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Introduction Tuberculosis (TB) continues to be one of the deadliest infectious diseases over the centuries, killing more people worldwide than any other single infectious disease. There is an urgent need for additional strategies which can expedite efforts to combat TB including a preventive vaccine. In this endeavour, we have developed a protocol for a multisite, double-blind, placebo-controlled clinical trial in India that aims to evaluate the efficacy and safety of two TB vaccines; namely, VPM1002 and Immuvac (M.w) (Mycobacterium Indicus Pranii) (MIP) among healthy household contacts (HHCs) of sputum smear-positive pulmonary TB (PTB) patients.Methods and analysis In the three-arm randomised double-blind placebo-controlled trial study protocol, a total of 12 000 HHCs (aged 6−99 years) of sputum smear-positive PTB patients will be randomised to receive either of the two vaccine candidates VPM1002 and MIP or placebo. The primary efficacy endpoint is the prevention of microbiologically confirmed TB. Secondary endpoints will include (1) prevention against Latent TB infection, (2) incidence of adverse events and serious adverse events in study participants, (3) efficacy of vaccine in prevention of PTB/extra PTB in different age groups (6–18 years, 19–35 years, 36–60 years and above 60 years) and (4) immunogenicity of VPM1002 and MIP at month 2 and month 6 after first vaccination in terms of flow cytometric analysis of M.Tb specific CD4+ and CD8+ T cells secreting cytokines and Luminex assays for the presence of different cytokines in the sera and supernatants of peripheral blood mononuclear cells cultures stimulated with whole cell lysates of M.Tb and subsequently similar analysis for the cases who develop TB postvaccination during the follow-up period.Ethics and dissemination Ethics committees’ approvals have been granted by the Institutional Human Ethics Committees of all participating centres in this study and the names of the ethics committees and approvals are as follows: (1) National Institute for Research in Tuberculosis (NIRT)-Chennai (including subsites): ECR/135/Inst/TN/2013/RR-19, Approval No. 390/NIRT-Institutional Ethics Committee (IEC)/2018 dated 5 December 2018 (NIRT-Madurai-ECR/1365/Inst/TN/2020; approval dated 8 June 2020; NIRT, Vellore: ECR/1215/Inst/TN/2019; approval dated 26 September 2020); (2) All India Institute of Medical Sciences (AIIMS), Delhi (including subsites)-Institute Ethics Committee, ECR/547/Inst/DL/2014/RR-17 ECR/538/Inst/DL/2014/RR-20; approval No.IEC-385/06-07-2018, approval OP-28/05.04.2019 and SFH- ECR/593/Inst/DL/2014/RR-20 IEC/VMMC/SJH/project/2019-05/25 ; 23 May 2019; (3) National Institute of Tuberculosis and Respiratory Diseases (NITRD), Delhi: ECR/315/Inst/DL/2013/RR-19; approval IEC-No-NITRD/EC/2019/9004; 8 January 2019; (4) Pune-National AIDS Research Institute (NARI) and subsite-ECR/23/Inst/MH/2013/RR-19; IEC-NARI/EC/approval/2018/196; 29 May 2018; (5) Regional Medical Research Centre-Bhubaneshwar-ECR/911/Inst/OR-2017/RR-21; approval, dated 25 April 2018; Subsites- AIIMS, Bhubaneshwar ECR/534/Inst/OD/2014/RR-17 and 20 approval No. T/EMF/Pulm. Med/19/01 dated 13 May 2019; SCB, Cuttack No. No.ECR/84/Inst/OR/2013/RR-20; approval no.186 dated 7 February 2020; (6) NTI-Bengaluru: Ethics Committee-No-ECR/1819/Inst/KA/2019; approval No NTI-IEC/1.2019/principal investigator, dated 31 January 2019; (7) BMMRC, Hyderabad- ECR/450/Inst/AP/2013/RR-16 approval No. 779/BMMRC/2018/IEC, dated 11 June 2018 (Subsite Share India- Mediciti Ethics Committee-ECR/283/Inst/AP/2013/RR-20; Approval no. EC/11/VII/2K20(1) dated 11 July 2020) and (8) SJMC-Bengaluru: ECR/238/Inst/KA/2013/RR-19; approval IEC/1/491/2020; 7 August 2020.The trial findings will be published in accordance with the Consolidated Standards of Reporting Trials guidance. The results of this clinical trial will be presented at scientific conferences and disseminated through publications in peer-reviewed journals, conference presentations and shared with Ministry of Health and Family Welfare, policy-makers and other stakeholders.Trial registration number CTRI/2019/01/017026.

