Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD.

Effective therapies are urgently needed to safely target TDP-43 pathology as it is closely associated with the onset and development of devastating diseases such as frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 pathology is present as a co-pathology in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Our approach is to develop a TDP-43-specific immunotherapy that exploits Fc gamma-mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP-43 function. Thus, using both in vitro mechanistic studies in conjunction with the rNLS8 and CamKIIa inoculation mouse models of TDP-43 proteinopathy, we identified the key targeting domain in TDP-43 to accomplish these therapeutic objectives. Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs (RRM) reduces TDP-43 pathology and avoids neuronal loss in vivo. We demonstrate that this rescue is dependent on Fc receptor-mediated immune complex uptake by microglia. Furthermore, monoclonal antibody (mAb) treatment enhances phagocytic capacity of ALS patient-derived microglia, providing a mechanism to restore the compromised phagocytic function in ALS and FTD patients. Importantly, these beneficial effects are achieved while preserving physiological TDP-43 activity. Our findings demonstrate that a mAb targeting the C-terminal domain of TDP-43 limits pathology and neurotoxicity, enabling clearance of misfolded TDP-43 through microglia engagement, and supporting the clinical strategy to target TDP-43 by immunotherapy. SIGNIFICANCE STATEMENT: TDP-43 pathology is associated with various devastating neurodegenerative disorders with high unmet medical needs such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Thus, safely and effectively targeting pathological TDP-43 represents a key paradigm for biotechnical research as currently there is little in clinical development. After years of research, we have determined that targeting the C-terminal domain of TDP-43 rescues multiple patho-mechanisms involved in disease progression in two animal models of FTD/ALS. In parallel, importantly, our studies establish that this approach does not alter the physiological functions of this ubiquitously expressed and indispensable protein. Together, our findings substantially contribute to the understanding of TDP-43 pathobiology and support the prioritization for clinical testing of immunotherapy approaches targeting TDP-43.

Long-Term Safety Analysis of the BBV152 Coronavirus Vaccine in Adolescents and Adults: Findings from a 1-Year Prospective Study in North India.

BACKGROUND AND OBJECTIVE: Evidence on the long-term safety of COVID-19 vaccines is scarce. Here, in continuation of our previously published results on short-term safety, we provide data on the long-term safety of the BBV152 vaccine in adolescents and adults. METHODS: This was a prospective observational study conducted from January 2022 to August 2023. Adolescents and adults receiving the BBV152 vaccine were interviewed telephonically about long-term adverse events of special interest (AESIs) after 1 year of vaccination. Risk factors of AESIs and AESIs persistent for at least 1 month were identified. RESULTS: Out of 1024 individuals enrolled, 635 adolescents and 291 adults could be contacted during the 1-year follow-up. Viral upper respiratory tract infections were reported by 304 (47.9%) adolescents and 124 (42.6%) adults in this period. New-onset skin and subcutaneous disorders (10.5%), general disorders (10.2%), and nervous system disorders (4.7%) were the common AESIs in adolescents. General disorders (8.9%), musculoskeletal disorders (5.8%), and nervous system disorders (5.5%) were the common AESIs in adults. Menstrual abnormalities were noticed in 4.6% of female participants. Ocular abnormalities and hypothyroidism were observed in 2.7% and 0.6% of participants, respectively. Among serious AESIs (1%), stroke and Guillain-Barre syndrome were identified in 0.3% and 0.1% of participants, respectively. Among adolescents, female individuals, those with a history of allergy and post-vaccination typhoid were respectively at 1.6, 2.8, and 2.8 times higher risk of AESIs. The majority of the AESIs persisted at the 1-year follow-up. Female individuals, adolescents with pre-vaccination COVID-19, those with co-morbidities, and those with post-vaccination typhoid had respectively 1.6, 2, 2.7, and 3.2 times higher odds of persistent AESIs. Adults with co-morbidities had more than 2 times higher odds of AESIs and persistent AESIs. CONCLUSIONS: The patterns of AESIs developing after BBV152 differed from those reported with other COVID-19 vaccines as well as between adolescents and adults. With the majority of AESIs persisting for a significant period, extended surveillance of COVID-19-vaccinated individuals is warranted to understand the course and outcomes of late-onset AESIs. Serious AESIs might not be uncommon and necessitate enhanced awareness and larger studies to understand the incidence of immune-mediated phenomena post-COVID-19 vaccination. The relationship of AESIs with sex, co-morbidities, pre-vaccination COVID-19, and non-COVID illnesses should be explored in future studies.

