection.

BACKGROUND: Acute respiratory infections (ARI) are the leading cause of morbidity and mortality in children below 5 years of age. METHODS: This multisite prospective observational study was carried out in the Pediatrics' out-patient departments of 5 medical colleges across India with an objective to assess the feasibility of establishing Acute Respiratory Infection Treatment Unit (ATU) in urban medical college hospitals. ATU (staffed with a nurse and a medical officer) was established in the out-patient areas at study sites. Children, aged 2-59 months, with cough and/ breathing difficulty for < 14 days were screened by study nurse in the ATU for pneumonia, severe pneumonia or no pneumonia. Diagnosis was verified by study doctor. Children were managed as per the World Health Organization (WHO) guidelines. The key outcomes were successful establishment of ATUs, antibiotic usage, treatment outcomes. RESULTS: ATUs were successfully established at the 5 study sites. Of 18,159 under-five children screened, 7026 (39%) children were assessed to have ARI. Using the WHO criteria, 938 were diagnosed as pneumonia (13.4%) and of these, 347 (36.9%) had severe pneumonia. Ambulatory home-based management was done in 6341 (90%) children with ARI; of these, 16 (0.25%) required admission because of non-response or deterioration on follow-up. Case-fatality rate in severe pneumonia was 2%. Nearly 12% of children with 'no pneumonia' received antibiotics. CONCLUSIONS: Setting up of ATUs dedicated to management of ARI in children was feasible in urban medical colleges. The observed case fatality, and rate of unnecessary use of antibiotics were lower than that reported in literature.

Role of procalcitonin in diagnosis of community acquired pneumonia in Children.

BACKGROUND: The role of serum Procalcitonin (PCT) in adults in diagnosis of Community acquired pneumonia (CAP) is well established, however, role in pediatric CAP remains controversial. OBJECTIVES: The objective of this study was to investigate the utility of serum procalcitonin in differentiating bacterial community-acquired lower respiratory tract infection from non-bacterial respiratory infection in children; radiologically confirmed pneumonia was used as the reference. In addition, we assessed the utility of adding the PCT assay to the clinical criteria for diagnosis of pneumonia. STUDY DESIGN: Subanalysis of a larger prospective,multicentriccohort study. PARTICIPANTS: Children, 2 months to 59 months of age, attending paediatric OPD of 5 urban tertiary care hospitals, suffering from acute respiratory infection (ARI). INTERVENTION: Detailed clinical history and examination findings of enrolled children were recorded on predesigned case record form. Samples for PCT were obtained at admission and were measured centrally at the end of the study except for one site using VIDAS® B.R.A.H.M.S PCT kit (Biomerieux SA, France). OUTCOMES: Sensitivity and specificity of procalcitonin for diagnosis of radiologically confirmed pneumonia. RESULTS: Serum Procalcitonin was measured in 370 patients; median (IQR) age of these children being 12 (7, 22) months, 235 (63.5%) were boys. The median (IQR) serum procalcitonin concentration was 0.1(0.05, 0.4) ng/mL.Sensitivity and specificity of raised PCT (> 0.5 ng/mL) for pneumonia as per any CXR abnormalities were 29.7% and87.5%,(P < 0.001) respectively. Raised PCT was also significantly associated with consolidation (34.5%,79.2%,P < 0.02)and pleural effusion(54.6%,79%,P < 001). Adding PCT to the existing clinical criteria of WHO did not improve the sensitivity for diagnosis of pneumonia. PCT was significantly higher in children with severe pneumonia. CONCLUSION: Positive PCT (> 0.5 ng/mL) is significantly associated with radiographic pneumonia but not with pneumonia based on WHO criteria.However, it can act as a surrogate marker for severe pneumonia.

Bed sharing versus no bed sharing for healthy term neonates.

