Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BACKGROUND: Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. METHODS: Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. RESULTS: We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. CONCLUSIONS: Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

Review of Satralizumab for Neuromyelitis Optica Spectrum Disorder: A New Biologic Agent Targeting the Interleukin-6 Receptor.

Currently, three monoclonal antibodies (MABs) have received regulatory approval from the federal agency, the United States Food and Drug Administration (USFDA), for the medical management of neuromyelitis optica spectrum disorder (NMOSD). Satralizumab was the third approved therapy after MABs like eculizumab and inebilizumab for NMOSD, an uncommon but severe enfeebling autoimmune neurological disease. Satralizumab, a humanized monoclonal antibody, exerts its action in NMOSD by acting against cytokine interleukin-6 (IL-6), a foremost mediator in the pathological process of NMOSD. Two pivotal clinical trials carried out in NMOSD patients had established that satralizumab significantly decreased the rate of relapse in patients suffering from NMOSD as opposed to placebo. The trials also demonstrated that satralizumab is relatively safe. Thus, satralizumab provides an efficacious and safe treatment option for this rare, disabling central nervous system (CNS) disease. Our review aimed to elucidate the pharmacological characteristics of satralizumab and illustrate the available evidence regarding its safety and efficacy in patients with NMOSD.

Comparison of Efficacy and Safety of Azilsartan and Amlodipine Combination Versus Telmisartan and Amlodipine Combination in Hypertensive Patients: A Non-inferiority Trial.

Introduction Hypertension (HTN) is one of the most common conditions encountered in daily practice in hospitals. Combination therapy is mostly initiated in the management of HTN when target blood pressure is not achieved with monotherapy. There are few studies comparing the antihypertensive effect of a combination of azilsartan and amlodipine with a combination of amlodipine and other angiotensin receptor blockers (ARBs), however, the results are contradictory. The objective of this study was to compare the efficacy and safety of the azilsartan and amlodipine combination versus the telmisartan and amlodipine combination in hypertensive patients. Methods The present study was a prospective, randomized, active-controlled, open-label, parallel-group clinical trial. Hypertensive patients were randomized into two groups of 25 patients each. Baseline evaluations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and high-sensitivity troponin I (hsTnI) were done. Patients were reassessed after 12 weeks of drug therapy with azilsartan 40 mg and amlodipine 5 mg combination or telmisartan 40 mg once daily (QD) and amlodipine 5 mg combination QD. Results The response rate (defined as a reduction of more than 20 mm Hg in SBP or 10 mm Hg in DBP or both from baseline at 12 weeks) for HTN in the test group and control groups was found to be 88% and 96% respectively. The response rate of the azilsartan amlodipine group was found to be non-inferior to the telmisartan amlodipine group (odds ratio, OR, 0.31, p = 0.61) at the end of 12 weeks of drug therapy. At 12 weeks of follow-up, there was a significant decrease in SBP (p < 0.001), DBP (p < 0.001), and hsTnI levels (p < 0.001) in both groups from baseline values. However, differences between the test and control groups for blood pressure and hsTnI were found to be not statistically significant at 12 weeks of follow-up. The most commonly reported adverse effect in both groups was headache. Conclusion Azilsartan amlodipine combination had an 88% response rate, which was non-inferior to the telmisartan and amlodipine combination. Biomarkers such as hsTnI showed a significant decrease in both groups after 12 weeks of follow-up. However, there was no significant difference between the two groups.

Levothyroxine Therapy and Predictors of Cardiovascular Risk in Clinical Hypothyroidism: A Prospective Cohort Study.

