Real-World Safety of TwinRab, the World's First Novel Cocktail of Rabies Monoclonal Antibodies, in a Clinical Setting.

OBJECTIVES: Every year, 18,000-20,000 people die from rabies in India, with children younger than the age of 15 accounting for 30%-60% of all cases. Wound cleaning, vaccination, and rabies immunoglobulin (RIG) administration are all part of treatment. TwinRabTM, a unique combination of two monoclonal antibodies (mAbs), docaravimab and miromavimab, effectively neutralizes rabies and rabies-like viruses. We conducted this study to evaluate the safety of the cocktail in patients infected with category-III animal bites according to WHO guidelines. METHODS: This open-label observational study was conducted in patients with WHO category-III animal bites by suspected rabid animals. All participants were screened, enrolled, and were administered the TwinRabTM manufactured by Zydus Lifesciences Ltd. at the rate of 40 IU/kg by infiltration in and around the wound along with anti-rabies vaccine (ARVs). Participants were assessed at various intervals, and any adverse events (AEs) were documented and reported to the sponsor within 24 hours. RESULT: The study enrolled 401 participants, 55.61% (n = 223) male, whose median age was 34 years. Adults made up 69.83% (n = 280) of the participants. The most exposed sites were the lower parts of the body (60.6%, n = 243); 99.75% (n = 400) of the population showed normal cardiovascular, gastrointestinal, and central nervous systems. After seven days of the last postexposure prophylaxis (PEP) dose, 9.98% of the total study population experienced 80 mild local solicited AEs and were assessed and treated. CONCLUSION: The study concluded that TwinRabTM when given in a 40 IU/kg dose with Essen or the updated Thai Red Cross Vaccine regimen, provides safe and effective rabies prophylaxis in WHO category III patients exposed to suspected rabied animal bites.

A phase 2 single center open label randomised control trial for convalescent plasma therapy in patients with severe COVID-19.

A single center open label phase 2 randomised control trial (Clinical Trial Registry of India No. CTRI/2020/05/025209) was done to assess clinical and immunological benefits of passive immunization using convalescent plasma therapy. At the Infectious Diseases and Beleghata General Hospital in Kolkata, India, 80 patients hospitalized with severe COVID-19 disease and fulfilling the inclusion criteria (aged more than 18 years, with either mild ARDS having PaO2/FiO2 200-300 or moderate ARDS having PaO2/FiO2 100-200, not on mechanical ventilation) were recruited and randomized into either standard of care (SOC) arm (N = 40) or the convalescent plasma therapy (CPT) arm (N = 40). Primary outcomes were all-cause mortality by day 30 of enrolment and immunological correlates of response to therapy if any, for which plasma abundance of a large panel of cytokines was quantitated before and after intervention to assess the effect of CPT on the systemic hyper-inflammation encountered in these patients. The secondary outcomes were recovery from ARDS and time taken to negative viral RNA PCR as well as to report any adverse reaction to plasma therapy. Transfused convalescent plasma was characterized in terms of its neutralizing antibody content as well as proteome. The trial was completed and it was found that primary outcome of all-cause mortality was not significantly different among severe COVID-19 patients with ARDS randomized to two treatment arms (Mantel-Haenszel Hazard Ratio 0.6731, 95% confidence interval 0.3010-1.505, with a P value of 0.3424 on Mantel-Cox Log-rank test). No adverse effect was reported with CPT. In severe COVID-19 patients with mild or moderate ARDS no significant clinical benefit was registered in this clinical trial with convalescent plasma therapy in terms of prespecified outcomes.

Plasma Gradient of Soluble Urokinase-Type Plasminogen Activator Receptor Is Linked to Pathogenic Plasma Proteome and Immune Transcriptome and Stratifies Outcomes in Severe COVID-19.

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.

