Prevalence of Metabolic Abnormalities and their Association with Asthma Symptom Control in Children.

OBJECTIVES: To determine the prevalence of insulin resistance (IR), dyslipidemia and metabolic syndrome (MS) in children with asthma, aged 10 to 15 y, and to determine if these metabolic abnormalities showed an association with asthma symptom control and lung function. METHODS: A cross-sectional study was conducted at a tertiary centre in north India. Consecutive children with physician diagnosed asthma were enrolled. Asthma symptom control over previous four weeks was assessed as per Global Initiative for Asthma (GINA) recommendations. Fasting plasma glucose, serum insulin and lipid levels were estimated. Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) was used as a marker of IR. Spirometry was performed for assessing lung function. RESULTS: Eighty-three children were enrolled. Median (IQR) age was 12.0 (11.0, 13.5) y and mean (SD) body mass index (BMI) Z score was -0.42 (1.0). Median (IQR) HOMA-IR was 1.65 (1.06, 2.39). Prevalence of IR was 42.3% (95% CI: 31.7-52.9%). Number of children with elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL)-cholesterol was 4 (4.8%), 4 (4.8%) and 5 (6%), respectively. Sixty-seven (80.7%) children had low high-density lipoprotein (HDL)-cholesterol. Only one subject was found to have metabolic syndrome. Presence of IR and elevation in serum insulin and triglycerides were associated with poorer asthma control, independent of BMI. None of the metabolic parameters were associated with lung function, after adjusting for height. CONCLUSIONS: Among children with asthma, aged 10 to 15 y, the prevalence of IR was 42.3% (95% CI: 31.7-52.9%). Elevated serum insulin, triglycerides, and presence of IR were associated with poorer asthma control, after adjusting for BMI.

Evidence-Based Guidelines for the Management of Allergic Bronchopulmonary Aspergillosis (ABPA) in Children and Adolescents with Asthma.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) frequently complicates asthma. There is urgent need to develop evidence-based guidelines for the management of ABPA in children. The Evidence Based Guideline Development Group (EBGDG) of the Indian Academy of Pediatrics (IAP) National Respiratory Chapter (NRC) addressed this need. METHODS: The EBGDG shortlisted clinical questions relevant to the management of ABPA in asthma. For each question, the EBGDG undertook a systematic, step-wise evidence search for existing guidelines, followed by systematic reviews, followed by primary research studies. The evidence was collated, critically appraised, and synthesized. The EBGDG worked through the Evidence to Decision (EtD) framework, to formulate recommendations, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Seven clinical questions were prioritized, and the following recommendations formulated. (1) Children with poorly controlled asthma should be investigated for ABPA (conditional recommendation, moderate certainty of evidence). (2) Low dose steroid therapy regimen (0.5 mg/kg/d for the first 2 wk, followed by a progressive tapering) is preferable to higher dose regimens (conditional recommendation, very low certainty of evidence). (3) Oral steroid regimens longer than 16 wk (including tapering), should not be used (conditional recommendation, very low certainty of evidence). (4) Antifungals may or may not be added to steroid therapy as the evidence was neither in favour nor against (conditional recommendation, low certainty of evidence). (5) For clinicians using antifungal agents, the EBGDG recommends against using voriconazole instead of itraconazole (conditional recommendation, very low certainty of evidence). (6) No evidence-based recommendation could be framed for using pulse steroid therapy in preference to conventional steroid therapy. (7) Immunotherapy with biologicals including omalizumab or dupilumab is not recommended (conditional recommendation, very low certainty of evidence). CONCLUSIONS: This evidence-based guideline can be used by healthcare providers in diverse clinical settings.

Multi-pathogen based chimeric vaccine to fight against COVID-19 and concomitant coinfections.

BACKGROUND: COVID-19 has proved to be a fatal disease of the year 2020, due to which thousands of people globally have lost their lives, and still, the infection cases are at a high rate. Experimental studies suggested that SARS-CoV-2 interacts with various microorganisms, and this coinfection is accountable for the augmentation of infection severity. METHODS AND RESULTS: In this study, we have designed a multi-pathogen vaccine by involving the immunogenic proteins from S. pneumonia, H. influenza, and M. tuberculosis, as they are dominantly associated with SARS-CoV-2. A total of 8 antigenic protein sequences were selected to predict B-cell, HTL, and CTL epitopes restricted to the most prevalent HLA alleles. The selected epitopes were antigenic, non-allergenic, and non-toxic and were linked with adjuvant and linkers to make the vaccine protein more immunogenic, stable, and flexible. The tertiary structure, Ramachandran plot, and discontinuous B-cell epitopes were predicted. Docking and MD simulation study has shown efficient binding of the chimeric vaccine with the TLR4 receptor. CONCLUSION: The in silico immune simulation analysis has shown a high level of cytokines and IgG after a three-dose injection. Hence, this strategy could be a better way to decrease the disease's severity and could be used as a weapon to prevent this pandemic.

