Background: Tuberculous meningitis (TBM) in children causes high mortality and frequent disability. Intensified anti-tuberculosis treatment (ATT) and adjunctive aspirin may improve outcomes. Methods: SURE (ISRCTN 40829906) was a factorial, partially blinded, randomised-controlled trial in African (Zimbabwe, Zambia, Uganda) and Asian (India, Vietnam) children (29 days to <18 years) with confirmed or suspected TBM. Participants were randomised to receive intensified-ATT [isoniazid(20mg/kg), rifampicin(30mg/kg), pyrazinamide(40mg/kg), levofloxacin(20mg/kg) daily for 24-weeks] or standard-ATT [isoniazid(10mg/kg), rifampicin(15mg/kg), pyrazinamide(35mg/kg), ethambutol(20mg/kg) daily for 8 weeks, then isoniazid(10mg/kg) and rifampicin(15mg/kg) for 40 weeks] and simultaneously to receive aspirin(20mg/kg) or placebo daily for 8 weeks; all received corticosteroids for 8 weeks. Primary outcomes for ATT and aspirin/placebo randomisations were mortality and modified Rankin Scale (mRS) respectively at 48 weeks, analysed by modified-intention-to-treat. We specified a 10% non-inferiority margin for ATT and 16% minimal clinically significant difference for aspirin. Findings: Between March 2021 and July 2024, 369 children were randomised; five children were lost-to-follow-up before week-48, and 17 had no week-48 mRS. 174(47%) were female; median(IQR) age was 4.8(1.3-10) years, 15(4%) were HIV-infected, and 203(55%) had moderate/severe (MRC grade 2/3) disease. 29/177(16%) randomised to intensified-ATT died versus 21/181(12%) standard-ATT (adjusted risk difference 5.1%; 95% confidence interval -1.7% to +12.0%; p=0.14), not meeting the 10% non-inferiority margin. Severe disability/death (mRS 5/6) occurred in 38/176(22%) children randomised to aspirin versus 25/170(15%) placebo (adjusted odds ratio 1.80; 95%CI 0.95-3.41; p=0.07). Grade 3/4 adverse events were more frequent in intensified-ATT than standard-ATT (86/186(46%) versus 65/183(36%); p=0.03). Drug-liver injury (grade 2 or above) were also more frequent (64/186(34%) versus 32/183(17%); p<0.001). Grade 3/4 adverse events were also more frequent with aspirin than placebo 86/185(46%) versus 65/184(35%); p=0.03); bleeding events were rare and similar between arms. Interpretation: Neither 24-week intensified-ATT nor aspirin improved outcomes in children with TBM. New therapeutic strategies are urgently needed to increase survival and reduce disability from TBM.

Thalidomide has emerged as a fetal hemoglobin-inducer with potential to reduce transfusion burden in transfusion-dependent thalassemia (TDT). However, optimal dosing remains undefined A prospective, randomized, open-label, multicentric clinical trial was conducted at four centres in India to compare efficacy and safety of thalidomide at 1 mg/kg/day (Group 1) versus 2 mg/kg/day (Group 2) in patients with TDT aged ≥12 years. The primary endpoint was reduction in transfusion requirement at week 24, categorized as good (>50%), moderate (25-50%), or no (<25%) response. Responders underwent stepwise dose tapering during weeks 25-72 to evaluate response sustainability. Safety assessments were performed every 4 weeks. Of 188 enrolled patients (94 per group), 82.4% completed the week-24 evaluation. The overall response rate (ORR) was 58.5%, significantly higher in Group 1 than Group 2 (67.1% vs 50.0%, p=0.012). Good, moderate, and no response were observed in 20.5%, 37.8%, and 41.6% of patients, respectively, with transfusion independence in 9 patients (5.6%). Clinical benefit was observed within 12 weeks in 71.8% of good responders and 100% moderate responders. Sustained response at week 72 was seen in 49% and 57.5% of initial responders in Groups 1 and 2, respectively. Adverse effects were mostly grade 1; drug discontinuation due to toxicity was required in 10.6 % participants. These findings suggest that Thalidomide at 1 mg/kg/day was non-inferior to 2 mg/kg/day in reducing transfusion burden in patients with TDT, with an acceptable safety profile. Low-dose thalidomide appears to be a feasible treatment option in resource-limited settings. ICMR trial registry (Trial no. CTRI/2022/05/042781).

