Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

BACKGROUND: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-ß peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Clinical Characteristics and Outcomes in Patients With Heart Failure: Are There Thresholds and Inflection Points in Left Ventricular Ejection Fraction and Thresholds Justifying a Clinical Classification?

BACKGROUND: Recent guidelines proposed a classification for heart failure (HF) on the basis of left ventricular ejection fraction (LVEF), although it remains unclear whether the divisions chosen were biologically rational. Using patients spanning the full range of LVEF, we examined whether there was evidence of LVEF thresholds in patient characteristics or inflection points in clinical outcomes. METHODS: Using patient-level information, we created a merged dataset of 33 699 participants who had been enrolled in 6 randomized controlled HF trials including patients with reduced and preserved ejection fraction. The relationship between the incidence of all-cause death (and specific causes of death) and HF hospitalization, and LVEF, was evaluated using Poisson regression models. RESULTS: As LVEF increased, age, the proportion of women, body mass index, systolic blood pressure, and prevalence of atrial fibrillation and diabetes increased, whereas ischemic pathogenesis, estimated glomerular filtration rate, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased. As LVEF increased >50%, age and the proportion of women continued to increase, and ischemic pathogenesis and NT-proBNP decreased, but other characteristics did not change meaningfully. The incidence of most clinical outcomes (except noncardiovascular death) decreased as LVEF increased, with a LVEF inflection point of around 50% for all-cause death and cardiovascular death, around 40% for pump failure death, and around 35% for HF hospitalization. Higher than those thresholds, there was little further decline in the incidence rate. There was no evidence of a J-shaped relationship between LVEF and death; no evidence of worse outcomes in patients with high-normal ("supranormal") LVEF. Similarly, in a subset of patients with echocardiographic data, there were no structural differences in patients with a high-normal LVEF suggestive of amyloidosis, and NT-proBNP levels were consistent with this conclusion. CONCLUSIONS: In patients with HF, there was a LVEF threshold of around 40% to 50% where the pattern of patient characteristics changed, and event rates began to increase compared with higher LVEF values. Our findings provide evidence to support current upper LVEF thresholds defining HF with mildly reduced ejection fraction on the basis of prognosis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT00634309, NCT00634400, NCT00634712, NCT00095238, NCT01035255, NCT00094302, NCT00853658, and NCT01920711.

Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure With Reduced Ejection Fraction : A Post Hoc Analysis of the DAPA-HF Trial.

BACKGROUND: Frailty may modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. OBJECTIVE: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). DESIGN: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124). SETTING: 410 sites in 20 countries. PATIENTS: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. INTERVENTION: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MEASUREMENTS: The primary outcome was worsening HF or cardiovascular death. RESULTS: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were -3.5 (95% CI, -5.7 to -1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. LIMITATION: Enrollment criteria precluded the inclusion of very high-risk patients. CONCLUSION: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients. PRIMARY FUNDING SOURCE: AstraZeneca.

Optimum dose of oral folic acid supplementation in transfusion-dependent thalassemia: a randomized controlled trial.

