Can BCG vaccine protect against COVID-19 via trained immunity and tolerogenesis?

As the number of infections and mortalities from the SARS-CoV-2 pandemic continues to rise, the development of an effective therapy against COVID-19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID-19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting "trained immunity" in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID-19 requires a therapy that induces early priming of anti-viral immune responses and regulates aberrant hyperactivity of innate-immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID-19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG-mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS-CoV-2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg.

Correlation of plasma levels of itraconazole with treatment response at 4 weeks in chronic dermatophytosis: Results of a randomised controlled trial.

BACKGROUND: Itraconazole in varying doses and duration is being frequently used for the management of dermatophytosis. There is a scarcity of studies on the bioavailability of various itraconazole brands available in the market. AIMS AND OBJECTIVES: The aim of this study was to determine the plasma concentration of itraconazole of various brands and its correlation with clinical efficacy in chronic dermatophytosis. MATERIALS AND METHODS: One hundred patients with chronic dermatophytosis with age >18 years were studied at the outpatient clinic of our tertiary care hospital. Plasma itraconazole level was estimated on Week 2 and Week 4 after randomly dividing the patients into Groups A, B and C who received cap itraconazole 100 mg twice a day of innovator, multinational and local generic brands, respectively, for 4 weeks. Both efficacy (cure, partial cure or no cure), safety and recurrence were compared between the three groups. RESULTS: At 4 weeks, number of patients classified as 'cured' were 10/26 (38.4%) in Group A, 5/22 in Group B (22.7%) and 3/21 (14.2%) in Group C (p = .002). Mycological cure rates at Week 4 in Groups A, B and C were 21 (80.8%), 17 (81.0%) and 5 (26.3%), respectively (p = .006). Plasma levels of itraconazole were comparable between the three groups at Week 2 and Week 4. No statistically significant correlation was found between itraconazole levels and treatment response in any of the groups at 4 weeks. Incidence of adverse effects and recurrence rates was also similar among the three groups. CONCLUSION: Cure rates for chronic dermatophytosis were poor with all three itraconazole brands at 4 weeks of treatment. Higher cure rates were obtained with innovator drug as compared to multinational and local generic brands at 4 weeks. Plasma levels of the three drugs were however similar, indicating that factors other than serum bioavailability are at play in determining response of chronic dermatophyte infections to oral itraconazole.

Incidence and risk factors for dysglycaemia in Asian-Indians: a 10-year population-based prospective cohort study.

BACKGROUND: Diabetes prevalence estimates suggest an increasing trend in South-East Asia region, but studies on its incidence are limited. The current study aims to estimate the incidence of type 2 diabetes and pre-diabetes in a population-based cohort from India. METHODS: A subset of Chandigarh Urban Diabetes Study cohort (n=1878) with normoglycaemia or pre-diabetes at baseline was prospectively followed after a median of 11 (0.5-11) years. Diabetes and pre-diabetes were diagnosed as per WHO guidelines. The incidence with 95% CI was calculated in 1000 person-years and Cox proportional hazard model was used to find the association between the risk factors and progression to pre-diabetes and diabetes. RESULTS: The incidence of diabetes, pre-diabetes and dysglycaemia (either pre-diabetes or diabetes) was 21.6 (17.8-26.1), 18.8 (14.8-23.4) and 31.7 (26.5-37.6) per 1000 person-years, respectively. Age (HR 1.02, 95% CI 1.01 to 1.04), family history of diabetes (HR 1.56, 95% CI 1.09 to 2.25) and sedentary lifestyle (HR 1.51, 95% CI 1.05 to 2.17) predicted conversion from normoglycaemia to dysglycaemia, while obesity (HR 2.43, 95% CI 1.21 to 4.89) predicted conversion from pre-diabetes to diabetes. CONCLUSION: A high incidence of diabetes and pre-diabetes in Asian-Indians suggests a faster conversion rate to dysglycaemia, which is partly explained by sedentary lifestyle and consequent obesity in these individuals. The high incidence rates call for a pressing need for public health interventions targeting modifiable risk factors.

