Molecular epidemiology of anaplasmosis in Indian dromedary camels.

The present study aimed to investigate the molecular epidemiology, risk factors, and haemato-biochemical changes in anaplasmosis in Indian dromedary camels. Blood samples collected from 103 camels were analysed using blood smear examination and semi-nested PCR based on the 16s rRNA gene to diagnose anaplasmosis. The prevalence of anaplasmosis was estimated to be 42.72% (95% CI: 33.59-52.37) by PCR assay and 16.5% (95% CI: 10.47-24.95%) by blood smear examination. Phylogenetic analysis of six partial sequences of 16s rRNA gene obtained in the present study indicated the involvement of multiple Anaplasma species, including A. marginale and A. platys, showing genetic similarity with cattle strains. A novel genotype related to A. camelii/A. cinensis/A. platys group was also identified. Hemato-biochemical examination revealed mild anaemia, increased serum urea nitrogen and creatinine levels, and decreased total protein and albumin levels in Anaplasma-positive animals. The infections were largely subclinical in nature, except in one camel that revealed fever, inappetence, and pale mucous membrane and responded well to treatment with oxytetracycline. To our knowledge, this is the first molecular study on camel anaplasmosis in India, indicating a high prevalence of infection and involvement of multiple Anaplasma species with potential risk for interspecies transmission.

Toll like receptor 4 (TLR4) gene polymorphism and its association with somatic cell score and milk production traits in Indian dromedary camels.

Our study aimed to explore the genetic variation in the Toll-like receptor 4 (TLR4) gene and establish its association with somatic cell score (SCS) and milk production traits in four Indian camel breeds namely Bikaneri, Kachchhi, Jaisalmeri and Mewari. TLR4 gene fragment of 573 bp spanning 5' UTR, exon-1 and partial intron-1 region was amplified and genotyped using the PCR-sequence based typing method. Only one SNP located at position C472T was identified. Genotyping revealed two alleles (C and T) and three genotypes: CC, CT and TT. The genotype frequencies for CC, CT and TT were 0.116, 0.326 and 0.558 and allele frequencies for C and T alleles were 0.279 and 0.721, respectively. Association study inferred that the effect of genotype on SCS, lactation yield (LY) and peak yield (PY) was non-significant however heterozygote (CT) genotypes recorded lower SCS and higher LY and PY. It can be concluded that the TLR4 gene possesses limited genetic variation, depicting polymorphism at a single locus in Indian camel breeds with a predominance of the TT genotype. The association study indicated that heterozygote animals possess better udder health and production performance, the statistical significance of which needs to be established using a large data set.

VRT: A Video Restoration Transformer.

Video restoration aims to restore high-quality frames from low-quality frames. Different from single image restoration, video restoration generally requires to utilize temporal information from multiple adjacent but usually misaligned video frames. Existing deep methods generally tackle with this by exploiting a sliding window strategy or a recurrent architecture, which are restricted by frame-by-frame restoration. In this paper, we propose a Video Restoration Transformer (VRT) with parallel frame prediction ability. More specifically, VRT is composed of multiple scales, each of which consists of two kinds of modules: temporal reciprocal self attention (TRSA) and parallel warping. TRSA divides the video into small clips, on which reciprocal attention is applied for joint motion estimation, feature alignment and feature fusion, while self attention is used for feature extraction. To enable cross-clip interactions, the video sequence is shifted for every other layer. Besides, parallel warping is used to further fuse information from neighboring frames by parallel feature warping. Experimental results on five tasks, including video super-resolution, video deblurring, video denoising, video frame interpolation and space-time video super-resolution, demonstrate that VRT outperforms the state-of-the-art methods by large margins (up to 2.16dB) on fourteen benchmark datasets. The codes are available at https://github.com/JingyunLiang/VRT.

The first molecular characterization of Sarcocystis cameli in the Indian dromedary camels (Camelus dromedarius).

