Antenatal risk stratification for preeclampsia with sFlt-1/PlGF ratio: Which is the best time to test?

OBJECTIVE: To find out the predictive value of sFlt-1/PlGF ratio for antenatal risk stratification (ARS) of women at high risk of preeclampsia (PE). METHODS: Antenatal women at high risk of PE underwent sFlt-1/PlGF ratio at 20-22, 28-30 and 34-36 weeks and were followed till delivery. Those who developed PE were cases those who had normal outcome were controls, the cases and controls were compared. RESULTS: Hypertension in pregnancy was seen in 116/287 (40.4 %), 46/287(16.0 %) had PE and 21(7.3 %) had early onset PE. Mean arterial pressure at 20-22 weeks was the high in those who developed early onset PE (109.08 ± 9.74 mmHg). The sFlt-1/PlGF ratio of 38 or more at 20-22 weeks resulted in either PE or adverse fetal outcome in all cases. Whereas, the ratio of less than 38 ruled out PE in all cases up to 29 + 6 weeks. At 28-30 weeks, the ratio less than 38 predicted no PE up to 34 weeks and no complication up to 29+6 weeks. The sensitivity for the detection at later gestation further decreased as the gestation advanced however the specificity was above 98 % at all gestations. The positive predictive value of the test increased with the advancing gestation, the negative predictive value was 93 % or higher at all gestations. CONCLUSION: The usefulness of sFlt-1/PlGF ratio ≥38 for risk stratification was validated in the study, the testing at 28-30 weeks appeared to be the best time to test for PE prediction in high risk women.

Daily vs. monthly oral vitamin D3 for treatment of symptomatic vitamin D deficiency in infants: a randomized controlled trial.

OBJECTIVES: Compare the efficacy and safety of daily vs. monthly oral vitamin D3 in treating symptomatic vitamin D deficiency in infants. METHODS: 90 infants with symptomatic vitamin D deficiency were randomized into Daily (D) [46 infants] and Bolus (B) [44 infants] groups to receive oral vitamin D3, daily (2000 IU/day) and bolus (60,000 IU/month) for three months respectively. Both groups received daily oral calcium @50 mg/kg/day. Serum calcium (Ca), phosphate (P), alkaline phosphatase (ALP), 25-hydroxy cholecalciferol [25(OH)D], parathyroid hormone (PTH) levels, urine calcium: creatinine ratio and radiological score were assessed at baseline, 4 and 12 weeks. At the end of 12 weeks, 78 infants were available for evaluation of efficacy and safety of both regimens. RESULTS: Both regimens led to a statistically significant increase in Ca and P levels and fall in ALP and PTH levels from baseline to 4 and 12 weeks of therapy, with no inter-group difference. Infants in group D had statistically significant higher mean 25(OH)D levels as compared to group B at 4 weeks (group D 130.89 ± 43.43 nmol/L, group B - 108.25 ± 32.40 nmol/L; p - 0.012) and 12 weeks (group D - 193.69 ± 32.47 nmol/L, group B - 153.85 ± 33.60 nmol/L; p<0.001). Eight infants [group D - 6/41 (14.6 %); group B - 2/37 (5.4 %), p=0.268] developed mild asymptomatic hypercalcemia without hypercalciuria at 12 weeks that corrected spontaneously within a week. CONCLUSIONS: Both daily and monthly oral vitamin D3 in equivalent doses are efficacious and safe for treating symptomatic vitamin D deficiency in infants.

Diagnosis of bacterial infection in children with relapse of nephrotic syndrome: a personalized decision-analytic nomogram and decision curve analysis.

BACKGROUND: Infections associated with nephrotic relapses (NR) are often managed according to physician preferences. A validated prediction tool will aid clinical decision-making and help in rationalizing antibiotic prescriptions. Our objective was to develop a biomarker-based prediction model and a regression nomogram for the prediction of the probability of infection in children with NR. We also aimed to perform a decision curve analysis (DCA). METHODS: This cross-sectional study included children (1-18 years) with NR. The outcome of interest was the presence of bacterial infection as diagnosed using standard clinical definitions. Total leucocyte count (TLC), absolute neutrophil count (ANC), quantitative C-reactive protein (qCRP), and procalcitonin (PCT) were the biomarker predictors. Logistic regression was used to identify the best biomarker model, followed by discrimination and calibration testing. Subsequently, a probability nomogram was constructed and DCA was done to determine the clinical utility and net benefits. RESULTS: We included 150 relapse episodes. A bacterial infection was diagnosed in 35%. Multivariate analysis showed the ANC + qCRP model to be the best predictive model. This model displayed excellent discrimination (AUC: 0.83), and calibration (optimism-adjusted intercept: 0.015, slope: 0.926). A prediction nomogram and web-application was developed. The superiority of the model was also confirmed by DCA in the probability threshold range of 15-60%. CONCLUSIONS: An ANC-based and qCRP-based internally validated nomogram can be used for the prediction of probability of infection in non-critically ill children with NR. Decision curves from this study will aid in the decision-making of empirical antibiotic therapy, incorporating threshold probabilities as a surrogate of physician preference. A higher resolution version of the Graphical abstract is available as Supplementary information.

