Therapeutic high-dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double-blind, placebo-controlled study (SHADE-S).

BACKGROUND: efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied. OBJECTIVE: effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19. METHODS: participants with moderate to severe COVID-19 with PaO2/FiO2 ratio < 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo. OUTCOMES: primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality. RESULTS: in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10-16) and 13 (12-18) ng/ml (P = 0.06) at baseline; and 60 (55-65) ng/ml and 4 (1-7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2-5) versus 5 (95% CI, 3-7), P = 0.01, intergroup difference - 2 (95% CI, -4 to -0.01); r = 0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P = 0.046)] was observed with vitamin D. CONCLUSIONS: single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19. ClinicalTrials.gov  id: NCT04952857 registered dated 7 July 2021. What is already known on this topic-vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs. What this study adds-high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D > 50 ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19. How this study might affect research, practice or policy-vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced.

Fixed-Dose Combination of Canagliflozin and Metformin as an Adjunct to Diet and Exercise in Indian Adults with Type 2 Diabetes Mellitus: Results from a Multicentric, Open-Label, Single-Arm, Phase IV Study.

BACKGROUND: Canagliflozin and metformin fixed-dose combination (CANA/MET FDC), an approved treatment for type 2 diabetes mellitus (T2DM) in India, effectively lowers glycated hemoglobin (HbA1c), promotes weight loss, and improves patient adherence. As a regulatory requirement, we aimed to evaluate the safety and efficacy of CANA/MET FDC in Indian patients with T2DM. RESEARCH DESIGN AND METHODS: This prospective, multicenter, open-label, single-arm, phase IV study included Indian patients with T2DM (aged 18-65 years) inadequately controlled on diet and exercise. Patients received CANA/MET (50/500 and 50/1000 mg) immediate-release (IR) FDC twice daily for 24 weeks. The primary endpoint was safety assessment, including adverse events (AEs) and serious AEs (SAEs). The secondary endpoint included a change in HbA1c from baseline to weeks 12 and 24. Descriptive statistics were used for all continuous safety variables and efficacy parameters. RESULTS: Of the 310 patients screened, 276 were enrolled. 114/274 (41.6%) patients had ≥1 treatment-emergent AE [treatment-emergent AEs (TEAEs), among which 29 (10.6%) were related to study intervention]. The most common TEAEs were dyslipidemia (4.7%), pyrexia (4.7%), genital infections (3.3%), hypoglycemia (3.3%), and urinary tract infections (2.6%). Three (1.1%) patients had serious TEAEs, and all cases were resolved. No deaths were reported. The mean change in HbA1c from baseline was -0.92 and -0.93% at weeks 12 and 24, respectively. CONCLUSION: The study demonstrates the safety and efficacy of CANA/MET FDC in Indian patients with T2DM, presenting a safe therapeutic option for diabetes management in India.

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.

Comparison of Profile of Primary Hyperparathyroidism With and Without Type 2 Diabetes Mellitus: Retrospective Analysis From the Indian Primary Hyperparathyroidism Registry.

OBJECTIVE: To describe the prevalence and compare the clinicobiochemical profile of patients with primary hyperparathyroidism (PHPT) with and without type 2 diabetes mellitus (T2DM). METHODS: We conducted a retrospective observational study wherein the details of patients with PHPT with T2DM (PHPT-T2DM) and without T2DM were retrieved from the Indian PHPT Registry (www.indianphptregistry.com) between 2005 and 2019. We compared the clinical, biochemical, and postoperative findings of patients with PHPT-T2DM with age-, sex-, and body mass index-matched patients with PHPT without T2DM (in 1:2 ratio). RESULTS: Of the 464 patients with PHPT, 54 (11.6%) had T2DM. We observed an increase in the prevalence of PHPT-T2DM cases over time; only 7 (7.1%) of the total patients with PHPT had T2DM between 2005 and 2009 that increased to 31 (12.8%) in the last half decade (2015-2019). Patients with PHPT-T2DM had a significantly lower prevalence of nephrolithiasis (18.5% vs 36.1%, respectively; P = .03) and a higher prevalence of pancreatitis (22.2% vs 5.6%, respectively; P = .007) than those without T2DM. Furthermore, intact parathyroid hormone (203 pg/mL [139.8-437.3 pg/mL] vs 285 pg/mL [166-692 pg/mL], respectively; P = .04) and serum creatinine (0.90 mg/dL [0.67-1.25 mg/dL] vs 1.10 mg/dL [0.73-1.68 mg/dL], respectively; P = .03) levels were significantly lower in patients with PHPT-T2DM than those without T2DM. Also, tumor weight tended to be lower in patients with PHPT-T2DM than in the non-T2DM counterparts (1.05 g [0.5-2.93 g] vs 2.16 g [0.81-7.0 g], respectively; P = .06). CONCLUSION: The prevalence of T2DM in Asian Indians with PHPT is 11.6%. Patients with PHPT-T2DM are characterized by a higher prevalence of pancreatitis, a lower prevalence of nephrolithiasis, and lower levels of intact parathyroid hormone/creatinine. Part of the clinical picture can possibly be explained by early detection of PHPT in patients with T2DM consequent to more frequent screening.

