Procalcitonin for Detecting Culture-Positive Sepsis in Neonates: A Prospective, Multicenter Study.

INTRODUCTION: It is unclear if serum procalcitonin (PCT) estimated at sepsis suspicion can help detect culture-positive sepsis in neonates. We evaluated the diagnostic performance of PCT in culture-positive sepsis in neonates. METHODS: This was a prospective study (February 2016 to September 2020) conducted in four level-3 units in India. We enrolled neonates suspected of sepsis in the first 28 days of life. Neonates with birth weight <750 g, asphyxia, shock, and major malformations were excluded. Blood for PCT assay was drawn along with the blood culture at the time of suspicion of sepsis and before antibiotic initiation. The investigators labeled the neonates as having culture-positive sepsis or "no sepsis" based on the culture reports and clinical course. PCT assay was performed by electrochemiluminescence immunoassay, and the clinicians were masked to the PCT levels while assigning the label of sepsis. Primary outcomes were the sensitivity, specificity, and likelihood ratios to identify culture-positive sepsis. RESULTS: The mean birth weight (SD) and median gestation (IQR) were 2,113 (727) g and 36 (32-38) weeks, respectively. Of the 1,204 neonates with eligible cultures, 155 (12.9%) had culture-positive sepsis. Most (79.4%) were culture-positive within 72 h of birth. The sensitivity, specificity, and positive and negative likelihood ratios at 2 ng/mL PCT threshold were 52.3% (95% confidence interval: 44.1-60.3), 64.5% (60.7-68.1), 1.47 (1.23-1.76), and 0.74 (0.62-0.88), respectively. Adding PCT to assessing neonates with 12.9% pretest probability of sepsis generated posttest probabilities of 18% and 10% for positive and negative test results, respectively. CONCLUSION: Serum PCT did not reliably identify culture-positive sepsis in neonates.

Prevalence of arrhythmia in COVID-19 patients with mild/moderate and severe illness: a prospective cohort study.

OBJECTIVES: The type of arrhythmias, and their prevalence in mild/moderate and severe COVID-19 patients admitted to the hospital are unknown from a prospective cohort study. METHODS: We did continuous electrocardiograms along with multiple ECGs in 305 consecutive hospitalized COVID-19 patients. RESULTS: The incidence of arrhythmias was 6.8% (21/305) in the target population. The incidence of arrhythmias was 9.2% (17/185) in patients with severe COVID-19 illness and 3.3% (4/120) in patients with mild/moderate COVID-19 illness with no significant difference (p = 0.063). All the arrhythmias were new-onset arrhythmias in this study. 95% (20/21) of these arrhythmias were atrial arrhythmia with 71.42% (15/21) being atrial fibrillation and one episode of sustained polymorphic ventricular tachycardia. No episode of high-grade atrioventricular block, sustained monomorphic ventricular arrhythmia, or torsades de pointes arrhythmias were observed in this study. The patients with arrhythmias were admitted to the intensive care unit (80.9% vs. 50.7%; p: 0.007), were on a ventilator (47.6% vs. 21.4%; p: 0.006), and had high in-hospital mortality (57.1% vs. 21.1%; p: 0.0001) than patients without arrhythmias. CONCLUSION: Atrial arrhythmias were the most frequent arrhythmias in hospital-admitted COVID-19 patients with atrial fibrillation being the most common arrhythmia. TRIAL REGISTRATION: Clinical Trial Registry India (CTRI) (CTRI/2021/01/030788). (https://www.ctri.nic.in/).

Study of Clinical, Hematological and Molecular Characteristics of Patients of Thalassemia and Hemoglobinopathies in Tertiary Care Hospital.