Keerthana Raghu,1,&ast; Tamilselvi S,2,&ast; Chitralekha S Devishamani,1 Suchetha M,2 Ramachandran Rajalakshmi,3 Rajiv Raman1 1Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India; 2Centre for Health Care Advancement, Innovation, and Research Department, Vellore Institute of Technology, Chennai, Tamil Nadu, India; 3Department of Diabetology, Ophthalmology and Epidemiology, Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, Chennai, Tamil Nadu, India&ast;These authors contributed equally to this workCorrespondence: Rajiv Raman, Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Sankara Nethralaya (Main Campus), No. 41 (Old 18), College Road, Chennai, Tamil Nadu, 600006, India, Tel +91-444288708, Fax +91-44-28254180, Email rajivpgraman@gmail.comPurpose: To evaluate the ability of an artificial intelligence (AI) model, ChatGPT, in predicting the diabetic retinopathy (DR) risk.Methods: This retrospective observational study utilized an anonymized dataset of 111 patients with diabetes who underwent a comprehensive eye examination along with clinical and biochemical assessments. Clinical and biochemical data along with and without central subfield thickness (CST) values of the macula from OCT were uploaded to ChatGPT-4, and the response from the ChatGPT was compared to the clinical DR diagnosis made by an ophthalmologist.Results: The study assessed the consistency of responses provided by ChatGPT, yielding an Intraclass Correlation Coefficient (ICC) value of 0.936 (95% CI, 0.913– 0.954, p < 0.001) (with CST) and 0.915 (95% CI, 0.706– 0.846, p < 0.001) (without CST), both situations indicated excellent reliability. The sensitivity and specificity of ChatGPT in predicting the DR cases were evaluated. The results revealed a sensitivity of 67% with CST and 73% without CST. The specificity was 68% with CST and 54% without CST. However, Cohen’s kappa revealed only a fair agreement between ChatGPT predictions and clinical DR status in both situations, with CST (kappa = 0.263, p = 0.005) and without CST (kappa = 0.351, p < 0.001).Conclusion: This study suggests that ChatGPT has the potential of a preliminary DR screening tool with further optimization needed for clinical use.Keywords: ChatGPT, artificial intelligence, diabetic retinopathy, diabetes

Ramyaa Srinivasan,&ast; Krishnakanta Roy,&ast; Meenakshi Mahesh, Janani Surya, Rajiv Raman Shri Bhagwan Mahavir Vitreoretinal Services, Vision Research Foundation – Sankara Nethralaya, Chennai, Tamil Nadu, India&ast;These authors contributed equally to this workCorrespondence: Rajiv Raman, Shri Bhagwan Mahavir Vitreoretinal Services, Vision Research Foundation – Sankara Nethralaya, Sankara Nethralaya (Main Campus), No. 41 (Old 18), College Road, Chennai, Tamil Nadu, 600006, India, Tel +91 9444288708, Fax +91-44-28254180, Email rajivpgraman@gmail.comPurpose: To determine the functional and anatomical outcomes of patients with endophthalmitis with concurrent or delayed onset retinal detachment (RD), and compare the preoperative, intraoperative and postoperative features.Patients and Methods: This was a retrospective review of 121 eyes in 121 patients presenting with endophthalmitis and RD. Subjects were categorized into two groups: endophthalmitis with delayed onset RD (group 1, N=76) and endophthalmitis with concurrent RD (group 2, N=45).Results: The mean age of patients in groups 1 and 2 was 38.21± 21.60 and 46.78± 24.42 years, respectively (P=0.047). Exogenous endophthalmitis was common in both groups 1 and 2 (86.84% and 84.44%, respectively). No significant differences were found between the groups in the type of RD, retinal breaks, number of quadrants involved or proliferative vitreoretinopathy grade. In the overall cohort, visual acuity improved post-surgery in one-third of the patients who were in the near or total blindness category at presentation. We found good anatomical success rates of an attached retina in both groups 1 and 2 (84.3% and 77.7%, P=0.376).Conclusion: Our study presents the results of patients with endophthalmitis and delayed onset RD or concurrent RD. It shows a few differences in presentation between the groups, but the anatomical and functional outcomes were almost the same.Keywords: endophthalmitis, delayed onset retinal detachment, concurrent retinal detachment, functional outcomes and anatomical outcomes

Keerthana Raghu,1,&ast; Tamilselvi S,2,&ast; Chitralekha S Devishamani,1 Suchetha M,2 Ramachandran Rajalakshmi,3 Rajiv Raman1 1Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India; 2Centre for Health Care Advancement, Innovation, and Research Department, Vellore Institute of Technology, Chennai, Tamil Nadu, India; 3Department of Diabetology, Ophthalmology and Epidemiology, Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, Chennai, Tamil Nadu, India&ast;These authors contributed equally to this workCorrespondence: Rajiv Raman, Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India, Email rajivpgraman@gmail.com