Clinical Profile, Intensive Care Needs and Outcome of Children with Dilated Cardiomyopathy Associated with Vitamin D Deficiency: A 5-year PICU Experience.

Aim: To describe the clinical profile, treatment details, intensive care needs, and long-term outcome of children with dilated cardiomyopathy (DCM) associated with Vitamin D deficiency (VDD). Materials and methods: Case records of 14 children with DCM associated with VDD [25(OH)D3 levels <20 ng/mL] admitted to the pediatric intensive care unit (PICU) of a tertiary care teaching hospital between January 2017 and December 2021 were retrospectively analyzed for clinical features, echocardiographic findings, treatment details, intensive care needs, and outcomes. Results: The median (IQR) age was 6 (2-9) months and 71% (n=10) were males. The common modes of presentation included respiratory distress or failure (78.6%), congestive cardiac failure (71.4%), cardiogenic shock (37.5%), and seizures and encephalopathy (14.3% each). The median (IQR) serum calcium was 8.7 (7-9.5) mg%, ionized calcium 0.7 (0.7-1.1) mmol/L, alkaline phosphatase 343 (316-415) IU/L, phosphate 3.5 (2.6-4.5) mg%, PTH 115 (66-228) pg/mL, and 25(OH)D3 5 (3-7) ng/mL. The median (IQR) left ventricular ejection fraction (LVEF) at admission was 22 (17-25)%. The treatment included intravenous calcium infusion (35.7%), vitamin D supplementation in all (57.1% parenteral and 42.9% oral), mechanical ventilation (35.7%), and vasoactive drugs (57.1%). There was no mortality. The median (IQR) duration of PICU and hospital stay was 76 (31-98) hours and 6 (4.7-10) days, respectively. Out of 14 children, 10 (71.4%) were followed-up till median (IQR) of 10 (7-58) months. All were asymptomatic and had normal LEVF (except one had residual moderate mitral regurgitation). Conclusion: Vitamin D deficiency is a potentially treatable and reversible cause of DCM in children. How to cite this article: Kumar S, Randhawa MS, Angurana SK, Nallasamy K, Bansal A, Kumar MR, et al. Clinical Profile, Intensive Care Needs and Outcome of Children with Dilated Cardiomyopathy Associated with Vitamin D Deficiency: A 5-year PICU Experience. Indian J Crit Care Med 2023;27(7):510-514.

TLR9 signalling activation via direct ligation and its functional consequences in CD4 + T cells.

CpG Oligodeoxynucleotides (ODNs) are established TLR9 ligands; however, their functional responses in CD4+ T cells are believed to be independent of TLR9 and MyD88. We studied ligand-receptor interactions of ODN 2216 and TLR9 in human CD4+ T cells and assessed their consequences in terms of TLR9 signalling and cell phenotype. We demonstrated that the uptake of ODN 2216, a synthetic TLR9 agonist, is controlled by TLR9 signalling molecules and results in an increase in the expression of TLR9 signalling molecules, regulated via a feedback mechanism. Next, the uptake of ODN 2216 resulted in TLR9 signalling dependent but MyD88 independent increase in expression of TGF-ß. Finally, ODN 2216 treated CD4+ T cells showed an anti-inflammatory phenotype that was similar to Th3 type of regulatory T cells. These Th3-like cells were able to suppress the proliferation of untreated CD4+ T cells. Collectively, our results demonstrate a direct and interdependent relationship between ODN 2216 uptake and TLR9 signalling in CD4+ T cells. Our findings thus pave the way for future research to explore direct modulation of adaptive immune cells, using innate immune ligands, to subvert exaggerated inflammatory responses.

Efficacy of multi-strain probiotic along with dietary and lifestyle modifications on polycystic ovary syndrome: a randomised, double-blind placebo-controlled study.