Nature and Dimensions of Systemic Hyperinflammation and its Attenuation by Convalescent Plasma in Severe COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has led to significant morbidity and mortality. While most suffer from mild symptoms, some patients progress to severe disease with acute respiratory distress syndrome (ARDS) and associated systemic hyperinflammation. METHODS: First, to characterize key cytokines and their dynamics in this hyperinflammatory condition, we assessed abundance and correlative expression of a panel of 48 cytokines in patients progressing to ARDS as compared to patients with mild disease. Then, in an ongoing randomized controlled trial of convalescent plasma therapy (CPT), we analyzed rapid effects of CPT on the systemic cytokine dynamics as a correlate for the level of hypoxia experienced by the patients. RESULTS: We identified an anti-inflammatory role of CPT independent of its neutralizing antibody content. CONCLUSIONS: Neutralizing antibodies, as well as reductions in circulating interleukin-6 and interferon-γ-inducible protein 10, contributed to marked rapid reductions in hypoxia in response to CPT. CLINICAL TRIAL REGISTRY OF INDIA: CTRI/2020/05/025209. http://www.ctri.nic.in/.

A prospective study on COVID-19 convalescent plasma donor (CCP) recruitment strategies in a resource constrained blood centre.

Background and Objectives: The COVID-19 pandemic has spread across 87 million people with more than 1·8 million deaths in the world. As there is no definite treatment modality, the use of convalescent plasma has become increasingly popular worldwide. This study aimed to identify an appropriate strategy of donor recruitment and to evaluate the appropriateness of pre-set plasma donation guidelines. Material and Methods: In this prospective study conducted from May to September 2020, the donors were recruited under the following two circumstances: Group I, patients in the post-COVID-19 follow-up in the clinic, and Group II, patients recovered from COVID-19 recruited through mass and electronic media. A pre-set donor selection criteria and laboratory investigation was designed according to national and international guidelines. Approximately 500 ml of COVID-19 convalescent plasma (CCP) was collected from recovered individuals in each group by two different cell separators. The overall donor's attendance rate, deferral rate, adverse events and donor compliance was analysed and compared between the two groups. Results: There was a significant difference in attendance in relation to registration between the groups (P < 0·0001). Donor deferral was significantly higher in group II compared with group I. The single most frequent cause of donor deferral was low antibody index (P = 0·0001). The total donor adverse event rate in CCP donation was significantly lower compared with routine plateletpheresis procedures. The donor's compliance to blood centre's protocol was satisfactory in both the groups. Conclusion: Recruitment of patients in the post-COVID-19 follow-up in the clinic was more effective than the general recruitment through mass and electronic media for convalescence plasma donation in a resource-constrained blood centre.

Forced flow cryogenic cooling in fusion devices: A review.

The constantly increasing energy consumption along with the depleting fossil fuel resources as well as owing to the fact that the nuclear fission not being an intrinsically safe method of energy generation, it has become necessary to look for other solutions to fulfil the future energy demands. Nuclear fusion, the source of energy for billions of stars, has attracted the attention of scientists and engineers despite a lot of technical challenges in the replication of the fusion process in laboratories. For fusion to take place in a device, one of the major challenges faced is the strong magnetic confinement of the plasma using large superconducting (SC) magnets, which need efficient cryogenic cooling techniques to maintain the required low temperatures for the superconducting state. In order to maintain the compactness, the SC magnets generally employ Cable in Conduit Conductor (CICC) windings, carrying high current densities, which are cooled by the forced flow of helium at ~4 K temperature to maintain the required superconducting temperatures. The construction of CICC aims to maintain the superconductivity state by optimization of various parameters such as thermal stability, the ratio of normal conductor to SC material, mechanical strength, low hydraulic impedance, current density, magnetic field, etc. The cryogenic thermal stability of the CICC is of prime importance for safe, stable and reliable operation of SC magnets. The prediction of thermal and hydraulic behavior of the CICC in large SC magnets is difficult due to the complex geometry involved, the variation in fluid properties, various heat in-flux incidences over the long length of CICC and a complex heat transport phenomenon. Another application which utilizes a forced flow cryogenic cooling in the fusion devices is a cryo-adsorption pump for creating clean and high vacuum with large pumping speed. This paper presents an overview of the forced flow cryogenic cooling schemes in fusion devices along with a systematic review of the thermal and hydraulic studies related to CICC and cryo-adsorption pump, thereby highlighting the challenges and opportunities for further improvement in their design and performance.

Compound Heterozygote of Hb S (HBB: c.20A>T)/Hb Westdale (HBB: c.380_396delTGCAGGCTGCCTATCAG): Report of Four Cases from Odisha State, India.