Rajiv Raman,1 Kim Ramasamy,2 Utkarsh Shah3 1Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India; 2Aravind Eye Hospital, Madurai, Tamil Nadu, India; 3Novartis Healthcare Private Limited, Mumbai, IndiaCorrespondence: Rajiv Raman, Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India, Tel +91-9444288708, Email rajivpgraman@gmail.comAbstract: Diabetic retinopathy (DR) is considered one of the leading causes of vision loss globally. It principally causes upregulation of pro-angiogenic, proinflammatory, and vascular permeability factors such as vascular endothelial growth factor (VEGF), leading to neovascularisation. The advanced stage of DR or proliferative diabetic retinopathy (PDR) is of more concern, as it leads to vitreous haemorrhage and traction retinal detachment. Various risk factors associated with PDR include hyperglycemia, hypertension, neuropathy, dyslipidemia, anaemia, nephropathy, and retinal complications of drugs used for diabetes. Current management approaches for PDR have been stratified and involve pan-retinal photocoagulation, vitrectomy, and anti-VEGF agents. Given the emerging role of anti-VEGF agents as a favourable adjunct or alternative therapy, they have a critical role in the management of PDR. The review emphasises current management approaches for PDR focusing on anti-VEGF therapy. The review also highlights the risk/benefit evaluation of the various approaches employed for PDR management in various clinical scenarios.Keywords: neovascularisation, diabetic retinopathy, pan-retinal photocoagulation, vitrectomy, anti-VEGF, PDR in India

Janarthanam Jothi Balaji,1 Rajiv Raman,2 Vasudevan Lakshminarayanan3 1Department of Optometry, Medical Research Foundation, Chennai, Tamil Nadu, 600006, India; 2Shri Bhagwan Mahavir Vitreoretinal Services, Medical Research Foundation, Chennai, Tamil Nadu, 600006, India; 3Theoretical and Experimental Epistemology Lab, School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, CanadaCorrespondence: Janarthanam Jothi Balaji, Department of Optometry, Medical Research Foundation, 18, College Road, Nungambakkam, Chennai, Tamil Nadu, 600006, India, Tel +91 44-42271500, Email jothibalaji@gmail.comBackground: Posterior vitreous detachment (PVD) can result in serious pathologic events at the vitreoretinal interface. This study aims to assess the relationship between PVD, macular thickness (MT), and the foveal avascular zone (FAZ) in myopic eyes.Methods: This retrospective study evaluated 63 myopic subjects’ data who were examined between January 1 and June 30, 2019. The myopes were grouped on a severity scale, namely mild, moderate, high, and very high using their spherical equivalent (SE). The PVD classification was based on OCT images. The status of the PVD and MT were evaluated with the Macular Cube 200× 200 images, the FAZ with an OCTA Angioplex, and the dimensions were calculated using a customized algorithm.Results: The study population (114 eyes) had a median (range) age was 26.00 (22.00– 28.00) years and the females constituted 62.3% of the dataset. In this population, 10 eyes had no PVD in any quadrant, and 73 eyes had incomplete PVD in all four quadrants. The inferior quadrant had the maximum rate of PVD occurrences and the nasal quadrant had the least number of occurrences. High myopic eyes exhibited significantly increased low foveal volume (p = < 0.01). The inferior part of the para- and perimacular area showed a significant thinning in very high myopic eyes (p = < 0.050). The very high myopic eyes showed a significant alteration of FAZ’s circularity index (p = 0.002).Conclusion: In high and very high myopic eyes, an increasing trend of partial PVD is seen, most commonly in the inferior quadrant. A significant alteration in foveal volume and circularity index of the FAZ is seen in high and very high myopic eyes.Keywords: posterior vitreous detachment, foveal avascular zone, OCT, macular thickness, myopia

Recurrent Tuberculosis patients contribute to a significant proportion of TB burden in India. A nationwide survey was conducted during 2019-2021 across India among adults to estimate the prevalence of TB. A total of 322480 individuals were screened and 1402 were having TB. Of this, 381 (27.1%) had recurrent TB. The crude prevalence (95% CI) of recurrent TB was 118 (107-131) per 100,000 population. The median duration between episodes of TB was 24 months. The proportion of drug resistant TB was 11.3% and 3.6% in the recurrent group and new TB patients respectively. Higher prevalence of recurrent TB was observed in elderly, males, malnourished, known diabetics, smokers, and alcohol users. (p

