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Coronavirus disease 2019 (COVID-19) is a fatal pandemic viral disease caused by the severe acute respiratory syndrome corona virus type-2 (SARS-CoV-2). The aim of this study is to observe the associations of IL-6, SARS-COV-2 viral load (RNAemia), IL- 6 gene polymorphism and lymphocytes and monocytes in peripheral blood with disease severity in COVID-19 patients. This study was carried out from March 2021 to January 2022. RT-PCR positive 84 COVID-19 patients and 28 healthy subjects were enrolled. Blood was collected to detect SARS-COV-2 viral RNA (RNAemia) by rRT-PCR, serum IL-6 level by chemiluminescence method, SNPs of IL-6 by SSP-PCR, immunophenotyping of lymphocytes and monocyte by flow cytometry. Serum IL-6 level (pg/ml) was considerably high among critical patients (102.02 +/- 149.7) compared to severe (67.20 +/- 129.5) and moderate patients (47.04 +/- 106.5) and healthy controls (3.5 +/- 1.8). Serum SARS-CoV-2 nucleic acid positive cases detected mostly in critical patients (39.28%) and was correlated with extremely high IL-6 level and high mortality (R =.912, P < 0.001). Correlation between IL-6 and monocyte was statistically significant with disease severity (severe group, p < 0.001, and 0.867*** and critical group p < 0.001 and 0.887***). In healthy controls, moderate, severe and critically ill COVID-19 patients, IL-6 174G/C (rs 1800795) GG genotype was 82.14%, 89.20%, 67.85% and 53.57% respectively. CC and GC genotype had strong association with severity of COVID-19 when compared with GG genotype. Significant statistical difference found in genotypes between critical and moderate groups (p < 0.001, OR-10.316, CI-3.22-23.86), where CC genotype was associated with COVID-19 severity and mortality. The absolute count of T cell, B cell, NK cell, CD4+ T cells and CD8+ T cells were significantly decreased in critical group compared to healthy, moderate and severe group (P < 0.001). Exhaustion marker CD94/NKG2A was increased on NK cells and CD8+ cytotoxic T cell among critical and severe group. Absolute count of monocyte was significantly increased in critical group (P < 0.001). Serum IL-6, IL-6 174 G/C gene and SARS-CoV-2 RNAaemia can be used in clinical practice for risk assessment;T cell subsets and monocyte as biomarkers for monitoring COVID-19 severity. Monoclonal antibody targeting IL-6 receptor and NKG2A for therapeutics may prevent disease progression and decrease morbidity and mortality.Copyright © 2023 Elsevier Inc.
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Background: Sickle cell disease (SCD) is one of the most common single gene disorders worldwide and is characterised by significant morbidity and early mortality.[1] Pregnancy in SCD is associated with an increased risk of maternal and foetal complications.[2,3] The 2011 RCOG and the 2021 BSH guidelines[5,6] on the management of pregnancy in SCD have provided the basis for best practice care in the UK over the past decade and is the guidance which we follow in Ireland. To date, there is no published data on outcomes for pregnant women with SCD in Ireland. The number of Irish patients with SCD has risen over the past 20 years. Without a national database, the exact prevalence is not known but currently there are at least 600 adults and children with SCD in Ireland, whose population is just over 5 million.[4] Aims: Our study assesses outcomes of pregnant patients with SCD from 2015 to 2022. Our aims were to: * Assess adherence to current guidelines * Assess pregnancy outcomes and maternal complications * Assess transfusion rates amongst our patient cohort. Method(s): This is a retrospective cohort study. We do not have a directly matched cohort, but have compared our findings to published data on Irish pregnancy outcomes from the Irish Maternity Indicator System National Report and have correlated our findings with studies of women with SCD who were managed in UK centres.[8,9,10] Results: We reviewed outcomes of 29 pregnancies in 19 women over a 7-year period. The median age was 29 (range 20-41) and the predominant maternal sickle genotype was HbSS (65.5%). Before conception, 55.2% of cases had pre-existing complications of SCD, including acute chest syndrome (ACS), pulmonary hypertension (PHTN) and prior stroke. In accordance with current guidelines, 100% of women (n=29) were prescribed folic acid, penicillin, and aspirin prophylaxis. 51.7% (n=15) of women had documented maternal complications during pregnancy, including ACS (34%), vaso-occlusive crisis (34%), gestational diabetes (10%), VTE (3%) and UTI (3%). Two women (7%) developed Covid-19 pneumonitis despite vaccination. There was one case of maternal bacteraemia (3%). 65.5% of cases (n=19) required blood transfusion during pregnancy. One woman was already on a blood transfusion programme for disease modification prior to pregnancy. In 6 cases (20.6%), a transfusion programme was commenced during pregnancy due to prior pregnancy complications or intrauterine growth restriction. During pregnancy, 27.6% (n=8) of women required emergency red cell exchange for ACS. Prior studies have suggested that between 30% and 70% of pregnant women with SCD require at least one blood transfusion during pregnancy.[8,9,10] By comparison, only 2.6% of the Irish general obstetric population required transfusion during pregnancy.[7] 20.6% (n=6) of births were preterm at <37 weeks' gestation. There was one live preterm birth (3%) at <34 weeks and one intrauterine death (3%) at 23 weeks' gestation. Similar to UK data[9], 31% of women required critical care stay (n=9) during pregnancy, in comparison with 1.44% nationwide in 2020.[7] Conclusion(s): It is well established that pregnancy in SCD is high risk, and despite adherence to current guidelines, we have shown very high rates of critical care admission, significant transfusion requirement and hospital admissions. Our findings are comparable to published UK outcomes and they further support the need for a comprehensive specialist care setting for this patient cohort.