Background Hypothyroidism is associated with hypoadiponectinemia, insulin resistance, and increased cardiovascular risk. The association of adiponectin, insulin resistance, and future cardiovascular risk in clinical hypothyroidism and the effect of levothyroxine are non-conclusive because of the contradictory results. The present prospective cohort study has been conducted to evaluate the effect of levothyroxine on serum adiponectin, insulin resistance, and cardiovascular risk in patients with clinical hypothyroidism. Methods Sixty patients with clinical hypothyroidism who were prescribed levothyroxine were recruited following selection criteria and changes in Zulewski's score, glycemic parameters, homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), lipid profile, serum adiponectin, serum high-sensitivity C-reactive protein (hs-CRP), cardiovascular risk indices, and Framingham risk score were assessed 12 weeks post-levothyroxine therapy. Receiver operating characteristic (ROC) analysis was done to detect the cut-off for adiponectin levels to differentiate between responders and non-responders. Neural network models were created to predict the risk of cardiovascular morbidity. Results Post-levothyroxine therapy, there was a significant improvement in body mass index (BMI) (p = 0.025), diastolic blood pressure (p = 0.021), Zulewski's score (p < 0.001), serum insulin (p = 0.005), fasting sugar (p < 0.001), serum adiponectin (p < 0.001), thyroid profile (p < 0.001), total cholesterol (p < 0.001), low-density lipoprotein (p < 0.001), high-density lipoprotein (p = 0.007), triglycerides (p = 0.002), and subcutaneous fat (p = 0.015). Serum adiponectin showed significant improvement in hypothyroid patients compared to euthyroid individuals (mean difference: -2.21; 95% CI: -2.52 to -1.91; p < 0.001). Mean difference in insulin resistance (HOMA-IR: 0.3, p < 0.001; QUICKI: -0.002, p < 0.001) and cardiovascular risk (atherogenic index: 0.12, p = 0.04; coronary risk index: 0.14, p = 0.038; Framingham risk score: 0.65, p = 0.041) also showed improvement. Serum adiponectin and thyroid-stimulating hormone levels were directly correlated with insulin resistance and cardiovascular risk scores. Conclusion The reduced serum adiponectin level and increased cardiovascular risk in clinical hypothyroidism were improved with hormone replacement, and serum adiponectin level was found to be a good prognostic marker for the treatment response.

Cost of Ambulatory Care in Diabetes: Findings From a Non-Communicable Disease Clinic of a Tertiary Care Institute in Eastern India.

BACKGROUND: This study was conducted to evaluate the cost of ambulatory care of diabetes in a non-communicable disease (NCD) clinic in eastern India. METHODS: This hospital-based cross-sectional cost description study was conducted from July to August 2018. A total of 192 diagnosed cases aged 18-70 years with a minimum history of one year since diagnosis attending the NCD clinic for the first time were included. Information was collected using a pre-tested schedule based on the cost of illness approach that consisted of socio-demographic details, disease status, and cost of ambulatory care. Cost of the drugs was calculated using a standardized repository of drug costs. The estimated expenditure of previous three months was calculated and extrapolated to one year to calculate yearly expenditure. RESULTS: The mean age of the study participants was 43.93±10.41 years and the mean duration of diabetes was 6.64±6.08 years. The median direct cost due to diabetes was Rs 9560 (136.57 USD) annually. It was higher in females (Rs 10,056, 143.45 USD) than in males (Rs 9020, 128.85 USD). In direct medical costs, a major part was constituted by the drugs, oral hypoglycemic agents, and/or insulin (approximately 70%). CONCLUSIONS: In an ambulatory framework too, diabetes causes a substantial financial burden on the individual in India. In the wake of resource constraints in Indian health settings, the public health system needs to be adequately strengthened by policymakers to address the growing number of diabetics and long-standing complications.

Comparative Study of the Effects of Azilsartan and Telmisartan on Insulin Resistance and Metabolic Biomarkers in Essential Hypertension Associated With Type 2 Diabetes Mellitus.