PURPOSE: Effect of multi-strain probiotic along with dietary and lifestyle modifications in the management of polycystic ovary syndrome (PCOS) has rarely been reported. We thus aimed to investigate the effect of multi-strain probiotic (Lactobacillus acidophilus UBLA-34, L. rhamnosus UBLR-58, L. reuteri UBLRu-87 (each of 2 billion colony forming units (CFU)); L. plantarum UBLP-40, L. casei UBLC-42, L. fermentum UBLF-31, Bifidobacterium bifidum UBBB-55 (each of 1 billion CFU) and fructo-oligosaccharides (100 mg)) and dietary and lifestyle modifications on restoration of menstrual regularity, weight reduction, metabolic and hormonal profile in women with PCOS. METHODS: A 104 participants (age 18-40 years) were randomly allocated to receive probiotic or placebo capsules for 6 months. Baseline and end line assessment were performed for menstrual cycle regularity, ultrasonography scan for ovaries, total testosterone, dehydroepiandrosterone (DHEAS), insulin, luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, fasting blood sugar (FBS), homeostatic model assessment-insulin resistance (HOMA-IR), weight reduction, waist-/hip circumference (WC, HC), waist to hip ratio (WHR), and body mass index (BMI). Plasma lipopolysaccharide and effect of intervention on quality of life was investigated. Diet and exercise were controlled during the trial. RESULTS: Probiotic supplement along with dietary and lifestyle modifications significantly regularised menstrual cycle (p 0.023), improved levels of total testosterone (p 0.043), WC (p 0.030), WHR (p 0.027) and menstrual domain of quality of life (p 0.034) as compared to placebo. No adverse events related to study were reported. CONCLUSION: Multi-strain probiotic along with dietary and lifestyle modifications were effective in the management of PCOS. TRIAL REGISTRATION: CTRI: CTRI/2016/07/007086, dated 13 July 2016.

Comparison of the efficacy and cost-effectiveness of an immunologically targeted low-dose rituximab protocol with the conventional rheumatoid arthritis protocol in severe pemphigus.

BACKGROUND: Various dosing protocols of rituximab have been used in pemphigus. B-cell repopulation following rituximab treatment can be considered a forerunner of clinical relapse. Immunologically guided dosing may remove the need for fixed timepoint maintenance dosing, hence being more cost-effective and perhaps safer. AIM: To compare the overall efficacy and cost-effectiveness of a low-dose rituximab regimen (500 mg, 2 weeks apart) with immunologically guided, ultralow-dose (200 mg) top-up infusions on immunological relapse vs. the use of a rheumatoid arthritis (RA) protocol with rituximab 500 mg repeat infusion to treat clinical relapse in severe pemphigus, over a 1-year period, METHODS: In total, 23 patients with severe pemphigus were randomized into Group A (RA protocol: 1000 mg given as two doses, 2 weeks apart) and Group B (low-dose rituximab 500 mg given as two doses, 2 weeks apart). Both groups also received short-term oral corticosteroids, and underwent clinical and immunological (3-monthly flow cytometry assessments of B-cell subtypes) monitoring. Group A received a top-up dose of rituximab 500 mg upon clinical relapse, while Group B received an ultralow top-up dose (200 mg) following detection of B-cell repopulation, which was intended to prevent clinical relapse. Outcome parameters [complete remission off treatment (CROT), relapse (clinical and immunological), total corticosteroid dose and direct cost of therapy] were compared. RESULTS: The mean ± SD time to CROT (Group A, 27.1 ± 1.6 weeks; Group B, 26 ± 1.2 weeks, P = 0.09) and the cumulative prednisolone dose (P = 0.28) were comparable between the two groups. In Group A, 3 of 9 (33.3%) patients had clinical relapse (mean ± SD time of 9.3 ± 0.4 months). In Group B, B-cell repopulation was seen in 10 of 11 (90.9%) patients within a mean time of 8.4 ± 2.4 months, and a single top-up dose of 200 mg successfully prevented clinical relapse. The overall cost of therapy was 37.4% cheaper in Group B. CONCLUSION: An immunologically guided low-dose rituximab regimen can be an equally effective but more affordable alternative to conventional rituximab regimens in pemphigus.