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Background/Objectives: During COVID-19 pandemic, it is essential to detect patients potentially at risk of life-threatening complications, due to possible specific genetic mutations. The aim of our work is to show a practical application of genetic testing, allowing a diagnosis of alpha 1 antitrypsin deficiency in cases with a severe clinical course during COVID-19 infection. Method(s): During hospitalization for COVID-19, we identified 5 patients (3 female, 2 males from two different families, age range 18-47 years) with a severe course of COVID-19 infection, requiring high pressure ventilation with high volume oxygen supply. Two months after discharge, those patients were reevaluated with respiratory function tests, biochemical tests, genetic counselling and genetic testing. A peripheral blood sampling for SERPINA1 genetic testing has been performed, using Sanger sequencing. Result(s): Two months after discharge, in all 5 patients respiratory function tests were consistent with a dysventilatory obstructive syndrome, in contrast with usual findings related to COVID-19 infection. Blood test still showed increase plasmatic transaminase concentration in 3 out of 5 patients, one having increased serum bilirubin as well. We performed SERPINA1 genetic testing showing homozygosity for SERPINA1 pathogenic mutations (c.193del and c.875C>T, respectively) in all 5 patients. Conclusion(s): These cases showed the importance of genetic testing for patients with unexplained severe COVID-19 infection. Genetic testing allowed the diagnosis of cases affected by alpha 1 antitrypsin deficiency, associated with dysventilatory obstructive syndrome, that may worsen the short and long term prognosis of COVID-19.
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Background: Approximately two years ago, COVID-19 was declared a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and through genomic surveillance, we have seen the emergence of variants of SARS-CoV-2. In the United States, over 78 million cases and >900,000 deaths attributable to COVID-19 have been reported. SCD was identified as a risk factor for severe COVID-19 disease in adults and pediatric patients. The emergence of novel SARs- CoV-2 variants has led to challenges in diagnosis, treatment, and prediction of long-term sequelae in individuals with SCD and COVID-19. Aim(s): We compare the overall seasonal variation of COVID-19 variants and patterns of healthcare utilization and clinical presentation over time in pediatric patients with SCD and COVID-19 at Children's National Hospital (CNH). Method(s): Our single-center, observational cohort study included 193 pediatric patients with SCD (0-21 years) with PCR-confirmed SARSCoV- 2 infection between March 31, 2020, and January 31, 2022. Per the SECURE SCD Registry definitions, clinical severity was classified as asymptomatic, mild, moderate, and severe. Result(s): A total of 193 unique patients with SCD and positive SARS-CoV-2 PCRs between March 2020-January 2022 were included in our registry. Most patients were female (51.8%), and the mean age was 11.2 years (SD 6.5 years). Most of the cohort resides in Maryland (N=135), and HbSS was the dominant genotype (69.4%). During the alpha dominant variant of the COVID-19 pandemic (March 2020- June 2021) there were 70 cases, followed by 40 cases during the Delta variant (July 2021- December 19, 2021), and 83 cases during the Omicron variant dominance (from December 20, 2021-January 31,2022). There were 149 patients (77%) that presented to the emergency department (ED) or were hospitalized. There were a total of 80 hospitalizations (41.5%), and a relative comparison showed that the percentage of hospitalizations was highest during the delta wave (47.5%) and lowest during the omicron wave (36.1%) (p= 0.407). ED-only utilization was highest in the era of omicron (43.4%, N=36), followed by delta (32.5%, N=13), and then alpha (30%, N=21)(p=0.197). The most common SCD-related complication was vaso-occlusive (VOC) pain (33%, N=64) which accounted for half of all hospital admissions (51%, N=41 of 80). Acute chest syndrome (ACS) was reported in 40% (N=32) of admitted patients and was highest in the alpha era (54.8%, N=17). The use of blood transfusion therapy was highest in the alpha (N=17) and delta (N=14) variants, while Remdesivir use was highest in omicron (N=15). A total of 6 patients received monoclonal antibodies (Delta, N=4;omicron, N=2). Throughout all the variants, there was a significant difference in COVID-19 clinical severity (p>0.005). Of the patients classified as asymptomatic (13%, N=25), seventy-two percent (n=18) were diagnosed during the alpha variant. Mild severity was the most prevalent (69%, N=134), with the omicron variant having the highest cases (51.5%, N=69). Severe cases were observed in all variants (6.7%, N=13) but were most prevalent during the alpha variant (46.2%, N=6). Summary - Conclusion(s): Interestingly, while the relative percentage of hospitalizations was lowest during the omicron wave, it saw the highest percentages of ER utilization. Overall, COVID-19 remains mild in pediatric patients with SCD, and notably, there was higher health care utilization in the omicron era.