We report the case of a critically sick previously healthy 14-year-old girl who presented with subacute dry cough, respiratory distress, chest pain, hepatosplenomegaly, lytic bone lesions, splenic involvement, and bilateral chylothorax. Radiological evaluation established a diagnosis of Generalized Lymphatic Anomaly (GLA). The patient showed limited response to propranolol and pleurodesis but improved after initiation of sirolimus and vincristine. Notably, pleural fluid culture yielded Mycobacterium tuberculosis, leading to the addition of antitubercular therapy (ATT). The child subsequently demonstrated sustained clinical improvement with combined sirolimus and ATT. This case highlights the rare coexistence of GLA and tuberculosis, emphasizing the need to consider dual pathology when evaluating persistent pleural effusions in children.

BackgroundAnnually, an estimated 2.3 million infants die within their first month of life, primarily in sub-Saharan Africa and South Asia. Infections, including sepsis are among the major contributors to these deaths. Effective interventions added to standard antimicrobial therapy can reduce sepsis mortality. A recent meta-analysis suggests that adjunct zinc treatment of young infants with sepsis could reduce case fatality risk. This study evaluated the efficacy of zinc as an adjunct to antibiotics in young infants with suspected sepsis, defined as clinical severe infection (CSI).Methods and findingsWe conducted a randomized, double-blind, placebo-controlled trial across seven hospitals in India and Nepal from February 28, 2017, to February 22, 2022. Infants aged 3-59 days hospitalized with suspected sepsis, defined as CSI, adapted from the WHO Integrated Management of Childhood Illness (IMCI) criteria, were randomly assigned to receive 10 mg of elemental zinc daily or placebo orally for 14 days, in addition to standard of care. The primary outcomes were death during hospitalization and death within 12 weeks after enrollment. Among 3,153 enrolled infants (1,203 [38%] females), the median age at enrollment was 25 days (interquartile range 13-41 days), and the mean weight was 2.9 kg (standard deviation 0.8). During the hospital stay, 64 (4.1%) of 1,576 infants died in the zinc arm compared to 77 (4.9%) of 1,577 in the placebo arm (relative risk [RR] 0.83 (95% CI [0.60, 1.15]; p = 0.267)). Among those who completed 12 weeks of follow-up, 140 of 1,554 infants (9.0%) died in the zinc arm, and 133 of 1,550 (8.6%) in the placebo arm (RR 1.05 (95% CI [0.84, 1.32]; p = 0.674)). Adverse events were similar across trial arms, except for a slight increase in vomiting in the zinc arm; no events were attributed to the intervention. The main limitation of the study is that it was underpowered due to lower-than-anticipated event rates and a shortfall in the achieved sample size.ConclusionsIn this setting, we found little evidence for an effect of adjunct zinc therapy on young infants with CSI on the risk of dying during hospitalization or for the subsequent 3 months. Our findings contrast previous studies that used more specific case definitions. This underscores the need for further RCTs to evaluate the effect of zinc in young infant sepsis before it can be recommended in treatment guidelines.Trial registrationClinical Trials Registry-India (CTRI/2017/02/007966) on February 27, 2017, and Universal Trial Number is U1111-1187-6479.