Cerebrospinal fluid and plasma procalcitonin for the diagnosis of neonatal bacterial meningitis.

AIM: There is a paucity of data on cerebrospinal fluid (CSF) procalcitonin (PCT) to diagnose neonatal meningitis. We evaluated CSF PCT to diagnose bacterial meningitis among neonates with suspected sepsis. METHODS: Neonates undergoing lumbar puncture (LP) as part of sepsis workup were included. INDEX TESTS: CSF PCT, plasma PCT, CSF:plasma PCT ratio and CSF cytochemistry. Reference Standards: 'Definite meningitis' defined by positive CSF culture and/or gram stain and/or broad-based primer 16S rDNA polymerase chain reaction. 'Definite or probable' meningitis is defined as definite meningitis or abnormal cytochemistry. RESULTS: Of 216 eligible neonates, 18 had 'definite meningitis' and 37 'definite or probable meningitis'. Median (Q1 , Q3 ) CSF PCT level was significantly higher in 'definite meningitis' compared to 'no definite meningitis' (0.429 (0.123, 1.300) vs. 0.181 (0.119, 0.286) ng/mL respectively, P = 0.028). Likewise, it was significantly higher in 'definite or probable meningitis' compared to no meningitis (0.245 (0.136, 0.675) vs. 0.170 (0.116, 0.28), P = 0.01). The area under the receiver operator characteristics curve of CSF PCT level for definite meningitis was 0.656 and for 'definite or probable meningitis' 0.635. Paired comparisons of area under the receiver operator characteristics curve of CSF PCT with the other index tests showed no significant differences. Based on a priori cut-off of 0.2 ng/mL, CSF PCT level had a sensitivity (95% confidence interval) of 67% (50, 80), specificity 58% (54, 61), LR+ 1.6 (1.1, 2.0) and LR- 0.6 (0.3, 0.9). CONCLUSIONS: Higher values of CSF PCT are associated with neonatal bacterial meningitis. However, the diagnostic performance of CSF PCT is modest and not significantly different from standard tests.

Procalcitonin and C-reactive protein for diagnosing post-operative sepsis in neonates.

AIM: To determine whether serum procalcitonin (PCT) or C-reactive protein (CRP) can diagnose post-operative sepsis among neonates undergoing major non-cardiac surgery. METHODS: In this diagnostic study, we included neonates who underwent major non-cardiac surgery and were monitored for post-operative sepsis. We excluded pre-existing septic, inflammatory or life-threatening conditions. Subjects either had 'definite' (culture-positive, n = 14), 'probable' (clinical sepsis, culture-negative, n = 25) or no sepsis (n = 31). We measured serum CRP and PCT at 48 ± 6 h, 72 ± 6 h and 96 ± 6 h post-operatively and compared 'definite or probable sepsis' with 'no sepsis'. RESULTS: Median (Q1, Q3) CRP (mg/L) in 'definite or probable' sepsis group was higher than 'no sepsis' at 72 h (91.48 (57.87, 143.50) vs. 51.32 (33.0, 80.1); P = 0.009) and 96 h (87.51 (45.19, 128.22) vs. 31.00 (25.3, 45.2); P < 0.001). Median (Q1, Q3) PCT (ng/mL) in 'definite or probable' sepsis was higher than 'no sepsis' at 72 h (4.22 (2.04, 12.73) vs. 1.78 (0.9, 6.4); P = 0.01) and 96 h (3.54 (1.96, 9.65) vs. 0.97 (0.4, 3.0); P < 0.001). Ninety-six-hour CRP and PCT cut-offs (based on Youden's index) were 74.16 mg/L and 1.65 ng/mL, respectively. If both CRP and PCT were positive, specificity was 100% (95% confidence interval: 88.78-100). If either one was positive, sensitivity was 88.89% (95% confidence interval: 73.94-96.89). CONCLUSIONS: Septic neonates have significantly higher serum CRP and PCT compared to non-septic neonates at 72 and 96 h post-operatively. If both CRP and PCT are positive at 96 h after surgery, it has 100% specificity, and if either one is positive, 89% sensitivity.

Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study).

BACKGROUND: Vitamin D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in SARS-CoV-2 infection is not known. AIM: Effect of high dose, oral cholecalciferol supplementation on SARS-CoV-2 viral clearance. DESIGN: Randomised, placebo-controlled. PARTICIPANTS: Asymptomatic or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH)D<20 ng/ml) individuals. INTERVENTION: Participants were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for 7 days with therapeutic target 25(OH)D>50 ng/ml (intervention group) or placebo (control group). Patients requiring invasive ventilation or with significant comorbidities were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was continued for those with 25(OH)D <50 ng/ml in the intervention arm. SARS-CoV-2 RNA and inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured periodically. OUTCOME MEASURE: Proportion of patients with SARS-CoV-2 RNA negative before day-21 and change in inflammatory markers. RESULTS: Forty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers. CONCLUSION: Greater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation. TRIAL REGISTER NUMBER: NCT04459247.

Seasonal variation and Incidence of rupture of intracranial aneurysm : A prospective study and Literature review.

OBJECTIVES: Some studies have found an association of incidence of aneurysmal Sub arachnoid hemorrhage (aSAH) seasonal variations and weather patterns but others have refuted this. With conflicting reports in the literature, we tried to find out whether climatic conditions influence the incidence of aSAH. PATIENTS AND METHODS: This was a prospective single centre study involving patients with aSAH operated in a tertiary care hospital over one calendar year. Meteorological parameters like temperature, barometric pressure, humidity and sunshine hours were noted for 2 consecutive days prior to the ictus and on the day of ictus. RESULTS: 392 patients of aSAH who underwent clipping were enrolled. There was no significant difference in the incidence of aSAH across various seasons (p > 0.05). Pre ictus fall in temperature lead to a surge in number of cases. 241 patients (61.5%) reported were from geographical areas which had experienced a fall in temperature over preceding 2 days, with a mean fall in temperature of 1.1(SD 2.1) degree celsius (p less then 0.05). The incidence of aSAH patients in low sunshine hour seasons (1.13 patients/day) was significantly more than that in higher sunshine hour seasons (0.9 patients/day) (p less than 0.05 ). CONCLUSIONS: Seasonal variation had no direct bearing on the incidence of aSAH. Pre ictus fall in temperature lead to a rise in number of cases. Also, higher incidence of aneurysmal subarachnoid haemorrhage was seen in lower sunshine hour seasons.

Association of birth weight with risk factors of cardiovascular diseases: A birth cohort analysis from a rural area of Northern India.

Background: Fetal origin of cardiovascular diseases (CVD) hypothesis has been explored mostly in retrospective studies. Objectives: A prospective study was conducted to find the association of birth weight with CVD risk factors. Methods: A cohort of 243 babies born in 1992-1993 in ten villages of Raipur Rani Block in India, were followed-up in 2016-2017. WHO STEPS methods were used to assess the risk factors of CVDs. A total of 213 (87.8%) participants were examined; blood samples were collected from 207. Multivariable regression analysis was done to adjust for the confounding variables. Results: Study participants were 22-24 year old, 27.7% were exposed to tobacco and 24.8% consumed alcohol, 3.3% were taking >5 servings of fruits and vegetables per day, 35.7% were physically inactive, 28.6% were overweight (body mass index [BMI] ≥23 kg/m2), 12.2% had hypertension, 16% had high cholesterol (≥200 mg/dl), 16.4% had insulin resistance (IR) (Homeostatic Model Assessment-IR >3), and 20.7% were born with low birth weight (<2.5 kg). Multivariable regression analysis revealed inverse relationship between birth weight and systolic blood pressure (regression coefficient ‒3.72 mmHg, 95% confidence interval ‒7.249; ‒0.183, P < 0.05). Conclusion: Birth weight has inverse relationship with blood pressure. Effect of birth weight on CVDs should also be studied in future follow-ups.