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Background: After two years of COVID in which activities were reduced due to the pandemic and each one's life was affected by restrictions and limitations, the Sickle Cell Disease (SCD) Association in Padova teamed up with the Sickle Cell Group at the Pediatric Hematology Oncology and Bone Marrow Transplant Unit to celebrate the Sickle Cell Disease world day by organizing an online meeting with children/youths and their families. Theme of the meeting was: "My Life with SCD: poems, pictures and writings express our view on disease and care". Aim(s): One of the goals of this meeting was to create an opportunity for individuals with SCD to meet and have a constructive discussion with each other about the disease and express their feelings after two years of pandemic. Method(s): One month before the meeting children, teenager and parents were asked to sharer with the organizing team any drawing, painting, poem, writing, that they felt could express their feelings or experience of the disease itself or how it affected their life, or their experience in the hospital. The materials received were organized in a power point presentation and At the meeting, families were able to see a PowerPoint presentation with the poems, drawings, writings. Each author had the choice to personally share their production or have it read out loud by a member of the team. Free time to comment or share experiences was given. Result(s): 20 children, teenagers and parents participated. Countries of origin (Nigeria, Ghana, Congo, Albania, Italy), religious background (catholic, muslim, no religion, other) were different as well as disease genotype (HbSS, HbSC, HbSBdegree), severity or treatment received (Hydroxyurea, transfusion, Hematopoietic stem cell transplantation -HSCT, none). Drawings and writings regarded experience with the disease (mechanism of action, admissions), feelings experienced (fear, hope, light at the end of the tunnel), aspirations (sports) and gratitude (to the social and medical team, to parents) (Figure 1). Surprisingly, families who had a child having undergone HSCT, reported on the need and importance to talk about this experience for years after the event and made a request of a support goup. Finally, all families underlined the need to meet again soon to discuss together issues related to personal experience with SCD, even via web. of discussion with each other and with the drepanocytosis group;and that throug the online telematics platform it is still possible to involve all families, listening and trying to comfort them on doubts and perplexities about the disease, In conclusion, it can be said that after two years of pandemic, in our setting, online meeting can help patients and families reconnect with each other and activities can be planned to aid experiences and feelings. Patients' associations and Health Care Teams can collaborate in this area.
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Background/Objectives: Genetic variants affecting host defense against pathogens may help explain COVID-19 fatal outcomes. Our aim was to identify rare genetic variants related to COVID-19 severity in a selected group of patients under 60 years who required intubation or resulting in death. Method(s): Forty-four very severe COVID-19 patients were selected from the Spanish STOP-Coronavirus cohort, which comprises more than 3,500 COVID-19 patients. Genotype was performed by whole exome sequencing and variants were selected by using a gene panel of 867 candidate genes (immune response, primary immunodeficiencies or coagulation, among other). Variants were filtered, priorized and their potential pathogenicity was assessed following ACGM criteria. Result(s): We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic (26%). Mostly, the candidate variants were located in genes related to immune response (38%), congenital disorders of glycosylation (14%) or damaged DNA binding genes (9%). A network analysis, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks enriched in carbohydrate metabolism and in DNA metabolism and repair processes. Conclusion(s): The variants identified affect different, but interrelated, functional pathways such as immune response and glycosylation. Further studies are needed for confirming the ultimate role of the new candidate genes described in the present study on COVID-19 severity.