We report four cases of compound heterozygotes for Hb S (HBB: c.20A>T) and a rare ß0-thalassemia (ß0-thal) mutation, Hb Westdale (HBB: c.380_396delTGCAGGCTGCCTATCAG), characterized by a 17 bp deletion between codons 126 to 131 in exon 3 of the ß-globin gene of human hemoglobin (Hb) confirmed by direct ß-globin gene sequencing. All four cases were from four unrelated families belonging to the Agharia caste, an endogamous ethnic community of the Sundargarh and Jharsuguda districts of Odisha State, India. Detailed observations indicated that all four cases of Hb S/Hb Westdale were clinically severe. On family screening, six family members were found to be heterozygous for Hb Westdale and were asymptomatic. Deletional α-thalassemia (α-thal) and XmnI polymorphism were studied for all the Hb Westdale cases. The Hb S/Hb Westdale cases had an early median age at onset of symptoms and presentation, more requirement of blood transfusions, splenomegaly and hepatomegaly and were found to be clinically more severe when compared with the Hb S-ß-thal with IVS-I-5 (G>C) (HBB: c.92 + 5G>C) cases. Overall, the findings indicate that this rare and hitherto unreported compound heterozygosity of Hb S/Hb Westdale is a clinically significant hemoglobinopathy and its finding in a large endogamous community of Odisha State, India will have important implication in the epidemiology and understanding of the clinical spectrum of sickle cell disease in Indian context and prenatal diagnosis.

Combined association of Presenilin-1 and Apolipoprotein E polymorphisms with maternal meiosis II error in Down syndrome births

Abstract Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin −1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The control group consisted of 186 mothers of karyotypically normal children. The frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE ε4 allele, were significantly higher among young mothers (< 35 years) with meiosis II nondisjunction than in young control mothers (96.43% vs. 65.91% P = 0.0002 and 92.86% vs. 45.45% P < 0.0001 respectively) but not among mothers with meiosis I nondisjunction. We infer that the co-occurrence of the PSEN-1 T allele and the APOE ε4 allele associatively increases the risk of meiotic segregation error II among young women.

Combined association of Presenilin-1 and Apolipoprotein E polymorphisms with maternal meiosis II error in Down syndrome births.

Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin -1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The control group consisted of 186 mothers of karyotypically normal children. The frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE ε4 allele, were significantly higher among young mothers (< 35 years) with meiosis II nondisjunction than in young control mothers (96.43% vs. 65.91% P = 0.0002 and 92.86% vs. 45.45% P < 0.0001 respectively) but not among mothers with meiosis I nondisjunction. We infer that the co-occurrence of the PSEN-1 T allele and the APOE ε4 allele associatively increases the risk of meiotic segregation error II among young women.

The promise of discovering population-specific disease-associated genes in South Asia.

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

Hb Tianshui (HBB: C.119A > G) in Compound Heterozygosity with Hb S (HBB: C.20A > T) from Odisha, India.

We describe here a rare ß-globin gene variant, Hb Tianshui [ß39(C5)Glu→Arg; HBB: c.119A > G], detected during routine screening in Odisha, India. This is the second report of Hb Tianshui and the first to describe the cation exchange high performance liquid chromatography (HPLC) and DNA studies of two cases of this variant. Both cases had coinherited Hb S (HBB: c.20A > T) but none presented with typical symptoms of sickle cell disease. One of the cases was heterozygous for a common α-thalassemia (α-thal) allele (-α(3.7)) (rightward) (NG_000006.1: g.34164_37967del3804) and marginally raised Hb F percentage, while the other Hb S/Hb Tianshui case was completely benign and healthy. An atypical Asian Indian haplotype [+ - + - +] could be assigned to the Hb Tianshui variant. Hb Tianshui seems to mimic a few other Hb variants in cation exchange HPLC. However, we report two specific patterns in the chromatograms that are characteristic to Hb Tianshui. Combining an alkaline electrophoresis result with cation exchange HPLC at screening would be preferred to detect this rare variant, especially in regions with considerable frequency of Hb E [ß26(B8)Glu→Lys; HBB: c.79G > A] or Hb S.

First Report of Hb Limassol [ß8(A5)Lys→Asn; HBB: c.27G>C] from Odisha, India.

