A novel cleanroom-free technique for simultaneous electrodeposition of polypyrrole onto array of IDuEs: Towards low-cost, stable and accurate point-of-care TBI diagnosis without trained manpower.

Drop-casted polypyrrole (PPY) nanomaterial-based point-of-care Traumatic Brain Injury (TBI) immunosensing platforms reported previously demand trained manpower at field-test, due to poor adhesion between nanomaterial and electrode surface, limiting the point-of-care purpose. The usage of conventional clean-room-based physical and chemical vapor deposition techniques in creating strong adhesion is limited on account of cost and process complexity. Addressing this technical gap, we report a novel low-cost clean-room-free technique that can effectively electrodeposit the PPY simultaneously onto the working areas of array of Interdigitated microelectrodes (IDµEs) from the precursor solution. Through optimization of deposition cycles and molar concentration ratio of monomer and oxidizing agents, a high-quality nanomaterial was electrodeposited on IDµEs' surface. Further, by using the electrodeposited PPY as a bioelectrical transducer, the TBI-specific UCHL1 and GFAP target analytes were simultaneously detected in terms of variation of DC-Resistance and AC-Capacitance parameters, recorded through chemiresistive I-V and chemicapacitive C-F responses of bioelectrodes, respectively. Such simultaneous multianalyte-detection in terms of multiple parameters increases the diversity of decision-making parameters by several folds, inherently aids in enhancing the diagnostic accuracy of TBI test kit. Here, the efficiency of the electrodeposited PPY-based chemiresistive and chemicapacitive immunosensing platforms in detecting TBI-specific target analytes simultaneously in real-time human-plasma samples was analyzed in terms of sensitivity, resolution, LoD, RoD, long-term stability (30 weeks), and the same is compared with drop-cast PPY-based immunosensing platform. Notably, the electrodeposited PPY sensing platforms showed superior performance in terms of sensitivity, LoD, device variability and long-term stability without demanding any trained manpower in the field.

Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia.

Metabolic reprogramming occurs to meet cancer cells' high energy demand. Its function is essential to the survival of malignancies. Comparing cancer cells to non-malignant cells has revealed that cancer cells have altered metabolism. Several pathways, particularly mTOR, Akt, PI3K, and HIF-1 (hypoxia-inducible factor-1) modulate the metabolism of cancer. Among other aspects of cancer biology, gene expression in metabolism, survival, invasion, proliferation, and angiogenesis of cells are controlled by HIF-1, a vital controller of cellular responsiveness to hypoxia. This article examines various cancer cell metabolisms, metabolic alterations that can take place in cancer cells, metabolic pathways, and molecular aspects of metabolic alteration in cancer cells placing special attention on the consequences of hypoxia-inducible factor and summarising some of their novel targets in the treatment of cancer including leukemia. A brief description of HIF-1α's role and target in a few common types of hematological malignancies (leukemia) is also elucidated in the present article.

Exploring novel protein biomarkers for early-stage diagnosis and prognosis of T-acute lymphoblastic leukemia (T-ALL).

BACKGROUND: Efficient classification of T-acute lymphoblastic leukemia (T-ALL) involves considering various factors, such as age, white blood cell count, and chromosomal alterations. However, studying protein markers are crucial to improving T-ALL patients' diagnosis and treatment. A study analyzing the expression of proteomes was conducted to identify promising early-stage biomarkers for T-ALL patients METHODS: Label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the blood proteins of both patients and healthy individuals to identify new biomarkers for T-ALL. The findings were validated by RT-PCR, ELISA and computational analysis RESULTS: The study identified 1467 proteins in the blood, of which nine were upregulated and 35 were downregulated by more than 2-fold. T-ALL patients showed a significant increase in specific disease-related proteins, such as eleven-nineteen lysine-rich leukemia protein, triggering receptor expressed on myeloid cells 1, cisplatin resistance-associated-overexpressed protein, X-ray radiation resistance-associated protein 1, tumor necrosis factor receptor superfamily member 10D, protein S100-A8, and copine-4, by more than 3-fold CONCLUSION: The findings of this study provide a valuable protein map of leukemic cells and identify potential biomarkers for leukemic aggressiveness. However, further studies using larger T-ALL patient samples must confirm these preliminary results.