IL-6 is associated with expansion of myeloid-derived suppressor cells and enhanced immunosuppression in pancreatic adenocarcinoma patients.

Chronic inflammation favours the expansion of myeloid-derived suppressor cells (MDSCs) by secreting pro-inflammatory mediators. The role of MDSCs in mediating immunosuppression in pancreatic adenocarcinoma and in defining a premalignant route from chronic pancreatitis remains unclear. We aimed to study the immunosuppressive potential of all subsets of MDSCs and their correlation with inflammatory cytokines in pancreatic adenocarcinoma and chronic pancreatitis. Relative frequencies of MDSCs, immunosuppressive markers arginase-1 (ARG-1), programmed death-ligand 1 (PD-L1), reactive oxygen species (ROS) and cytokines in circulation and surgically resected local pancreatic tissue of chronic pancreatitis and pancreatic adenocarcinoma patients were analysed by multicolour flow cytometry and cytokine bead array, respectively. Levels of cytokines involved in MDSCs activation were analysed by ELISA, and the immunosuppressive nature of MDSCs was confirmed by T-cell suppression assay. Frequencies of circulating MDSCs and ARG-1, PD-L1, and ROS were significantly higher in pancreatic adenocarcinoma than healthy controls and showed a significant positive correlation with MDSCs burden in cancer tissue. Serum levels of cytokines IL-6, IL-8 and IL-10 were significantly elevated in pancreatic adenocarcinoma. IL-6 serum levels showed a significant positive correlation with frequencies of circulating MDSCs in pancreatic adenocarcinoma patients, and MDSCs mediated suppression of T-cell proliferation in vitro was associated with elevated IL-6 levels in the cell culture medium. Collectively, our results suggest that IL-6 plays a crucial role in the expansion of MDSCs and activating their immunosuppressive nature in pancreatic adenocarcinoma. The relative frequency of MDSCs in circulation can be used as a potential diagnostic biomarker for pancreatic cancer.

A high potency multi-strain probiotic improves glycemic control in children with new-onset type 1 diabetes mellitus: A randomized, double-blind, and placebo-controlled pilot study.

BACKGROUND: Studies in animal models and humans with type 1 diabetes mellitus (T1DM) have shown that probiotic supplementation leads to decreased pro-inflammatory cytokines (responsible for damaging ß-cells of the pancreas), improved gut barrier function, and induction of immune tolerance. OBJECTIVE: To study the effect of supplementation of probiotics in children with T1DM on glycemic control, insulin dose, and plasma C-peptide levels. METHODS: A single-centered, double-blinded, and randomized placebo-controlled pilot trial was conducted in children (2-12 years) with new-onset T1DM. Ninety-six children were randomized and allocated to Placebo or Intervention groups. The intervention included high dose (112.5 billion viable lyophilized bacteria per capsule) multi-strain probiotic De Simone formulation (manufactured by Danisco-Dupont) sold as Visbiome® in India. The probiotic was supplemented for 3 months and HbA1c, fasting C-peptide, blood sugar records, and insulin dose was recorded at baseline and 3 months. RESULTS: A total of 90 patients (45 in each group) were analyzed for outcome parameters. We found a significant decrease in HbA1c (5.1 vs. 3.8; p = 0.021) and a significant decline in total and bolus insulin dose (U/kg/day; p = 0.037 and 0.018, respectively) in the intervention group when compared with the placebo group. A significantly higher (p = 0.023) number of children achieved remission in the treatment group. We did not notice adverse effects in either of the study groups. CONCLUSION: Children with newly diagnosed T1DM managed with standard treatment along with probiotics showed better glycemic control and a decrease in insulin requirements; however, more extensive studies are further warranted.