Genotypic characterization of dengue virus strains circulating during 2007-2009 in New Delhi.

Dengue is an important arboviral disease of tropical and subtropical regions, with significant morbidity and mortality. Dengue virus is antigenically classified into four serotypes, which are further classified into 4-5 genotypes based on their genetic diversity. Since genotypes vary in their virulence, their detection and analysis of spatial and temporal transition are essential. We utilized sequence information from the E-NS1 gene region for molecular and phylogenetic characterization of dengue viruses isolated from dengue patients between 2007 and 2009. All four serotypes and multiple genotypes were detected, with predominance and emergence of DENV-1 genotype V. Phylogenetic analysis revealed the emergence of DENV-1 genotype V from India for the first time, which has replaced the earlier circulating genotype III and genotype I. The circulation of multiple genotypes and genotype replacement is critical, since genotypes vary in their virulence, and this should be a point of concern for healthcare agencies.

A Prospective Observational Study on BBV152 Coronavirus Vaccine Use in Adolescents and Comparison with Adults: Interim Results of the First Real-World Safety Analysis.

INTRODUCTION: The BBV152 coronavirus disease 2019 (COVID-19) vaccine (COVAXIN) has recently been approved for adolescents. OBJECTIVE: We provide the first real-world safety data of COVAXIN use in adolescents and compare with adults. METHODS: A prospective observational study was initiated in January 2022. Enrolled adolescents and adults were contacted by telephone after 14 days of receiving the BBV152 vaccine. The primary outcome was vaccine safety assessed as rate of adverse events following immunization (AEFIs). Severity grading of AEFIs was done using the Food and Drug Administration (FDA) scale. Interim results are presented. RESULTS: A total of 698 adolescents and 326 adults were enrolled. AEFIs after the first dose developed in 243 out of 670 adolescents (36.3%), with 21% reporting only local AEFIs and 15.2% reporting systemic AEFIs. Among 340 adolescents who had received the second dose of vaccine, 129 (37.9%) developed AEFIs, with only local involvement in 20.3% and systemic involvement in 17.6%. Injection site pain and fever were the common AEFIs. The majority of AEFIs were mild-moderate. Nearly 0.9% of adolescents receiving the first dose reported severe AEFIs. Atypical AEFIs were observed in 0.6-0.9% of adolescents. The majority of the AEFIs resolved in 1-2 days. AEFIs were persistent in > 2% of adolescents at day 14 after the second dose, and also in 3.7% of adults overall at follow-up. No difference was observed in AEFI incidence and patterns between adolescents and adults. Regression analysis showed females and those with a history of allergy to be, respectively, at 1.6 times and 3 times increased risk of AEFIs among adolescents. CONCLUSIONS: COVAXIN carries an overall favorable short-term safety profile in adolescents. The observed AEFI rates in adolescents are much lower than that reported with mRNA vaccines, but head-head comparisons in the same population are required to generate relative vaccine safety data. Female adolescents and those with a history of allergy need watchfulness for severe and persistent AEFIs. With some AEFIs persisting at 14 days, a longer follow-up is recommended to strengthen the safety data of COVAXIN.

Persistent Health Issues, Adverse Events, and Effectiveness of Vaccines during the Second Wave of COVID-19: A Cohort Study from a Tertiary Hospital in North India.