Unveiling the Influence of Glutathione in Suppressing the Conversion of Aspirin to Salicylic Acid: A Fluorescence and DFT Study.

Aspirin is a commonly used nonsteroidal anti-inflammatory drug, associated with many adverse effects. The adverse effects of aspirin such as tinnitus, Reye's syndrome and gastrointestinal bleeding are caused due to conversion of aspirin into its active metabolite salicylic acid after oral intake. Glutathione is a naturally occurring antioxidant produced by the liver and nerve cells in the central nervous system. It helps to metabolize toxins, break down free radicles, and support immune function. This study aims to investigate and explore the possibility of inhibiting aspirin to salicylic acid conversion in presence of glutathione at a molecular level using spectroscopic techniques such as UV-Visible absorption, time-Resolved and time-dependent fluorescence and theoretical DFT/ TD-DFT calculations. The results of steady state fluorescence spectroscopy and time-dependent fluorescence indicated that the aspirin to salicylic acid conversion is considerably inhibited in presence of glutathione. Further, the results presented here might have significant clinical implications for individuals with variations in glutathione level.

Expression of CXCL8 (IL-8) in the Pathogenesis of T-Cell Acute Lymphoblastic Leukemia Patients.

Background Inflammation plays a very important role in the pathogenesis of a wide range of diseases, such as atherosclerosis myocardial infarction, sepsis, rheumatoid arthritis, and cancer. This study aimed to investigate the association of IL-8 in T-cell acute lymphoblastic leukemia (T-ALL) patients. Methodology IL-8 levels were estimated in 52 individuals. Of the study population, 26 were T-ALL patients (all phases of leukemia were included in the study) and 26 were disease-free healthy volunteers. In this study, we employed flow cytometry, enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction test, and western blot analysis. Results IL-8 was significantly higher in all T-ALL patients than in healthy volunteers. IL-8 levels showed a significant positive correlation in T-ALL patients at the genomic and proteomic levels. Conclusions Higher serum IL-8 levels were associated with the advanced disease stage of the clinicopathological parameters. Our results indicate that monitoring IL-8 has a role in modulating disease sensing in T-ALL and may represent a target for innovative diagnostic and therapeutic strategies.

Antimicrobial peptide moricin induces ROS mediated caspase-dependent apoptosis in human triple-negative breast cancer via suppression of notch pathway.

BACKGROUND: Breast cancer is the world's most prevalent cancer among women. Microorganisms have been the richest source of antibiotics as well as anticancer drugs. Moricin peptides have shown antibacterial properties; however, the anticancer potential and mechanistic insights into moricin peptide-induced cancer cell death have not yet been explored. METHODS: An investigation through in silico analysis, analytical methods (Reverse Phase-High Performance Liquid Chromatography (RP-HPLC), mass spectroscopy (MS), circular dichroism (CD), and in vitro studies, has been carried out to delineate the mechanism(s) of moricin-induced cancer cell death. An in-silico analysis was performed to predict the anticancer potential of moricin in cancer cells using Anti CP and ACP servers based on a support vector machine (SVM). Molecular docking was performed to predict the binding interaction between moricin and peptide-related cancer signaling pathway(s) through the HawkDOCK web server. Further, in vitro anticancer activity of moricin was performed against MDA-MB-231 cells. RESULTS: In silico observation revealed that moricin is a potential anticancer peptide, and protein-protein docking showed a strong binding interaction between moricin and signaling proteins. CD showed a predominant helical structure of moricin, and the MS result determined the observed molecular weight of moricin is 4544 Da. An in vitro study showed that moricin exposure to MDA-MB-231 cells caused dose dependent inhibition of cell viability with a high generation of reactive oxygen species (ROS). Molecular study revealed that moricin exposure caused downregulation in the expression of Notch-1, NF-ƙB and Bcl2 proteins while upregulating p53, Bax, caspase 3, and caspase 9, which results in caspase-dependent cell death in MDA-MB-231 cells. CONCLUSIONS: In conclusion, this study reveals the anticancer potential and underlying mechanism of moricin peptide-induced cell death in triple negative cancer cells, which could be used in the development of an anticancer drug.