Role of sFLT-1/PlGF ratio in predicting severe adverse materno-fetal outcome in high risk women.

OBJECTIVE: To evaluate the role of angiogenic biomarkers in predicting severe adverse materno-fetal outcome (SAO) among women at high risk of preeclampsia (PE). METHOD: All antenatal women at high risk of PE underwent MAP estimation, sFlt-1/PlGF ratio, uterine artery evaluation at 20-22, 28-30 and 34-36 weeks of gestation and were followed until delivery. The severe adverse outcome included severe PE, severe fetal growth restriction with Doppler changes and intrauterine death or early neonatal death. Those who developed SAO were cases and rest were controls, the cases and controls were compared using univariate and multivariate logistic regression analysis. RESULTS: In 54/287(18.8 %) SAO was observed, and they comprised of severe PE (21/287, 7.3 %), FGR with absent or reverse diastolic flow on Doppler (23/287, 8.0 %) and intrauterine death or early neonatal death (10/287, 3.5 %). For detecting complications up to 30 weeks, the sFLT-1/PlGF ratio at 20 weeks (cut off ≥ 38) was the best test (accuracy- 97.6 %) followed by MAP and uterine artery Doppler PI. For detecting complications up to 34 weeks, prediction was good (accuracy -80.4 %) when sFLT-1/PlGF ratio was combined with uterine artery PI. The predictive value of the complications before 34 weeks was far superior to that after 34 weeks. Combining the sFLT-1/PlGF ratio with the uterine artery PI improved the accuracy of the test (79 % to 87 %). CONCLUSION: Increased sFlt-1/PlGF ratio, was a good predictive marker for SAO in the study population. The accuracy of prediction was better for those who developed the complications before 34 weeks.

Association of Paraoxonase-2 (C1053G) Gene Polymorphism with the Expression of Paraoxonase-2 Gene in Patients of Ischemic Stroke - A Pilot Study in Indian Population.

Background and Objective: Oxidative stress plays an important role in atherosclerosis and ischemic stroke. Due to antioxidant properties of Paraoxonase-2, we studied the implication of Paraoxonase-2 gene polymorphism (C1053G) on expression of Paraoxonase-2 gene at mRNA level in ischemic stroke patients. Material and Methods: 40 patients of ischemic stroke and 40 age and sex-matched controls were included. Paraoxonase-2 genotypes were evaluated by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and expression of Paraoxonase-2 gene at mRNA level was determined by quantitative real time Polymerase Chain Reaction analysed as delta-CT (△CT). Result and Discussion: The observed allele frequencies in patients for C and G allele were 0.61 and 0.39 respectively, and were 0.72 and 0.28 in control group. No significant association was found in C allele of C1053G polymorphism and ischemic stroke. The average △ CT value is significantly (p = 0.0001) higher in patients group (7.68 ± 2.0) as compared to controls (5.70 ± 1.8). We found a significant difference in the average delta-CT value (p = 0.0001), wherein down-regulated paraoxonase-2 gene expression (approximately 0.25 fold) was observed in case of patients as compared to controls. Down-regulated expression of paraoxonase-2 gene was observed in patients with GG genotype as compared to CG and CC genotypes in patients with ischemic stroke (p = 0.0001). Conclusion: Down-regulated Paraoxonase-2 gene expression, as evidenced by low mRNA levels in GG genotype may be one of the contributory factors in the progression of ischemic stroke.

Chronic Spontaneous Urticaria: An Etiopathogenic Study.

