scholarly journals Substitution of the CD81 Binding Site and β-Sandwich Area in E2 of HCV in Cambodia

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 551
Author(s):  
Chikako Yamamoto ◽  
Shintaro Nagashima ◽  
Channarena Chuon ◽  
Ko Ko ◽  
Son Huy Do ◽  
...  
Keyword(s):  
Binding Site ◽  
Vaccine Development ◽  
Mutation Rates ◽  
Hcv Rna ◽  
Blood Samples ◽  
Synonymous Substitutions ◽  
Epidemiological Surveys ◽  
Positive Rate ◽  
Cd81 Binding

The high genetic variability of hepatitis C virus (HCV) is the main obstacle to developing a vaccine. E2 has attracted attention for vaccine development because targeting this protein could potentially overcome issues related to the genetic diversity of HCV. In this study, we analyzed HCV genes in the general population of Cambodia and investigated the E2 locus as a candidate for vaccine development. HCV sero-epidemiological surveys were conducted between the period 2010 and 2014, with an HCV RNA–positive rate of 1.3% (11/868). Follow-up blood samples were collected from four anti-HCV– and HCV RNA– positive patients (genotype 1b: 2 cases, 6e: 1 case, 6r: 1 case) after 4.12 years. Analysis of HCV full-length nucleotide sequences in paired specimens revealed that the mutation rates of HCV genotypes 1b and 6e/6r were 1.61–2.03 × 10−3 and 2.52–2.74 × 10−3 substitutions/site/year, respectively. Non-synonymous substitutions were detected in HVR1, the front layer of the CD81 binding site, and the β-sandwich, but not in the N-terminal region or adjacent to the CD81 binding site. Therefore, we conclude that the CD81 binding site is a promising locus for HCV vaccine development.

scholarly journals HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development

2020 ◽  
Vol 21 (18) ◽  
pp. 6781
Author(s):  
Luisa J. Ströh ◽  
Thomas Krey
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Structural Features ◽  
Cell Vaccine ◽  
Receptor Binding Site ◽  
High Level ◽  
Direct Acting ◽  
Cd81 Binding

Despite the approval of highly efficient direct-acting antivirals in the last decade Hepatitis C virus (HCV) remains a global health burden and the development of a vaccine would constitute an important step towards the control of HCV. The high genetic variability of the viral glycoproteins E1 and E2, which carry the main neutralizing determinants, together with their intrinsic structural flexibility, the high level of glycosylation that shields conserved neutralization epitopes and immune evasion using decoy epitopes renders the design of an efficient vaccine challenging. Recent structural and functional analyses have highlighted the role of the CD81 receptor binding site on E2, which overlaps with those neutralization epitopes within E2 that have been structurally characterized to date. This CD81 binding site consists of three distinct segments including “epitope I”, “epitope II” and the “CD81 binding loop”. In this review we summarize the structural features of the HCV glycoproteins that have been derived from X-ray structures of neutralizing and non-neutralizing antibody fragments complexed with either recombinant E2 or epitope-derived linear peptides. We focus on the current understanding how neutralizing antibodies interact with their cognate antigen, the structural features of the respective neutralization epitopes targeted by nAbs and discuss the implications for informed vaccine design.

Improving diagnosis of acute appendicitis with atypical findings by Tc-99m HMPAO leukocyte scan

2002 ◽  
Vol 41 (01) ◽  
pp. 37-41 ◽  
Author(s):  
S. Shung-Shung ◽  
S. Yu-Chien ◽  
Y. Mei-Due ◽  
W. Hwei-Chung ◽  
A. Kao
Keyword(s):  
Acute Appendicitis ◽  
False Positive ◽  
False Positive Rate ◽  
Accurate Method ◽  
Clinical Findings ◽  
Pathological Findings ◽  
Lower Quadrant ◽  
Predictive Values ◽  
Positive Rate