Exploring the Role of Glycolytic Enzymes PFKFB3 and GAPDH in the Modulation of Aß and Neurodegeneration and Their Potential of Therapeutic Targets in Alzheimer's Disease.

Alzheimer's disease (AD) is presently the 6th major cause of mortality across the globe. However, it is expected to rise rapidly, following cancer and heart disease, as a leading cause of death among the elderly peoples. AD is largely characterized by metabolic changes linked to glucose metabolism and age-induced mitochondrial failure. Recent research suggests that the glycolytic pathway is required for a range of neuronal functions in the brain including synaptic transmission, energy production, and redox balance; however, alteration in glycolytic pathways may play a significant role in the development of AD. Moreover, it is hypothesized that targeting the key enzymes involved in glucose metabolism may help to prevent or reduce the risk of neurodegenerative disorders. One of the major pro-glycolytic enzyme is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3); it is normally absent in neurons but abundant in astrocytes. Similarly, another key of glycolysis is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which catalyzes the conversion of aldolase and glyceraldehyde 3 phosphates to 1,3 bisphosphoglycerate. GAPDH has been reported to interact with various neurodegenerative disease-associated proteins, including the amyloid-ß protein precursor (AßPP). These findings indicate PFKFB3 and GAPDH as a promising therapeutic target to AD. Current review highlight the contributions of PFKFB3 and GAPDH in the modulation of Aßand AD pathogenesis and further explore the potential of PFKFB3 and GAPDH as therapeutic targets in AD.

Robot-assisted and conventional urology surgical procedures: comparison of average length of stay, economic status, operative time and patient's expenditure in a tertiary care hospital of North India.

Robot-assisted surgeries allows the surgeons to operate using remote-controlled robotic arms that are more effective in comparison to conventional (open/laparoscopic) surgeries. However, there is substantial lack of evidence on the effectiveness of robot-assisted surgeries in low to middle income countries (LMICs) like India. A study was conducted with an aim to evaluate the average length of stay (ALOS), Operative time, economic status (patient's) and cost borne by the patient (patient's expenditure) for undergoing robot-assisted surgeries and conventional surgeries. Grouping of the surgical procedures was done wherein patients who were treated with robot-assisted surgical procedures were placed in Group-01 whereas those treated with conventional surgical procedures were placed under Group-02. Comparative evaluation of the two surgical groups revealed that in robot-assisted surgical procedure, the ALOS was less (18.43 vs. 23.14 days, p = 0.06) whereas operative time (316.7 vs. 252.63 min, p = 0.05) and patient's expenditure were more (INR 70,654.29 vs. INR 41,314.73, p = 0.00). However, there was no significant difference between the economic statuses of patients in both groups. The study concluded that in this era of rapidly expanding health care scenario; targeted, regular, rigorous and repeated training programmes in future may shorten the learning curve thereby paving a way to reduce the cost as well as the operative time of robot-assisted surgeries in LMICs.

Time intervals and patient-level factors in oral cancer diagnostic pathways: An application of the WHO framework in India.