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.

Unmet Need for Further LDL-C Lowering in India despite Statin Therapy: Lipid Association of India Recommendations for the Use of Bempedoic Acid.

Lipid-lowering therapy plays a crucial role in reducing adverse cardiovascular (CV) events in patients with established atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia. Lifestyle interventions along with high-intensity statin therapy are the first-line management strategy followed by ezetimibe. Only about 20-30% of patients who are on maximally tolerated statins reach recommended low-density lipoprotein cholesterol (LDL-C) goals. Several factors contribute to the problem, including adherence issues, prescription of less than high-intensity statin therapy, and de-escalation of statin dosages, but in patients with very high baseline LDL-C levels, including those with familial hypercholesterolemia and those who are intolerant to statins, it is critical to expand our arsenal of LDL-C-lowering medications. Moreover, in the extreme risk group of patients with an LDL-C goal of ≤30 mg/dL according to the Lipid Association of India (LAI) risk stratification algorithm, there is a significant residual risk requiring the addition of non-statin drugs to achieve LAI recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hsCRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. However, the CV outcomes trial results are still pending. In this LAI consensus document, we discuss the pharmacology, indications, contraindications, advantages, and evidence-based recommendations for the use of bempedoic acid in clinical practice.

The role of diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging for the diagnosis of diabetic foot osteomyelitis: a preliminary report.

Purpose: To assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusionweighted imaging (DWI) in diagnosing diabetic foot osteomyelitis (DFO). Material and methods: Twenty-five participants with suspected osteomyelitis were included, who underwent MRI including DCE-MRI and DWI sequences. It was subsequently followed by bone biopsy and microbiological analysis (gold standard). The participants were divided into 2 groups based on biopsy results: DFO-positive or DFO-negative. The semi-quantitative DCE-MRI parameters (SI0, SImax, SIrel, wash-in rate [WIR], and type of curve) and apparent diffusion coefficient (ADC) values were subsequently compared between the 2 groups. Results: Out of the 25 cases, 19 were DFO-positive and 6 were DFO-negative on bone biopsy. The SI0, SImax, and WIR were significantly higher in DFO-positive cases (p-value 0.050, 0.023, and 0.004, respectively). No difference was seen in SIrel. 100% negative cases revealed type-I curve, and 94% of positive cases showed type-II curve. SI0 > 143.4 revealed a sensitivity of 94.7% and specificity of 83.3%. SImax had a sensitivity of 89.5% but lower specificity of 67.7% at a cut-off value of 408.35. The most significant difference was seen with WIR; p-value ~0.004. At the cut-off value of > 1.280, it had a specificity and sensitivity of 100% and 76%, respectively. Also, ADC values below 1.57 × 10-3 had a sensitivity of 88.2% and specificity of 80% for diagnosing DFO. Conclusions: DWI and DCE-MRI provide non-invasive sequences, which can help to increase the overall specificity and sensitivity of conventional MRI for the diagnosis of osteomyelitis, differentiating it from acute Charcot's arthropathy.