Background: Earlier serosurveys in India revealed seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) of 0.73% in May–June 2020 and 7.1% in August–September 2020. A third serosurvey was conducted between December 2020 and January 2021 to estimate the seroprevalence of SARS-CoV-2 infection among the general population and healthcare workers (HCWs) in India. Methods: The third serosurvey was conducted in the same 70 districts as the first and second serosurveys. For each district, at least 400 individuals aged ≥10 years from the general population and 100 HCWs from subdistrict-level health facilities were enrolled. Serum samples from the general population were tested for the presence of immunoglobulin G (IgG) antibodies against the nucleocapsid (N) and spike (S1-RBD) proteins of SARS-CoV-2, whereas serum samples from HCWs were tested for anti-S1-RBD. Weighted seroprevalence adjusted for assay characteristics was estimated. Results: Of the 28,598 serum samples from the general population, 4585 (16%) had IgG antibodies against the N protein, 6647 (23.2%) had IgG antibodies against the S1-RBD protein, and 7436 (26%) had IgG antibodies against either the N protein or the S1-RBD protein. Weighted and assay-characteristic-adjusted seroprevalence against either of the antibodies was 24.1% [95% confidence interval (CI) 23.0–25.3%]. Among 7385 HCWs, the seroprevalence of anti-S1-RBD IgG antibodies was 25.6% (95% CI 23.5–27.8%). Conclusions: Nearly one in four individuals aged ≥10 years from the general population as well as HCWs in India had been exposed to SARS-CoV-2 by December 2020.

SARS-CoV-2 vaccines are needed to fight the pandemic. Here, authors show protective efficacy and immunogenicity of the inactivated SARS-CoV-2 vaccine BBV152 in rhesus macaques. This vaccine is currently in clinical development.

BackgroundMany cognitively unimpaired older adults are interested in learning their Alzheimer's disease (AD) biomarker status, but little is known about motivations to undergo biomarker testing and result disclosure in the setting of preclinical AD trials.ObjectivesExamine whether motivations to undergo AD biomarker testing and disclosure differ for individuals who have elevated amyloid compared to those with not elevated amyloid, and whether disclosure of amyloid results impacts participants' motivations.Design, setting, participantsWe conducted post-hoc analyses using data from the EARLY study, a preclinical AD trial of the beta-secretase inhibitor atabecestat. As part of the screening process of the trial, participants underwent biomarker testing and disclosure. We analyzed data from n=2241 participants.MeasurementsWe analyzed data from the Views and Perceptions of Amyloid Imaging (VPAI), a 9-item questionnaire assessing how strongly participants agreed with motivating factors for undergoing amyloid testing. The VPAI was administered at the first screening visit and again after amyloid disclosure.ResultsPrior to amyloid disclosure, a greater proportion of participants in the elevated amyloid group responded at the two highest levels of endorsement for the items, "to confirm the feeling that I might already be developing symptoms of AD dementia" (p

Prema K Chande,1 Rajiv Raman,2 Preethi John,3 Sangeetha Srinivasan4 1Chitkara School of Health Sciences and Lotus College of Optometry, Mumbai, India; 2Sankara Nethralaya, Medical Research Foundation, Chennai, India; 3Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, India; 4Vision Research Foundation, Chennai, IndiaCorrespondence: Prema K ChandeLotus College of Optometry, 13th North South Road, Vithal Nagar, Juhu, Mumbai, Maharashtra 400049, India, Tel +91-98-2016-4222Email prema@lcoo.edu.inPurpose: The purpose of this study was to assess contrast sensitivity and macular function test in prediabetes.Methods: Participants aged 25– 45 years with or without diabetes were enrolled and classified as normal, prediabetic, and diabetic based on their HbA1C values. They underwent a comprehensive eye examination, and those with diabetic retinopathy, cataract, glaucoma, and high myopia were excluded. Participants with best-corrected visual acuity of 0 logMAR were included. Contrast-sensitivity function (CSF) was measured using a Pelli–Robson chart, and photo stress–recovery time (PSRT) assessed using direct ophthalmoscopy for the 70 eligible participants. Mean values were compared among the three groups.Design: This was a cross-sectional observational study.Results: In the 70 participants, mean CSF was 1.71± 0.10, 1.64± 0.11, and 1.61± 0.08 log units in the normal, prediabetic, and diabetic groups, respectively (p< 0.001). Similarly, PSRT was found to be 35.80 seconds, 41.63 seconds, and 47.77 seconds in the normal, prediabetic, and diabetic groups, respectively (p< 0.001).Conclusion: The data suggested that reduced CSF and delayed PSRT seen in subjects with prediabetes could give valuable clinical insight into early changes before diabetes and microvascular damage is incurred. A future study with a larger sample could help substantiate the results.Keywords: contrast-sensitivity function, prediabetes, diabetes, HbA1C, photo stress–recovery test