BACKGROUND: Oral cancer, a leading cancer-site in India, is often detected at advanced stages. We evaluated the time intervals from first symptom to help-seeking and diagnosis among oral cancer patients. METHODOLOGY: In this cross-sectional study, we recruited 226 consecutive oral cancer patients (mean age ( ± SD) 51.9 years ( ± 10.9); 81.9% men; 70.3% advanced stage) registered for diagnosis and treatment, between 2019 and 2021 at a cancer care centre in South India. We used WHO framework and previously standardized tools to record time intervals (appraisal, help-seeking and diagnostic) and baseline characteristics. We utilized multivariable logistic regression models to test the associations between 'prolonged (i.e., over 1 month) time intervals') and patient-level factors to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Over a half of patients presented with prolonged appraisal (60%) and help-seeking intervals (57%), and a third (34%) reported prolonged diagnostic interval. Patients with no formal education, no routine healthcare visits, no self-reported risk factors, and those who did not perceive initial symptoms to be serious were 2-4 times more likely to have prolonged appraisal and help-seeking than the rest. High travel costs and self-decision for visiting healthcare facility prolonged help-seeking. Diagnostic interval was prolonged only among women OR= 2.7 (95% CI: 1.2-6.1)) and in patients whose first doctor's opinion was 'nothing to worry' OR (=7.3 (95% CI: 2.6-20.5)). 'Correct knowledge of cancer' shortened appraisal and help-seeking intervals and 'incorrect knowledge and negative beliefs' prolonged diagnostic interval. CONCLUSION: Our findings highlight that interventions targeting sociocultural and economic determinants, symptom awareness, sensitizing persons at risk (especially women) and primary care providers might reduce overall time to diagnosis. Further, patients without any known risk factors for oral cancer might be at-risk for prolonged appraisal interval. These might help inform 'pull' strategies for cancer control in India and similar settings.

The Molecular Role of HIF1α Is Elucidated in Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is potentially fatal blood cancer, but there is an unmet need to discover novel molecular biomarkers. The hypothesis of this study aimed to elucidate the relationship of HIF1α with the redox system, Krebs cycles, notch1, and other regulatory proteins to better understand the pathophysiology and clinical relevance in chronic myeloid leukemia (CML) patients, as the molecular mechanism of this axis is still not clear. This study included CML patient samples (n = 60; 60: blood; 10: bone marrow tissues) and compared them with healthy controls (n = 20; blood). Clinical diagnosis confirmed on bone marrow aspiration, marrow trephine biopsy, and BCR/ABL1 translocation. Cases were subclassified into chronic, accelerated, and blast crises as per WHO guidelines. Molecular experiments included redox parameters, DNA fragmentation, Krebs cycle metabolites, and gene expression by RT-PCR/Western blot/LC-MS, PPI (STRING), Pearson correlation, and ROC curve analysis. Here, our findings show that p210/p190BCR/ABL1 translocation is common in all blast crisis phases of CML. Redox factor/Krebs oncometabolite concentrations were high, leading to upregulation and stabilization of HIF1α. HIF1α leads to the pathogenesis in CML cells by upregulating their downstream genes (Notch 2/4/Ikaros/SIRT1/Foxo-3a/p53, etc.). Whereas, downregulated ubiquitin proteasomal and apoptotic factors in CML pateints, can trigger degradation of HIF1α through proline hydroxylation. However, HIF1α showed a negative corelation with the notch1 pathway. Notch1 plays a tumor-suppressive role in CML and might have the potential to be used as a diagnostic marker along with other factors in CML patients. The outcome also revealed that oxidant treatment could not be effective in augmentation with conventional therapy because CML cells can enhance the levels of antioxidants for their survival. HIF1α might be a novel therapeutic target other than BCR/ABL1 translocation.

The bioengineered HALOA complex induces anoikis in chronic myeloid leukemia cells by targeting the BCR-ABL/Notch/Ikaros/Redox/Inflammation axis.