Background There is paucity of real-world data on COVID-19 vaccine effectiveness from cohort designs. Variable vaccine performance has been observed in test-negative case-control designs. There is also scarce real-world data of health issues in individuals receiving vaccines after prior COVID-19, and of adverse events of significant concern (AESCs) in the vaccinated. Methods: A cohort study was conducted from July 2021 to December 2021 in a tertiary hospital of North India. The primary outcome was vaccine effectiveness against COVID-19 during the second wave in India. Secondary outcomes were AESCs, and persistent health issues in those receiving COVID-19 vaccines. Regression analyses were performed to determine risk factors of COVID-19 outcomes and persistent health issues. Results: Of the 2760 health care workers included, 2544 had received COVID-19 vaccines, with COVISHIELD (rChAdOx1-nCoV-19 vaccine) received by 2476 (97.3%) and COVAXIN (inactivated SARS-CoV-2 vaccine) by 64 (2.5%). A total of 2691 HCWs were included in the vaccine effectiveness analysis, and 973 COVID-19 events were reported during the period of analysis. Maximum effectiveness of two doses of vaccine in preventing COVID-19 occurrence was 17% across three different strategies of analysis adopted for robustness of data. One-dose recipients were at 1.27-times increased risk of COVID-19. Prior SARS-CoV-2 infection was a strong independent protective factor against COVID-19 (aOR 0.66). Full vaccination reduced moderate-severe COVID-19 by 57%. Those with lung disease were at 2.54-times increased risk of moderate-severe COVID-19, independent of vaccination status. AESCs were observed in 33/2544 (1.3%) vaccinees, including one case each of myocarditis and severe hypersensitivity. Individuals with hypothyroidism were at 5-times higher risk and those receiving a vaccine after recovery from COVID-19 were at 3-times higher risk of persistent health issues. Conclusions: COVID-19 vaccination reduced COVID-19 severity but offered marginal protection against occurrence. The possible relationship of asthma and hypothyroidism with COVID-19 outcomes necessitates focused research. With independent protection of SARS-CoV-2 infection, and high-risk of persistent health issues in individuals receiving vaccine after recovery from SARS-CoV-2 infection, the recommendation of vaccinating those with prior SARS-CoV-2 infection needs reconsideration.

Distribution of human rotavirus G and P genotypes in a hospital setting from Northern India.

Rotavirus gastroenteritis is a major cause of severe dehydrating diarrhea in children worldwide. Rotavirus G and P genotyping is essential for epidemiological surveillance and for better formulation of candidate rotavirus vaccines. Out of 862 diarrheal stool samples collected from hospitalized children aged < 2 years during February 2005 - March 2007, 318 (36.9%) were positive for rotavirus by ELISA. G and P genotyping was performed on 100 randomly selected positive samples using a seminested multiplex RT-PCR assay. The result of G genotyping indicates G1 (60%) was the most predominant VP7 type, followed by G2 (16%), G9 (8%) and G3 (3%). Two cases of G12 genotype were also observed. P genotypes identified were P[8] (40%) followed by P[4] (26%) and P[6] (17%). The most common G-P combinations were G1P[8] (26%), followed by G1P[4] and G1P[6]. Mixed infection involved 28% of strains. In this study the G1 and P[8] genotypes were the leading G and P types. Two cases with G12 genotype were also observed during the study.

Comparison of multiplex RT-PCR and real-time HybProbe assay for serotyping of dengue virus using reference strains and clinical samples from India.

BACKGROUND: Dengue virus serotyping is crucial from clinical management and epidemiological point of view. AIMS: To compare efficacy of two molecular detection and typing methods, namely, multiplex reverse transcription polymerase chain reaction (RT-PCR) and real-time Hybprobe assay using a panel of known dilution of four reference Dengue virus strains and a panel of sera collected from clinically suspected dengue patients. SETTINGS: This study was conducted at a tertiary-care teaching hospital in Delhi, India. MATERIALS AND METHODS: Dengue serotype specific virus strains were used as prototypes for serotyping assays. Viral load was quantified by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR). Acute phase serum samples were collected from 79 patients with clinically suspected Dengue fever on their first day of presentation during September-October 2012. Viral RNA from serum and cell culture supernatant was extracted. Reverse transcription was carried out. Quantitative detection of DENV RNA from reference strain culture supernatants and each of the 79 patient samples by real-time PCR was performed using light cycler Taqman master mix kit. Serotyping was done by multiplex RT-PCR assay and Hybprobe assay. RESULTS: The multiplex RT-PCR assay, though found to be 100% specific, couldn't serotype either patient or reference strains with viral load less than 1000 RNA copies/ml. The Hybprobe assay was found to have 100% specificity and had a lower limit of serotype detection of merely 3.54 RNA copies/ml. CONCLUSIONS: HybProbe assay has an important role especially in situations where serotyping is to be performed in clinical samples with low viral load.