To study clinical, hematological and molecular characteristics of patients of thalassemia and hemoglobinopathies and to correlate the molecular characteristics with clinical and hematological presentations. Material: This observational cross sectional study included 100 patients of age >12 years of all genders with chronic haemolytic anemia and history of multiple blood transfusion. Blood and radiological investigations were done. Clinical, hematological and molecular characteristics were studied. Observation and Clinical: Pallor was present in all cases and icterus in 32% cases. Total 48% of the patients had hepatomegaly and 98% had splenomegaly. Among genotypes, 15% cases had α-thalassemia, 62% had ß thalassemia + 뫧 thalassemia, 7% had HbS hemoglobinopathy, and 16% had HbE hemoglobinopathy. Hematological: Hemoglobin showed significant association with molecular genotypes of thalassemia with lowest being present in ß-thalassemia + 뫧 thalassemia and HbE.MCV showed significant association with molecular genotypes, with HbE having the lowest MCV of 65.5 fl. LDH levels showed a significant association with molecular genotype with highest being in HbS hemoglobinopathy. Molecular Characteristics: Common mutations in compound α-thalassemia were 3.7, 4.2 and 20.5 deletion. As for ß-thalassemia and 뫧 thalassemia, 47 cases had heterozygous type and 15 cases had homozygous types. In ß-thalassemia, the homozygous type showed IVS1- 5(G→C),CD 41/42(→CTT) and IVSII-654(G→T) while heterozygous type showed CD16(→G), CD 41/42(→CTT), IVS1-5(G→C), and IVSII-654(G→T) . In 뫧 thalassemia, the heterozygous type showed 뫧 inversion mutation.In HbS hemoglobinopathy, heterozygous type showed Codon 6(A→T) and compound heterozygous type showed IVS1- 5(G→C) and Codon 6(A→T). In HbE hemoglobinopathy,the homozygous type showed CD26(G→A) and compound heterozygous type showed IVS1-5(G→C) and IVSII 654(G→T). Conclusion: The common thalassemia genotypes observed in our study were α-thalassemia (15%), ß thalassemia + 뫧 thalassemia, (62%) HbS hemoglobinopathy (7%), and HbE hemoglobinopathy (16%). The patients presented with pallor, icterus, hepatomegaly, and splenomegaly which were comparable among all molecular genotypes of thalassemia and hemoglobinopathies. α-thalassemia had compound α-thalassemia with common mutations being 3.7, 4.2 and 20.5 deletion. As for ß-thalassemia and 뫧 thalassemia, 47 cases had heterozygous type and 15 cases had homozygous types. In 뫧 thalassemia, the heterozygous type showed 뫧 inversion mutation in 5 cases. MCH, Retic count, ferritin stores, and peripheral blood smear were similar in all molecular genotypes. Hemoglobin, MCV and LDH showed a significant association with molecular genotypes. Microcytic hypochromic anaemia was commonest among all.The findings of the present study show that the genotypes of thalassemia are characterized by diversity as well as significant genetic heterogeneities.

Hb Sun Prairie: A rare cause of chronic hemolysis in an Indian patient.

Haemolytic anaemia is a commonly encountered condition in clinical haematology practise. Dissecting the aetiology of haemolytic anaemia is of paramount importance for appropriate management. We describe a 29-years-old lady of Indian origin, who presented with fatigue and recurrent jaundice for 2 years. Examination revealed pallor, mild icterus, and splenomegaly. Blood tests showed anaemia, reticulocytosis, indirecthyperbilirubinemia, and high serum lactate dehydrogenase, consistent with haemolytic anaemia. Peripheral smear showed severely microcytic hypochromic red cells and polychromasia. Heinz bodies and inclusion bodies were seen with supravital staining. Haemoglobin high pressure liquid chromatography showed low HbA2 and normal HbF. Work-up for iron deficiency was negative. Polymerase chain reaction of the genomic DNA failed to identify common deletions in the HBA genes. Sangers sequencing of HBA2 gene revealed a homozygous missense mutation NM_000517.6: c.391G > C (p.Ala131Pro) leading to a highly unstable hemoglobin, Hb Sun Prairie. Mother was heterozygous for the same mutation, and father was unavailable for genetic testing. We highlight the role of sangers sequencing in unravelling the underlying aetiology of haemolytic anaemia. Pathophysiology and existing literature of Hb Sun Prairie has been discussed.

Prospective evaluation of variables affecting platelet function in patients with newly diagnosed chronic myeloid leukemia.