World Health Organization Guideline on the Management of Tuberculosis in Children: Critical Appraisal, Concerns, and Caution.

In September 2022, the World Health Organization (WHO) published a new guideline for the management of tuberculosis (TB) in children and adolescents. It included eight new recommendations. Xpert MTB/RIF Ultra (Xpert Ultra) has been designated as the preferred initial diagnostic test for pulmonary TB and detection of rifampicin resistance. But its place vis-à-vis the previously recommended GeneXpert has not been clarified. Further, the limited diagnostic accuracy of Xpert Ultra in some biological specimens like nasopharyngeal aspirates, and the inability to report the presence or absence of rifampicin resistance in 'trace' reports has not been addressed. The guideline also recommends a shortened 4-mo treatment regimen for non-severe drug-susceptible TB. This is based on a single trial having several methodological issues that limit its applicability and generalizability. Interestingly, the criteria for designating 'non-severe' TB in the trial is based on smear negativity, whereas the new WHO recommendation is to omit smear microscopy altogether. The guideline also recommends an alternative 6-mo intensive regimen for drug-susceptible TB meningitis, which needs more supportive evidence. The lower age limits for the use of bedaquiline and delamanid have been decreased to less than 6 and 3 y respectively. While this makes it feasible to treat drug resistant TB in children with oral medications, the resource implications need careful consideration. These concerns advocate caution before the WHO guideline recommendations can be universally implemented.

Translational vaccinomics and structural filtration algorithm to device multiepitope vaccine for catastrophic monkeypox virus.

Recent outbreak of monkeypox disease commenced in April 2022, and on May 7, the first confirmed case was reported. The world health organization then designated monkeypox disease as a public health emergency of international outrage on July 23, after it spread to 70 non-endemic nations in less than 15 days. This catastrophic viral infection encourages the development of antiviral therapeutics due to the lack of specific treatments with negligible adverse effects. This analysis developed a highly immunogenic multiepitope subunit vaccine against the monkeypox virus using an in silico translational vaccinomics technique. Highly antigenic B cell and T cell (HTL and CTL) epitopes were predicted and conjugated with the help of unique linkers. An adjuvant (ß-defensin) and a pan-HLA DR sequence were attached at the vaccine construct's N-terminal to invoke a robust immunological response. Additionally, physiochemical, allergic, toxic, and antigenic properties were anticipated. Interactions between the vaccine candidate and the TLR3 demonstrated that the vaccine candidate triggers a robust immunological response. Finally, the stability is confirmed by the molecular dynamics study. In contrast, the modified vaccine candidate's ability to produce a protective immune response were verified by an immune dynamics simulation study conducted via C-ImmSim server. This study validates the generation of B cell, Th cell, and Tc cell populations as well as the production of IFN-γ.

Nanobody-peptide-conjugate (NPC) for passive immunotherapy against SARS-CoV-2 variants of concern (VoC): a prospective pan-coronavirus therapeutics.

The COVID-19 crisis, incited by the zoonotic SARS-CoV-2 virus, has quickly escalated into a catastrophic public health issue and a grave threat to humankind owing to the advent of mutant viruses. Multiple pharmaceutical therapies or biologics envision stopping the virus from spreading further; however, WHO has voiced concerns about the variants of concern (VoCs) inability to respond. Nanobodies are a new class of antibody mimics with binding affinity and specificity similar to classical mAbs, as well as the privileges of a small molecular weight, ease of entry into solid tissues, and binding cryptic epitopes of the antigen. Herein, we investigated multiple putative anti-SARS-CoV-2 nanobodies targeting the Receptor binding domain of the WHO-listed SARS-CoV-2 variants of concern using a comprehensive computational immunoinformatics methodology. With affinity maturation via alanine scanning mutagenesis, we remodeled an ultrapotent nanobody with substantial breadth and potency, exhibiting pico-molar binding affinities against all the VoCs. An antiviral peptide with specificity for ACE-2 receptors was affixed to make it multispecific and discourage viral entry. Collectively, we constructed a broad-spectrum therapeutic biparatopic nanobody-peptide conjugate (NPC) extending coverage to SARS-CoV-2 VoCs RBDs. We PEGylated the biparatopic construct with 20kD maleimide-terminated PEG (MAL-(PEG)n-OMe) to improve its clinical efficacy limiting rapid renal clearance, and performed in silico cloning to facilitate future experimental studies. Our findings suggest that combining biparatopic nanobody conjugate with standard treatment may be a promising bivariate tool for combating viral entry during COVID-19 illness.