AIM AND OBJECTIVES: We compared the effect of different doses of oral folic acid (FA) supplementation (5 mg/day vs. 2.5 mg/day vs. 5 mg/week) on the proportion of children with folate excess (serum folate >20 ng/ml) and plasma homocysteine (Hcys) excess (>15 µmol/l) in transfusion-dependent thalassemia (TDT). MATERIALS AND METHODS: Children with TDT aged 5-18 years received oral FA in doses of 5 mg/day (Group 1), 2.5 mg/day (Group 2) and 5 mg/week (Group 3) for 9 months, after a wash-off period of 8 weeks. Folate levels (Serum and RBC) and plasma Hcys levels were measured after the therapy. RESULTS: Ninety children were randomized to receive one of the three interventions (30 per group). After wash-off period, the median serum folate levels were significantly lower and five children developed folate deficiency; the median [interquartile range (IQR)] serum folate levels (ng/dl) were comparable in the three groups [Group 1: 6.5 (3.3-14.2), Group 2: 5.1 (2.6-10.5) and Group 3: 4.8 (3.4-10.0)]. After 9 months of intervention, the median (IQR) serum folate levels (ng/ml) were comparable in all participants [Group 1: 18.0 (6.5-28), Group 2: 13.5 (6.4-24.5) and Group 3: 9.7 (5.3-22.5); p = 0.11]. Proportion of children with serum folate excess was 40%, 26.7% and 26.7% in Group 1, Group 2 and Group 3 (p = 0.48). Proportion of children with RBC folate excess was 92%, 86.7% and 86.7% in Group 1, Group 2 and Group 3 (p = 0.79). Hyperhomocysteinemia was seen in eight children with no significant difference between median Hcys levels in the groups (p = 0.75). CONCLUSION: Folic acid supplementation is recommended in TDT with 5 mg weekly dose being adequate.

Twice Weekly Vs. Thrice Weekly Low-Dose Prophylactic Factor VIII Therapy in Children with Hemophilia A: An Open Label Randomized Trial.

INTRODUCTION: Low dose factor VIII prophylactic therapy in hemophilia has not been well established till date. This randomized controlled trial compared the efficacy of twice vs. thrice weekly schedule of low dose prophylactic factor VIII in children with hemophilia A as evaluated by the bleeding rate and clinico-radiological evaluation. METHODS: Thirty-three children with severe hemophilia A (≤18 years) were randomized into two groups. Baseline evaluation included detailed history, clinical (HJHS 2.1 score and FISH score) and radiological examination (Pettersson score and ultrasound score). Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose being 10 U/kg in both groups. All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at the end of follow up were recorded. RESULTS: We analyzed 14 children in twice weekly prophylaxis group and 16 children in thrice weekly prophylaxis group. Statistically insignificant difference was found between the bleeding rates in both the groups after prophylaxis with the median values of monthly bleeding rate being 0.17 and p-value of 0.79. The differences between the initial and final clinical and radiological scores within each group were found to be statistically significant. There was no significant difference in the clinical and radiological scores in between the groups. CONCLUSION: Twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A. Lay summaryHemophilia A is one of the most common congenital coagulation factor deficiencies. Low dose factor VIII prophylaxis is recommended for hemophilia in resource-poor settings to reduce the bleeding episodes and improve the quality of life, although the optimal schedule for the same has not been well established. A randomized controlled trial on 33 children with hemophilia A (≤18 years) was done to compare the efficacy of twice versus thrice weekly schedule of prophylactic factor VIII. Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose in both groups being 10 U/kg. They were evaluated by the bleeding rate and clinical (HJHS 2.1 score and FISH score) and radiological scores (Pettersson score and ultrasound score). All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at end of follow up were recorded. When analyzed, statistically insignificant difference was found between the bleeding rates after the two prophylaxis regimes. There was a significant improvement between initial and final clinical and radiological scores in both the groups and no difference was recorded in between the groups. To conclude, twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A.

Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.

BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Low dose depot oral vitamin D3v. daily oral vitamin D3 for treating nutritional rickets: a randomised clinical trial.