BACKGROUND: There is great global variation in the sleeping arrangements for healthy newborn infants. Bed sharing is a type of sleeping practice in which the sleeping surface (e.g. bed, couch or armchair, or some other sleeping surface) is shared between the infant and another person. The possible physiological benefits include better oxygen and cardiopulmonary stability, fewer crying episodes, less risk of hypothermia, and a longer duration of breastfeeding. On the other hand, the most important harmful effect of bed sharing is that it may increase the risk of sudden infant death syndrome (SIDS). Studies have found conflicting evidence regarding the safety and efficacy of bed sharing during infancy. OBJECTIVES: To evaluate the efficacy and safety of bed sharing, started during the neonatal period, on breastfeeding status (exclusive and total duration of breastfeeding), incidence of SIDS, rates of hypothermia, neonatal and infant mortality, and long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 7) in the Cochrane Library; MEDLINE via PubMed (1966 to 23 July 2020), CINAHL (1982 to 23 July 2020), and LILACS (1980 to 23 July 2020). We also searched clinical trials databases, and the reference lists of retrieved articles, for randomised controlled trials (RCTs) and quasi-RCTS. SELECTION CRITERIA: We planned to include RCTs or quasi-RCTs (including cluster-randomised trials) that included term neonates initiated on bed sharing within 24 hours of birth (and continuing to bed share with the mother in the first four weeks of life, followed by a variable time period thereafter), and compared them to a 'no bed sharing' group. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. We planned to use the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Our search strategy yielded 6231 records. After removal of duplicate records, we screened 2745 records by title and abstract. We excluded 2739 records that did not match our inclusion criteria. We obtained six full-text studies for assessment. These six studies did not meet the eligibility criteria and were excluded. AUTHORS' CONCLUSIONS: We did not find any studies that met our inclusion criteria. There is a need for RCTs on bed sharing in healthy term neonates that directly assess efficacy (i.e. studies in a controlled setting, like hospital) or effectiveness (i.e. studies conducted in community or home settings) and safety. Future studies should assess outcomes such as breastfeeding status and risk of SIDS. They should also include neonates from high-income countries and low- and middle-income countries, especially those countries where bed sharing is more prevalent because of cultural practices (e.g. Asian countries).

Comparison of performances of loop-mediated isothermal amplification, XPERT MTB/RIF and BACTEC MGIT in the diagnosis of childhood tuberculosis.

AIM: Key to the successful management of paediatric pulmonary tuberculosis (PTB) lies in the early detection and proper treatment. We evaluated the performances of modern diagnostic tests: loop-mediated isothermal amplification (LAMP-IS6110), Xpert MTB/RIF (Cepheid) and mycobacteria growth indicator tube (BACTEC MGIT 960 culture) against a modified version of international consensus diagnostic definition (i.e. composite reference standard (CRS)). METHODS: A cross-sectional analytical study was conducted in a tertiary care hospital in North India from July 2016 to December 2017 involving 100 children <14 years with suspected PTB. Respiratory specimens (sputum, gastric lavage and/or bronchoalveolar lavage) were collected and subjected to LAMP-IS6110, Xpert MTB/RIF and BACTEC MGIT 960 culture assay. RESULTS: Fifty-five children had confirmed and probable TB according to the CRS (prevalence = 58.5%). The sensitivity of BACTEC MGIT 960 culture, Xpert MTB/RIF and LAMP-IS6110 assay was 14%, 9.1% and 10.91%, respectively, when compared against the predefined CRS. The specificity for all these tests was 100%. When compared with BACTEC MGIT 960 culture as the gold standard, the LAMP-IS6110 assay and Xpert MTB/RIF assay had the sensitivity of 85.71% (95% CI: 42.13-99.64%) and 71.43% (95% CI: 29.04-96.33%), respectively. The specificity of both assays was 100%. CONCLUSIONS: We noted that LAMP-IS6110 performed better than Xpert MTB/RIF (Cepheid) in terms of sensitivity when compared against BACTEC MGIT 960 culture as reference standard, though specificity of both the tests was comparable. The diagnostic performance of BACTEC MGIT 960 culture was better than LAMP-IS6110 and Xpert MTB/RIF in paediatric PTB, when compared against CRS.

Clinical Profile and Risk Factors for Severe Disease in 402 Children Hospitalized with SARS-CoV-2 from India: Collaborative Indian Pediatric COVID Study Group.

INTRODUCTION: There is a lack of large multicentric studies in children with COVID-19 from developing countries. We aimed to describe the clinical profile and risk factors for severe disease in children hospitalized with COVID-19 from India. METHODS: In this multicentric retrospective study, we retrieved data related to demographic details, clinical features, including the severity of disease, laboratory investigations and outcome. RESULTS: We included 402 children with a median (IQR) age of 7 (2-11) years. Fever was the most common symptom, present in 38.2% of children. About 44% had underlying comorbidity. The majority were asymptomatic (144, 35.8%) or mildly symptomatic (219, 54.5%). There were 39 (9.7%) moderate-severe cases and 13 (3.2%) deaths. The laboratory abnormalities included lymphopenia 25.4%, thrombocytopenia 22.1%, transaminitis 26.4%, low total serum protein 34.7%, low serum albumin 37.9% and low alkaline phosphatase 40%. Out of those who were tested, raised inflammatory markers were ferritin 58.9% (56/95), c-reactive protein 33.3% (41/123), procalcitonin 53.5% (46/86) and interleukin-6 (IL-6) 76%. The presence of fever, rash, vomiting, underlying comorbidity, increased total leucocyte count, thrombocytopenia, high urea, low total serum protein and raised c-reactive protein was factors associated with moderate to severe disease. CONCLUSION: Fever was the commonest symptom. We identified additional laboratory abnormalities, namely lymphopenia, low total serum protein and albumin and low alkaline phosphatase. The majority of the children were asymptomatic or mildly symptomatic. We found high urea and low total serum protein as risk factors for moderate to severe disease for the first time.