In this short report, we describe the clinical presentation of a rare hemoglobin (Hb) variant, Hb Limassol [ß8(A5)Lys→Asn; HBB: c.27G>C] with a faster electrophoretic mobility than Hb A and that elutes in the P3 window on cation exchange high performance liquid chromatography (HPLC). This sequence variation at codon 8 (AAG>AAC) of the HBB gene was found in the four heterozygous cases, all of whom were clinically asymptomatic.

Profile of Patients with Allergic Rhinitis (AR): A Clinic Based Cross-Sectional Study from Kolkata, India.

BACKGROUND: Allergic Rhinitis (AR) though quite common in India, does not receive its due importance as it deserves. AIM OF THE STUDY: To identify the demographic and clinical profile of the patients with AR and to find the association of pre-dominant disease symptoms with common allergens, type and severity of the disease and other co-morbidities. SETTINGS AND DESIGN: This clinic-based cross-sectional, observational study was conducted among adult patients presenting with signs and symptoms suggestive of AR. METHODS AND MATERIAL: Consecutive 548 patients were initially screened for possible cases of AR by proper history taking and physical examination and confirmation was done by a battery of investigations, including modified skin prick test. A total of 462 patients who were finally diagnosed with AR were included in the study. Categorization of these patients was done following Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. Pulmonary function tests and X-ray/CT-scan of the para-nasal sinuses were done to confirm the presence of bronchial asthma and sinusitis, respectively. STATISTICAL ANALYSIS USED: Data were analyzed by Statistical Package for Social Scientists (SPSS version 10). Z-test was applied to compare between two rates, at 5% level of significance. RESULTS: Proportion of "blockers" was found to be much higher than that of "sneezers-runners" (64.1% vs. 35.9%). "Blockers" had significantly more sensitization to polyvalent house dust, house dust mites and fungi (p < 0.05), while, "sneezers-runners" had more sensitization to pollens (p < 0.05). Significantly more "blockers" had "moderate/severe persistent" and "mild persistent" types of the disease (p < 0.05), while "mild intermittent" and moderate/severe intermittent" type of disease were significantly more common among "sneezers-runners" (p < 0.05). Both bronchial asthma and sinusitis were significantly more common among the "blockers" (p < 0.05). CONCLUSION: It can be concluded from the present study that the clinical profiles of the two main categories of AR namely "sneezers-runners" and "blockers" were distinct from each other. This knowledge can be useful to physicians at all levels for better management of patients with AR.

Menarcheal age of type 1 diabetic Bengali Indian females.

BACKGROUND: It has been observed that menstrual characteristics are generally influenced by lifestyle, socio-cultural and biological factors. AIM: The present study examines: (a) variation in menstrual characteristics between Type1 Diabetic females of rural and urban adolescents, i.e. the resident status; and (b) whether these characteristics can be predicted from various socio-economic, stress variables related to place of residence. SUBJECTS AND METHODS: The sample of the present study constituted 103T1DM females from West Bengal, a State of India. These girls belong to a Bengali-speaking ethnic group. Data on socio-economic variables and menstrual characteristics were collected using pretested questionnaires. RESULTS: Menstrual irregularity was common in our study participants, with age of menarche, but was not associated with current BMI, physical activity or insulin dose. CONCLUSIONS: Our study displays that age at menarche is delayed in young women with T1DM compared to the concurrent overall mean age at menarche in the West Bengal population.

HLA class II SNP interactions and the association with type 1 diabetes mellitus in Bengali speaking patients of Eastern India.

BACKGROUND: Several studies have demonstrated a fundamental role for the HLA in the susceptibility of, or protection to, type 1 diabetes mellitus (T1DM). However, this has not been adequately studied in Asian Indian populations. To assess the frequency of HLA class II (DPA1, DPB1, DQA1, DQB1 and DRB1) associated to susceptibility or protection toT1DM in a Bengali population of India with diabetes. RESULTS: Single nucleotide polymorphism study. The HLA genotyping was performed by a polymerase chain reaction followed by their HLA-DP, DQ, and DRB1 genotypes and haplotypes by sequencing method. The results are studied by Plink software. The χ2 tests were used for the inferential statistics. To our knowledge, this study is the first of a kind which has attempted to check the HLA association with T1DM by SNPs analysis. The study recruited 151 patients with T1DM and same number of ethno-linguistic, sex matched non-diabetic controls. The present study found a significant SNP rs7990 of HLA-DQA1 (p = 0.009) negative correlation, again indicating that risk from HLA is considerably more with T1DM. CONCLUSIONS: This study demonstrates that the HLA class-II alleles play a major role in genetic basis of T1DM.