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BackgroundLupus is a heterogenous diseases which results in significant premature mortality. Most studies have evaluated risk factors for lupus mortality using regression models which considers the phenotype in isolation. Identifying clusters of patients on the other hand may help overcome the limitations of such analyses.ObjectivesThe objectives of this study were to describe the causes of mortality and to analyze survival across clusters based on clinical phenotype and autoantibodies in patients of the Indian SLE Inception cohort for Research (INSPIRE)MethodsOut of all patients, enrolled in the INSPIRE database till March 3st 2022, those who had <10% missing variables in the clustering variables were included in the study. The cause of mortality and duration between the recruitment into the cohort and mortality was calculated. Agglomerative unsupervised hierarchical cluster analysis was performed using 25 variables that define SLE phenotype in clinical practice. The number of clusters were fixed using the elbow and silhouette methods. Survival rates were examined using Cox proportional hazards models: unadjusted, adjusted for age at disease onset, socio-economic status, steroid pulse, CYC, MMF usage and cluster of the patients.ResultsIndian patients with lupus have significant early mortality and the majority of deaths occurs outside the hospital setting.Out of 2211 patients in the cohort, 2072 were included into the analysis. The median (IQR) age of the patients was 26 (20-33) years and 91.7% were females. There were 288 (13.1%) patients with juvenile onset lupus. The median (range) duration of follow up of the patients was 37 (6-42) months. There were 170 deaths, with only 77 deaths occurring in a health care setting. Death within 6 months of enrollment occured in in 80 (47.1%) patients. Majority (n=87) succumbed to disease activity, 23 to infections, 24 to coexisting disease activity and infection and 21 to other causes. Pneumonia was the leading cause of death (n=24). Pneumococcal infection led to death in 11 patients and SARS-COV2 infection in 7 patients. The hierarchical clustering resulted in 4 clusters and the characteristics of these clusters are represented in a heatmap (Figure-1A,B). The mean (95% confidence interval [95% CI] survival was 39.17 (38.45-39.90), 39.52 (38.71-40.34), 37.73 (36.77-38.70) and 35.80 (34.10-37.49) months (p<0.001) in clusters 1, 2, 3 and 4, respectively with an HR (95% CI) of 2.34 (1.56, 3.49) for cluster 4 with cluster 1 as reference(Figure 1C). The adjusted model showed an HR (95%CI) for cluster 4 of 2.22 (1.48, 3.22) with an HR(95%CI) of 1.78 (1.29, 2.45) for low socioeconomic status as opposed to a high socioeconomic status (Table 1).ConclusionIndian patients with lupus have significant early mortality and the majority of deaths occurs outside the hospital setting. Disease activity as determined by the traditional activity measures may not be sufficient to understand the true magnitude of organ involvement resulting in mortality. Clinically relevant clusters can help clinicians identify those at high risk for mortality with greater accuracy.Table 1.Univariate and multivariate Cox regression models predicting mortalityUnivariateMultivariateVariablesHazard ratio (95% Confidence interval)P valueHazard ratio (95% Confidence interval)P valueCluster1Reference-Reference-20.87 (0.57, 1.34)0.5320.89 (0.57, 1.38)0.59831.22 (0.81, 1.84)0.3371.15 (0.76, 1.73)0.51342.34 (1.56, 3.49)<0.0012.22(1.48, 3.22)<0.001Socioeconomic statusLower1.78 (1.29, 2.45)<0.001Pulse steroidYes1.6 (0.99, 2.58)0.051MMFYes0.71 (0.48, 1.05)0.083CYCYes1.42 (0.99, 2.02)0.052Proliferative LNYes0.99 (0.62, 1.56)0.952Date of birth age0.99 (0.98, 1.01)0.657CYC- cyclophosphamide, MMF- Mycophenolate mofetilFigure 1.A. Agglomerative clustering dendrogram depicting the formation of four clusters. B.Heatmap depicting distribution of variables used in clustering C. Kaplan-Meier curve showing the survival function across the 4 clusters[Figure omitted. See PDF]REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone eclared.
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Background/Objectives: Runaway inflammation is a key feature of COVID-19. NR3C1 gene encodes for glucocorticoid receptor which plays an important role in inflammation reaction. The variant rs41423247 cause increased glucocorticoid receptors sensitivity. This study aimed to investigate the impact of variants of NR3C1 gene on the course of COVID-19 pneumonia in patients with necessarily artificial lung ventilation. Method(s): The study group included 20 patients (9 women and 11 men) with diagnosis viral COVID-19 pneumonia on artificial lung ventilation at the intensive care unit. All patients underwent daily standard examinations according clinical protocols. Determination of NR3C1 gene variants was carried out by using PCRRFLP. Result(s): There were found the significant negative correlations between NR3C1 gene variants and level of SpO2 (rS = -0.601, p = 0.008), Glasgow Coma Scale score (rS = -0.523, p = 0.026). Also, it was defined a protective effect of genotype CC at risk of development acute respiratory distress syndrome in this patients (chi2 = 4.38, p = 0.037, OR = 0.05 (CI:0.01-0.66)). Conclusion(s): The investigated variant rs41423247 of the NR3C1 gene may be the genetic predictor of complicated course of COVID-19 pneumonia. .
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The proceedings contain 90 papers. The topics discussed include: characterization of nonalcoholic fatty liver disease in children with psoriasis: a pilot study;management of pediatric psoriasis: a representative US survey;severity and patient-related outcomes in atopic dermatitis do not correlate with deprivation index as an indicator of socioeconomic setting in a US metropolitan area;pediatric atopic dermatitis: assessment of burden based on lesional morphology;metered dose applicators: a potential solution for improving topical medication adherence in atopic dermatitis patients;serial staged punch excision technique for linear epidermal nevus and nevus sebaceous;the molecular basis of superficial vascular lesions of the skin: genotype-phenotype correlation of capillary malformations;utilization and effect of telehealth for the treatment of hemangioma before and after COVID;image analysis of port wine birthmarks using optical coherence tomography;image analysis of port wine birthmarks using optical coherence tomography;and responsiveness to change of the morphea activity measure.