In the present study, tissue samples (tongue, esophagus and heart) were investigated from dromedary camels of India for identification and characterization of Sarcocystis spp. using histopathology, PCR and gene sequencing. Genomic DNA extracted from these tissue samples was used for PCR amplification of the cytochrome c oxidase subunit I gene (cox1) of Sarcocystis spp. and the partial sequence of small subunit ribosomal RNA (18S rRNA) gene of the S. cameli. The PCR products were purified, sequenced and analyzed using bioinformatics tools. Based on phylogenetic analysis of the cox1 gene, the sequences of the present study clustered with those of S. cameli, hosted by dromedary camels of Iraq and a close association was observed with S. masoni hosted by dogs and alpacas of China. Until now, there are no 18S rRNA sequences of S. cameli available in GenBank and this is the first study recording 18S rRNA sequences of S. cameli which were grouped with S. masoni from alpaca of China and guanaco and llama of Argentina in phylogenetic analysis. These findings could be useful for further studies on the characterization through molecular epidemiology, genetic diversity and host specificity of S. cameli.

Effect of Excess Fluoride Exposure on Radiographic and Histopathological Changes in Long Bones of Rabbit.

The present study aimed to investigate the effects of excess fluoride exposure on long bones in young rabbits (Oryctolagus cuniculus). New Zealand White rabbits (n = 30) were randomly divided into five equal groups and were provided drinking water containing 0, 50, 100, 200, and 400 µg added fluoride per ml ad lib for a period of 90 days. Blood samples were collected on days 0, 45, and 90 of the experiment, and femur samples were collected for fluoride estimation on day 90 after radiography of long bone before sacrifice. Study revealed significant increase in serum fluoride concentration following oral intake of excess fluoride. Alterations in activities of alkaline phosphatase, aspartate transaminase, alanine transaminase, and concentrations of creatinine and urea nitrogen in blood plasma were also recorded in animals receiving excess fluoride, though changes revealed inconsistent pattern. Radiographic changes in long bones in fluoride exposed rabbits included widening of metaphysis, thinning of cortical region, and a variety of osteopenic changes like osteoporosis and osteomalacia that were more prominent in animals receiving 200 ppm or more than 200 ppm fluoride in drinking water. Important changes in histomorphology of growth plate in long bones recorded in excess fluoride (> 100 ppm) exposed rabbits included irregular thickening of epiphyseal growth plate with haphazard orientation of chondrocytes forming nodular protrusion into metaphysis. Fluoride exposure induced both osteogenesis and osteoporosis to a degree varying with dose of fluoride exposure.

Molecular investigations of camelpox virus circulating in dromedary camel population in Rajasthan, India.

Camelpox is an important viral disease of dromedary camel in Rajasthan, India. In the present study, partial C18L gene sequences (n = 6) of camelpox virus (CMLV) obtained in an outbreak in Bikaner, Rajasthan, India in year 2022 were compared with other similar sequences obtained in the past in similar geographical location. Clinical and epidemiological features of the disease were also compared. Genomic study suggested variations in C18L gene sequences obtained in the present outbreak from those obtained during the past outbreaks. CMLV were genetically different from cowpox viruses, but appeared identical to CMLV causing disease in Israel, Egypt and Kazakhstan. Genomes of CMLV virus circulating in dromedary camel population of Rajasthan, India appeared diverse and changing, hence complete genome sequencing and identification of genomic changes altering infectivity and pathogenicity is warranted for designing control strategies.

Cryo-EM structure of antibacterial efflux transporter QacA from Staphylococcus aureus reveals a novel extracellular loop with allosteric role.

Efflux of antibacterial compounds is a major mechanism for developing antimicrobial resistance. In the Gram-positive pathogen Staphylococcus aureus, QacA, a 14 transmembrane helix containing major facilitator superfamily antiporter, mediates proton-coupled efflux of mono and divalent cationic antibacterial compounds. In this study, we report the cryo-EM structure of QacA, with a single mutation D411N that improves homogeneity and retains efflux activity against divalent cationic compounds like dequalinium and chlorhexidine. The structure of substrate-free QacA, complexed to two single-domain camelid antibodies, was elucidated to a resolution of 3.6 Å. The structure displays an outward-open conformation with an extracellular helical hairpin loop (EL7) between transmembrane helices 13 and 14, which is conserved in a subset of DHA2 transporters. Removal of the EL7 hairpin loop or disrupting the interface formed between EL7 and EL1 compromises efflux activity. Chimeric constructs of QacA with a helical hairpin and EL1 grafted from other DHA2 members, LfrA and SmvA, restore activity in the EL7 deleted QacA revealing the allosteric and vital role of EL7 hairpin in antibacterial efflux in QacA and related members.