Blast crisis (BC) is an outcome that arises during the treatment process of chronic myeloid leukemia (CML), which is possibly attained by the dysregulation of the Notch and Ikaros signaling pathways, BCR-ABL translocation, redox, and inflammatory factors. This study demonstrated that biotherapeutic agents target aberrant molecular axis in CML-BC cells. The HALOA complex was synthesized by simple mixing of apo α-lactalbumin with oleic acid, which manages to inhibit BCR-ABL (b3a2 in K562 cells) translocation. It elevates the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and protein carbonyl, which induces DNA fragmentation in K562 cells but not in NIH cells. The complex manages to reduce the toxicity surrounding apoptotic cells by enhancing the production of superoxide dismutase (SOD) and the total antioxidant level. The HALOA complex increases leptin to maintain normoxic conditions, ultimately preventing angiogenesis. This complex downregulates the expression of IL-8 and MMP-9 and elevates the expression levels of Notch 4, Ikaros, and integrin alpha-D/CD-11d (tumor-suppressive), which conjointly prevents inflammation, metastasis, and epithelial-mesenchymal transition (EMT) in CML cells. Meanwhile, the complex downregulates Notch 1 and 2 (oncogenic), consequently inducing anoikis in CML cells. Overall, the HALOA complex shows credibility by targeting the combined molecular factors responsible for the pathogenesis of the disease and will also help to overcome MDR conditions in leukemia.

Comparison of Crestal Bone Loss and Osteocalcin Release Kinetics in Immediately and Delayed Loaded Implants: A Randomized Controlled Trial.

PURPOSE: To compare concentration and release kinetics of osteocalcin and crestal bone loss under immediate and delayed loading conditions during osseointegration. MATERIALS AND METHODS: Forty-one patients who were indicated for rehabilitation with dental implants randomly received either implant with placement of permanent prosthesis after 3 months (delayed loading) or implant with placement of permanent prosthesis within 7 days (immediate loading). Radiographic assessment of crestal bone loss at the mesial and distal surface was done at 3, 6, and 12 months after implant placement. Peri-implant sulcular fluid was collected immediately from the buccal surface at two sites after implant insertion and also, at 7, 15, 30, and 90 days after surgery. The level of osteocalcin was evaluated using ELISA and data were compared using two sample t-test. Differences between two groups were analyzed by unpaired Student's t test. Intragroup comparison was done by repeated measures ANOVA. RESULTS: Mean crestal bone loss was lower in the immediate loading group compared to the delayed loading group at 3, 6, and 12 months (p < 0.001). Intragroup comparison revealed a statistically significant increase in osteocalcin levels in both group I (delayed loading) (F = 26712.2) and group II (immediate loading) (F = 10497.2) at the predetermined time intervals. CONCLUSIONS: Less crestal bone loss and early release of osteocalcin was found in the immediately loaded group than in the delayed loaded group. The study substantiates that immediately loaded implants show less crestal bone as well as early release of osteocalcin facilitating upregulation of bone metabolism, improving long term health of bone and prognosis of implants. Immediately loaded implants can be a better treatment protocol provided there is adequate bone and primary stability.

Towards point-of-care diagnosis of Alzheimer's disease: Multi-analyte based portable chemiresistive platform for simultaneous detection of ß-amyloid (1-40) and (1-42) in plasma.

Label-free simultaneous detection of Alzheimer's disease (AD) specific biomarkers Aß40 and Aß42 peptides on a single platform using polypyrrole nanoparticle-based chemiresistive biosensors is reported here. The proposed interdigitated-microelectrode based inexpensive multisensor-platform can concurrently detect Aß40 and Aß42 in spiked-plasma in the range of 10-14 - 10-6 g/mL (with LoDs being 5.71 and 9.09 fg/mL, respectively), enabling the estimation of diagnostically significant Aß42/Aß40 ratio. A detailed study has been undertaken here to record the individual sensor responses against spiked-plasma samples with varying amounts and proportions of the two target peptides, towards enabling disease-progression monitoring using the Aß-ratio. As compared to the existing cost-ineffective brain-imaging techniques such as PET and MRI, and the high-risk CSF based invasive AD biomarkers detecting procedures, the proposed approach offers a viable alternative for affordable point-of-care AD diagnostics, with possible usage in performance evaluation of therapeutic drugs. Towards point-of-care applications, the portable readout used in this work was conjugated with an android-based mobile app for data-acquisition and analysis.