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SUMMARY. Different genetic and immunological factors can affect the severity of Coronavirus disease 19. Angiotensin-converting enzyme 2 is a human receptor for Severe Acute Respiratory Syndrome Coro-navirus-2, and the successful interaction between the spike protein of the novel virus and Angiotensin-converting enzyme 2 is responsible for the initial and complete infection. The study aimed to evaluate the correlation between Single Nucleotide Polymorphisms of Angiotensin converting-enzyme 2, with disease severity of Coronavirus disease 19 in AL-Najaf province. The allele Specific-polymerase Chain reaction method was used for investigating Single Nucleotide polymorphisms of Angiotensin converting-enzyme 2 rs4646116 A/G in different states of Coronavirus disease 19 (COVID-19). The wild genotypes (GG) for ACE2 rs4646116 gene recorded a highly significant association p = 0.0009, and a high ratio in the control group (90%) in comparison with moderate cases of COVID-19 (60%). While the heterozygote genotype (GA) of the same gene showed a significant (p-value = 0.0144) and high ratio in moderate cases (30%) in comparison with the control group (10%). Conclusion(s): the wild genotype (GG) for Angiotensin convert-ing-enzyme 2 rs4646116 gene may be associated with more protection from infection with COVID-19. While the polymorphism heterozygote genotype (GA) for the same gene may be associated with more susceptibility to infection with COVID-19.Copyright © 2023, Colegio de Farmaceuticos de la Provincia de Buenos Aires. All rights reserved.
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Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.
Subject(s)
Chromosome Disorders , Intellectual Disability , Humans , DNA Copy Number Variations , Intellectual Disability/genetics , Intellectual Disability/complications , Nerve Tissue Proteins/genetics , Chromosome Disorders/diagnosis , Chromosome Disorders/genetics , Chromosome Disorders/pathology , Chromosome Deletion , Phenotype , Syndrome , Chromosomes, Human, Pair 22/geneticsABSTRACT
Since March 2020, the pandemic caused by SARS-CoV-2 has affected nearly all aspects of daily life. In this study, we investigated the age-stratified prevalence and genotype distribution of human papillomavirus (HPV) among females in Shandong province (eastern China) and aimed to provide guidance on HPV-based cervical cancer screening and vaccination. The distribution of HPV genotypes was analyzed using PCR-Reverse Dot Hybridization. The overall infection rate of HPV was 16.4%, which was dominated by high-risk genotypes. The most prevalent genotype was HPV16 (2.9%), followed by HPV52 (2.3%), HPV53 (1.8%), HPV58 (1.5%), and HPV51 (1.3%). Among the positive cases with HPV infection, single-genotype infection was significantly higher than that of multi-genotype infection. In subgroup analyses by age (≤25, 26-35, 36-45, 46-55, >55), HPV16, 52, and 53 were consistently the three most common hrHPV genotypes in all age groups. The infection rate of multi-genotypes in the ≤25 and >55 age groups was significantly higher than that in other age groups. A bimodal distribution of HPV infection rate was observed in different age groups. Among lrHPV genotypes, HPV6, HPV11, and HPV81 were the three most common types in the ≤25 age group, while in other age groups, HPV81, HPV42, and HPV43 are the three most common lrHPV genotypes. This study provides basic information on the distribution and genotypes of HPV in the female population in eastern China, which could improve the application of HPV diagnostic probes and vaccines.
Subject(s)
COVID-19 , Papillomavirus Infections , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/prevention & control , Papillomavirus Infections/prevention & control , Human Papillomavirus Viruses , Pandemics , Prevalence , Early Detection of Cancer , COVID-19/epidemiology , SARS-CoV-2/genetics , Genotype , Papillomaviridae/genetics , Human papillomavirus 16/genetics , China/epidemiologyABSTRACT
BRAF mutations are uncommon in non-small cell lung cancer (NSCLC), accounting for less than 5% of all NSCLC cases. The utilization of targeted therapies in non-V600E BRAF mutant NSCLC is considered controversial, although non-V600E genotype is reported in ~50% of all BRAF mutant patients. We document the case of a 63-year-old patient with NSCLC harbouring a rare BRAF E501Q mutation, who had prolonged response to immunotherapy combined with chemotherapy in Vietnam. The patient was diagnosed with metastatic PD-L1-negative lung adenocarcinoma and received pembrolizumab plus chemotherapy as first-line treatment. After completing 35 cycles of pembrolizumab and pemetrexed, his disease has remained stable during the treatment-free follow-up period, and he is alive 38 months after treatment initiation at the latest follow-up. Immune-based therapy is an appropriate option for lung adenocarcinoma with rare non-V600E BRAF mutation. Further clinical studies are necessary to determine the effectiveness of using immune-based therapy in this specific population.