A good point-of-care diagnostic test holds a promise to reduce inappropriate use of antibiotics by enabling early detection of the pathogen and facilitating rapid testing of antimicrobial susceptibility. India has taken many initiatives in the recent past to augment the development and deployment of diagnostics in Indian health care system. Funding opportunities to promote innovation in diagnostics development were started in early 2000s through various ministries and departments. India released National Essential Diagnostics List which enlists essential tests and there is now Free Diagnostics Service Initiative of Government of India under National Health Mission that mandates to provide all essential tests free of cost. We wanted to understand how these initiatives have impacted the diagnostics that could be of use in containment of antimicrobial resistance (AMR) and whether there is a smooth process for bringing indigenously developed products relevant to AMR into the healthcare system. We conducted a longitudinal survey (January 2019 and January 2021) to understand the availability of market ready indigenous rapid diagnostics for AMR in the country and their progress towards introduction in the private market or uptake in healthcare system. We found that many innovators and developers are working towards development of rapid tests that can be useful in the containment of AMR in India. While there are many promising diagnostics on the horizon, the pathway for uptake of indigenously developed diagnostics in healthcare system remains disjointed and needs to be harmonised for the investments made towards development to translate as tangible gains. Since most of these efforts are government funded, it is incumbent upon the government to also provide a seamless pathway to make these diagnostics available in health care system. In absence of this guidance, most of these diagnostics will sit with the innovators/developers and will never be used for the purpose they were intended to serve.

A Migliore,1 G Gigliucci,1 RJ Petrella,2 RR Bannuru,3 X Chevalier,4 E Maheu,5 R Raman,6 G Herrero-Beaumont,7 N Isailovic,8 M Matucci Cerinc9 1Rheumatology Unit, San Pietro Fatebenefratelli Hospital, Rome, Italy; 2Department of Family Medicine, School of Kinesiology Western University, Western Centre for Public Health & Family, London, Ontario, Canada; 3Center for Treatment Comparison and Integrative Analysis Division of Rheumatology, Tufts Medical Center, Boston, MA, USA; 4Department of Rheumatology, Hôpital Henri Mondor, Creteil, France; 5Rheumatology Department, AP-HP, Saint-Antoine Hospital, Paris, France; 6Academic Department of Orthopaedics, Hull and East Yorkshire NHS Trust, Castle Hill Hospital, Cottingham, UK; 7Joint and Bone Research Unit, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain; 8Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy; 9Division of Rheumatology AOUC, Department of Experimental and Clinical Medicine, University of Florence, Florence, ItalyCorrespondence: N IsailovicDivision of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Milan, ItalyTel +39-02-8224-5118Email natasa.isailovic@humanitasresearch.itAbstract: Osteoarthritis (OA) is a rheumatic disease that affects the well-being of the patient, compromises physical and mental function, and affects other quality of life aspects. In the literature, several evidence-based guidelines and recommendations for the management of knee osteoarthritis (KOA) are available. These recommendations list the different therapeutic options rather than addressing a hierarchy between the treatments and defining the real target. Therefore, a question arises: are patients and physicians satisfied with the current management of KOA? Actually, the answer may be negative, thus suggesting a change in our therapeutic strategies. In this article, we address this challenge by suggesting that it is time to develop a “treat to target strategy” for KOA.Keywords: osteoarthritis, knee osteoarthritis, treat to target

We conducted a serosurvey of 155 healthcare workers and 124 household and community members who had close contact with 18 patients who had laboratory-confirmed Nipah virus infections in Kerala, India. We detected 3 subclinical infections; 2 persons had IgM and IgG and 1 only IgM against Nipah virus.

We retrieved Nipah virus (NiV) sequences from 4 human and 3 fruit bat (Pteropus medius) samples from a 2018 outbreak in Kerala, India. Phylogenetic analysis demonstrated that NiV from humans was 96.15% similar to a Bangladesh strain but 99.7%–100% similar to virus from Pteropus spp. bats, indicating bats were the source of the outbreak.