Importance: Exact etiopathogenesis of chronic spontaneous urticaria (CSU) remains elusive. Infections, pseudoallergens, autoimmunity, and contact sensitization are various postulated factors. Few studies are available measuring cytokine levels in CSU. Objectives: The aim was to study various etiological factors of CSU and levels of IL-6 and IFN-ϒ in cases and controls, and correlation between various etiologies with the levels of the abovementioned interleukins in the cases. Design: Case-control study performed over 2 years with no follow-up of the participants. Setting: It was a referral-center-based study. Participants: Sixty patients of CSU and equal age and sex-matched healthy controls were recruited on the basis of convenience sampling. Exposures: Biochemical and hematological investigations with hepatitis serology, thyroid function tests, anti-thyroid antibodies, and levels IL-6 and IFN-ϒ were performed in all cases and controls. All cases were subjected to ASST. Cases with all above negative tests were patch-tested with Indian standard series. Urticaria activity score (UAS7) was calculated for all the cases and repeated in patients with positive etiological factor after 3 weeks (improvement after allergen or drug avoidance, treatment of infection). Outcomes: To study the various etiological factors (food, infection, autoimmunity, autoreactivity, and contact sensitization) and the levels of IL-6 and IFN- γ in patients of chronic spontaneous urticaria. Results: Etiology was ascertained in 75% of patients (autoimmunity: 50%, contact sensitization: 21.67%, food and drug allergy: 1.67% each). Mean values of the interleukins and anti-thyroid antibodies were significantly higher in cases versus controls. Levels of IFN-ϒ were significantly elevated in patients with higher UAS7 scores. Conclusion: Antithyroid antibodies, ASST, and patch testing are important tools and should be considered in patients of CSU after a thorough history and history-based workup. Elevated levels of IL-6 and IFN- ϒ in cases suggest that both Th1 and Th2 type of immune responses are implicated in pathogenesis of CSU.

Perplexity vs Clarity in choosing the right molecular diagnostic techniques for SARS-COV2 detection in Indian setup.

After the havoc created by Spanish flu a century ago, the world is witnessing exactly a similar pandemic situation since the beginning of the year 2020. The unexplained respiratory illness with high morbidity & mortality which started in Wuhan, China and spread across the world was finally termed as COVID-19 disease caused by SARS-CoV-2 and later announced as pandemic by WHO. This novel virus SARS-CoV-2 is a new variant of SARS corona virus with high infectivity and mysterious pathophysiology. The major step towards containment of this pandemic is to scale up the testing for SARS-CoV-2 and thereby isolating and managing the patients at the earliest. Molecular amplification based methods such a Real time Polymerase chain reaction (RT-PCR), CBNAAT and TrueNAT are the most commonly used techniques for detection of SARS-CoV2. To utilize these diagnostic facilities optimally in the management of the suspected COVID 19 patients, it is of utmost importance for the healthcare providers to understand the intricacies related to these technologies. Thus, the technical details along with the pros & cons of these three amplification-based technologies for proper understanding of these diagnostic modalities for SARS COV-2 diagnosis are discussed herewith.

Prediction of hypertension in pregnancy in high risk women using maternal factors and serial placental profile in second and third trimester.

INTRODUCTION: To evaluate the role of placental profile markers in second and third trimester of pregnancy in predicting hypertensive disorders of pregnancy (HDP) in women at high risk of preeclampsia. METHOD: Women who were at high risk of preeclampsia underwent ßhCG, ultrasound assessment of placental length, thickness and its ratio, uterine artery Doppler at 20-24 weeks and 28-32 weeks of gestation, the outcome at delivery was noted. Those who developed HDP were cases and those with normal outcome were controls. The placental profile markers among cases and controls were compared. RESULTS: Hypertensive disorders of pregnancy was seen in 72/160 (45%) high risk women The serum ß hCG levels at 20-24 weeks (p = 0.001) and 28-32 weeks (p = 0.018) was significantly high in women who had preeclampsia. Placental thickness was found to be less in among all subgroups of HDP, for preeclampsia, it was significantly low at 20-24 weeks (AUC- 0.743; sensitivity- 75%, specificity- 66.3%) and 28 weeks (AUC -0.764, sensitivity - 75.0% specificity - 78.7%). Uterine artery S/D ratio was considerable high in women with chronic hypertension (AUC -0.765), gestational hypertension (AUC -0.771) and preeclampsia (AUC -0.726) at 20-24 weeks. In preeclampsia group, uterine artery PI was highest and the best marker at 20-24 weeks (AUC -0.935, sensitivity - 100.0%, specificity - 87.6%). DISCUSSION: The placental profile markers may be used to provide closer follow up in high risk pregnancies with abnormal placental profile levels, while less intense follow up in those with normal levels, thus channelizing the resources.

Brief Report: Subclinical Kidney Dysfunction in HIV-Infected Children: A Cross-Sectional Study.