We aimed to compare the efficacy of daily v. low dose depot oral vitamin D3 for treating nutritional rickets. We conducted a randomised controlled trial in the department of paediatrics of a tertiary care hospital catering to semi-urban and rural population in Delhi, India. We randomised sixty-six children aged 3 months to 5 years with nutritional rickets to receive either daily oral vitamin D3 drops (3-12 months: 2000 IU; > 12 months to 5 years: 4000 IU; n 33) for 12 weeks duration or a single oral depot dose of vitamin D3 granules (3-12 months: 60 000 IU; > 12 months to 5 years: 150 000 IU; n 33). Participants in both groups had comparable demographic characteristics, laboratory features and radiological severity of rickets. Thirty-three participants in each group received the assigned intervention and all were followed up till 12 weeks. At 12 weeks follow-up, children in both groups showed a significant improvement in all biochemical parameters (serum Ca, P, alkaline phosphatase (ALP), parathormone and 25(OH) vitamin D levels) as well as radiological healing. At 12 weeks, the mean serum 25(OH) vitamin D levels (nmol/l) were statistically comparable in both groups (daily: 120·2 (sd 83·2), depot: 108 (sd 74), P = 0·43) and 31 (93·9 %) children in each group had radiological healing (Thacher score < 1·5). Two children in each group persisted to have raised ALP, and one child each in the daily group continued to have hypocalcaemia and hypophosphataemia at 12 weeks. Low dose oral depot vitamin D3 is an effective alternative to daily oral vitamin D3 for nutritional rickets.

Procalcitonin Clearance, CD64, and HLA-DR as Predictors of Outcome in Febrile Neutropenic Children With Lymphoreticular Malignancies.

BACKGROUND: Febrile neutropenia (FN) is a dreaded complication of cancer chemotherapy. There has been a lot of improvement in supportive care in FN that has drastically reduced the infection-related mortality in these patients. The focus now is on reducing infection-related morbidity, healthcare costs and optimizing the quality of life of the child as well as their family during these episodes. In this study, biomarkers were studied as predictors of outcome so that outcome can be predicted earlier, and treatment modified accordingly. OBJECTIVE: To measure procalcitonin levels (at baseline and day 3), procalcitonin clearance, neutrophil CD64 expression levels (at baseline) and monocyte HLA-DR expression levels (at baseline), and their correlation with outcome. SETTING: Tertiary care hospital. STUDY TYPE: Cross-sectional observational study. POPULATION/PARTICIPANTS: Sixty-five episodes of FN in children below 12 years with lymphoreticular malignancies. Children receiving antibacterial and/or antifungal treatment within the last 7 days were excluded from the study. METHODS: The subjects recruited into the study had undergone complete clinical and laboratory evaluation as per hospital protocol. Procalcitonin (day 0 and 3), neutrophil CD64 expression, and monocytic HLA-DR expression levels were measured in these patients. RESULTS: Sixty-five episodes of FN were studied in children with lymphoreticular malignancy. It was found that procalcitonin and HLA-DR are very good markers of outcome, whereas CD64 although a good marker, was inferior to procalcitonin and HLA-DR in predicting outcome. Procalcitonin clearance was found to be superior to single value of procalcitonin. Furthermore, procalcitonin on day 3 was found to be a better predictor of outcome compared with its baseline value. Also, it was found that procalcitonin and HLA-DR had a significant correlation with baseline C-reactive protein levels. CONCLUSIONS: On the basis of the findings of the study we suggest that serial monitoring of procalcitonin levels be used in febrile neutropenic children with cancer. Procalcitonin levels on day 3 alone can be offered in resource poor setting. The role of HLA-DR and CD64 also seems promising and needs to be further explored in larger multicentric studies.

Early lactate measurements for predicting in-hospital mortality in paediatric sepsis.

AIM: We compared the performance of plasma lactate with high-sensitivity C-reactive protein (hs-CRP), and paediatric sepsis-related organ failure assessment (pSOFA) score for predicting mortality in septic children. METHODS: Serial plasma lactate and hs-CRP levels and pSOFA score was assessed during early hospital stay in septic children. RESULTS: Out of 149 participants, 45 died. Plasma lactate at 0 h and 6 h was significantly higher, and lactate clearance was significantly lower in non-survivors. The optimal cut-off of plasma lactate at 6h for identifying mortality was 2.5 mmol/L (sensitivity 85% and specificity 74%). pSOFA score had the best predictive ability for mortality (AUC 0.89) followed by hs-CRP at 0 h (AUC 0.86), hs-CRP at 48 h (AUC 0.83), plasma lactate levels at 6 h (AUC 0.83), and plasma lactate at 0 h (AUC 0.67). CONCLUSION: pSOFA score, hs-CRP and hyperlactemia at 6 h can identify septic children at risk of dying.