Summary Aim: Even with careful observation, the overall false-positive rate of laparotomy remains 10-15% when acute appendicitis was suspected. Therefore, the clinical efficacy of Tc-99m HMPAO labeled leukocyte (TC-WBC) scan for the diagnosis of acute appendicitis in patients presenting with atypical clinical findings is assessed. Patients and Methods: Eighty patients presenting with acute abdominal pain and possible acute appendicitis but atypical findings were included in this study. After intravenous injection of TC-WBC, serial anterior abdominal/pelvic images at 30, 60, 120 and 240 min with 800k counts were obtained with a gamma camera. Any abnormal localization of radioactivity in the right lower quadrant of the abdomen, equal to or greater than bone marrow activity, was considered as a positive scan. Results: 36 out of 49 patients showing positive TC-WBC scans received appendectomy. They all proved to have positive pathological findings. Five positive TC-WBC were not related to acute appendicitis, because of other pathological lesions. Eight patients were not operated and clinical follow-up after one month revealed no acute abdominal condition. Three of 31 patients with negative TC-WBC scans received appendectomy. They also presented positive pathological findings. The remaining 28 patients did not receive operations and revealed no evidence of appendicitis after at least one month of follow-up. The overall sensitivity, specificity, accuracy, positive and negative predictive values for TC-WBC scan to diagnose acute appendicitis were 92, 78, 86, 82, and 90%, respectively. Conclusion: TC-WBC scan provides a rapid and highly accurate method for the diagnosis of acute appendicitis in patients with equivocal clinical examination. It proved useful in reducing the false-positive rate of laparotomy and shortens the time necessary for clinical observation.

scholarly journals Correlates of SARS-CoV-2 Variants on Deaths, Case Incidence and Case Fatality Ratio among the Continents for the Period of 1 December 2020 to 15 March 2021

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1061
Author(s):  
Wajdy J. Al-Awaida ◽  
Baker Jawabrah Al Hourani ◽  
Samer Swedan ◽  
Refat Nimer ◽  
Foad Alzoughool ◽  
...  
Keyword(s):  
Negative Correlation ◽  
Significant Positive Correlation ◽  
Vaccine Development ◽  
Case Fatality ◽  
Significant Negative Correlation ◽  
Reference Sequence ◽  
Genome Sequences ◽  
Positive Correlation ◽  
Case Fatality Ratio ◽  
Epidemiological Surveys

The outbreak of coronavirus disease 2019 (COVID-19), by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly developed into a worldwide pandemic. Mutations in the SARS-CoV-2 genome may affect various aspects of the disease including fatality ratio. In this study, 553,518 SARS-CoV-2 genome sequences isolated from patients from continents for the period 1 December 2020 to 15 March 2021 were comprehensively analyzed and a total of 82 mutations were identified concerning the reference sequence. In addition, associations between the mutations and the case fatality ratio (CFR), cases per million and deaths per million, were examined. The mutations having the highest frequencies among different continents were Spike_D614G and NSP12_P323L. Among the identified mutations, NSP2_T153M, NSP14_I42V and Spike_L18F mutations showed a positive correlation to CFR. While the NSP13_Y541C, NSP3_T73I and NSP3_Q180H mutations demonstrated a negative correlation to CFR. The Spike_D614G and NSP12_P323L mutations showed a positive correlation to deaths per million. The NSP3_T1198K, NS8_L84S and NSP12_A97V mutations showed a significant negative correlation to deaths per million. The NSP12_P323L and Spike_D614G mutations showed a positive correlation to the number of cases per million. In contrast, NS8_L84S and NSP12_A97V mutations showed a negative correlation to the number of cases per million. In addition, among the identified clades, none showed a significant correlation to CFR. The G, GR, GV, S clades showed a significant positive correlation to deaths per million. The GR and S clades showed a positive correlation to number of cases per million. The clades having the highest frequencies among continents were G, followed by GH and GR. These findings should be taken into consideration during epidemiological surveys of the virus and vaccine development.

scholarly journals Serially measured cytokines and cytokine receptors in relation to clinical outcome in patients with stable heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Bouwens ◽  
A Schuurman ◽  
K.M Akkerhuis ◽  
S.J Baart ◽  
K Caliskan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Outcome ◽  
Primary Endpoint ◽  
Nyha Class ◽  
Cytokine Receptors ◽  
Funding Source ◽  
Compensatory Mechanism ◽  
Blood Samples ◽  
Two Samples