A detailed appraisal of renal manifestations in primary hyperparathyroidism from Indian PHPT registry: Before and after curative parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism (PHPT) is a systemic disorder characterized by hypercalcaemia and inappropriately elevated parathyroid hormone (PTH). Renal manifestations are one of the main presenting features both in symptomatic and asymptomatic PHPT patients. OBJECTIVES: We aimed to compare demographic, clinical and biochemical parameters of PHPT patients with and without renal manifestations and also analysed the influence of curative parathyroidectomy on renal functions. METHODS: We retrospectively analysed the data of PHPT patients from the last 25 years (1995- March 2019) and compared the demographic and clinical presentation and biochemical measurements between patients with and without renal manifestations and evaluated the changes in renal functions after 1 year of curative parathyroidectomy. RESULTS: Of the total 544 PHPT patients, 299 (55%) including 91 out of 141 (65%) males had renal manifestations. Among renal manifestations, nephrolithiasis and nephrocalcinosis were found in 41.7% and 27.6% PHPT patients, respectively. PHPT patients with renal manifestations had significantly higher creatinine (109.7 vs 79.6 µmol/L; P < .0001) and lower eGFR level (78.8 vs 93.9 mL/min/1.73 m2 ; P < .0001) compared to patients without renal manifestations. Parathyroidectomy resolved the clinical symptoms with biochemical cure in the patients from both the groups. Patients with renal manifestations showed improvement in creatinine and eGFR levels after 1 year of curative parathyroidectomy; however, patients without renal manifestations showed no change in creatinine and eGFR levels. CONCLUSION: Young age and male gender are predictors of renal manifestations in PHPT. Curative parathyroidectomy improves renal functions in PHPT patients with renal manifestations compared to PHPT patients without renal manifestation.

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.

Eumycetoma of the Foot due to Fusarium solani in a Person with Diabetes Mellitus: Report of a Case and Review of Literature.

Eumycetomas are chronic suppurative granulomas caused by fungi characterised by invasive tumefactive lesions, sinuses and discharging grains. Herein, we describe a case of pedal eumycetoma due to Fusarium solani sensu stricto in a person with diabetes mellitus. A 45-year-old gentleman presented with an insidious onset swelling over his right foot with nodules and discharging grains. He had received itraconazole and anti-tuberculous therapy elsewhere, without response. Re-evaluation included a biopsy which confirmed eumycetoma and newly diagnosed diabetes. Surgical excision followed by histopathological, microbiological and multigene sequencing analyses [translation elongation factor, calmodulin and internal transcribed spacer region of rDNA] of the mould on culture were performed. Histopathology revealed septate fungal hyphae amidst a dense inflammatory infiltrate (Splendore-Hoeppli) reaction. Oral voriconazole was started and good glycemic control attained. Tissue growth sequences showed > 99% similarity with Fusarium solani sensu stricto. Antifungal susceptibility testing showed lowest MIC to voriconazole (0.5 mg/L). The patient showed excellent response to combined therapeutic modality with a near-complete resolution in size of lesion and obliteration of sinuses following 4 months of therapy and is planned for prolonged voriconazole therapy till complete radiological resolution. Diabetes predisposes to fungal infections of foot but eumycetomas are uncommon. Combined surgery and antifungals can improve morbidity and avoid amputations.

Urinary exosomes: Potential biomarkers for diabetic nephropathy.

Diabetic nephropathy is the most common diabetic complication culminating often into end-stage renal disease. Classically, it is defined by the presence of albuminuria which has limited ability to be detected at early stages but deterioration in kidney function generally precedes albuminuria. This necessitates the development of newer diagnostic assays for diabetic nephropathy to determine the progression of the disease. Kidney associated diseases with non-albuminuria further complicates a timely diagnosis and thus demands an early biomarker. Urinary exosomes, the nanovesicular entities are released by every epithelial cells of the nephron. Their protein or molecular cargo varies in the diseased state which may provide the pathophysiology of the kidney associated diseases. This drives them to be exploited as non-invasive biomarker. This review thus integrates the recent findings on the significance of the urinary exosomes as diagnostic biomarker in kidney-associated diseases, primarily in diabetic nephropathy.

PREVALENCE AND PREDICTORS OF PRIMARY HYPERPARATHYROIDISM AMONG PATIENTS WITH UROLITHIASIS.