High Sensitivity C Reactive Protein: An Adjunct Diagnosis in Ruling Out Pediatric Tuberculosis.

The utility of C-reactive protein (CRP) as a marker of disease severity, therapeutic response and prognosis in tuberculosis has been suggested. This study aims to determine the levels of high sensitivity CRP (hs CRP) among the pediatric tuberculosis cases. A case control study was conducted on 60 clinically diagnosed (clinical findings and radiography and/or contact history and/or Mantoux test) or microbiologically confirmed (smear and/or culture and/or Cartridge based Nucleic Acid Amplification test positive) pediatric tuberculosis cases ≤ 12 years. hs CRP levels were estimated in the cases and healthy controls using ELISA. Median levels of serum hs CRP were significantly higher in pediatric tuberculosis cases (25 mg/l) as compared to controls (0.530 mg/l). No significant correlation was found with age, gender, site of tuberculosis or presence of dissemination. Lower levels were found with palpable lymphadenopathy. Levels were not significantly different between microbiologically confirmed cases and those who were negative by one or more of the microbiological tests of staining, culture and cartridge based nucleic acid amplification test. hs CRP can be used in diagnostic algorithms of pediatric tuberculosis to rule out tuberculosis. Further studies could help in determining the prognostic and therapeutic response of hs CRP among children leading to better management.

Income level and inequality as complement to geographical differences in cardiovascular trials.

BACKGROUND: Analyses of country or regional differences in cardiovascular (CV) trials are based on geographical subgroup analyses. However, apart from map location and related racial, ethnic, and genetic variations, identified differences may also depend on social structure and provision and access to health care, for which country income and income inequality are indicators. The aim of the study was to examine the association between country per capita income and income inequality and prognosis in patients with heart failure or an acute coronary syndrome in 3 international trials (EMPHASIS-HF, EPHESUS, and EXAMINE). METHODS: Countries were classified into high income or low-middle income (LMICs) and into low, middle, or high inequality using the Gini index. The main outcome measures were all-cause and CV death. RESULTS: Patients from LMICs and countries with higher inequality were younger, were less often white, had fewer comorbid conditions, and were less often treated with guideline-recommended therapies, including devices. These patients had higher adjusted mortality rates (+15% to +70%) compared with patients from high-income countries and countries with less inequality. Patients from countries with the combination of greater inequality and low-middle income had particularly high mortality rates (+80% to +190%) compared with those that did not have both characteristics. Living in a country that is poor and has inequality had more impact on death rates than any comorbidity. These findings were reproduced in 3 trials. CONCLUSIONS: Patients from LMICs and countries with greater inequality had the highest mortality rates. The prognostic impact of income and inequality is substantial and should be considered when looking into subgroup differences in CV trials.

Serum and Urinary Hepcidin for Diagnosing Iron-deficiency Anemia in Under-5 Children.

Bone marrow iron estimation remains the gold standard for diagnosing iron-deficiency anemia (IDA); serum ferritin, total iron-binding capacity, and transferrin saturation are routinely used as surrogate markers of IDA. However, these tests are marred by problems like poor specificity and sensitivity. Recently, hepcidin, a protein hormone synthesized in the liver and excreted in urine, has been shown to be related to iron status. We estimated the serum and urinary hepcidin levels in healthy children 6 to 60 months of age with (n=30) and without IDA (n=30). The mean (SD) serum hepcidin levels in children with IDA were significantly lower than those in children without IDA (3.03 [1.06] vs. 4.78 [3.94] ng/mL; P=0.02). The mean (SD) urinary hepcidin levels were also significantly lower in children with IDA than those in children without IDA (2.29 [0.53] vs. 2.79 [0.75] ng/mL; P=0.004). Performance of urinary and serum hepcidin compared with serum ferritin (<12 µg/L) for diagnosing IDA in terms of area under the receiver operating characteristic curve was 0.704 (P=0.007) and 0.59 (P=0.22), respectively. Serum hepcidin is not useful for diagnosing IDA in under-5 children. In contrast, urinary hepcidin holds promise as a noninvasive diagnostic tool for IDA in under-5 children.