BackgroundThirty-four CCHF cases (17 fatal; 17 survived) were confirmed from Gujarat state, India during the year 2019. We aimed to find out the viral load, antibody kinetics, cytokine profile and phylogenetic analysis between fatal and non- fatal cases.MethodsThirty four cases were included in this study. Blood and urine samples were collected from all the cases on the day of admission to hospital. Non-fatal cases were followed weekly for understanding the profile of viral kinetics, anti-CCHFV IgM and IgG antibodies. We also quantified the cytokines in both fatal and non-fatal cases. For epidemiological correlation, livestock were screened for anti-CCHF IgG antibodies and the tick pool specimens were tested by real time RT-PCR. Virus isolation was attempted on tick pools and human specimens and phylogenetic analysis performed on human and ticks complete genome sequences.ResultsCCHF cases were detected throughout year in 2019 with the peak in August. Out of 34 cases, eight secondary CCHF cases were reported. Cases were predominantly detected in males and in 19-45 years age group (55.88%). The persistence of viremia was observed till 76th POD (post onset date) in one case whereas anti-CCHFV IgM and IgG was detected amongst these cases from the 2nd and 20th POD respectively. Positivity observed amongst livestock and tick pools were was 21.57% and 7.4% respectively. The cytokine analysis revealed a significant increase in the level of serum IL-6, IL-10 and IFN-γ during the acute phase of the infection, but interestingly IL-10 lowered to normal upon clearance of the virus in the clinically recovered case. Fatal cases had high viral RNA copy numbers. Bleeding from one or two mucosal sites was significantly associated with fatality (OR-16.47;p-0.0034 at 95% CI). We could do CCHF virus isolation from two cases. Phylogenetic analysis revealed circulation of re-assortment of Asian-West African genotypes in humans and ticks.ConclusionsThe persistence of CCHF viral RNA was detected till 76th POD in one of the survivors. The circulation of a re-assortment Asian-West African genotype in a CCHF case is also reported first time from India.

Background: Early detection of symptoms of loss of smell and taste lately added for Coronavirus disease 2019 (COVID-19) has the potential for improving pandemic response. In the Indian context, we compared proportion experiencing new loss of smell or taste among COVID-19 positive and negative individuals in Chennai city, Southern India. Methods: We did an analytical cross-sectional study among individuals aged 18–80 years undergoing testing at COVID-19 sample collection centres. We ascertained loss of smell and taste using standardised self-reporting and clinical examination procedures. We administered Sino Nasal Outcome (SNOT 22) questionnaire for comprehensive understanding of these symptoms. We compared proportion having symptoms between COVID-19 positive and negative persons. We compared the two assessment methods to compute diagnostic validity indicators. Results: Of the 277 participants, 169 (61%) were men and mean age of 40.7 years [SD = 13.3]. Fifty eight (21%) had COVID-19 and 12 (36%) of them were asymptomatic. Predominantly reported symptoms were fever (30%), headache (18%) and cough (18%). Self-reported or clinically identified new loss of smell or taste was higher among COVID-19 positive (n = 13; 22%) than negative persons (n = 23; 11%) [p = 0.02]. Sensitivity was higher for self-reported or clinically identified loss of smell (17.2%) than that of loss of taste (6.9%). Negative predictive value for loss of smell or taste, self-reported or clinically identified was 81%. Likelihood ratio of positive test was 2.13. Conclusion: Loss of smell or taste are predominantly reported by COVID-19 confirmed individuals. Objective and subjective assessments of smell and taste may be required to identify those requiring COVID-19 testing.

Due to the COVID-19 pandemic, most graduate medical education (GME) training programs conducted virtual interviews for prospective trainees during the 2020–2021 application cycle. Many internal medicine (IM) subspecialty fellowship programs hosted virtual interviews for the first time with little published data to guide best practices. To evaluate how IM subspecialty fellowship applicants perceived the virtual interview day experience. We designed a 38-item questionnaire that was sent via email to applicants in eight IM subspecialty programs at a single tertiary academic medical center (University of California, San Francisco) from September–November, 2020. Seventy-five applicants completed the survey (75/244, 30.7%), including applicants from all eight fellowship programs. Most survey respondents agreed that the length of the virtual interview day (mean = 6.4 hours) was long enough to gather the information they needed (n = 65, 86.7%) and short enough to prevent fatigue (n = 55, 73.3%). Almost all survey respondents agreed that they could adequately assess the clinical experience (n = 71, 97.3%), research opportunities (n = 72, 98.6%), and program culture (n = 68, 93.2%). Of the respondents who attended a virtual educational conference, most agreed it helped to provide a sense of the program’s educational culture (n = 20, 66.7%). Areas for improvement were identified, with some survey respondents reporting that the virtual interview day was too long (n = 11) or that they would have preferred to meet more fellows (n = 10). Survey respondents indicated that the virtual interview was an adequate format to learn about fellowship programs. These findings can inform future virtual interviews for GME training programs.