Effect of persistent organic pollutants in patients with ischemic stroke and all stroke: A systematic review and meta-analysis.

The role of environmental contaminants and their association with stroke is still being determined. Association has been shown with air pollution, noise, and water pollution; however, the results are inconsistent across studies. A systematic review and meta-analysis of the effect of persistent organic pollutants (POP) in ischemic stroke patients were conducted; a comprehensive literature search was carried out until 30th June 2021 from different databases. The quality of all the articles which met our inclusion criteria was assessed using Newcastle-Ottawa scaling; five eligible studies were included in our systematic review. The most studied POP in ischemic stroke was polychlorinated biphenyls (PCBs), and they have shown a trend for association with ischemic stroke. The study also revealed that living near a source of POPs contamination constitutes a risk of exposure and an increased risk of ischemic stroke. Although our study provides a strong positive association of POPs with ischemic stroke, more extensive studies must be conducted to prove the association.

Role of PARP inhibitors beyond BRCA mutation and platinum sensitivity in epithelial ovarian cancer: a meta-analysis of hazard ratios from randomized clinical trials.

BACKGROUND: PARP inhibitors (PARPi) have a well-established role in platinum-sensitive ovarian cancer (PSOC), in BRCA mutant (BRCAm), and homologous recombination deficiency (HRD) population. However, their role in wild type and homologous recombination proficient population is still not clear. METHODS: A meta-analysis of hazard ratios (HR) of randomized control trials (RCTs) was conducted to study the role of PARPi. The published RCTs comparing the efficacy of PARP inhibitors alone or in combination with chemotherapy and/or target therapies versus placebo/chemotherapy alone/target therapy alone in primary or recurrent ovarian cancer settings were selected. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. RESULTS: A total of 14 primary studies and 5 updated studies are considered, consisting of 5363 patients. Overall, HR for PFS was 0.50 [95% CI 0.40-0.62]. HR of PFS was 0.94 [95% CI 0.76-1.15] in the PROC group, 0.41 [95% CI 0.29-0.60] was in HRD with BRCA unknown (BRCAuk), 0.38 [95% CI 0.26-0.57] in HRD with BRCAm, and 0.52 [95% CI 0.38-0.71] in HRD with BRCAwt. In the HRP group, overall HR for PFS was 0.67 [95% CI 0.56-0.80], 0.61 [95% CI 0.38-0.99] in HRD unknown with BRCA wt, and 0.40 [95% CI 0.29-0.55] in BRCAm HR for PFS. Overall, HR for OS was 0.86 [95% CI 0.73-1.031]. CONCLUSIONS: The results suggest that PARPi have a meaningful clinical benefit in PSOC, HRD, BRACm, and also in HRP and PROC; however, the evidence is not sufficient to recommend their routine use and further studies are needed to expand their role in the HRP and PROC groups.

Characterization of Polycyclic Aromatic Hydrocarbons (PAHs) associated with fine aerosols in ambient atmosphere of high-altitude urban environment in Sikkim Himalaya.

Polycyclic Aromatic Hydrocarbons (PAHs) compounds are ubiquitous in ambient air due to their persistence, carcinogenicity, and mutagenicity. Gangtok being one of the cleanest cities in India located in Eastern Himalayan region, witnesses high developmental activities with enhanced urbanization affecting the ambient air quality. The present study aims to measure PM2.5 and PAHs in the ambient atmosphere of the Sikkim Himalaya to understand the influence of natural and anthropogenic activities on aerosol loading and their chemical characteristics. The PM2.5 samples were collected and analysed for the duration from Jan 2020 to Feb 2021.The seasonal mean concentrations of PM2.5 and PAHs were observed to be high during autumn and low during summer season. Overall, the annual mean concentration of PM2.5 was found higher than the prescribed limit of World Health Organization and National Ambient Air Quality Standards. The concentration of the 16 individual PAHs were found to be highest during autumn season (55.26 ± 37.15 ng/m3). Among the different PAHs, the annual mean concentration of fluorene (3.29 ± 4.07 ng/m3) and naphthalene (1.15 ± 3.76 ng/m3) were found to be the highest and lowest, respectively. The Molecular Diagnostic Ratio (MDR) test reveals higher contribution from heavy traffic activities throughout the winter and autumn seasons. The other possible sources identified over the region are fossil fuel combustion, and biomass burning. The multivariate statistical analysis (Multifactor Principal Component Analysis) also indicates a strong association between PM2.5 /PAHs and meteorological variables across the region in different seasons. The precipitation and wind pattern during the study period suggests that major contribution of the PM2.5 and PAHs were from local sources, with minimal contribution from long-range transport. The findings are important for comprehending the trends of PAH accumulation over a high-altitude urban area, and for developing sustainable air quality control methods in the Himalayan region.