Clinical Spectrum of Pediatric Tuberculosis: A Microbiological Correlation from a Tertiary Care Center.

AIM AND OBJECTIVES: The paucibacillary nature of pediatric tuberculosis (TB) makes diagnosis difficult. The aim of the study was to correlate the clinical spectrum of pediatric TB with microbiological diagnosis. MATERIALS AND METHODS: Specimens from clinically suspected pediatric TB cases were subjected to Ziehl-Neelsen staining, culture on Lowenstein-Jensen medium and cartridge-based nucleic acid amplification test (CB-NAAT) for TB. RESULTS: Pulmonary TB was the predominant form affecting 36 of 62 (58%) patients. Tubercular meningitis was the commonest form of extrapulmonary type and affected 13 of 26 (50%) children. Microbiological diagnosis by any of the above methods could be established in 35 (56.45%) cases. While 33 of 36 (92%) patients diagnosed with pulmonary TB had radiological findings, of which only 25 (76%) could be microbiologically confirmed, only 24 of 31 (77%) patients with extrapulmonary symptoms had radiological evidence and microbiological confirmation could be achieved in 4 (17%) of these. CONCLUSION: An integrated approach of diagnosis, including clinical-radiological, microbiological and immunological evidence should be stressed on.

Glucose Homeostasis Markers in Beta-Thalassemia.

BACKGROUND: Glycosylated hemoglobin (HbA1c) has been a well-recognized marker of glucose homeostasis among thalassemics. Recently some studies have proposed the role of fructosamine as a better marker as compared with HbA1c. Hence, the study was carried out to find out which marker holds promise among Indian beta-thalassemic children. METHODS: In this case-control study, 60 diagnosed cases of beta-thalassemia major and equal number of normal controls who were ≥8 years of age were enrolled. HbA1c, fructosamine, and fasting insulin levels were measured in all. Oral glucose tolerance test was done as a gold standard and the measured parameters were compared. RESULTS: HbA1c was significantly higher in cases (7.10% [±0.47%]) than in controls (5.15% [±0.19%]) (P<0.001). Thalassemics with abnormal glucose tolerance had higher HbA1c level (7.34% [±0.57%]) than those with normal glucose tolerance (7.05% [±0.43%]) (P=0.05). Insulin resistance was noticed among thalassemics with abnormal glucose tolerance as compared with their normal counterparts (P=0.04). No significant difference was found in fructosamine levels between cases (239.80 [±31.80] µmol/L) and controls (234.10 [±21.34] µmol/L) (P=0.25) or between thalassemics with abnormal glucose tolerance (243.92 [±21.94] µmol/L) and their normal counterparts (238.77 [±33.93] µmol/L) (P=0.62). CONCLUSIONS: The use of HbA1c as a diagnostic marker for diabetes in hemolytic anemias has to be done with caution as its baseline values are higher in them. Despite this finding, HbA1c continues to be a good marker for worsening glucose homeostasis in thalassemics as higher values were found in thalassemics with abnormal glucose tolerance compared with their normal counterparts. The present study did not find any relationship of fructosamine levels with impaired glucose tolerance in beta-thalassemia.

Seven versus 10 days antibiotic therapy for culture-proven neonatal sepsis: A randomised controlled trial.

