Globally, COVID-19 vaccines have emerged as a boon, especially during the severe pandemic phases to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, ...saving millions of lives. However, mixed responses to vaccination with breakthrough challenges provided a rationale to explore the immune responses generated postvaccination, which plausibly alter the subsequent course of infection. In this regard, we comprehensively profiled the nasopharyngeal transcriptomic signature of double-dose-vaccinated individuals with breakthrough infections in comparison to unvaccinated infected persons. The vaccinated individuals demonstrated a gross downregulation of ribosomal proteins along with immune response genes and transcription/translational machinery that methodically modulated the entire innate immune landscape toward immune tolerance, a feature of innate immune memory. This coordinated response was orchestrated through 17 transcription factors captured as differentially expressed in the vaccination breakthroughs, including epigenetic modulators of
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and several immune response effectors, with
emerging as one of the important transcriptional regulators of the antiviral innate immune response. Deconvolution algorithm using bulk gene expression data revealed decreased T-cell populations with higher expression of memory B cells in the vaccination breakthroughs. Thus, vaccination might synergize the innate immune response with humoral and T-cell correlates of protection to more rapidly clear SARS-CoV-2 infections and reduce symptoms within a shorter span of time. An important feature invariably noted after secondary vaccination is downregulation of ribosomal proteins, which might plausibly be an important factor arising from epigenetic reprogramming leading to innate immune tolerance.
The development of multiple vaccines against SARS-CoV-2 infection is an unprecedented milestone achieved globally. Immunization of the mass population is a rigorous process for getting the pandemic under control, yet continuous challenges are being faced, one of them being breakthrough infections. This is the first study wherein the vaccination breakthrough cases of COVD-19 relative to unvaccinated infected individuals have been explored. In the context of vaccination, how do innate and adaptive immune responses correspond to SARS-CoV-2 infection? How do these responses culminate in a milder observable phenotype with shorter hospital stay in vaccination breakthrough cases compared with the unvaccinated? We identified a subdued transcriptional landscape in vaccination breakthroughs with decreased expression of a large set of immune and ribosomal proteins genes. We propose a module of innate immune memory, i.e., immune tolerance, which plausibly helps to explain the observed mild phenotype and fast recovery in vaccination breakthroughs.
Cerebrotendinous xanthomatosis is a rare and underreported lipid storage disorder caused by various mutations in the CYP27A1 gene. Here, we report a novel homozygous mutation in the CYP27A1 gene in ...an Indian family. A 30-year-old man presented with childhood cataracts in both eyes; recurrent, intractable watery diarrhea; progressive cognitive impairment; bilateral patellar and Achilles tendon xanthomas; and ataxic speech and gait. Out of five siblings, four had similar symptoms. Three of the patient’s siblings had the same novel mutation in the CYP27A1 gene on the chromosome 2 region with c.301delG (Pro102LeufsTer5 protein change), which was homozygous. To date, the variant status of this mutation has not been reported in the Human Gene Mutation Database, the Exome Aggregation Consortium, and 1000 Genomes Project. Despite the clinical confirmation of the diagnosis and molecular analysis, our patient’s symptoms did not improve with treatment for more than a year, because of delayed presentation with irreversible damage. Treatment with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reduce or reverse the progression of the disease; however, early diagnosis is key.
Introduction
There are limited data on family screening and genetic testing in pediatric cardiomyopathy from India. This study was conducted to describe the morphologic spectrum and identify ...potential familial and genetic causes of pediatric cardiomyopathies in this region.
Methods
From April 2018 to May 2020, all children from birth to 18 years of age with cardiomyopathy visiting a tertiary care hospital in North India were enrolled in this study. First-degree relatives of index patients were offered screening for cardiomyopathy; 260 clinically reported pathogenic/likely pathogenic variants in 17 genes were analyzed by a rapid genotyping method. Additionally, a subset of patients also underwent whole-exome sequencing.
Results
Of the 20 patients enrolled in this study (median age 42 months), 18 were clinically diagnosed with dilated cardiomyopathy. We observed a 44.4% mortality rate after a median follow-up of 15 months. 61.3% of the eligible first-degree relatives underwent screening, and one patient was identified to have familial cardiomyopathy. Multi-panel gene testing was performed on 18 patients, and none were found to have a pathogenic or likely pathogenic variant; 9 patients also underwent whole-exome sequencing, and pathogenic and likely pathogenic variants were identified in 50% (4/8) of them.
Conclusion
Dilated cardiomyopathy is the most common morphologic form of pediatric cardiomyopathy in India and has a high mortality rate. The prevalence of familial cardiomyopathy was low in this study. Future studies should evaluate the role of whole-exome sequencing in identifying genetic causes of cardiomyopathy in children.