Abstract Background Activation of the inflammatory response in heart failure (HF) may initially serve as a compensatory mechanism. However, on the longer term, this physiological phenomenon can become disadvantageous. Temporal patterns of inflammatory proteins other than CRP have not yet been investigated in patients with stable HF. Purpose We aimed to evaluate the association of 17 serially measured cytokines and cytokine receptors with clinical outcome in patients with stable heart failure. Methods In 263 patients, 1984 serial, tri-monthly blood samples were collected during a median follow-up of 2.2 (IQR: 1.4–2.5) years. The primary endpoint (PE) composed of cardiovascular mortality, HF-hospitalization, heart transplantation, and LVAD. We selected baseline blood samples in all patients, as well as the two samples closest to the primary endpoint, and the last sample available in event-free patients. Thus, in 567 samples we measured 17 cytokines and cytokine receptors using the Olink Proteomics Cardiovascular III multiplex assay. Associations between biomarkers and PE were investigated by joint modelling. Results Median age was 68 (IQR: 59–76) years, with 72% men, 74% NYHA class I-II and a median ejection fraction of 30% (23–38%). 70 patients reached a PE. After adjustment for clinical characteristics (age, sex, diabetes, atrial fibrillation, NYHA class at baseline, diuretics and systolic blood pressure), 7 biomarkers were associated with the PE (Figure). Interleukin-1 receptor type 1 (IL1RT1) showed the strongest association: HR 2.65 [95% CI: 1.78–4.21]) per standard deviation change in level (NPX) at any point in time during follow-up, followed by Tumor necrosis factor receptor 1 (TNF-R1): 2.25 [1.66–3.08], and C-X-C motif chemokine 16 (CXCL16): 2.18 [1.59–3.04]. After adjustment for baseline N-terminal pro–B-type natriuretic peptide, high-sensitive troponin T and C-reactive protein however, only IL1RT1 and TNF-R1 remained significantly associated with the PE. Conclusion Repeatedly measured levels of several cytokines and cytokine receptors are independently associated with clinical outcome in stable HF patients. These results suggest that repeated measurements of these biomarkers, in addition to established cardiac biomarkers, may contribute to personalized risk assessment and herewith better identify high-risk patients. Figure 1. Associations between levels of cytokines and cytokine receptors and the primary endpoint. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This work was supported by the Jaap Schouten Foundation and the Noordwest Academie.

scholarly journals Role of Invasive Urodynamic Studies in Establishing Cauda Equina Syndrome and Postoperative Recovery

2020 ◽  
pp. 219256822097964
Author(s):  
Abhinandan Reddy Mallepally ◽  
Bibhudendu Mohapatra ◽  
Kalidutta Das
Keyword(s):  
Clinical Symptoms ◽  
False Positive Rate ◽  
Cauda Equina ◽  
Postoperative Recovery ◽  
Normal Bladder ◽  
Acontractile Detrusor ◽  
Positive Rate ◽  
Acute Radiculopathy ◽  
Operative Recovery

Study design: Retrospective with prospective follow-up. Objective: Confirming the diagnosis of CES based purely on symptoms and signs is unreliable and usually associated with high false positive rate. A missed diagnosis can permanently disable the patient. Present study aims to determine the relationship between clinical symptoms/ signs (bladder dysfunction) with UDS, subsequently aid in surgical decision making and assessing post-operative recovery. Methods: A prospective follow-up of patients with disc herniation and bladder symptoms from January 2018 to July 2020 was done. All patients underwent UDS and grouped into acontractile, hypocontractile and normal bladder. Data regarding PAS, VAC, GTP, timing to surgery and onset of radiculopathy and recovery with correlation to UDS was done preoperatively and post operatively. Results: 107 patients were studied (M-63/F-44). Patients with PAS present still had acontractile (61%) or hypocontractile (39%) detrusor and with VAC present, 57% had acontractile and 43% hypocontractile detrusors. 10 patients with both PAS and VAC present had acontractile detrusor. 82% patients with acute radiculopathy (<2 days) improved when operated <24 hrs while only 47% showed improvement with chronic radiculopathy. The detrusor function recovered in 66.1% when operated <12 hours, 40% in <12-24 hours of presentation. Conclusion: Adjuvant information from UDS in combination with clinicoradiological findings help in accurate diagnosis even in patients with no objective motor and sensory deficits. Quantitative findings on UDS are consistent with postoperative recovery of patient’s urination power, representing improvement and can be used as a prognostic factor.