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BACKGROUND: Susceptibility to severe acute respiratory syndrome coronavirus 2 shows individual variability in un-vaccinated and previously un-exposed individuals. We investigated the impact of ABO blood group, titers of anti-A and anti-B, other blood group antigens, and the extracellular deposition of ABH antigens as controlled by secretor fucosyltransferase 2 (FUT2) status. STUDY DESIGN AND METHODS: We studied incidents in three different hospitals between April to September 2020, where un-diagnosed coronavirus disease 2019 (COVID-19) patients were cared for by health care workers without use of personal protection and with close contact while delivering therapy. We recruited 108 exposed staff, of whom 34 were diagnosed with COVID-19. ABO blood type, titer of anti-A and -B, blood group specific alleles, and secretor status were determined. RESULTS: Blood group O was associated with lower risk of COVID-19 (OR 0.39, 95 %CI (0.16-0.92), p = 0.03) compared to non-O, i.e., blood groups A, B and AB. High titer anti-A immunoglobulin G (IgG) compared to low titer was associated with lower risk of COVID-19 (OR 0.24 95 %CI (0.07-0.78), p = 0.017). High titer of anti-B immunoglobulin M (IgM) compared to no anti-B (IgM) was associated with lower risk of COVID-19 (OR 0.16, 95 %CI (0.039-0.608), p = 0.006) and the same applies to low titer anti-B (IgM) compared to no titer (OR 0.23, 95 %CI (0.07-0.72), p = 0.012). The 33Pro variant in Integrin beta-3, that is part of human platelet antigen 1b (HPA-1b), was associated with lower risk of COVID-19 (OR 0.23, 95 %CI (0.034-0.86), p = 0.028). CONCLUSION: Our data showed that blood group O, anti-A (IgG) titer, anti-B (IgM) titer as well as HPA-1b are associated with lower risk for COVID-19.
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Listeriosis is a saprozoonotic infection that occurs when eating foods contaminated with Listeria. Invasive forms of listeriosis can have extremely severe consequences. Respiratory viral diseases predispose to the occurrence of combined viral-bacterial infections. With a mixed infection of listeriosis and COVID-19, a severe course of the disease is observed, which has a serious prognosis. The aim of the study was to analyze the frequency of various variants of invasive listeriosis and their outcomes in the period before the COVID-19 pandemic and against the background of its development, as well as to determine the genetic diversity of L. monocytogenes isolates. Material and methods. We analyzed 55 cases of invasive listeriosis in patients observed in 2018-2021 in various medical organizations in Moscow. The diagnosis was established on the basis of epidemiological, clinical and laboratory data, listeriosis was confirmed by bacteriological and molecular genetic methods, COVID-19 was confirmed by the detection of SARS-CoV-2 RNA in an oropharyngeal swab using real-time RT-PCR, as well as computed tomography of the lungs. Results. During the current COVID-19 pandemic (2020-2021), the incidence of listeriosis in pregnant women and invasive listeriosis occurring in the form of sepsis and/or lesions of the central nervous system did not differ significantly from similar indicators registered in 2018-2019. Listeria sepsis and/or meningitis/meningoencephalitis in association with severe SARS-CoV-2 novel coronavirus infection are at high risk of death. During the years of the COVID-19 pandemic, the diversity and range of L. monocytogenes genotypes in invasive listeriosis changed, new genotypes appeared that were not previously characteristic of the Russian Federation. Conclusion. The likelihood of developing listeriosis sepsis and/or meningitis/meningoencephalitis against the background of a severe course of COVID-19, and a high risk of an adverse outcome, require increased awareness of medical workers in the field of diagnosis and treatment of invasive listeriosis in order to conduct the earliest and most adequate antibiotic therapy.Copyright © 2022 Geotar Media Publishing Group. All Rights Reserved.