Background: High-quality data are of prime importance in any health survey because survey data are considered as a gold standard for nationally representative data. The quality of data collection largely depends on the design of the questionnaire, training, and skills of the interviewer. Objectives: In the present study, we tried to evaluate three key components, such as questionnaire design, human resource and training of the field staff for Integrated Biological and Behavioural Surveillance carried out among the HIV high-risk subpopulation. Methods: A mixed-methods approach was used. Qualitative and quantitative data collection was carried out in the year 2015 with cross-sectional survey design in western states of India. The in-depth interviews of 10 stakeholders, structured interviews of the survey respondents (n = 560), and field investigators (n = 71) were conducted. Data triangulation was used to find out the concurrence of the qualitative and quantitative data. Results: Comprehensive and standardized survey questionnaire, structured training agenda, and strategic preparation for recruiting human resources were the overall strengths of the survey. However, during the implementation of the survey, there were some difficulties reported in data collection process. Overall, the respondents and investigators felt that the questionnaire was long and exhaustive. Difficulties were faced while collecting data on sexual history. The field staffs were not adequately experienced to work with sensitive population. Conclusions: In order to have accurate, reliable data, especially on sexual behavior; emphasis should be given on simple questionnaire with the use of community-friendly language, skilled and experienced interviewers for data collection, and extensive field training.

In September 2018, an epizootic infection caused by canine distemper virus emerged in an Asiatic lion population in India. We detected the virus in samples from 68 lions and 6 leopards by reverse transcription PCR. Whole-genome sequencing analysis demonstrated the virus strain is similar to the proposed India-1/Asia-5 strain.

Objective: The objective of this review was to assess the burden of HIV drug resistance mutations (DRM) in Indian adults exposed to first-line antiretroviral therapy (ART) as per national guidelines. Methods: An advanced search of the published literature on HIV drug resistance in India was performed in the PubMed and Scopus databases. Data pertaining to age, sex, CD4 count, viral load, and prevalence of nucleoside reverse transcriptase inhibitor (NRTI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) DRM were extracted from each publication. Year-wise Indian HIV-1 reverse transcriptase (RT) sequences were retrieved from the Los Alamos HIV database and mutation analyses were performed. A time trend analysis of the proportion of sequences showing NRTI resistance mutations among individuals exposed to first-line ART was conducted. Results: Overall, 23 studies (1046 unique RT sequences) were identified indicating a prevalence of drug resistance to NRTI and NNRTI. The proportion of RT sequences with any DRM, any NRTI DRM, and any NNRTI DRM was 78.39%, 68.83%, and 73.13%, respectively. The temporal trend analysis of individual DRM from sequences retrieved during 2004–2014 indicated a rising trend in K65R mutations (p = 0.013). Conclusions: Although the overall burden of resistance against first-line ART agents remained steady over the study decade, periodic monitoring is essential. There is the need to develop an HIV-1 subtype C-specific resistance database in India.

BACKGROUND: Converging evidence suggests that markers of Alzheimers disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimers disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p

The free antiretroviral therapy (ART) program in India still relies on the clinico-immunological monitoring for diagnosis of treatment failure. As the nucleoside reverse transcriptase inhibitor (NRTI) backbone is shared in first- and second-line regimens, accumulation of drug resistant mutations (DRMs) can compromise the efficacy of NRTI. This study was undertaken to describe the pattern of HIV DRMs following immunological monitoring and investigate its impact on the cycling of NRTI between first- and second-line ART.This cross-sectional study was performed at a state-sponsored ART clinic of Pune city in western India between January and June 2016. Consecutive adults receiving first-line ART with immunological failure (IF) were recruited for plasma viral load (PVL) estimation. Randomly selected 80 participants with PVL >1000 copies/mL underwent HIV drug resistance genotyping. Of these, 75 plasma sample were successfully genotyped. The median CD4 count and duration of ART at the time of failure were 98 (IQR: 61.60-153.50) cells/μL and 4.62 (IQR: 3.17-6.15) years, respectively. The prevalence of NRTI, non-NRTI, and major protease inhibitor resistance mutations were 89.30%, 96%, and 1.33%, respectively. Following first-line failure, sequences from 56.67% of individuals indicated low- to high-level resistance to all available NRTI. The proportion of sequences with ≥2 thymidine analogue mutations (TAMs) and ≥3 TAMs were 62.12% and 39.39%, respectively. An average of 1.98 TAMs per sequence were observed following IF as compared to 0.37 TAMs per sequence following targeted PVL monitoring at 12 months of ART from a prior study; this difference was significant (p