Personalized, ctDNA analysis to detect minimal residual disease and identify patients at high risk of relapse with multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8029-8029
Author(s):  
Binod Dhakal ◽  
Shruti Sharma ◽  
Svetlana Shchegrova ◽  
Minu Maninder ◽  
Meenakshi Malhotra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Unmet Need ◽  
Progression Free Survival ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Blood Samples ◽  
Ctdna Analysis

8029 Background: Despite treatment with high-dose chemotherapy followed by autologous stem cell transplantation (AHCT), MM patients invariably relapse. MRD-negativity post-AHCT has emerged as the most important prognostic marker. Currently, MRD in MM is monitored via bone marrow aspirate sampling. Marrow MRD assays are limited by the spatial heterogeneity of marrow MM localization; extramedullary disease and sampling variability of marrow aspiration. Sensitive, non-invasive blood-based MRD assay is an unmet need. ctDNA as a noninvasive biomarker can be utilized to predict relapse in MM. Here we attempt to evaluate MRD using ctDNA in AHCT recipients with MM. Methods: In this retrospective, single-center study, we analyzed ctDNA MRD in blood samples collected from 28 patients with MM after upfront AHCT. A total of 80 plasma timepoints were available pre and post AHCT with a median follow-up of 92.4 months. Multiparameter flow cytometry (MFC) at 10-4 level was used to assess the MRD from the BM biopsy. Individual bone marrow aspirates or FFPE slides from the time of MM diagnosis and matched normal blood were whole-exome sequenced, and somatic mutations were identified. MRD assessment at 3 months post-AHCT was performed by ctDNA analysis using a personalized, tumor-informed (SignateraTM, bespoke mPCR NGS assay). The prognostic value of ctDNA was evaluated by correlating MRD status with clinical outcomes. Results: Table provides the baseline disease characteristics. Median age was 67 [41-75] years and 16 [57.1%] were males. ctDNA was detectable in 70.8% (17/24) of pre-AHCT, 53.6% (15/28) of ̃3 months post-AHCT, and 39.2% (11/28) of patients during the surveillance phase post-AHCT. Of the 15 ctDNA MRD positive patients, 93.3% (n=14) experienced relapse on follow-up (hazard ratio: 5.64; 95% CI: 1.8-17; p=0.0003). Patients negative for ctDNA at 3 months post-AHCT had significantly superior progression-free survival (PFS) compared to positive (median PFS, 84 months vs. 31 months; p=0.003) The positive predictive value (PPV) for relapse among patients positive for ctDNA at 3 months post-AHCT was 93.3%, and significantly higher than marrow MFC of 68.4%. Conclusions: Our study shows the feasibility that a tumor-informed assay on archival blood samples is predictive of relapse post-AHCT. Future prospective studies with real-time marrow NGS and ctDNA samples are needed to define the role of ctDNA in MM and its prognostic significance.[Table: see text]

Evaluation of a multimarker panel in chronic heart failure: a 10-year follow-up

2021 ◽  
Author(s):  
Susanne Bauer ◽  
Christina Strack ◽  
Ekrem Ücer ◽  
Stefan Wallner ◽  
Ute Hubauer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Prognostic Role ◽  
Blood Samples ◽  
Kaplan Meier ◽  
Risk Of Mortality ◽  
Patients With Heart Failure ◽  
All Cause Mortality ◽  
Long Time

Aim: We assessed the 10-year prognostic role of 11 biomarkers with different pathophysiological backgrounds. Materials & methods/results: Blood samples from 144 patients with heart failure were analyzed. After 10 years of follow-up (median follow-up was 104 months), data regarding all-cause mortality were acquired. Regarding Kaplan–Meier analysis, all markers, except TIMP-1 and GDF-15, were significant predictors for all-cause mortality. We created a multimarker model with nt-proBNP, hsTnT and IGF-BP7 and found that patients in whom all three markers were elevated had a significantly worse long-time-prognosis than patients without elevated markers. Conclusion: In a 10-year follow-up, a combination of three biomarkers (NT-proBNP, hs-TnT, IGF-BP7) identified patients with a high risk of mortality.