In contrast to other breast surgeries, modified radical mastectomy (MRM) with axillary lymph node clearance involves intense tissue dissection, with postoperative seroma formation and pain being the ...major complaints affecting patients. Among these, 40% of females experience acute postoperative pain, and between 25 to 60% develop persistent chronic postsurgical pain. The rationale of this study was that minimally invasive procedures can result in immediate pain relief in patients undergoing mastectomy, which has been proven to satisfy their needs and lead to early discharge in the local population.
This study determined to find out the efficacy of instilling bupivacaine on wounds by means of surgical drains in controlling pain after MRM.
This was a randomized control study trial that was carried out in Surgical Unit 1, Ward 3, Jinnah Postgraduate Medical Centre, Karachi, from November 2020 to April 2021. All patients tested negative for coronavirus disease 2019 (COVID-19) by PCR test before randomly allocating them into two groups. Thirty women in Group B received 40 ml of 0.25% injection bupivacaine, and 30 in Group C received no drug. Duration of analgesia was recorded as time in hours when the patient was received after surgery in the post-anesthesia care unit until the patient felt ache and discomfort of > three scores according to the visual analog pain score chart (VAS).
The average age was 52.48±4.76 years. The mean period of time during which analgesia was observed was significantly higher in Group B as compared to Group C (10.93±1.84 vs 5.03±1.35 hours, p=0.0005).
There is improvement in postoperative analgesia after instilling bupivacaine through surgical drains on wound beds in MRM patients.
Recombination serves as a common strategy employed by RNA viruses for their genetic evolution. Extensive genomic surveillance during the COVID-19 pandemic has reported SARS-CoV-2 Recombinant strains ...indicating recombination events during the viral evolution. This study introspects the phenomenon of genome recombination by tracing the footprint of prominent lineages of SARS-CoV-2 at different time points in the context of on-going evolution and emergence of Recombinants.
Whole genome sequencing was carried out for 2,516 SARS-CoV-2 (discovery cohort) and 1,126 (validation cohort) using nasopharyngeal samples collected between the time period of March 2020 to August 2022, as part of the genomic surveillance program. The sequences were classified according to the different lineages of SARS-CoV-2 prevailing in India at respective time points.
Mutational diversity and abundance evaluation across the 12 lineages identified 58 Recombinant sequences as harboring the least number of mutations (
= 111), with 14 low-frequency unique mutations with major chunk of mutations coming from the BA.2. The
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trends of mutations highlight the loss of mutations in the Recombinants that were associated with the SARS-CoV-2 replication efficiency, infectivity, and disease severity, rendering them functionally with low infectivity and pathogenicity. Linkage disequilibrium (LD) analysis revealed that mutations comprising the LD blocks of BA.1, BA.2, and Recombinants were found as minor alleles or as low-frequency alleles in the LD blocks from the previous SARS-CoV-2 variant samples, especially Pre-VOC. Moreover, a dissipation in the size of LD blocks as well as LD decay along with a high negative regression coefficient (R squared) value was demonstrated in the Omicron and BA.1 and BA.2 lineages, which corroborated with the breakpoint analysis.
Together, the findings help to understand the evolution and emergence of Recombinants after the Omicron lineages, for sustenance and adaptability, to maintain the epidemic spread of SARS-CoV-2 in the host population already high in immunity levels.
COVID-19 pandemic saw emergence of multiple SAR-CoV-2 variants. Exacerbated risk of severe outcome and hospital admissions led us to comprehend differential host-immune kinetics associated with ...SARS-CoV-2 variants. Longitudinal investigation was conducted through different time periods of Pre-VOC and VOCs (Delta & Omicron) mapping host transcriptome features. Robust antiviral type-1 interferon response marked Omicron infection, which was largely missing during Pre-VOC and Delta waves. SARS-CoV-2-host protein-protein interactions and docking complexes highlighted N protein to interact with HNRNPA1 in Pre-VOC, demonstrating its functional role for enhanced viral replication. Omicron revealed enhanced binding efficiency of LARP1 to N protein, probably potentiating antiviral effects of LARP1. Differential expression of zinc finger protein genes, especially in Omicron, mechanistically support induction of strong IFN (Interferon) response, thereby strengthening early viral clearance. Study highlights eventual adaptation of host to immune activation patterns that interrupt virus evolution with enhanced immune-evasion mutations and counteraction mechanisms, delimiting the next phase of COVID-19 pandemic.
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•Omicron infection was marked by a robust type 1 interferon response•SARS-CoV-2 N protein exhibited differential host protein interaction in VOCs infection•Docking showed better viral replication in Pre-VOC whilst viral clearance in Omicron•ZFPs in Omicron infection further supported its strong antiviral response
Health sciences; Medicine; Virology
•IPSC cell line established for acromesomelic dysplasia, PRKG2 type (AMDP) phenotype.•The iPSC line exhibits the novel protein truncating PRKG2 genetic defect.•The mechanism of bone maldevelopment ...caused by mutant PRKG2 can be studied.