An Investigation to Examine the Effect of the Elastomeric Surface Treatment on Protein Stability.

Various kinds of treatments on the surface of the elastomeric components can have negative impacts on the quality of protein therapeutics. We compared the effects of bare (non-siliconized and nonlaminated), siliconized, and fluoropolymer-laminated elastomeric components on the stability of ß-lactoglobulin, human serum albumin, adalimumab, abatacept, and immunoglobulin antibodies. The study was conducted in two main parts. Part I was to evaluate the stability of proteins under agitation-induced stress. Protein aggregate formation, turbidity, and protein recovery were analyzed using dynamic FI, absorbance at 350 nm, and size-exclusion high-performance liquid chromatography, respectively. Proteins were found to be more stable with laminated stoppers as compared with bare or siliconized stoppers. Part II was to identify the chemical modifications when the proteins were stored in contact with the same three stoppers. Capillary isoelectric focusing analysis of the adalimumab samples showed formation of acidic variants in siliconized and bare stoppers. Reverse-phase high-performance liquid chromatography suggested chemical changes to the human serum albumin. Analysis of tryptic digest of human serum albumin by liquid chromatography/mass spectrometry/mass spectrometry indicated that the amino acids most susceptible to oxidation (cysteine, tryptophan, and methionine) were also the ones that were modified. Part III of this study investigated the barrier property of the fluoropolymer film with no drug product. Our results were consistent with the suggestion that the fluoropolymer lamination provides a barrier that prevents leachables from the elastomeric components into the protein therapeutics. Our work provided an in-depth understanding of the effects of elastomeric surface treatments on the biophysical and chemical stability of protein drugs.

Clinical Presentation, Treatment, and Challenges in the Management of Child Sexual Assault at a Tertiary Care Referral Center in India.

BACKGROUND: Child Sexual Assault (CSA) is not an uncommon but an under-reported crime. Along with social and psychological critical issues, there are multiple challenges faced by the surgical team for the treatment of complex perineal injuries associated with CSA. This study was conducted to find clinical presentation and management of CSA along with its problems and challenges encountered by the pediatric surgical team. MATERIALS AND METHODS: This was a retrospective study from 2010 to 2019, conducted in the department of pediatric surgery at a tertiary referral center. All-female patients with a definitive history of sexual assault were included in the study. RESULTS: Seven patients fulfilled the inclusion criteria and the mean age was 5.3 years. After a primary survey, all patients were taken up for examination under anesthesia (EUA). Three patients were managed by the primary repair of the wound and did well during follow-up. Four patients had grade 4 perineal injury and required stage reconstruction. As a first stage, repair of rectal tear, vaginal tear, and the perineal body reconstruction was done along with diversion colostomy. One patient required redo repair of the perineal body and one had developed a rectovaginal fistula. Three patients completed all stages and they are fully continent. CONCLUSION: The spectrum of injuries varies widely in CSA and more chances of high-grade perineal injuries in children due to distinctive local anatomy. EUA is crucial to assess the extent of the injury and to decide the course of management. Meticulous anatomical repair and diversion stoma is the key for successful complex repair and excellent long-term outcomes in terms of continence for the severe grade of perineal injuries.