Introduction The complex interplay between the autonomic nervous system, renin-angiotensin-aldosterone system (RAAS), and immunity contributes to the pathogenesis of hypertension in diabetes mellitus. The objective of this study was to investigate and compare the effect of azilsartan and telmisartan on insulin resistance and metabolic biomarkers in patients with both hypertension and type 2 diabetes mellitus. Methods The present study was a prospective, randomized, active-controlled, open-label, parallel-group clinical trial. Patients with grade I or II essential hypertension with type 2 diabetes mellitus were randomized into two groups of 25 patients each. Baseline evaluation of homeostasis model assessment-insulin resistance (HOMA-IR), plasma glucose, insulin, leptin and adiponectin levels, and systolic and diastolic blood pressure (SBP and DBP) of patients was done. Patients were reassessed after 12 weeks of drug therapy with azilsartan 40 mg OD (once daily) or telmisartan 40 mg OD. Results The mean changes in HOMA-IR from the baseline at the end of 12 weeks of treatment were 0.15 (-0.64, 0.94.52) in the azilsartan group and 0.32 (-0.61, 1.26) in the telmisartan group. The mean difference in the changes from the baseline in HOMA-IR between the two groups was 0.3 (-0.87, 1.48), which was not statistically significant. No statistically significant changes were observed between the two groups in metabolic biomarkers (leptin: -0.84, CI: -4.83 to 3.14, and adiponectin: -0.12, CI: -0.62 to 0.37). Systolic (SBP) and diastolic blood pressure (DBP) decreased at the end of the 12-week treatment in both the groups; however, there was no significant difference between the two groups (SBP: -2.6, CI: -10.35 to 5.1, and DBP: -3.0, CI: -7.7 to 1.7). Conclusion Neither azilsartan nor telmisartan had any significant effects on insulin resistance and metabolic biomarkers after 12 weeks of drug therapy in hypertension patients associated with type 2 diabetes mellitus. However, they showed a comparable antihypertensive effect. The adverse effects observed were mild in nature, and their incidence was comparable between the two groups.

Vasculotoxic snakebite envenomation: Management challenges in pregnancy.

Snakebite envenomation in pregnancy is rare. We report two cases of vasculotoxic snakebite in pregnancy and discuss the management challenges in pregnancy for successful maternal and perinatal outcomes. The first case was a 19-year-old woman who was eight weeks of gestation in her second pregnancy when she was bitten. She subsequently delivered by caesarean section at 33 weeks and 3 days because she developed eclampsia. The second case was a 24 year old woman in her third pregnancy, who was bitten at 29 weeks of gestation, who delivered vaginally at 36 weeks of gestation. Both were treated with multidisciplinary team approach including antisnake venom and antibiotics, along with fasciotomy for the second case. Both mothers recovered completely, without evidence of attributable fetal or neonatal morbidity. To conclude, antisnake venom, if indicated, and a multidisciplinary team approach plays an important role for successful maternal and perinatal outcomes in snakebite envenomation in pregnancy.

Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers.

Introduction Healthcare workers (HCWs) are vulnerable to getting infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Preventing HCWs from getting infected is a priority to maintain healthcare services. The therapeutic and preventive role of ivermectin in coronavirus disease 2019 (COVID-19) is being investigated. Based on promising results of in vitro studies of oral ivermectin, this study was conducted with the aim to demonstrate the prophylactic role of oral ivermectin in preventing SARS-CoV-2 infection among HCWs at the All India Institute of Medical Sciences (AIIMS) Bhubaneswar. Methods A prospective cohort study was conducted at AIIMS Bhubaneswar, which has been providing both COVID and non-COVID care since March 2020. All employees and students of the institute who provided written informed consent participated in the study. The uptake of two doses of oral ivermectin (300 µg/kg/dose at a gap of 72 hours) was considered as exposure. The primary outcome of the study was COVID-19 infection in the following month of ivermectin consumption, diagnosed as per Government of India testing criteria (real-time reverse transcriptase polymerase chain reaction [RT-PCR]) guidelines. The log-binomial model was used to estimate adjusted relative risk (ARR), and the Kaplan-Meier failure plot was used to estimate the probability of COVID-19 infection with follow-up time. Results Of 3892 employees, 3532 (90.8%) participated in the study. The ivermectin uptake was 62.5% and 5.3% for two doses and single dose, respectively. Participants who took ivermectin prophylaxis had a lower risk of getting symptoms suggestive of SARS-CoV-2 infection (6% vs 15%). HCWs who had taken two doses of oral ivermectin had a significantly lower risk of contracting COVID-19 infection during the following month (ARR 0.17; 95% CI, 0.12-0.23). Females had a lower risk of contracting COVID-19 than males (ARR 0.70; 95% CI, 0.52-0.93). The absolute risk reduction of SARS-CoV-2 infection was 9.7%. Only 1.8% of the participants reported adverse events, which were mild and self-limiting. Conclusion Two doses of oral ivermectin (300 µg/kg/dose given 72 hours apart) as chemoprophylaxis among HCWs reduced the risk of COVID-19 infection by 83% in the following month. Safe, effective, and low-cost chemoprophylaxis has relevance in the containment of pandemic alongside vaccine.