Antimicrobial Agents Based on Metal Complexes: Present Situation and Future Prospects.

The rise in antimicrobial resistance is a cause of serious concern since the ages. Therefore, a dire need to explore new antimicrobial entities that can combat against the increasing threat of antibiotic resistance is realized. Studies have shown that the activity of the strongest antibiotics has reduced drastically against many microbes such as microfungi and bacteria (Gram-positive and Gram-negative). A ray of hope, however, was witnessed in early 1940s with the development of new drug discovery and use of metal complexes as antibiotics. Many new metal-based drugs were developed from the metal complexes which are potentially active against a number of ailments such as cancer, malaria, and neurodegenerative diseases. Therefore, this review is an attempt to describe the present scenario and future development of metal complexes as antibiotics against wide array of microbes.

A prospective randomized comparison of simultaneous integrated boost with sequential boost intensity-modulated radiotherapy in locally advanced head and neck cancer.

Purpose: A comparison of simultaneous integrated boost (SIB) with sequential boost (SEQ) using intensity-modulated radiotherapy along with concurrent cisplatin in locally advanced head and neck cancer (HNC) was made with regard to their survival outcomes and toxicity profile. Materials and Methods: A total of 34 patients were enrolled between October 2016 and March 2019. They were randomized into two arms, SIB and SEQB. All patients were treated with 6 MV photon beam on Linear Accelerator with weekly concurrent cisplatin at 35 mg/m2. Overall survival (OS) and disease-free survival (DFS) were the primary end points and acute and late toxicities were the secondary end points. Results: The median follow-up period was 40.6 and 37.3 months for SIB and SEQB, respectively. At the end of 5 years, the median OS was 40.6 and 37.3 months (P = 0.947) and the median DFS was 35.1 and 37.3 months in the SIB and SEQB arms, respectively (P = 0.991). Complete response at 3 months was 64.7% and 76.5% and partial response was 23.5% and 17.6%, whereas progressive disease was 11.8% and 5.9% in SIB and SEQB arms, respectively. Acute dermatitis, mucositis, dysphagia, and salivary gland toxicities were higher in the SIB arm compared to the SEQB arm. Conclusion: SIB and SEQ arms were comparable in terms of OS and DFS. However, the acute toxicities were higher in the SIB arm, although the difference was not significant, compared to the SEQB arm.

Genomic approaches for improving grain zinc and iron content in wheat.

More than three billion people worldwide suffer from iron deficiency associated anemia and an equal number people suffer from zinc deficiency. These conditions are more prevalent in Sub-Saharan Africa and South Asia. In developing countries, children under the age of five with stunted growth and pregnant or lactating women were found to be at high risk of zinc and iron deficiencies. Biofortification, defined as breeding to develop varieties of staple food crops whose grain contains higher levels of micronutrients such as iron and zinc, are one of the most promising, cost-effective and sustainable ways to improve the health in resource-poor households, particularly in rural areas where families consume some part of what they grow. Biofortification through conventional breeding in wheat, particularly for grain zinc and iron, have made significant contributions, transferring important genes and quantitative trait loci (QTLs) from wild and related species into cultivated wheat. Nonetheless, the quantitative, genetically complex nature of iron and zinc levels in wheat grain limits progress through conventional breeding, making it difficult to attain genetic gain both for yield and grain mineral concentrations. Wheat biofortification can be achieved by enhancing mineral uptake, source-to-sink translocation of minerals and their deposition into grains, and the bioavailability of the minerals. A number of QTLs with major and minor effects for those traits have been detected in wheat; introducing the most effective into breeding lines will increase grain zinc and iron concentrations. New approaches to achieve this include marker assisted selection and genomic selection. Faster breeding approaches need to be combined to simultaneously increase grain mineral content and yield in wheat breeding lines.