Alloimmunisation is a significant problem that can considerably complicate the management of transfusion dependent β-thalassemia patients. Extended prophylactic red cell matching/Better match approach has been proposed to reduce the risk of alloimmunisation. There is limited literature on efficacy of Better Match Approach in preventing alloimmunisation. This cross-sectional analytical study was performed to evaluate the efficacy of prophylactic antigen matching (for c, E and K antigens) versus Usual match approach (matching only for ABO and D antigens) for issuing blood to transfusion dependent thalassemia patients, over 14 years follow up period. 329 transfusion dependent thalassemia patients were included and were divided into three categories: Category I (Usual match to better match approach), Category II (patients who received ≤5 transfusions at ≤18 months as UM before BM), Category III (Better match approach). Presence and rate of alloimmunisation in each category was evaluated. Alloantibodies were seen in 28 out of total 329 (8.51

ObjectiveTo explore the stakeholders' perspectives on barriers and facilitators influencing childhood cancer care delivery in India.MethodsA nationwide survey was conducted across 26 states and 4 Union Territories, involving childhood cancer physicians from tertiary and secondary hospitals, state nodal officers (SNOs) for the National Programme for Control of Non-Communicable Diseases (NP-NCD), and representatives from Civil Society Organizations (CSOs) and Non-Governmental Organizations (NGOs). A hub-and-spoke sampling model was employed, with designated tertiary hospitals coordinating data collection from secondary hospitals. An online survey tool assessed perceived challenges and facilitators in childhood cancer care. Data collection occurred from July to September 2021, and descriptive statistics were used for analysis.ResultsResponses were received from 137 tertiary hospitals (100%), 92 secondary hospitals (91%), 16 SNOs (53.3%), and 9 CSO/NGO representatives (23.1%). Key barriers to diagnosis and treatment included shortage of human resources, beds, and equipment, along with advanced-stage presentation and inadequate back-referrals from tertiary to secondary hospitals. Treatment abandonment and denial were highlighted as major concerns. SNOs and CSOs identified financial constraints, limited insurance coverage, and reliance on traditional healers as additional challenges. Facilitators included strengthening referral networks, expanding diagnostic capabilities, ensuring free treatment and medications, and improving infrastructure and workforce capacity.ConclusionResource constraints, late-stage presentation, treatment abandonment, and financial challenges are the significant barriers to childhood cancer care in India. Addressing these through improved referral systems, expanded diagnostic services, financial support mechanisms, and policy-level interventions are needed to enhance childhood cancer care outcomes and quality of life.

Tuberculosis (TB) remains a major global health challenge. Children, adolescents, and young mothers are high-risk populations for TB with unique challenges and needs. Children are often misdiagnosed or diagnosed too late, resulting in long-term sequelae or mortality, while adolescents, despite having more recognizable adult-type TB and being an important source of community transmission, can be difficult to engage in care as they often fall between pediatric and adult models of care. TB during pregnancy poses significant risks to the mother-infant pair, yet antenatal screening to ensure timely treatment initiation is often inadequate. Recent research advancements to address these challenges include more accessible TB management aids, shorter effective drug regimens, child-friendly drug formulations, strategies for active case finding to expand treatment coverage including of asymptomatic disease, and more options for preventive therapy. These advances have informed global policy and guidelines; however, major gaps in translation from policy to practice remain. This narrative review discusses the progress and identifies potential solutions with insights from the Asia-Pacific region to ongoing challenges in TB detection, treatment, and prevention in children and young people, with a view to TB elimination.

Introduction Childhood tuberculous meningitis (TBM) is a devastating disease. The long-standing WHO recommendation for treatment is 2 months of intensive phase with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by 10 months of isoniazid and rifampicin. In 2022, WHO released a conditional recommendation that 6 months of intensified antituberculosis therapy (ATT) could be used as an alternative for drug-susceptible TBM. However, this has never been evaluated in a randomised clinical trial. Trials evaluating ATT shortening regimens using high-dose rifampicin and drugs with better central nervous system penetration alongside adjuvant anti-inflammatory therapy are needed to improve outcomes.Methods and analysis The Shortened Intensive Therapy for Children with Tuberculous Meningitis (SURE) trial is a phase 3, randomised, partially blinded, factorial trial being conducted in Asia (India and Vietnam) and Africa (Uganda, Zambia and Zimbabwe). It is coordinated by the Medical Research Council Clinical Trial Unit at University College London (MRCCTU at UCL). 400 children (aged 29 days to <18 years) with clinically diagnosed TBM will be randomised, using a factorial design, to either a 24-week intensified regimen (isoniazid (20 mg/kg), rifampicin (30 mg/kg), pyrazinamide (40 mg/kg) and levofloxacin (20 mg/kg)) or the standard 48-week ATT regimen and 8 weeks of high-dose aspirin or placebo. The primary outcome for the first randomisation is all-cause mortality, and for the second randomisation is the paediatric modified Rankin Scale (mRS), both at 48 weeks. Nested substudies include pharmacokinetics, pharmacogenetics, pathophysiology, diagnostics and prognostic biomarkers, in-depth neurodevelopmental outcomes, MRI and health economics.Ethics and dissemination Local ethics committees at all participating study sites and respective regulators approved the SURE protocol. Ethics approval was also obtained from UCL, UK (14935/001). Informed consent from parents/carers and assent from age-appropriate children are required for all participants. Results will be published in international peer-reviewed journals, and appropriate media will be used to summarise results for patients and their families and policymakers.Trial registration ISRCTN40829906 (registered 13 November 2018).