Role of HLA class II loci polymorphism in the manifestation of type 1 diabetes in a Bengali Indian patient population.

To assess the contribution of the HLA class II region for susceptibility to type 1 diabetes mellitus (T1DM), we investigated the association of HLA class II alleles-DP, DQ, and DRB1. Here, we present an extensive molecular typing for HLA class II alleles and their haplotypes in a Bengali-speaking Indian population of T1DM patients (n=151) and controls (n=151) from West Bengal. HLA typing was done by DNA sequencing using a 3730 DNA Analyzer. The individual analysis of each gene gave the following alleles to be higher in cases than in controls, thus making them susceptible alleles-DPA1*020103, DPB1*020102, DQA1*050101, DQA1*0201, and DQB1*020101G. Similarly, the following alleles are protective alleles in our study-DPA1*010602, DPB1*040101, DQA1*010201, DQA1*0103, and DRB1*15. Our result confidently establishes that HLA-DP allelic, and its haplotypic, diversity contributes significantly to the risk for T1DM. The DQA1*0103 allele is a novel allele with a significant association with the protection from T1DM. Among the various haplotypes tested, the DQA1*0201:DQB1*020101G, DQA1*050101:DQB1*020101G, and DQA1*0201:DQB1*030101G were the most frequently found in T1DM patients. In India, very few investigations have been undertaken to study the impact of the genetic background on the risk to develop T1DM in its population, where the annual average incidence is 10.5/100,000/year. In conclusion, the present study highlights the genetic effect of HLA haplotypes that contributes to the susceptibility to T1DM.

Systemic Sclerosis Presenting with Simultaneous Retinal Vasculitis in One Eye and Optic Neuritis in the other along with Severe Immune Haemolytic Anaemia.

Systemic Sclerosis (SSc) is a connective tissue disorder which involves multiple systems in a chronic progressive manner. Micro-angiopathic haemolytic anaemia is a distinguished feature of "scleroderma renal crisis", which is manifested by severe hypertension, a rapidly progressing renal dysfunction and hyperreninaemia and is seen in patients with an early, diffuse form of the disease. A nervous system involvement is rare, though entrapment neuropathies have been reported. Who presented with a sequential loss of vision in both eyes; due to retinal vasculitis in right eye and optic nerve demyelination in the left eye. She also had severe Coombs' negative haemolytic anaemia in absence of any renal dysfunction or hypertension. Both the ophthalmologic and the haematologic manifestations are very rare and both responded well to oral prednisolone therapy.

Polymorphic haplotypes of CRELD1 differentially predispose Down syndrome and euploids individuals to atrioventricular septal defect.

To explore the role of CRELD1 variants on congenital heart defects, we sequenced the entire reading frame of CRELD1 in the samples from Kolkata and adjoining areas. Nearly, 400 participants were included in the genetic association study and they were stratified as Down syndrome (DS) with atrioventricular septal defect (AVSD), DS without AVSD, euploid with AVSD, and euploid without AVSD. A significant association was found between AVSD and three polymorphisms, namely rs9878047 (c.1049-129T > C), rs3774207 (c.1119C > T), and rs73118372 (c.1136T > C) among the Down syndrome and euploid individuals. The polymorphism rs73118372, involves a transition (c.1136T > C) that leads to change in amino acid methionine to threonine which alters protein secondary structure as confirmed by the bioinformatics software SOPMA. In addition, two haplotypes, C-T-C and C-T-T, in the order of loci rs9878047-rs3774207-rs73118372 were associated with incidence of AVSD among euploid and Down syndrome, with a slightly higher odds ratio in the later group. We hypothesize that these haplotypes increase the risk of AVSD, and the susceptibility is exacerbated in DS, possibly due to the trisomy 21 genetic background. Moreover, we report for the first time on an interaction between the mutant alleles of rs3774207 and rs73118372 which could disrupt the delicate balance between different CRELD1 isoforms.