AIM: Optimal duration of parenteral antibiotics for treating neonatal sepsis ranges from 7-14 days. We compared the efficacy of 7 versus 10 days duration of intravenous antibiotics for neonatal septicaemia. METHODS: We randomised blood culture-proven septic neonates (≥32 weeks and birth weight ≥1.5 kg) to receive either 7 or 10 days duration of intravenous antibiotics. We followed up neonates upto 28 days after stopping antibiotics for treatment failure defined by reappearance of clinical sepsis with a blood culture growing the same organism as cultured earlier, or in the absence of a positive culture, the presence of C-reactive protein and as adjudicated by an expert committee. RESULTS: A total of 132 neonates were randomised to receive either 7 (n = 66) or 10 (n = 66) days duration of antibiotic therapy. Out of 128 neonates (64 per group) followed up, two (one per group) were regarded as 'treatment failure', and two were labelled as fresh episodes of sepsis (both in 10-day group). The risk (95% confidence interval) for treatment failure in the 7-day group was (1.0 (0.064-15.644) was not significantly higher. Neonates in both groups had comparable need for oxygen, inotropic support and blood products, duration of oxygen therapy and time to attainment of full feeds. The duration of hospitalisation was significantly longer in the 10-day group. CONCLUSION: A 7-day course of intravenous antibiotics may be sufficient to treat neonatal sepsis with the advantage of shorter hospital stay, but a larger meta-analysis would be required to state this with a degree of certainty.

Mid-upper arm circumference v. weight-for-height Z-score for predicting mortality in hospitalized children under 5 years of age.

OBJECTIVE: To compare the performance of mid-upper arm circumference (MUAC) against weight-for-height Z-score (WHZ) for predicting inpatient deaths in children under 5 years of age. DESIGN: Diagnostic test accuracy study. SETTING: Paediatric emergency department of a tertiary care hospital catering to semi-urban and rural population in Delhi, India. SUBJECTS: Hospitalized children (n 1663) aged 6 months to 5 years, for whom discharge outcome was available, were consecutively recruited over 14 months. MUAC (cm), weight (kg) height (cm), clinical details and the outcome were recorded. MUAC (index test) was compared with WHZ based on the WHO growth standards (reference test) for predicting the outcome. RESULTS: One hundred and twenty-four (7 %) children died during hospital stay. Both MUAC < 11·5 cm (adjusted OR (95 % CI): 3·7 (2·43, 5·60), P<0·001) and WHZ<-3 (2·0 (1·37, 2·99), P<0·001) served as independent predictors of inpatient mortality. However, MUAC was a significantly better predictor of mortality compared with WHZ in terms of area under the receiver-operating characteristic curve (MUAC=0·698, WHZ=0·541, P<0·001). MUAC<11·5 cm had the best trade-off of sensitivity and specificity for predicting inpatient mortality. A combination of WHZ<-3 and/or MUAC<11·5 cm did not significantly improve the predictive value over that of MUAC/WHZ, assessed individually. CONCLUSION: MUAC<11·5 cm is a better predictor of mortality in hospitalized under-5 children, as compared with WHZ<-3. It should be measured in all emergency settings to identify the children at higher risk of death.

MazF-induced growth inhibition and persister generation in Escherichia coli.

Toxin-antitoxin systems are ubiquitous in nature and present on the chromosomes of both bacteria and archaea. MazEF is a type II toxin-antitoxin system present on the chromosome of Escherichia coli and other bacteria. Whether MazEF is involved in programmed cell death or reversible growth inhibition and bacterial persistence is a matter of debate. In the present work the role of MazF in bacterial physiology was studied by using an inactive, active-site mutant of MazF, E24A, to activate WT MazF expression from its own promoter. The ectopic expression of E24A MazF in a strain containing WT mazEF resulted in reversible growth arrest. Normal growth resumed on inhibiting the expression of E24A MazF. MazF-mediated growth arrest resulted in an increase in survival of bacterial cells during antibiotic stress. This was studied by activation of mazEF either by overexpression of an inactive, active-site mutant or pre-exposure to a sublethal dose of antibiotic. The MazF-mediated persistence phenotype was found to be independent of RecA and dependent on the presence of the ClpP and Lon proteases. This study confirms the role of MazEF in reversible growth inhibition and persistence.