Serum Periostin Level in Children with Asthma.

OBJECTIVES: To determine the average serum periostin level in children with asthma between 6 and 16 y of age, and to find out if the levels correlated with markers of eosinophilic inflammation, asthma control, and severity. METHODS: Children under follow-up at a tertiary care centre were enrolled. Children with conditions causing elevated serum periostin other than asthma, or history of systemic steroid use in the past 6 mo were excluded. Serum total IgE and periostin were estimated by ELISA. RESULTS: The median (IQR) serum periostin level was 52.6 (45.4, 58.3) ng/mL. Levels did not vary with age, gender, duration of symptoms, positive family history, or history of exacerbations in the last 6 mo. There was no significant correlation with anthropometric parameters or their z scores, or markers of eosinophilic inflammation in blood including serum total IgE, eosinophil percentage or absolute eosinophil count. There was no difference in median periostin levels of children with different asthma symptom control or asthma severity. CONCLUSIONS: In a group of 26 Indian children with physician-diagnosed asthma, serum periostin showed no significant correlation to markers of eosinophilic inflammation.

High-throughput virtual screening of small-molecule inhibitors targeting immune cell checkpoints to discover new immunotherapeutics for human diseases.

Immunotherapy is widely used to treat various cancers, and the drugs used are called immune checkpoint (ICP) inhibitors. Overexpression of immune cell checkpoints is reported for other human diseases such as acute infections (malaria), chronic viral infection (HIV, hepatitis B virus, TB infections), allergy, asthma, neurodegeneration, and autoimmune diseases. Some mAbs (monoclonal antibodies) are available against ICPs, but they have side effects. Small molecule seems to be safer in comparison with mAbs. Three independent small-molecule inhibitor libraries consisting of 9466 compounds were screened against seven immune cell checkpoints by applying high-throughput virtual screening approach. A total of 13 ICP inhibitors were finalized based on docking, MM-GBSA scores, and ADME properties. Six compounds were selected for MD simulation, and then, rutin hydrate (targeting all seven immune cell checkpoints), amikacin hydrate (targeting six), and 6-hydroxyluteolin (targeting three) were found to be the best immune cell checkpoint inhibitors. These three potential inhibitors have shown the potential to activate human immune cells and thus may control the spread of human lifestyle or infectious diseases. Proposed inhibitors warrant the in vitro and in vivo validation to develop it as an immunotherapeutic.

Confirmation of pleural displacement of central venous catheter tip in an infant, by bedside contrast injection.

A 14-week infant, with respiratory distress since birth, was referred to our institution. Chest radiography and ultrasonographic examination confirmed right-sided diaphragmatic eventration. Owing to difficulty in securing a peripheral venous access, a double-lumen 4-Fr central venous catheter (CVC) was inserted into the right internal jugular vein, under ultrasonographic guidance. Aspiration of blood from both ports confirmed intravascular placement. A frontal radiograph done after the procedure showed the catheter tip in the right atrium, hence it was withdrawn to a level just below the carina. Surgical plication of the right dome of the diaphragm was performed, following which an intercostal tube was placed. After 3 days, there was increased drainage of clear fluid. Biochemical analysis ruled out exudative effusion, hence displacement of the CVC into the pleural cavity was suspected. A frontal chest radiograph was done to confirm this, but it did not suggest CVC tip displacement. Bedside ultrasonography was done but the CVC tip could not be visualized. The patient was too unstable to perform a chest CT scan or echocardiography. Therefore, a bedside chest radiograph was taken while injecting 1 ml of iohexol (diluted with 4 ml of normal saline) into the CVC. This showed the contrast leaking out of the CVC, flowing into the mediastinal pleural space, and ultimately into the ICD tube, confirming displacement of the CVC tip. The catheter was immediately removed, and an alternate venous access was established.