Determinants of brain swelling in pediatric and adult cerebral malaria.

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A-EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A-EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.

Biosimilars in India; Current Status and Future Perspectives.

Many key biologics are scheduled to lose their patent by the year 2020, which will provide the opportunity to other biopharmaceutical companies to develop the similar biologics. Biosimilar or similar biologic used has increased in the recent year following the approval of the first biosimilar in early 2000. India is one of the leading manufacturers of similar biologics. India has developed a new guideline in 2012 for the pre- and post-marketing approval of similar biologics.

Magnetic Resonance Imaging of Cerebral Malaria Patients Reveals Distinct Pathogenetic Processes in Different Parts of the Brain.

The mechanisms underlying the rapidly reversible brain swelling described in patients with cerebral malaria (CM) are unknown. Using a 1.5-Tesla (T) magnetic resonance imaging (MRI) scanner, we undertook an observational study in Rourkela, India, of 11 Indian patients hospitalized with CM and increased brain volume. Among the 11 cases, there were 5 adults and 6 children. All patients had reduced consciousness and various degrees of cortical swelling at baseline. The latter was predominately posterior in distribution. The findings on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps were consistent with vasogenic edema in all cases. Reversibility after 48 to 72 h was observed in >90% of cases. DWI/ADC mismatch suggested the additional presence of cytotoxic edema in the basal nuclei of 5 patients; all of these had perfusion parameters consistent with vascular engorgement and not with ischemic infarcts. Our results suggest that an impairment of the blood-brain barrier is responsible for the brain swelling in CM. In 5 cases, vasogenic edema occurred in conjunction with changes in the basal nuclei consistent with venous congestion, likely to be caused by the sequestration of Plasmodium falciparum-infected erythrocytes. While both mechanisms have been individually postulated to play an important role in the development of CM, this is the first demonstration of their concurrent involvement in different parts of the brain. The clinical and radiological characteristics observed in the majority of our patients are consistent with posterior reversible encephalopathy syndrome (PRES), and we show for the first time a high frequency of PRES in the context of CM. IMPORTANCE The pathophysiology and molecular mechanisms underlying cerebral malaria (CM) are still poorly understood. Recent neuroimaging studies demonstrated that brain swelling is a common feature in CM and a major contributor to death in pediatric patients. Consequently, determining the precise mechanisms responsible for this swelling could open new adjunct therapeutic avenues in CM patients. Using an MRI scanner with a higher resolution than the ones used in previous reports, we identified two distinct origins of brain swelling in both adult and pediatric patients from India, occurring in distinct parts of the brain. Our results support the hypothesis that both endothelial dysfunction and microvascular obstruction by Plasmodium falciparum-infected erythrocytes make independent contributions to the pathogenesis of CM, providing opportunities for novel therapeutic interventions.

Evolution of titanium(IV) alkoxides and raney nickel for asymmetric reductive amination of prochiral aliphatic ketones.

[reaction: see text] A new method for the one-pot asymmetric reductive amination of prochiral aliphatic ketones has been developed. The previously unexplored reagent combination of Ti(O(i)Pr)(4)/Raney Ni/H(2) in the presence of (R)- or (S)-alpha-methylbenzylamine provides good to excellent yield (76-90%) and diastereomeric excess (72-98%). The second step, hydrogenolysis, provides the corresponding primary amine in high yield (88-93%) and with uncompromised enantiomeric excess.