Lymphobronchial tuberculosis (TB) is particularly common in children and is characterized by tuberculous lymphadenopathy affecting the airways, leading to various radiological findings. Computed tomography (CT) is the preferred imaging modality for diagnosing lymphobronchial TB due to its ability to detect mediastinal lymph nodes and airway involvement. CT findings include lymphadenopathy, bronchial narrowing, and a range of parenchymal complications. We describe the case of a 1-year-old girl who presented with chest complaints and focal lung hyperinflation, which was subsequently proven to be due to lymphobronchial TB.

INTRODUCTION Respiratory syncytial virus(RSV)is the leading cause of severe acute lower respiratory tract infection(LRTI)in infants and young children,resulting in an estimated 33 million infections annually,＞3 million hospitalizations,and＞100 000 deaths in children under 5 years globally,with a mortality rate of up to 9％in low-resource coun-tries,which have 99％of the global RSV mortality.

Tracheal agenesis is a rare and life-threatening airway malformation, and currently, there is no curative treatment available. The described case involves a preterm male newborn at 30 weeks of gestational age who could not be intubated during resuscitation, despite multiple attempts. However, the baby could be ventilated after oesophageal intubation. Tracheal stenosis/ atresia was suspected, and airway evaluation was performed using a thin, flexible fiberoptic bronchoscope. No tracheal opening could be identified, and upon introducing the bronchoscope into the oesophagus, a triluminal opening was found, through which the scope could not be further navigated. To further delineate the anatomy, a Contrast-enhanced Computed Tomography (CECT) thorax was performed, revealing the absence of a tracheal lumen and the communication of both bronchi at the carina with the oesophagus. Unfortunately, the baby succumbed to the illness after three days. Tracheal agenesis is an anatomical malformation that typically presents as respiratory distress and the absence of an audible cry at birth. Attempts to establish a definite airway are unsuccessful, which may result in early neonatal death. Oesophageal intubation may temporarily establish ventilation until palliative surgery is performed.

Lignocellulolytic enzymes from a novel Myceliophthora verrucosa (5DR) strain was found to potentiate the efficacy of benchmark cellulase during saccharification of acid/alkali treated bagasse by 2.24 fold, indicating it to be an important source of auxiliary enzymes. The De-novo sequencing and analysis of M. verrucosa genome (31.7 Mb) revealed to encode for 7989 putative genes, representing a wide array of CAZymes (366) with a high proportions of auxiliary activity (AA) genes (76). The LC/MS QTOF based secretome analysis of M. verrucosa showed high abundance of glycosyl hydrolases and AA proteins with cellobiose dehydrogenase (CDH) (AA8), being the most prominent auxiliary protein. A gene coding for lytic polysaccharide monooxygenase (LPMO) was expressed in Pichia pastoris and CDH produced by M. verrucosa culture on rice straw based solidified medium were purified and characterized. The mass spectrometry of LPMO catalyzed hydrolytic products of avicel showed the release of both C1/C4 oxidized products, indicating it to be type-3. The lignocellulolytic cocktail comprising of in-house cellulase produced by Aspergillus allahabadii strain spiked with LPMO CDH exhibited enhanced and better hydrolysis of mild alkali deacetylated (MAD) and unwashed acid pretreated rice straw slurry (UWAP), when compared to Cellic CTec3 at high substrate loading rate.