MiRNA-SARS-CoV-2 dialogue and prospective anti-COVID-19 therapies.

COVID-19 is a highly transmissible disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), affects 226 countries and continents, and has resulted in >6.2 million deaths worldwide. Despite the efforts of all scientific institutions worldwide to identify potential therapeutics, no specific drug has been approved by the FDA to treat the COVID-19 patient. SARS-CoV-2 variants of concerns make the potential of publicly known therapeutics to respond to and detect disease onset highly improbable. The quest for universal therapeutics pointed to the ability of RNA-based molecules to shield and detect the adverse effects of the COVID-19 illness. One such candidate, miRNA (microRNA), works on regulating the differential expression of the target gene post-transcriptionally. The prime focus of this review is to report the critical miRNA molecule and their regular expression in patients with COVID-19 infection and associated comorbidities. Viral and host miRNAs control the etiology of COVID-19 infection throughout the life cycle and host inflammatory response, where host miRNAs are identified as a double-edged showing as a proviral and antiviral response. The review also covered the role of viral miRNAs in mediating host cell signaling expression during disease pathology. Studying molecular interactions between the host and the SARS-CoV-2 virus during COVID-19 pathogenesis offers the chance to use miRNA-based therapeutics to reduce the severity of the illness. By utilizing an appropriate delivery vehicle, these small non-coding RNA could be envisioned as a promising biomarker in designing a practical RNAi-based treatment approach of clinical significance.

Flexible Fibreoptic Bronchoscopy and Bronchoalveolar Lavage for Confirmation of Pulmonary Hydatid Disease in Children: A Case Series.

Hydatid disease of the lungs is common in endemic regions. It can be suspected clinically by non-specific respiratory symptoms in children living in endemic regions, especially when they are close to sheep or dogs. Chest imaging X-ray or computed tomography may show characteristic cysts in some cases, but typical findings are absent in many children. Hydatid serology may contribute to the diagnosis, but does not have sufficient sensitivity for pulmonary cysts. Thus, there is no confirmatory diagnostic test, other than surgical excision and histopathologic examination. Hence, there is a need for more reliable diagnostic tests. We present a series of children, both with and without suspected pulmonary hydatid, wherein flexible fibreoptic bronchoscopy (FFOB) performed under conscious sedation, revealed hydatid membranes in the airways. Bronchoalveolar lavage (BAL) analysis revealed hydatid in most of them. Thus the diagnosis could be confirmed even before surgical excision of cysts was performed. We propose that FFOB with BAL could be useful to confirm the diagnosis of pulmonary hydatid in children. This will be particularly helpful in children without characteristic radiological or serological findings. To the best of our knowledge, this is a completely novel approach to the condition with potential to alter the diagnostic paradigm Lay summary Hydatid disease of the lungs is commonly encountered in endemic regions. However, there is no confirmatory diagnostic test for pulmonary hydatid cyst, other than surgical excision and histopathologic examination. Imaging including chest X-ray and computed tomography may not be typical, especially in complicated cysts and hydatid serology does not have a satisfactory sensitivity for diagnosing lung cysts. Thus, there is a need for more reliable diagnostic tests. We present a series of children, both with and without suspected pulmonary hydatid, wherein flexible fibreoptic bronchoscopy (FFOB) under conscious sedation, revealed hydatid membranes in the airways. Bronchoalveolar lavage (BAL) analysis confirmed hydatid in most of them. We propose FFOB with BAL as a useful diagnostic modality to confirm pulmonary hydatid in children, prior to surgical excision. To the best of our knowledge, this is a completely novel approach to the condition with potential to alter the diagnostic paradigm.

Hypothesis-Driven Palladium-Catalyzed Transformations for the Construction of New Molecular Architectures.

The development of new synthetic protocols to access diverse molecular scaffolds from readily available starting compounds is of significance in both academia and industry. Towards this, the catalysis by transition metals has been employed as a powerful tool to access molecules with broad structural and functional diversity. An overview of the recent literature manifested the tremendous potential of transition metal-catalyzed processes in advancing organic synthesis in a new direction. This account compiles new conceptual advancements in the palladium-catalyzed Alder-ene type cycloisomerization reactions, C-H functionalizations, and one-pot multicatalytic processes, which have become essential tools to access new classes of molecules.