: Platelet function in chronic myeloid leukemia (CML) could be affected by either hyperleucocytosis, clonal megakaryopoiesis, or tyrosine kinase inhibitors. However, these variables have never been prospectively evaluated. We conducted a prospective study over a period of 1.5 years in a tertiary care center of north India. Patients with CML in chronic phase, more than 18 years, and treated with imatinib were enrolled (n = 32). Age, and sex-matched controls were also included. Platelet function test was performed using two-channel Chrono-Log aggregometer 490 at four time-points: first, at diagnosis; second, after leucoreduction (total leucocyte count, <10 × 10/l) achieved with hydroxycarbamide; third, on-imatinib at BCR-ABL less than 1%; and fourth, in an independent cohort (off-imatinib) at deep molecular response (DMR) (BCR-ABL < 0.01%). Statistical analysis was performed using IBM SPSS statistics (version 22.0). Median age of patients was 42 years (15-65), and M : F ratio was 1 : 1. At diagnosis, platelet function correlated negatively with total leucocyte count, but not with platelet count. As compared with baseline, platelet aggregation with ADP (2.5 µl), and collagen (2.5 µl) improved significantly after leucoreduction (P = 0.05 and 0.009, respectively). Imatinib further caused significant impairment of aggregation with ADP (2.5 µl), collagen (2.5 µl), and collagen (1 µl) (P = 0.04, 0.008, and 0.02, respectively). Patients in DMR also demonstrated a significant impairment of platelet aggregation with all the agonists as compared with controls. While leucoreduction alone can improve the baseline platelet function derangement in CML, imatinib further impairs it. Residual CML stem cells, or effect of imatinib on normal common myeloid progenitors might account for platelet function derangement at DMR.

Safety and effectiveness of intravenous iron sucrose versus standard oral iron therapy in pregnant women with moderate-to-severe anaemia in India: a multicentre, open-label, phase 3, randomised, controlled trial.

BACKGROUND: Intravenous iron sucrose is a promising therapy for increasing haemoglobin concentration; however, its effect on clinical outcomes in pregnancy is not yet established. We aimed to assess the safety and clinical effectiveness of intravenous iron sucrose (intervention) versus standard oral iron (control) therapy in the treatment of women with moderate-to-severe iron deficiency anaemia in pregnancy. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial at four government medical colleges in India. Pregnant women, aged 18 years or older, at 20-28 weeks of gestation with a haemoglobin concentration of 5-8 g/dL, or at 29-32 weeks of gestation with a haemoglobin concentration of 5-9 g/dL, were randomly assigned (1:1) to receive intravenous iron sucrose (dose was calculated using a formula based on bodyweight and haemoglobin deficit) or standard oral iron therapy (100 mg elemental iron twice daily). Logistic regression was used to compare the primary maternal composite outcome consisting of potentially life-threatening conditions during peripartum and postpartum periods (postpartum haemorrhage, the need for blood transfusion during and after delivery, puerperal sepsis, shock, prolonged hospital stay [>3 days following vaginal delivery and >7 days after lower segment caesarean section], and intensive care unit admission or referral to higher centres) adjusted for site and severity of anaemia. The primary outcome was analysed in a modified intention-to-treat population, which excluded participants who refused to participate after randomisation, those who were lost to follow-up, and those whose outcome data were missing. Safety was assessed in both modified intention-to-treat and as-treated populations. The data safety monitoring board recommended stopping the trial after the first interim analysis because of futility (conditional power 1·14% under the null effects, 3·0% under the continued effects, and 44·83% under hypothesised effects). This trial is registered with the Clinical Trial Registry of India, CTRI/2012/05/002626. FINDINGS: Between Jan 31, 2014, and July 31, 2017, 2018 women were enrolled, and 999 were randomly assigned to the intravenous iron sucrose group and 1019 to the standard therapy group. The primary maternal composite outcome was reported in 89 (9%) of 958 patients in the intravenous iron sucrose group and in 95 (10%) of 976 patients in the standard therapy group (adjusted odds ratio 0·95, 95% CI 0·70-1·29). 16 (2%) of 958 women in the intravenous iron sucrose group and 13 (1%) of 976 women in the standard therapy group had serious maternal adverse events. Serious fetal and neonatal adverse events were reported by 39 (4%) of 961 women in the intravenous iron sucrose group and 45 (5%) of 982 women in the standard therapy group. At 6 weeks post-randomisation, minor side-effects were reported by 117 (16%) of 737 women in the intravenous iron sucrose group versus 155 (21%) of 721 women in the standard therapy group. None of the serious adverse events was found to be related to the trial procedures or the interventions as per the causality assessment made by the trial investigators, ethics committees, and regulatory body. INTERPRETATION: The study was stopped due to futility. There is insufficient evidence to show the effectiveness of intravenous iron sucrose in reducing clinical outcomes compared with standard oral iron therapy in pregnant women with moderate-to-severe anaemia. FUNDING: WHO, India.