Lymphadenectomy in ovarian cancers: a meta-analysis of hazard ratios from randomized clinical trials.

BACKGROUND: The debate surrounding systematic lymphadenectomy in the epithelial cancers of the ovary (EOC) was temporarily put to rest by the LION trial. However, there was a glaring disparity between the number of patients registered and the number of patients randomized suggesting inadvertent selection. A subsequent meta-analysis after this trial included all types of studies in the literature (randomized, non-randomized, case series, and, retrospective cohort), thus diluting the results. METHODS: We conducted a meta-analysis of hazard ratios of randomized controlled trials, to study the role of systematic para-aortic and pelvic lymph node dissection in the EOC. A detailed search of MEDLINE, Cochrane, and Embase databases was done to look for the published randomized controlled trials (RCT) comparing lymphadenectomy versus no lymphadenectomy in EOC. A meta-analysis of hazard ratios (HR) was performed for overall survival (OS) and progression-free survival (PFS) using fixed and random effect models. The quality of the RCTs was evaluated on Jadad's score, and the risk of bias was estimated by the Cochrane tool. RESULTS: A total of 1342 patients with EOC were included for quantitative analysis. On meta-analysis, HR for PFS was 0.9 (95% CI 0.79-1.04) favoring lymphadenectomy. HR for OS was 1 (95% CI 0.84-1.18) signifying no benefit of systematic lymphadenectomy. CONCLUSION: The results show a trend towards increased PFS which did not reach statistical significance nor translate into any meaningful benefit in OS. There is still a need for a greater number of well-conducted, suitably powered trials to convincingly answer this question.

Prognostic Role of Procalcitonin and C-reactive Protein in Surgical Neonates: A Single-Institution Experience.

Introduction Neonatal sepsis is a dynamic process where the rigorous evaluation of clinical signs along with appropriately selected biomarkers guides the diagnosis of sepsis. Procalcitonin (PCT) and C-reactive protein (CRP) are the two most commonly used diagnostic biomarkers used in sepsis. Sepsis remains the most important cause of mortality and morbidity in surgical neonates. A cross-sectional study was conducted to assess the prognostic predictability of PCT and CRP in neonatal surgical sepsis. Methods All the neonates admitted to the neonatal surgical intensive care unit between January 2019 and December 2020 with features of sepsis were included in the study. Blood cultures, CRP, and PCT on Day one (PCT1) and Day three (PCT3) of suspicion of sepsis were evaluated. The receiver operating characteristics curve was studied to estimate the probability of two markers to predict the mortality in neonatal sepsis. Results Of 102 surgical neonates, 63 neonates had early-onset sepsis while 23 (22.5%) neonates died and 30 neonates reported positive blood culture. There was a decline in the overall PCT trend from PCT1 and PCT3, while a significant PCT rise was noted for the non-survival group (p= 0.003). At cut-off of 5 mg/dl for CRP and 2.5 ng/dl for PCT1 and PCT3, the sensitivity (36.0%, 25.8%, 100%), specificity (84.1%, 83.3%, 97.5%), positive predictive value (52.2%, 73.9%, 91.3%), and negative predictive values (73.4%, 38.0%, 100%) were observed. Conclusion PCT on Day three of suspected sepsis has higher sensitivity, specificity, and accuracy for prognostication of surgical neonatal sepsis at the cut-off value of 2.5 ng/ml. The rising trend of PCT levels is indicative of a poor prognosis.

Case Report: Congenital tuberculosis in an aborted dromedary camel fetus.