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome.

OBJECTIVE: To examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size. METHODS: This was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma). RESULTS: CD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m2; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005). CONCLUSION: Our cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.

Use of convalescent plasma for COVID-19 in India: A review & practical guidelines.

Convalescent plasma (CP) therapy is one of the promising therapies being tried for COVID-19 patients. This passive immunity mode involves separating preformed antibodies against SARS-CoV-2 from a recently recovered COVID-19 patient and infusing it into a patient with active disease or an exposed individual for prophylaxis. Its advantages include ease of production, rapid deployment, specificity against the target infectious agent, and scalability. In the current pandemic, it has been used on a large scale across the globe and also in India. However, unequivocal proof of efficacy and effectiveness in COVID-19 is still not available. Various CP therapy parameters such as donor selection, antibody quantification, timing of use, and dosing need to be considered before its use. The current review attempts to summarize the available evidence and provide recommendations for setting up CP protocols in clinical and research settings.

Incidence and risk factors for dysglycaemia in Asian-Indians: a 10-year population-based prospective cohort study.

BACKGROUND: Diabetes prevalence estimates suggest an increasing trend in South-East Asia region, but studies on its incidence are limited. The current study aims to estimate the incidence of type 2 diabetes and pre-diabetes in a population-based cohort from India. METHODS: A subset of Chandigarh Urban Diabetes Study cohort (n=1878) with normoglycaemia or pre-diabetes at baseline was prospectively followed after a median of 11 (0.5-11) years. Diabetes and pre-diabetes were diagnosed as per WHO guidelines. The incidence with 95% CI was calculated in 1000 person-years and Cox proportional hazard model was used to find the association between the risk factors and progression to pre-diabetes and diabetes. RESULTS: The incidence of diabetes, pre-diabetes and dysglycaemia (either pre-diabetes or diabetes) was 21.6 (17.8-26.1), 18.8 (14.8-23.4) and 31.7 (26.5-37.6) per 1000 person-years, respectively. Age (HR 1.02, 95% CI 1.01 to 1.04), family history of diabetes (HR 1.56, 95% CI 1.09 to 2.25) and sedentary lifestyle (HR 1.51, 95% CI 1.05 to 2.17) predicted conversion from normoglycaemia to dysglycaemia, while obesity (HR 2.43, 95% CI 1.21 to 4.89) predicted conversion from pre-diabetes to diabetes. CONCLUSION: A high incidence of diabetes and pre-diabetes in Asian-Indians suggests a faster conversion rate to dysglycaemia, which is partly explained by sedentary lifestyle and consequent obesity in these individuals. The high incidence rates call for a pressing need for public health interventions targeting modifiable risk factors.

Metabolic Bone Profile of Healthy Adult North Indian Population from Chandigarh Urban Bone Epidemiological Study (CUBES).

We aimed to estimate metabolic bone profile in a large cohort of healthy, adult Indian population to generate reference standards of serum calcium, phosphate and alkaline phosphatase (ALP), 25 (OH) Vitamin D and iPTH, and also to find out the prevalence of Vitamin D deficiency in healthy population. Apparently healthy people in the age group of 20-80 years, residing in the union territory of Chandigarh were chosen. Fasting samples for serum calcium, phosphate, albumin, alkaline phosphatase (ALP), 25 (OH) D and iPTH were collected and were processed on the same day. We recruited 930 healthy subjects from different subsectors of Chandigarh. Final analysis was done for 915 subjects. Out of this, 530 (58%) were women and 385 (42%) were men. The study participants were divided into two groups, less than and more than 50 years for the men and pre and post-menopausal for the women. The serum calcium, phosphate, ALP and iPTH were significantly higher in the post-menopausal women compared to the pre-menopausal women. The median plasma 25 (OH) D in men and women was 12.5 ng/mL and 14.3 ng/mL, respectively. 25 (OH) D deficiency was seen in 65.4% of individuals. 25 (OH) D levels co-related negatively with iPTH levels (r = - 0.4, p < 0.0001), and showed an increasing trend with age. We have thus presented metabolic bone profile of healthy, adult north Indian population. These reference values can be used for diagnosis and monitoring of various MBDs. Vitamin D deficiency is still rampant in our population in spite of increasing awareness.