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia.

BACKGROUND: Alzheimer's disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-ß plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern. METHODS: In this study, we have prepared and stabilized hTau40WT oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1-sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-ß sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40WT oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis. RESULTS: Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50 nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11+ Iba1high microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau. CONCLUSION: The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer's disease condition.

Microglial priming of antigen presentation and adaptive stimulation in Alzheimer's disease.

The prominent pathological consequences of Alzheimer's disease (AD) are the misfolding and mis-sorting of two cellular proteins, amyloid-ß and microtubule-associated protein Tau. The accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of amyloid-ß-associated signaling cascade and vice versa. Neuroinflammation-driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors that prove their diverse functions in maintaining CNS homeostasis via collaboration with astrocytes and T lymphocytes. Age-related senescence and chronic inflammation activate microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis. But the improper processing of misfolded protein via lysosomal pathway destines the spreading of 'seed' constituents to the nearby healthy neurons. Primed microglia process and present self-antigen such as amyloid-ß and modified Tau to the infiltrated T lymphocytes through MHC I/II molecules. After an effective conversation with CD4+ T cells, microglial phenotype can be altered from pro-active M1 to neuro-protective M2 type, which corresponds to the tissue remodeling and homeostasis. In this review, we are focusing on the change in functionality of microglia from innate to adaptive immune response in the context of neuroprotection, which may help in the search of novel immune therapy in AD.

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study.

BACKGROUND & OBJECTIVES: In India, the burden of Plasmodium vivax malaria has been projected to be highest in some areas. This study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate (AM) 37.5 mg and piperaquine phosphate 187.5 mg (PQP) dispersible tablets and (not with) chloroquine in the treatment of uncomplicated vivax malaria in pediatric patients. METHODS: This multicentric, open-label trial was carried out at 12 sites in India. A total of 164 patients aged 6 months to 12 years with P. vivax malaria were randomized in a ratio of 2:1 to AM-PQP (111 patients) or chloroquine (53 patients) arms. The duration of follow up was 42 days. RESULTS: At 72 hours, the proportion of a parasitaemic and afebrile patients was 100% in both treatment arms in per protocol (PP) population, and 98.2% and 100% [95% CI: -1.8 (-6.33 to 5.08)] in AM-PQP and chloroquine arms, respectively, in intent to treat (ITT) population. The efficacy and safety of AM-PQP was found to be comparable to chloroquine in the treatment of uncomplicated P. vivax malaria in pediatric patients. Overall, the cure rate at Day 28 and 42 was >95% for both AM-PQP or CQ. The commonly reported clinical adverse event was vomiting. No patient was discontinued for any QTc abnormality. INTERPRETATION & CONCLUSION: The efficacy and safety of FDC of arterolane maleate and piperaquine phosphate was found to be comparable to chloroquine for treatment of uncomplicated P. vivax malaria in pediatric patients.

Mutualistic benefit in the self-sorted co-aggregates of peri-naphthoindigo and a 4-amino-1,8-naphthalimide derivative.

Photoluminescence enhancement for all the members of a self-sorted co-aggregate was observed for the first time by successfully amalgamating AIEE and social self-sorting. Intermolecular H-bonding and π-π stacking were utilised to prepare several co-aggregates of peri-naphthoindigo (PNI) and a 4-amino-1,8-naphthalimide derivative dye, NH2-NMI. In the heteromeric aggregates, photoluminescence intensities were increased by 28% for the imide and more than 400% for PNI. Due to spectral overlap between the emission of the imide and the absorption of PNI, energy transfer took place from the former to the latter. The heteromeric aggregates are dual emissive and the relative intensities of the emissions can easily be tuned by varying the stoichiometry of the dyes.

Effect of Severe Vitamin D Deficiency at Admission on Shock Reversal in Children With Septic Shock: A Prospective Observational Study.