Tuberculosis (TB) is a serious public health problem worldwide, especially in tropical developing countries. Nevertheless, reports on congenital TB in humans and animals are extremely rare. In this study, abortion was reported in an 8-year-old she-camel at the 9th month of gestation. The she-camel appeared healthy in clinical examination, had a good body condition score, normal appetite, and had no signs of respiratory disease and fever. The expelled placenta was dark red-colored, thickened, and edematous with multifocal to coalescing ecchymotic hemorrhages on the allantoic surface. The striking finding was multiple, white-yellow, solid nodular lesions in the fetal lung, the pleura, and the liver. On histopathology, typical granulomatous lesions were detected in the lung and the liver characterized by caseous necrosis surrounded by lymphocyte and macrophage infiltration and concentric layers of fibrosis. The Ziehl-Neelsen staining detected scarce acid-fast bacilli in lung and liver tissues. The DNA extracted from tubercular lesions from the lung and liver showed amplification of the IS6110 region of the Mycobacterium tuberculosis complex by PCR. The sequencing and phylogenetic analysis revealed a close association of these sequences with Mycobacterium tuberculosis. The she-camel was detected positive for a single intradermal tuberculin test performed 24 h after abortion. This is the first report on congenital TB caused by M. tuberculosis in a dromedary camel fetus with a possible vertical transmission.

Pneumatic spray delivery-based solid set canopy delivery system for oblique banded leaf roller and codling moth control in a high-density modern apple orchard.

BACKGROUND: Pneumatic spray delivery (PSD)-based solid set canopy delivery systems (SSCDS) have demonstrated comparable spray deposition and reduced off-target drift compared with axial-fan airblast sprayers in high-density apple orchards. An important next step is to quantify whether PSD-based SSCDS can provide effective pest management. This study evaluated the biological efficacy of this fixed spray system variant and compared it with that of an axial-fan airblast sprayer. Partial field trials were conducted in a commercial apple orchard (cv. Jazz) trained in tall spindle architecture. Insecticides were applied at a rate of 935 L ha-1 (100 gallons per acre) for both application systems. Twenty-four hours after spraying, leaves and fruits were collected to prepare the laboratory bioassays enabling evaluation of efficacy against obliquebanded leafroller (OBLR) and codling moth (CM). RESULTS: OBLR mortality for SSCDS, airblast sprayer and untreated control treatments after 24 h of larval exposure was 91%, 98% and 4%, respectively and increased to 98%, 100% and 19% after 48 h. First-instar CM leaf bioassay mortality was 100% for SSCDS and airblast sprayer treatment, and 13% for the untreated control at 24 h post exposure. Larval CM mortality on fruit was 100% for SSCDS and airblast sprayer treatments, and 33% on the untreated control. CONCLUSIONS: Insecticides applied using SSCDS and an airblast sprayer had comparable larval mortality in all three assays, significantly higher than the untreated controls. These results suggest that PSD-based SSCDS may provide a viable alternative to axial-fan airblast sprayers in high-density apple orchards. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Translation and reliability of the caregiver quality of life index-cancer (CQOLC) Scale in Hindi and it's association with the Kessler psychological distress scale (K10) for cancer caregivers at a tertiary radiotherapy centre in India.

BACKGROUND: With increasing incidence of cancer worldwide and increasing burden of treatment over the patients with cancer, the caregivers of those patients with cancer also suffer from psychological distress which ultimately affects their Quality of Life (QOL). This aspect is often overlooked which may ultimately lead to compromised patient care. PURPOSE: To translate the Caregiver Quality of Life Index-Cancer (CQOLC) Scale in Hindi and assess its association with Kesslers's psychological distress scale (K-10) for determining the quality of life (QoL) of caregivers of patients with cancer in India. METHODS: This is a single institute, hospital based cross sectional study performed from July 2020 to March 2021. Caregiver Quality of Life Index-Cancer (CQOLC) Scale, employing standard 'forward-backforward' translation procedure, the English-language version of the questionnaire was translated into Hindi-language by experts and administered to each caregiver. Cronbach's alpha was used for internal consistency. Kesslers's psychological distress scale (K-10) was analysed on interview basis. RESULTS: A total evaluated responders were 264. The hindi versions of the CQOLC was validated by cronbach's alpha method with internal consistency between 0.8 and 0.91. The majority of the caregivers were of the age group 31-40 yrs (42.05%). The male to female ratio was 6.54:1. CQOLC good score(0-45) was obtained in 27.27%, fair(46-90) in 55.30% and poor(91-140) in 17.42%. For K-10 distress scale very mild(10-19), mild(20-24), moderate(25-29) and severe(30-50) was observed in 47.73%, 11.74%, 11.74% and 28.79% respectively. A strong relation was found between the caregivers with poor CQOLC score and severe K-10 score(p<0.001). CONCLUSION: The Hindi version of CQOLC was accepted and its correlation with the point psychological distress predictor (K-10) scale was a valuable method to identify caregivers with poor QOL and severe distress levels.