Low vasopressin and progression of neonatal sepsis to septic shock: a prospective cohort study.

The study objective was to analyze the association between low plasma vasopressin and progression of sepsis to septic shock in neonates < 34 weeks gestation. Septic neonates of < 34 weeks gestation were consecutively enrolled; moribund neonates and those with major malformations were excluded. Subjects were monitored for progression of sepsis to septic shock over the first 7 days from enrolment. Plasma vasopressin levels and inducible nitric oxide synthase levels were measured at the onset of sepsis (T0), severe sepsis (T1), and septic shock (T2). Primary outcome was plasma vasopressin levels at the point of sepsis in those who progressed to septic shock in comparison with matched nested controls in the non-progression group. Forty-nine (47%) enrolled subjects developed severe sepsis or septic shock. Plasma vasopressin levels (pg/ml) at the onset of sepsis were significantly low in those who progressed to septic shock (median (IQR), 31 (2.5-80) versus 100 (12-156); p = 0.02). After adjusting for confounders, vasopressin levels were independently associated with progression to septic shock (adjusted OR (95% CI), 0.97 (0.96, 0.99); p = 0.01).Conclusion: Preterm septic neonates who progressed to septic shock had suppressed vasopressin levels before the onset of shock. Low vasopressin levels were independently associated with progression to septic shock.What is known:• In animal sepsis models and adult septic patients, exuberant production of nitric oxide metabolites and low vasopressin levels have been reportedly associated with progression to septic shock.• Vasopressin levels have been variably reported as low as well as elevated in children with septic shock.What is New:• Preterm neonates who progressed from sepsis to septic shock had significantly lower levels of vasopressin before the onset of shock in comparison with those who did not progress.• Low vasopressin levels independently predicted the progression from sepsis to septic shock in this population.

Acquired neuro-secretory defect in growth hormone secretion due to Imatinib mesylate and the efficacy of growth hormone therapy in children with chronic myeloid leukemia.

Imatinib results in growth retardation in children with chronic myeloid leukemia (CML). The study was planned to assess the GHRH-GH-IGF1 axis in children with CML, receiving Imatinib and to evaluate the efficacy of human growth hormone (hGH) therapy. Twenty children with CML, receiving Imatinib for a period exceeding 6 months, with resultant growth retardation were included. The GHRH-GH-IGF1 axis was assessed using growth hormone stimulation tests. IGF-1 generation test was performed for the evaluation of GH insensitivity. The mean age at inclusion was 15.2 years. The mean duration of treatment with Imatinib was 5.7 years. The mean decrease in height SDS since the start of Imatinib was -0.95 (p = 0.008). IGF-1 SDS was <-2 in all the patients. 71.4% of patients had a suboptimal GH response following stimulation with GHRH-Arginine. All patients had stimulable, although a delayed GH response with glucagon stimulation. 20% of patients had GH insensitivity. Four patients were treated with hGH for a mean duration of 5.75 months, achieved normalization of IGF-1 levels and improvement in growth velocity improved from 0.21 to 0.86 cm/month. Imatinib results in an acquired neurosecretory defect in GH secretion. Treatment with growth hormone leads to an improvement in growth velocity and normalization of IGF-1.