OBJECTIVES:: To evaluate the association of severe vitamin D deficiency with clinically important outcomes in children with septic shock. METHODS:: We enrolled children ≤17 years with septic shock prospectively over a period of 6 months. We estimated 25-hydroxyvitamin D [25 (OH) D] levels at admission and 72 hours. Severe deficiency was defined as serum 25 (OH) <10 ng/mL. We performed univariate and multivariate analysis to evaluate association with clinically important outcomes. RESULTS:: Forty-three children were enrolled in the study. The prevalence of severe vitamin D deficiency was 72% and 69% at admission and 72 hours, respectively. On univariate analysis, severe vitamin D deficiency at admission was associated with lower rates of shock reversal, 74% (23) versus 25% (3); relative risk (95% confidence interval [CI]): 2.9 (1.09-8.08), at 24 hours and greater need for fluid boluses (75 vs 59 mL/kg). On multivariate analysis, nonresolution of shock at 24 hours was significantly associated with severe vitamin D deficiency after adjusting for other key baseline and clinical variables, adjusted odds ratio (95% CI): 12 (2.01-87.01); 0.01. CONCLUSION:: The prevalence of severe vitamin D deficiency is high in children with septic shock admitted to pediatric intensive care unit. Severe vitamin D deficiency at admission seems to be associated with lower rates of shock reversal at 24 hours of ICU stay. Our study provides preliminary data for planning interventional studies in children with septic shock and severe vitamin D deficiency.

Clinical Profile, Etiology, and Outcome of Infantile Ocular Trauma: A Developing Country Perspective.

OBJECTIVE: The aim of this article was to study the clinical profile, etiology, and outcome of infantile ocular trauma in a developing country setting. METHODS: A retrospective study on corneal trauma in infants (≤12 months old) was undertaken in a tertiary care hospital during a 2-year period. An analysis of clinical profile, etiology, microbiological profile, clinical course, and outcome was studied. RESULTS: Seventy-six infants were included. Approximately 69% presented within 24 hours of injury. The common presentations were inability to open the eyelids, redness of eyes, and watering. Self-infliction by child's hand (49%) was found to be the main cause of corneal trauma. Corneal abrasion was seen in 34 cases (45%), isolated epithelial defects were seen in 30%, and infective keratitis was seen in 25%. Infection was found in 14 cases (fungal filaments in 7 and gram-positive cocci in 7). Only 36 infants followed up regularly in the hospital. All the infants following up in the hospital recovered in due course. CONCLUSIONS: Infantile ocular trauma is a common morbidity that is underreported. Self-infliction by child's hand was found to be the main cause of corneal trauma. Cases presenting early and following up regularly till recovery have a favorable clinical course with good outcome. A high loss to follow-up indicates that awareness needs to be created among the caregivers.

Effect of a Training Strategy in Improving Medication Fallacies During Pediatric Cardiopulmonary Resuscitation: A Before-and-After Study From a Developing Country.

OBJECTIVE: This study aims to evaluate the effect of structured training on resident performance in improving medication fallacies during pediatric cardiopulmonary resuscitation (CPR). METHODS: This before-and-after study was conducted in the pediatric acute care areas of tertiary care teaching hospitals of a developing country from August to December 2015. Case records of children younger than 18 years who underwent CPR were reviewed. Senior residents rotating through pediatric emergency department and pediatric intensive care unit were evaluated for their knowledge. Incidence of medication fallacies in pediatric CPR and change in the knowledge scores of residents posted in these areas were the main outcome measures. RESULTS: One-hundred records were evaluated (pre-intervention, 54; post-intervention, 46). In the pre-intervention period, 25 had medication fallacies (documentation, 16; dosing, 9). In the post-intervention period, 7 fallacies pertaining to documentation (not dosing) were found. The incidence of severe fallacies decreased from 20% pretraining to 0% posttraining. The mean (SD) knowledge scores of residents increased from 7.9 (2.9) pretraining to 13 (1.4) posttraining. On univariate analysis, fallacies were found to be less if the resident was formally trained (pediatric advanced life support certified), if the patient was older, and during morning and night shifts as compared with evening shift. On multivariate analysis, however, only status of training (posttraining) (adjusted odds ratio, 0.12; 95% confidence interval, 0.02-0.68) and the morning shift (adjusted odds ratio, 0.03; 95% confidence interval, 0.001-0.72) remained significant with lower incidence of fallacies associated with these variables. CONCLUSIONS: Rates of medication fallacies in pediatric CPR declined with structured training. Documentation fallacies may not be eliminated completely with only 1-time training.