OBJECTIVE: Most of the kidney dysfunction in HIV-positive children receiving antiretroviral therapy (ART) is attributed to tenofovir. There is a paucity of data on kidney dysfunction in tenofovir-naive children. The primary objective was to know the point prevalence of albuminuria and ß2-microglobulinuria in HIV-infected children aged 3-18 years receiving ART. Albuminuria and ß2-microglobulinuria were used as surrogates for glomerular and tubular dysfunction, respectively. The secondary objective was to determine their predictors. DESIGN: Cross-sectional study-design. METHODS: One hundred consecutive HIV-positive children (3-18 years) on ART were included. Spot urine sample was analyzed for urinary creatinine, total protein, microalbumin, and ß2-microglobulin. Albuminuria was defined as albumin to creatinine ratio of >30 mg/g; proteinuria as urine dipstick ≥trace or spot urine protein to creatinine ratio (uPCR) of ≥0.2. ß2-microglobulinuria was defined as ß2-microglobulin levels of >350 µg/L. RESULTS: There were 71 boys and 29 girls. Most of the children had WHO clinical stage I and were getting zidovudine-based regimen. Only 7 children were getting tenofovir. estimated Glomerular Filtration Rate and serum creatinine were normal in all children. Approximately half (48%) had renal dysfunction in the form of glomerular dysfunction (26%), tubular dysfunction (27%), or both (5%). Age at diagnosis was significantly associated with ß2-microglobulinuria (P = 0.044). None of the selected variables were associated with albuminuria. CONCLUSIONS: HIV-associated glomerular and tubular dysfunction is common in children receiving ART other than tenofovir. The standard guidelines should consider including routine urinary biomarker monitoring in children on ART.

Association of Single Nucleotide Polymorphisms (SNPs) in Genes Encoding for Folate Metabolising Enzymes with Glioma and Meningioma in Indian Population

Background: The association of primary brain tumors with Single Nucleotide polymorphisms (SNPs) in genes of folate metabolising enzymes have been reported to vary among different ethnic population. Here, we have studied the association of SNPs of folate metabolizing genes with the primary brain tumors (glioma and meningioma) in North Indian population. Methods: SNPs of genes coding for folate metabolizing enzymes was carried out in 288 study population from North India [Glioma (n=108), Meningioma (n=76) and healthy-control (n=104)]. The allele-specific polymerase chain reaction (ARMS-PCR) was used to analyse the SNP A1298C of the MTHFR (Methylenetetrahydrofolate-reductase) and the SNP A66G of the methionine synthase reductase (MTRR) genes. The PCR-RLFP (Restriction Fragment Length Polymorphism) was used to analyse the SNP C677T of the Methylene tetrahydrofolate-reductase and the SNP A2756G of the methionine-synthase (MTR) genes. Serum homocysteine, vitamin B12 and folate levels were evaluated in controls/ patients serum using Chemiluminescence immunoassay and the levels were correlated with SNPs genotype. Results: The CC genotype of MTHFR A1298C was observed to have reduced risk of having meningioma than AA genotype (odd ratio=0.62, 95%CI 0.32-0.97, p=0.03). Similarly, the AG genotype of MTRR A66G showed reduced risk of glioma than AA genotype (odd ratio=0.56, 95%CI 0.32-0.97, p=0.039). Furthermore, in patients with AA genotype of MTR A2756G and CT genotype of MTHFR C677T showed higher serum homocysteine level than GG genotype (8.6 µmol/L, p=0.048) and CC genotype (11.2µmol/L, p=0.039) respectively. Conclusion: Our findings provide an insight into the risk association of SNPs in MTHFR A1298C and MTRR A66G genes with glioma/meningioma patients. Further studies are needed to evaluate their clinical implications.

Acute Intermittent Porphyria in children: A case report and review of the literature.

Acute Intermittent Porphyria (AIP), an autosomal dominant inborn error of heme metabolism, typically presents in adulthood, most often in women in the reproductive age group. There are limited reports on the clinical presentation in children, and in contrast to the adults, most of the reported pediatric cases are male. While acute abdominal pain is the most common presenting symptom in children, seizures are commonly seen and may precede the diagnosis of AIP. As an example, we report a 9year old developmentally normal pre-pubertal boy who presented with acute abdominal pain, vomiting and constipation followed by hyponatremia, seizures, weakness and neuropathy. After a diagnostic odyssey, his urine porphobilinogen was found to be significantly elevated and genetic testing showed a previously unreported consensus splice-site mutation IVS4-1G>A in the HMBS gene confirming the diagnosis of AIP. Here, we discuss the clinical presentation in this case, and 15 reported pediatric cases since the last review 30years ago and discuss the differential diagnosis and challenges in making the diagnosis in children. We review the childhood-onset cases reported in the Longitudinal Study of the Porphyrias Consortium. Of these, genetically and biochemically confirmed patients, 11 of 204 (5%) reported onset of attacks in childhood. Most of these patients (91%) reported recurrent attacks following the initial presentation. Thus, AIP should be considered in the differential diagnosis of children presenting with unexplained abdominal pain, seizures, weakness and neuropathy.