OBJECTIVE: Urolithiasis may be the only presenting manifestation of primary hyperparathyroidism (PHPT), and early detection of PHPT in such patients may prevent future urolithiasis and other PHPT complications. This study was performed to study the prevalence and predictors of PHPT in patients presenting with urolithiasis. METHODS: Consecutive patients presenting with urolithiasis were evaluated for clinical and biochemical manifestations of PHPT with serum and urine calcium (Ca), serum intact parathyroid hormone and 25 (OH) vitamin D. We then compared the clinical and biochemical characteristics of PHPT patients presenting with urolithiasis (group A) and without (group B). RESULTS: During the 3-year study period, 381 patients with urolithiasis were seen with a mean age of 38.5 ± 13.9 years. Nineteen of the 381 (5%) patients had histologically proven PHPT (group A). Four patients in group A (21%) and 8 in group B (2%) had nephrocalcinosis (P<.0001), multiple stones (≥3), calcific pancreatitis, and neuropsychiatric manifestations were more common in group A (P<.0001). Presence of multiple or bilateral stones, and recurrent stone episodes predicted PHPT (odds ratio [OR]: 3.06, confidence interval [CI]: 0.87, 0.7). CONCLUSION: One out of every 20 patients with urolithiasis had PHPT, which is higher than the prevalence of PHPT in general population. The presence of nephrocalcinosis and multiple, bilateral, and recurrent stone disease increased the risk of PHPT among stone formers. ABBREVIATIONS: Ca = calcium; CI = confidence interval; iPTH = intact parathyroid hormone; nPHPT = normocalcemic PHPT; OR = odds ratio; PHPT = primary hyperparathyroidism.

Comparative study of clinical features of patients with celiac disease & those with concurrent celiac disease & type 1 diabetes mellitus.

BACKGROUND & OBJECTIVES: Celiac disease (CD) and type 1 diabetes mellitus (T1DM) share a common genetic locus and clinical manifestations. The present study was planned to compare clinical, biochemical and hormonal profiles of patients with CD and CD with T1DM. METHODS: Records of CD patients with age ≤20 yr, available anthropometric measurements, haematological, biochemical and hormonal workup with tissue transglutaminase IgA antibody and duodenal biopsy (Marsh grade) were screened. The patients were divided into two groups i.e., CD alone (Group A) and concurrent CD with T1DM (Group B). RESULTS: One hundred and nine patients of CD (57 male) with a mean age of 14.9±2.9 yr were evaluated. Of these, 86 (78.9%) patients had CD alone and 23 (13 females) (21.1%) patients had CD with T1DM. The age at diagnosis and the lag duration for the diagnosis of CD were 11.5±4.6 versus 13.8±3.4 yr (P<0.05) and 48.8 ±43.3 versus 20.2±31.8 months (P<0.05) in groups A and B, respectively. The most common histopathological grade was type 3b (59.2%) in group A and type 2 (42.1%) in group B. Short stature (87% vs. 40.9%; P<0.01), anaemia (80.9% vs. 45%, P<0.01) and delayed puberty (61.9% vs. 29.4%; P<0.01) were more common in group A. INTERPRETATION & CONCLUSIONS: Patients with CD alone have a longer lag time to diagnosis and consequent sequel in the form of anaemia, short stature and delayed puberty, as compared to patients with concurrent CD and T1DM.

Pregnancy and tumor outcomes in infertile women with macroprolactinoma on cabergoline therapy.

Hyperprolactinemia and prolactinomas cause infertility in significant number of women. But, pregnancy may lead to post-partum remission of hyperprolactinemia. The data on pregnancy and tumor outcome in women with macroprolactinoma conceiving on Cabergoline (CAB) therapy is increasing but still less than with Bromocriptine. We studied the incidence of fetal malformations, hyperprolactinemia and tumor course after gestation in infertile women harboring macroprolactinoma, who conceived on CAB therapy during the year 2005-2015. The cohort was divided into two groups based on the continuation of CAB therapy during gestation (Group A) or not (Group B). Forty-eight pregnancies in 33 women were recorded. CAB was continued throughout gestation in 25 pregnancies (Group A). The incidence of missed abortion (8.3%), still birth (4.2%) and low birth weight (7.7%) were not different in two groups. Neural tube defects were observed in 3 pregnancies (all in Group A). Post-partum, recurrence of hyperprolactinemia was observed in 64.6% and 60.9% (p = 0.8) of women in group A and B, respectively. Cabergoline was restarted after 60% and 60.9% (p = 0.9) pregnancies in the two groups in view of symptomatic hyperprolactinemia and/or persistence of macroadenoma. Post-partum, recurrence of hyperprolactinemia is common in spite of significant tumor reduction in infertile women with macroprolactinoma. Continuation of CAB during gestation does not influence the post-pregnancy recurrence of hyperprolactinemia or tumor remission.