A new variant of the human α-lactalbumin-oleic acid complex as an anticancer agent for chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. Although there have been advancements in treatment, there is still a need to develop a biotherapeutic agent. A new variant of the human alpha-lactalbumin-oleic acid (HALOA) complex has been synthesized, which showed similarities with SNARE. The native α-LA was treated with EDTA to remove Ca2+ ions confirmed by ICP-OES and Arsenazo III to unfold and attain apo structure. The apo LA was mixed with OA in a specific ratio, leading to HALOA complex formation. The conformational state from native to complex was elucidated by circular dichroism (far; 190-260 nm and near; 260-340 nm UV-CD), which confirmed that the complex consists of a majority of turns and ß-sheet structure. SDS-PAGE result showed the masking effect of OA on apo α-LA. In the lane of the complex, there was no band detected. However, 1-anilino-8-naphthalene sulfonate (ANS) dye has shown maximum fluorescence intensity with the complex because of the availability of hydrophobic patches, which was further validated by NMR spectroscopy indicating the masking effect of OA on the apo α-LA. The SNARE behavior of the complex (500 nm) has been confirmed by TEM. This new structural variant complex shows anti-tumor activity on chronic myeloid leukemia by targeting the IL-8, survivin, and induces apoptosis through DNA fragmentation, but not against normal cells. Overall, the formulated complex shows that SNARE-like behavior can be used as a promising anti-tumor agent with lower toxicity and maximum bioavailability.

Is IV iron sucrose a cost-effective option for treatment of severe anaemia in pregnancy as compared with oral iron?

Anaemia in pregnancy is a public health concern because it is strongly associated with maternal and perinatal morbidity and mortality. An open label randomized controlled trial (RCT) was conducted in India across four government medical colleges, comparing intravenous (IV) iron sucrose and oral iron for the treatment of anaemia in pregnancy. This RCT failed to demonstrate superiority of IV iron sucrose compared with oral iron therapy in reducing adverse clinical (maternal and foetal/neonatal) outcomes in moderate-to-severe anaemia in pregnancy. However, IV iron sucrose seemed to reduce the need for blood transfusion among women with severe anaemia. The study objective was to conduct a cost-effectiveness analysis of IV iron sucrose over oral therapy for treatment of severe anaemia in pregnancy, alongside the RCT, to inform policy. The outcome of interest in our study was a 'safe delivery' defined by the absence of composite maternal and foetal/neonatal adverse clinical outcomes. Incremental cost-effectiveness ratio (ICER) was calculated from a limited societal perspective. IV iron sucrose was found to be more costly but more effective than the oral therapy for treatment of severe anaemia. The ICER was calculated at INR 31 951 (USD 445.2) per safe delivery. We considered a threshold of half the gross national income for decision-making. Considering this threshold of India (INR 57 230, USD 797.4), IV iron-sucrose remained cost-effective in 67% of the iterations in the model. At the current ICER, for every 32 severely anaemic pregnant woman treated with IV iron sucrose one additional pregnant woman will have a safe delivery. Such analyses can complement the national strategy to support evidence-based action.

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.

Effect of Gender, Age, Diet and Smoking Status on the Circadian Rhythm of Serum Uric Acid of Healthy Indians of Different Age Groups.

The circadian rhythm of uric acid concentration was studied under near-normal tropical conditions in 162 healthy volunteers (103 males and 59 females; 7 to 75 year). They were mostly medical students, staff members and members of their families. They were classified into 4 age groups: A (7-20 y; N = 42), B (21-40 y; N = 60), C (41-60 y; N = 35) and D (61-75 y; N = 25). They followed a diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Blood samples were collected from each subject every 6 for 24 h (4 samples). Serum uric acid was measured spectrophotometrically. Data from each subject were analyzed by cosinor rhythmometry. Effects of gender, age, diet (vegetarian vs. omnivore), and smoking status on the rhythm-adjusted mean (MESOR) and circadian amplitude were examined by multiple-analysis of variance. A marked circadian variation was found in uric acid concentration in healthy Indians of all age groups. Furthermore, both the MESOR and circadian amplitude underwent changes with advancing age. In addition to effects of gender and age, diet and smoking were also found to affect the MESOR of circulating uric acid concentration in healthy Indians residing in northern India. The present observations confirmed a definite rhythm in uric acid concentrations with significant effect of gender, age, diet, and smoking status on uric acid concentration in clinical health. Mapping the circadian rhythm of serum uric acid is needed to explore their role in different pathophysiological conditions.