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Background: ALG-000184 is a prodrug of ALG-001075, a novel, potent, pan-genotypic Class II CAM. CAMs are thought to have two mechanisms of action (MoA). The primary MoA affects pgRNA encapsidation resulting in inhibition of HBV DNA/RNA replication, as confirmed in CHB subjects receiving ALG-000184. The secondary MoA, which occurs at higher concentrations, regulates the establishment and replenishment of cccDNA, resulting in lowering of HBsAg, an effect that has not been reported to date with ALG- 000184. Method(s): ALG-000184-201 is a multi-part, multicenter, doubleblind, randomized, placebo-controlled study. In healthy volunteers (HVs), single doses up to 500 mg and multiple doses up to 250 mg were well tolerated with linear PK (Gane E., HBV TAG and APASL 2021). In treatment naive (TN) subjects with CHB, daily oral doses of 10-100 mg ALG-000184 for 28 days were well tolerated with linear PK and were associated with profound reductions of DNA/RNA regardless of HBeAg status or dose (Yuen MF, EASL 2022). Plasma exposures required to engage the secondary MoA are expected to be achieved at the 300 mg dose level. Data from a 300 mg cohort treated for 28 days are described here. Data from another ongoing cohort treated with 300 mg for 12 weeks will be presented at the conference. Result(s): Ten subjects were randomized to 300 mg ALG-000184 for 28 days and two to placebo. Two subjects randomized to ALG- 000184 were replaced due to missing data due to Covid-19 lockdown. Subjects were Asian, HBeAg positive, and genotype B or C. Mean baseline HBV DNA and RNA levels were 8.4 log10 IU/mL and 7.3 log10 copies/mL, respectively. One subject experienced a serious adverse event (AE) of pneumothorax>8 weeks after last dose which was considered unlikely related to study drug. No subjects prematurely discontinued study drug. All treatment emergent AEs were Grade <= 2 except for 4 Grade >= 3 alanine aminotransferase (ALT) elevations, which an independent ALT Flare Committee assessed as not related to study drug toxicity. PK was similar to HBeAg negative and HV cohorts following body weight adjustment. Subjects dosed with 300 mg ALG-000184 experienced mean declines of 4.0 log10 IU/mL and 2.6 log10 copies/mL in HBV DNA and RNA levels, respectively, at Day 28. Three of 7 evaluable subjects who received ALG-000184 had HBsAg declines>0.2 log10 IU/mL (0.23-0.78 log10 IU/mL). One subject receiving ALG-000184 had unquantifiable HBsAg throughout the study. Additionally, one HBeAg positive subject in a prior 100 mg cohort had plasma exposures equivalent to the 300 mg dose level and experienced a 0.5 log10 IU/mL HBsAg decline. Conclusion(s): In TN HBeAg positive CHB subjects, 300 mg ALG- 000184 for 28 days was well tolerated, exhibited predictable PK and resulted in rapid and substantial declines in HBV DNA and RNA. Notably, 3 of 7 evaluable subjects from this cohort experienced HBsAg declines of up to 0.78 log10 IU/mL. These data suggest that ALG-000184 can engage the secondary MoA of CAM II. Cohorts evaluating 300 mg over longer durations are planned or ongoing.
ABSTRACT
Background and Aims: The treatment of chronic hepatitis C (CHC) has evolved from genotype-specific to pan-genotypic direct acting antivirals (DAAs) with high efficacy and safety. However, drug-drug interactions (DDIs) must be avoided when used in combination with other medications, especially with the possible concomitant use of COVID-19 infection antivirals during the COVID-19 pandemic. This study aimed to access the potential DDIs of concomitant drugs with pan-genotypic DAAs and COVID-19 infection antivirals, and actual incidence of DDIs in real-world experience. Method(s): From January 2022 to October 2022, consecutive 116 HCV patients receiving pan-genotypic DAAs were retrospectively enrolled in Taipei Veterans General Hospital. The number of comedications and their potential DDIs with three pan-genotypic DAA regimens and three COVID-19 infection antivirals were analyzed. The actual incidence of DDIs during DAAs treatment were also investigated. Result(s): The mean age was 60.9 years old, with male predominant (55.2%). Of them, 12 (10.3%) patients had cirrhosis, and 24 (20.7%) patients had diabetes mellitus. Most patients were within Child-Pugh class A (109/116, 94.0%). The distribution of HCV genotypes was 8.6% in GT 1a, 36.2% in GT 1b, 39.7% in GT 2, 6.9% in GT 6, and 8.6% in indeterminate genotype, respectively. Of them, 43 (37.1%) patients received GLE/PIB, 69 (59.5%) received SOF/VEL 7plusmn;RBV, and 4 (3.4%) received SOF/VEL/VOX as DAAs regimen. Noteworthy, four patients had COVID-19 infection during DAAs treatment course. The rates of ETVR and SVR12 were 97.6% and 95.3%. The mean number of concomitant medications was 2.01. The distribution of concomitant drugs was 64.7% with no concomitant drug, 11.2% with 1-3 drugs, 11.2% with 4-6 drugs, 9.5% with 7-9 drugs, and 3.4% had more than 9 drugs, respectively. In potential contraindicated (red) DDI class, GLE/PIB was the most prevalent (7.3%), followed by SOF/VEL/VOX (6.4%), and SOF/VEL (1.8%) for non-cirrhosis and compensated cirrhosis patients;and no red DDI occurred in decompensated cirrhosis patients. In addition, the percentage of patients without potential DDIs was higher with SOF/VEL (79.8%) than with the other regimens. The potential red DDIs were predominantly with lipid-lowering agents for DAAs. For potential red DDI class with COVID-19 infection antivirals, Nirmatrelvir/Ritonavir was the most prevalent (6%), followed by Remdesivir (0.9%), and no potential DDIs with Molnupiravir. For COVID-19 antivirals, the potential red DDIs was mainly with central nervous system drugs. Finally, the actual incidence of DDIs during DAAs treatment showed no red DDI occurred for all patients, and GLE/PIB was the most prevalent (93%) of no potential DDIs. Conclusion(s): The potential DDIs between these comedications differed, with the most potential DDIs occurring with GLE/PIB and Nirmatrelvir/Ritonavir. After careful assessment of comedications and their potential DDIs, the actual incidence of DDIs could be reduced, and optimize safety in real-world practice.