Expression of Apoptosis Related and Proliferative Proteins in Malignant Lympho-Proliferative Disorders.

BACKGROUND & OBJECTIVE: The current study aimed to perform an immunohistochemical analysis of patterns of apoptotic and cell proliferative related protein expression in different histological grades and immune phenotypes of malignant lymphomas and other lymphoproliferative disorders. METHODS: This observational study was carried on 60lymph node biopsies of lymphoproliferative disorders. The biopsies were analyzed histologically and immunohistochemically. RESULTS: A total of 60 lymph node biopsies were included in the study, of which 81.6% were of malignant lympho-proliferative lesions. The majority of the biopsies were B-cell (66%) and were grouped in the intermediate grade. Bax and BCL-2 protein expression was presented by percentage of immune positive neoplastic cells per 10fields and graded on a scale of 1 to4. A Bcl-2, Bax Protein Ratio (BBPR) was determined for each case by dividing the estimated Bcl-2 protein (percentage of Bcl-2 positive cells x Bcl-2 staining intensity) by the estimated Bax protein (percentage of Bax positive cells x Bax immunostaining intensity). The mean BBPR was found to be significantly higher in indolent lymphomas (2.64 ± 1.3) as compared to aggressive lymphomas (0.47 ± 0.9) (P<0.01). The expression of P53 and PCNA in 35 biopsies of Non Hodgkin Lymphomas (NHL) was found to increase from low to high grade tumors. CONCLUSIONS: A significant correlation was found between BBPR and predicted biological behavior of indolent and aggressive lymphomas. This indicates the important role of Bcl-2 and Bax in biological behavior of lymphomas. Furthermore, P53 and PCNA expression were found to increase from low to high-grade tumors suggesting their prognostic value in NHL.

Platelet functions and coagulation changes in Indian children with nephrotic syndrome.

INTRODUCTION: Only little is known on the effect of the platelet function in the paediatric nephrotic syndrome. The earlier studies which had been done on hypercoagulability have mainly featured the secondary forms of the nephrotic syndrome and the data on the minimal change type of disease is limited. We therefore, made an effort to study the platelet functions and the coagulation profile in children with the nephrotic syndrome,to find the relationship between the steroid response and the coagulation profile, and to look for the correlation between thromboembolism and the hypercoagulable states. METHODOLOGY: Twenty nine children with the steroid responsive nephrotic syndromewere studied to see the platelet aggregation and the coagulation parameters and their response to the steroid therapy. Doppler studies were done for the renal vein and the inferior vena cava (IVC) thrombus. RESULTS: It was seen that an increased aggregability of the platelets occurred with Adenosine diphosphate (ADP) and collagen (out of the four agonists, ADP, Collagen, Ristocetin and Arachidonic acid) which were used as agonists for the assay. We also observed that the Partial thromboplastin time (PTT) had become prolonged and a significant decline in the high values of the procoagulant proteins (Protein C and Protein S) was seen after the steroid therapy and when the children went into remission. These findings were suggestive of a reversibility of the changes in the steroid responsive nephrotic syndrome with the steroid therapy. One child was found to have thrombosis of the inferior vena cava (IVC) on Doppler studies, which resolved with treatment subsequently. CONCLUSIONS: An increased platelet aggregability contributes to the hypercoagulable states, that may increase the incidence of thrombosis in such patients. Although the incidence of such complications is very low, in a given child with the hypercoagulable states, Doppler may be used to look for any evidence of a latent thrombus and, an early intervention could be instituted. A change in the coagulation parameters points to the reversibility of the changes which are produced in a diseased state.

Imaging diagnosis of neonatal anemia: report of two unusual etiologies.

Anemia in neonatal period is rare, with the common causes being Rh and ABO blood group incompatibility, hemorrhagic disease of newborn, congenital hemolytic anemia, hemoglobinopathies, and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes virus) infections. Congenital leukemia and infantile osteopetrosis (OP) are among the rare causes of neonatal anemia. A review of the literature shows approximately 200 reported cases of congenital leukemia. Articles describing the imaging features of congenital leukemia are still rarer. Infantile OP, another rare disorder with a reported incidence of 1 in 250,000 has characteristic imaging features, which are diagnostic of the disease. We report a case each, of two rare diseases: Congenital leukemia and infantile osteopetrosis. Additionally, our report highlights the radiological and imaging features of congenital leukemia and infantile OP and their crucial role in arriving at an early diagnosis.