Bone cement.

The knowledge about the bone cement is of paramount importance to all Orthopaedic surgeons. Although the bone cement had been the gold standard in the field of joint replacement surgery, its use has somewhat decreased because of the advent of press-fit implants which encourages bone in growth. The shortcomings, side effects and toxicity of the bone cement are being addressed recently. More research is needed and continues in the field of nanoparticle additives, enhanced bone-cement interface etc.

Muscle-specific regulation of the mTOR signaling pathway in MuSK antibody seropositive (MuSK+) experimental autoimmune Myasthenia gravis (EAMG).

Myasthenia gravis (MG) patients with antibodies against muscle specific tyrosine kinase (MuSK+) typically present focal fatigue and atrophy of the facial and bulbar muscles, including the masseter muscle, whereas leg muscles often are clinically spared. This study addresses the regulation of the mTOR signaling pathway in the masseter muscle versus the leg muscle tibialis anterior (TA). We analyzed muscle morphology, protein levels of mTOR components as well as atrogenes and mitochondrial markers in these muscles of healthy control mice and mice with different clinical severity grades of MuSK+ experimental autoimmune MG (EAMG). Protein levels of mTOR components were reduced in the atrophic masseter muscle of MuSK+ EAMG mice, whereas enhanced accumulation of mTOR components was observed in the TA muscles. Two other muscles: omohyoid and soleus showed intermediate spectra. In conclusion, the anabolic mTOR signaling pathway is differentially regulated even in muscles with the same activity pattern in the same neuromuscular disease. This could in part explain the clinical phenotype in MuSK+ EAMG as well as in muscular dystrophies.

Hepatitis C virus core antigen assay: can we think beyond convention in resource limited settings?

Hepatitis C virus infects over 15 million patients from India and 2.86 million from Brazil. Detection of anti-hepatitis C virus antibodies has limited sensitivity during acute phase: the pre-seroconversion window period. Hepatitis C virus-RNA detection techniques are used to overcome this shortfall, but are costly and unavailable widely in developing countries. Estimation of hepatitis C virus core-antigen, a protein with highly conserved sequence, by enzyme-immunoassays is an economic and simpler alternative to RNA detection. This study was conducted in Delhi, involving 300 acute and chronic liver disease patients, tested for anti-hepatitis C virus 3rd-generation ELISA, hepatitis C virus core-antigen-ELISA and hepatitis C virus-RNA reverse transcription-polymerase chain reaction. Among the acute patients, hepatitis C virus core-antigen assay could identify 13 out of 14 pre-seroconversion window period cases and 6 out of 8 seroconverted cases, with a pre-seroconversion window period sensitivity of 92.9% and specificity of 100%. In hepatitis C virus core-antigen-positive cases, the viral load was in the range of 4900 to 1.46×10(6)IU/mL, whereas in hepatitis C virus core-antigen-negative cases, the range of viral load was 100-4500IU/mL. The cost of the hepatitis C virus core-antigen-ELISA was estimated around 3-4 times lesser than the in-house reverse transcription-polymerase chain reaction and 9-10 times lesser than the United States Food and Drug Administration approved reverse transcription-polymerase chain reaction. With a good sensitivity and specificity in the acute phase of infection, hepatitis C virus core-antigen-ELISA can thus be a useful alternative in the developing nations.