Biallelic PRKG2 (Protein Kinase, cGMP dependent Type-2) mutations cause a novel acromesomelic dysplasia PRKG2 type. We report generation of induced pluripotent stem cell line from lymphoblastoid cell lines of the patient carrying the reported frameshift mutation (p.Asn164Lysfs*2). The derived iPSC line exhibits all the features of pluripotency, free of major genetic alterations due to reprogramming process and has the capability to differentiate into three germ layers. This iPSC cell line may provide an opportunity to investigate the effect of PRKG2 mutations upon FGF (fibroblast-growth-factor) induced MAPK signalling involved in chondrocyte proliferation in-vitro and may aid in possible therapeutic screening of novel biomolecules.
Background Chronic cholecystitis is inflammation of the gall bladder usually caused by stones. The aim was to find out the prevalence of mucocele and empyema in chronic cholecystitis using ...cholecystectomy findings and histopathological reports. Methodology This was a cross-sectional observational study conducted in Surgical Ward 1, Jinnah Postgraduate Medical Center, Karachi from December 2019 to December 2021 for two years. Patients above 12 years of age diagnosed with chronic cholecystitis with cholelithiasis on clinical examination and investigations were included. Patients who were diagnosed with acute cholecystitis, mucocele, or empyema on clinical examination and ultrasonography were excluded from the study. Laparoscopic cholecystectomy was done and operative findings were noted. Gall bladder specimens were examined for mucocele and empyema and were sent for histopathology. Results were recorded and analyzed. Results There were 241 patients diagnosed with chronic cholecystitis with cholelithiasis on clinical examination and investigations. On examination, tenderness in the right hypochondrium was absent in all patients. Chronic cholecystitis was proved on histopathology in 231 patients (95.85%). Other findings diagnosed on peroperative findings and histopathology reports were strawberry gall bladder (2.41%), empyema (0.83%), mucocele (0.41%), and polyp (0.41%). Two hundred eight patients were female (86.31%), 33 were male(13.69%). The male to female ratio was 1:6.43. The average age was 31 years. Conclusion Inflammation and fibrosis of the gallbladder around Calot's triangle increase the chances of vascular and common bile duct injury. In such cases, cholecystectomy can become difficult. It was concluded that empyema, mucocele, and strawberry gall bladder could be found in chronic cholecystitis, and cholecystectomy becomes difficult in such cases.
•Genetic screening of SCA10 in large cohort of Indian SCA patients.•Estimation of at-risk haplotype using population genetics approach in south Asians.•Suggestive rarity of SCA10 in the Indian ...Population.
Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant cerebellar ataxia caused by nucleotide ATTCT expansion in ATXN10 gene. SCA10 has been reported in patients of cerebellar ataxia from Amerindian/Latin America and in East Asian ancestry. A common founder has been ascribed to the origin of ATTCT repeat expansion mutation in both the population. Here we present our investigation of the SCA10 pentanucleotide repeat expansion in 461 SCA patients of the Indian population. The analysis of multi-ethnic at-risk haplotype C-(ATTCT)n-GGC was performed using genotype data of various ethnic population included in the 1000 Genomes Project (KGP) to infer the prevalence of at-risk haplotype in the Indian populations. Unsurprisingly, none of the patient’s DNA samples with (ATTCT)n expansion was observed in pathological range, however, the observed normal range of (ATTCT)n was 8–22 repeats, suggesting very rare or absence of the occurrence of SCA10 in Indian SCA patients. The at-risk haplotype, CGGC was found to be the most prevalent haplotype across different populations and no segregation of CGGC haplotype with large normal or small normal ATTCT repeats length was observed. However, on extended haplotype analysis, some lineage of CGGC with a flanking divergence at 5′ end was observed specifically in the American or East Asian population but not in other population in KGP dataset. Together, these evidence points towards the absence of SCA10 in Indian population and haplotype-based analysis also suggests its occurrence to be rare in South Asian, European and African population. Further investigations are required to establish the present finding.
The implications of the findings of this study are 1.) For the diagnostic work-up of SCAs in the Indian population and to decide upon inclusion of SCA10 in panel based genetic investigations even for Indians living abroad. 2.) The haplotype based inference of its presumptive prevalence through the estimation of at-risk haplotype using population genetics approach (South-Asians as the background) allowed us to estimate the possible absence of SCA10 in Indian population. SCA10 is a rare autosomal dominant cerebellar ataxia mostly reported among SCA patients from Latin America and recently described in East Asia population. The genetic study of SCA10 performed in the unrelated Indian spinocerebellar ataxia patients with heterogeneous ethnicity confirmed its absence from the Indian population and that conforms to population genetic based inference of its rarity or absence. 3.) This approach may be adopted for the screening of other subtypes of SCAs, i.e. other rare SCAs e.g. SCA31, SCA36, and SCA37.
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