Abstract Context Children with human immunodeficiency virus (HIV) infection frequently present with opportunistic infections of the lung that may be associated with high mortality rate. There is no study, to the best of our knowledge, correlating specific radiographic patterns of chest infections with CD4 levels of immunity in HIV-infected children of Indian subcontinent (where prevalence of respiratory tuberculosis is very high). Aims To study the radiological patterns of chest infections in HIV-infected children, and to correlate these radiological findings with CD4 cell count and final diagnosis. Methods Forty-five HIV-infected children (1–18 years of age) with suspected chest infections were included in the study. The baseline and the most recent CD4 counts were recorded for each patient. Chest X-ray (CXR) was obtained in all the patients, and multi-detector computed tomography (MDCT) chest was done in 27 patients having clinical suspicion of infection with normal or equivocal findings on CXR. Chest radiographs and MDCT chest were analyzed for different radiological patterns of chest infections. Imaging findings were correlated with CD4 count range for disease spectrum. The final etiopathological diagnosis was achieved in combination with clinico-radiological findings, laboratory data, cytohistopathology and follow-up imaging. Results Out of 45 children confirmed to be HIV-infected, 27 (60%) had bacterial infection, 14 (31.11%) had tuberculosis, and four (8.89%) had fungal infection. Consolidation on CXR/CT strongly suggested bacterial etiology (P < 0.05). Mediastinal/hilar lymphadenopathy (with or without necrosis) strongly suggested tubercular etiology (P value < 0.05). Diffuse GGO/haziness on CXR/CT strongly suggested fungal etiology (P value < 0.05). On correlation with CD4 count (cells/mm3), the bacterial infections occurred at early stages of HIV infection when immune status was relatively preserved, and most of the patients with tubercular infection had moderate immunosuppression. On the other hand, all patients of fungal infection showed severe immunosuppression. Conclusion A wide spectrum of pulmonary disease encountered in HIV-infected children warrants an integrated approach of image interpretation. Familiarity with the imaging patterns, combined with relevant clinical/laboratory details, may greatly help to improve the diagnostic confidence and to reach to a more meaningful differential diagnosis.

The present study reports a highly thermostable β -glucosidase (GH3) from Rasamsonia emersonii that was heterologously expressed in Pichia pastoris . Extracellular β -glucosidase was purified to homogeneity using single step affinity chromatography with molecular weight of ~ 110 kDa. Intriguingly, the purified enzyme displayed high tolerance to inhibitors mainly acetic acid, formic acid, ferulic acid, vanillin and 5-hydroxymethyl furfural at concentrations exceeding those present in acid steam pretreated rice straw slurry used for hydrolysis and subsequent fermentation in 2G ethanol plants. Characteristics of purified β -glucosidase revealed the optimal activity at 80 °C, pH 5.0 and displayed high thermostability over broad range of temperature 50–70 °C with maximum half-life of ~ 60 h at 50 °C, pH 5.0. The putative transglycosylation activity of β -glucosidase was appreciably enhanced in the presence of methanol as an acceptor. Using the transglycosylation ability of β- glucosidase, the generated low cost mixed glucose disaccharides resulted in the increased induction of R. emersonii cellulase under submerged fermentation. Scaling up the recombinant protein production at fermenter level using temporal feeding approach resulted in maximal β- glucosidase titres of 134,660 units/L. Furthermore, a developed custom made enzyme cocktail consisting of cellulase from R. emersonii mutant M36 supplemented with recombinant β -glucosidase resulted in significantly enhanced hydrolysis of pretreated rice straw slurry from IOCL industries (India). Our results suggest multi-faceted β -glucosidase from R. emersonii can overcome obstacles mainly high cost associated enzyme production, inhibitors that impair the sugar yields and thermal inactivation of enzyme.