Aditi Gupta, Rajiv Raman, Tarun SharmaShri Bhagwan Mahavir Department of Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, IndiaWe read with great interest the recent article by Kashima et al,1 in which the authors report a case of asymmetric severity of diabetic retinopathy in Waardenburg syndrome. We want to highlight some concerns regarding this report. Previous reports have described many systemic and local factors associated with the development of asymmetric diabetic retinopathy.2,3 These include myopia ≥5 D, anisometropia >1 D, amblyopia, unilateral elevated intraocular pressure, complete posterior vitreous detachment, unilateral carotid artery stenosis, ocular ischemic syndrome, and chorioretinal scarring.2,3 In any suspected case of asymmetric diabetic retinopathy, it is prudent to rule out the abovementioned factors first. In the present case, although the authors clearly mention the absence of internal carotid and ophthalmic artery obstruction on magnetic resonance angiography, it would have been more informative if the authors had also provided the refractive error, intraocular pressure, and posterior vitreous detachment status of both the eyes.Likewise, it would have been useful to note the arm-retina time and retinal arteriovenous filling time in both the eyes on fundus fluorescein angiography, which is usually used to diagnose ocular ischemic syndrome by monitoring extension of the retinal circulation time, including time of blood circulation from the arm to the retina and the retinal arteriovenous filling time.4,5 The mere absence of internal carotid obstruction on magnetic resonance angiography cannot rule out the presence of ocular ischemic syndrome because, rarely, ocular ischemic syndrome can also occur secondary to other causes, such as arteritis.6,7 Comparing the arm-retina time and retinal arteriovenous filling time on fundus fluorescein angiography in both the eyes would be more helpful to rule out ocular ischemic syndrome.

The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.

The National Spherical Torus Experiment Upgrade (NSTX-U) will operate at axial toroidal fields of ≤ 1 T and plasma currents, Ip ≤ 2 MA. The development of non-inductive (NI) plasmas is a major long-term research goal for NSTX-U. Time dependent numerical simulations of 28 GHz electron cyclotron (EC) heating of low density NI start-up plasmas generated by Coaxial Helicity Injection (CHI) in NSTX-U predict a significant and rapid increase of the central electron temperature (Te(0)) before the plasma becomes overdense. The increased Te(0) will significantly reduce the Ip decay rate of CHI plasmas, allowing the coupling of fast wave heating and neutral beam injection. A megawatt-level, 28 GHz electron heating system is planned for heating NI start-up plasmas in NSTX-U. In addition to EC heating of CHI start-up discharges, this system will be used for electron Bernstein wave (EBW) plasma start-up, and eventually for EBW heating and current drive during the Ip flattop.

BackgroundThe COVID-19 pandemic created challenges in clinical research operations that required immediate and lasting changes.OjbectivesThe purpose of this study was to explore adaptations to clinical trial research due to COVID-19 and develop a theoretical framework of emergent strategies related to pandemic mitigation in a national network of Alzheimer's disease clinical trial sites.DesignThis qualitative study used a grounded theory approach including semi-structured interviews, constant comparative methods, and multi-level, iterative coding.ParticipantsTwenty-six member sites of the Alzheimer's Clinical Trial Consortium participated with a total of 49 participants.ResultsFindings demonstrate processes of adaptation following COVID-19 onset including establishing safety as priority, focus on scientific preservation, accommodations (creating policies, leadership mindset, maintaining operations, and determining research procedures), and evaluation of changes throughout the course of the pandemic. Communication and maintaining integrity were vital throughout these processes.ConclusionProcesses of accommodation among clinical research sites during the pandemic provide critical insights and direction for future clinical trials development and emergent methods in Alzheimer's disease and other therapeutic areas.

Due to the COVID-19 pandemic, most graduate medical education (GME) training programs conducted virtual interviews for prospective trainees during the 2020-2021 application cycle. Many internal medicine (IM) subspecialty fellowship programs hosted virtual interviews for the first time with little published data to guide best practices.To evaluate how IM subspecialty fellowship applicants perceived the virtual interview day experience.We designed a 38-item questionnaire that was sent via email to applicants in eight IM subspecialty programs at a single tertiary academic medical center (University of California, San Francisco) from September-November, 2020.Seventy-five applicants completed the survey (75/244, 30.7%), including applicants from all eight fellowship programs. Most survey respondents agreed that the length of the virtual interview day (mean = 6.4 hours) was long enough to gather the information they needed (n = 65, 86.7%) and short enough to prevent fatigue (n = 55, 73.3%). Almost all survey respondents agreed that they could adequately assess the clinical experience (n = 71, 97.3%), research opportunities (n = 72, 98.6%), and program culture (n = 68, 93.2%). Of the respondents who attended a virtual educational conference, most agreed it helped to provide a sense of the program's educational culture (n = 20, 66.7%). Areas for improvement were identified, with some survey respondents reporting that the virtual interview day was too long (n = 11) or that they would have preferred to meet more fellows (n = 10).Survey respondents indicated that the virtual interview was an adequate format to learn about fellowship programs. These findings can inform future virtual interviews for GME training programs.