Interim Analysis of Impact of Adding Low Dose Pulmonary Radiotherapy to Moderate COVID-19 Pneumonia Patients: IMpaCt-RT Study.

Background: Treatment for coronavirus disease 2019 (COVID-19) pneumonia remains largely supportive till date and multiple clinical trials took place within the short span of time to evaluate the role of investigational therapies. The anti-inflammatory effect of low dose whole lung radiation in treating pneumonia has been documented earlier. This clinical trial analyzed the effect of low dose radiation therapy (LDRT) in a moderately affected COVID-19 pneumonia patient cohort and has evaluated its effect in stopping the conversion of moderate disease into severe disease. Methods: Patients with moderate COVID-19 pneumonia as characterized by the Ministry of Health and Family Welfare (MOHFW), Government of India, were randomized (1:1) to low dose whole lung radiation versus no radiation. All treatment of patients was concurrently being given as per institutional protocol. Patients were followed up with clinical and laboratory parameters monitored on Days 1, 3, 7, and 14. Computed tomography scan (CT scan) of thorax was performed on Days 1 and 7. Patients were evaluated for conversion of moderate into severe disease as per National Early Warning Score-2 (NEWS-2 score) as the primary end point. The secondary endpoints included changes in ratio between peripheral capillary oxygen saturation and fraction of inspired oxygen (SpO2/FiO2), biochemical markers, 25-point CT severity score, and radiation induced acute pulmonary toxicities. Findings: At the interim analysis, there were seven patients in the radiation arm and six in the control. A whole lung LDRT improved the outcome of SpO2/FiO2 at Day 3; however it did not convert into a statistically significant improvement for the NEWS-2 score. The serum levels of LDH, CRP, Ferritin and D-dimer were significantly reduced on 14 days in the LDRT arm in comparison to the baseline value but were not significant between the two groups. Interpretation: LDRT seems to have the potential to prevent moderate COVID-19 pneumonia from a deteriorating to severe category. However, further randomized clinical trial with an adequate number of such patients is warranted to establish the definitive role of LDRT in the management of COVID-19 pneumonia. Funding: An intramural research project bearing code: I-27/621, was sanctioned from the All India Institute of Medical Sciences, Patna, India. Clinical Trial Registration: Clinical Trials Registry-India (CTRI/2021/06/033912, 25th May 2021) ctri.nic.in/Clinicaltrials/login.php.

Somatic mutations involving TSC 1 and TSC2 genes in two children with focal cortical dysplasia.

BACKGROUND: The role of PI3K/AKT/mTOR pathway hyperactivation in localized brain overgrowth is evolving. We describe two patients with focal cortical dysplasia (FCD) who demonstrated somatic mutations in TSC1 and TSC2 genes in the dysplastic brain tissue but not peripheral blood. METHODS: Paired whole-exome sequencing was performed on genomic DNA extracted from blood and excised brain tissue in two children with FCD who underwent excision of dysplastic tissue. RESULTS: Patient 1, a 14-year boy, had drug-resistant focal epilepsy with onset at 20 months. His brain MRI showed abnormalities suggestive of FCD in the left superior and middle frontal lobes. Patient 2 presented at the age of 10 years with pharmaco-resistant focal epilepsy (onset at six years). His MRI suggested FCD in the left insular lobe. Both patients underwent surgical excision of FCD, and excised tissues were pathologically confirmed to have type IIb FCD. For patient 1, a missense mutation (c.64C > T; p.Arg22Trp) was detected in the TSC1 gene in DNA of dysplastic brain tissue but not peripheral blood lymphocytes. Similarly, for patient 2, a frameshift mutation (c.4258_4261delCAGT; p.Ser1420GlyfsTer55) in the TSC2 gene was identified in the brain tissue but not blood. Both gene variants are likely pathogenic and cause mTOR pathway activation. CONCLUSION: Our report of TSC1/TSC2 somatic mutations in patients with non-syndromic FCD suggests that localized hyperactivation of the mTOR pathway can cause focal malformations during cortical development and presents pharmacological targets for precision therapy in FCD management.