ABSTRACT
The A and B oligosaccharide antigens of the ABO blood group system are produced from the common precursor, H substance, by enzymatic reactions catalyzed by A and B glycosyltransferases (AT and BT) encoded by functional A and B alleles at the ABO genetic locus, respectively. In 1990, my research team cloned human A, B, and O allelic cDNAs. We then demonstrated this central dogma of ABO and opened a new era of molecular genetics. We identified four amino acid substitutions between AT and BT and inactivating mutations in the O alleles, clarifying the allelic basis of ABO. We became the first to achieve successful ABO genotyping, discriminating between AA and AO genotypes and between BB and BO, which was impossible using immunohematological/serological methods. We also identified mutations in several subgroup alleles and also in the cis-AB and B(A) alleles that specify the expression of the A and B antigens by single alleles. Later, other scientists interested in the ABO system characterized many additional ABO alleles. However, the situation has changed drastically in the last decade, due to rapid advances in next-generation sequencing (NGS) technology, which has allowed the sequencing of several thousand genes and even the entire genome in individual experiments. Genome sequencing has revealed not only the exome but also transcription/translation regulatory elements. RNA sequencing determines which genes and spliced transcripts are expressed. Because more than 500,000 human genomes have been sequenced and deposited in sequence databases, bioinformaticians can retrieve and analyze this data without generating it. Now, in this era of genomics, we can harness the vast sequence information to unravel the molecular mechanisms responsible for important biological phenomena associated with the ABO polymorphism. Two examples are presented in this review: the delineation of the ABO gene evolution in a variety of species and the association of single nucleotide variant (SNV) sites in the ABO gene with diseases and biological parameters through genome-wide association studies (GWAS).Copyright © Annals of Blood. All rights reserved.
ABSTRACT
Infectious bronchitis virus (IBV) is a vital pathogen in poultry farms, which can induce respiratory, nephropathogenic, oviduct, proventriculus, and intestinal diseases. Based on the phylogenetic classification of the full-length S1 gene, IBV isolates have been categorized into nine genotypes comprising 38 lineages. GI (GI-1, GI-2, GI-3, GI-4, GI-5, GI-6, GI-7, GI-13, GI-16, GI-18, GI-19, GI-22, GI-28, and GI-29), GVI-1 and GVII-1 have been reported in China in the past 60 years. In this review, a brief history of IBV in China is described, and the current epidemic strains and licensed IBV vaccine strains, as well as IBV prevention and control strategies, are highlighted. In addition, this article presents unique viewpoints and recommendations for a more effective management of IBV. The recombinant Newcastle Disease virus (NDV) vector vaccine expressed S gene of IBV QX-like and 4/91 strains may be the dominant vaccine strains against NDV and IBV.
ABSTRACT
Background: The pathophysiology of viral-infections is highly complex and involves host immunocompetence, host genetics, and gene-environment interactions. We hypothesized that polymorphic variants in host genes, blood group and previous vaccination status against H1N1 may affect the clinical course of covid-19 infection. Method(s): A total of 202 subjects who were RT-PCR negative after Covid-19 infection were recruited. We investigated association between Covid-19 infection (Severity and recovery period) and multiple factors including ABO and Rh blood groups, H1N1 vaccination, polymorphism in Viral susceptibility genes (ACE2 G8790A), and polymorphism in host response genes (ACE I/D rs4646994, IL6- 174G/C, GSTT1/GSTM1 I/D and GSTP1 Ile 105 Val). Result(s): B-ve and O-ve ABO and Rh blood groups had significantly higher Covid-19 recovery period applied on one-vs.-all in a nonparametric t-test (p<0.05). Subjects who had vaccinated themselves against H1N1 presented with a lower recovery-period (p<0.05). Both variables (blood group and H1N1 vaccination) were not however associated with Covid-19 severity. Out of the studied polymorphisms, ACE2 G8790A and GSTT1/GSTM1 were significantly associated with covid-19 infection. Our results indicated that G/G genotype of ACE2 G8790A (OR 3.52, P 0.007) and GSTT1/ GSTM1 null (M1 - / - OR = 3.98, P = 0.0004;T1 - / - OR 3.84, P = 0.004) and double null (M1 - / - /T1 - / - OR = 9.66, P = 0.001) are likely to be associated with an increased risk for severe-critical outcomes in individuals with COVID-19. Other polymorphisms analyzed in this study were found to have no significant association with Covid-19 outcome. Conclusion(s): This study suggests that outcome of Covid-19 infection is affected by both clinical and genetic factors. Thus it seems plausible to utilize these factors as prediction and susceptibility markers in the prognosis of COVID-19, which may help to personalize the treatment.