COMPARISON OF ARTIFICIAL INSEMINATION AND NATURAL MATING ON REPRODUCTIVE PERFORMANCE OF FIVE STRAINS OF SHEEP DURING THE ANESTROUS SEASON IN AN INTENSIVE SYSTEM

1979 ◽  
Vol 59 (4) ◽  
pp. 675-683 ◽  
Author(s):  
A. J. HACKETT ◽  
H. A. ROBERTSON ◽  
E. K. INSKEEP ◽  
J. N. B. SHRESTHA ◽  
M. S. WOLYNETZ
Keyword(s):  
Reproductive Performance ◽  
Artificial Insemination ◽  
Hormone Treatment ◽  
Corpora Lutea ◽  
Blood Samples ◽  
Natural Mating ◽  
Main Effects ◽  
Mating Method ◽  
Intensive System

Synchronized estrus and ovulation were induced during the anestrous season (April–May 1974) in 373 ewes of three synthetic (one sire and two dam) strains and two unselected (Suffolk and Finnish Landrace) purebred strains by treatment with 30 mg fluorogestone acetate (FGA) impregnated in polyurethane intravaginal sponges for 12 days. Following sponge removal each ewe received 500 IU pregnant mares’ serum gonadotrophin (PMSG) IM. Of these, 167 were bred by artificial insemination (AI) at 48 and 60 h post sponge removal with 0.2 ml raw unextended semen collected by electroejaculation (EE). Five days after AI, ewes were exposed to a follow up ram for 16 days for subsequent mating if a second estrus occurred. The remaining 206 were exposed to rams for a period of 22 days for natural mating. Blood samples were collected from 69 ewes, 9, 19 and 27 days post sponge removal and analyzed for progesterone to ascertain if corpora lutea were formed and whether the ewes recycled. The age of ram by mating method interaction significantly affected both fertility and fecundity mainly because some of the younger rams lacked libido and experience for natural mating. There were no significant differences in prolificacy due to any of the main effects tested. Among the 69 ewes examined for progesterone levels, 93% had formed corpora lutea after hormone treatment and 16% recycled. Only 16 of the 255 ewes that did not conceive to the synchronized estrus lambed to the subsequent estrus.

scholarly journals Bidirectional Associations Between Inflammatory Biomarkers and Depressive Symptoms in Adolescents: Potential Causal Relationships

2019 ◽  
Author(s):  
Daniel Moriarity
Keyword(s):  
Depressive Symptoms ◽  
Causal Relationship ◽  
Inflammatory Biomarkers ◽  
Causal Relationships ◽  
Blood Samples ◽  
Extant Literature ◽  
Tnf Α ◽  
Multi Level ◽  
Bidirectional Associations

There are inconsistent findings in the literature about the directionality and magnitude of the association between inflammation and depressive symptoms. This study separates predictors into between-person and within-person components in an attempt to gain greater clarity about this relationship. Blood samples were collected and depressive symptoms assessed in 140 adolescents (54% female, 59% Black, Mage = 16.1 years) with at least three blood draws and a total of 394 follow-up evaluations. Multi-level modeling indicated that the within-person effect of TNF-α predicted future total depressive symptoms, suggesting a potential causal relationship. Additionally, there were bidirectional, between-person effects of IL-6 on total depressive symptoms and vice-versa. Exploratory analyses examined the associations between five biomarkers and five subsets of depressive symptoms. These findings inform modeling decisions that may explain inconsistences in the extant literature as well as suggest potential causal relationships between certain biomarkers with significant within-person effects on depressive symptoms, and vice-versa.

scholarly journals ‘Pediatric Bipolar Disorder’ Rates are Still Lower than Claimed – A Re-examination of Eight Epidemiological Surveys used by an Updated Meta-analysis

2020 ◽  
Author(s):  
Peter Parry ◽  
Stephen Allison ◽  
Tarun Bastiampillai
Keyword(s):  
Bipolar Disorder ◽  
Narrative Analysis ◽  
Meta Analysis ◽  
Pediatric Bipolar Disorder ◽  
Bipolar Spectrum ◽  
Community Surveys ◽  
Bipolar Spectrum Disorder ◽  
Epidemiological Surveys ◽  
Highly Cited

Abstract Background: ‘Pediatric bipolar disorder’ (PBD) is a controversial diagnosis with varying rates of clinical diagnosis. A highly cited meta-analysis (Van Meter et al. 2011) of a dozen epidemiological surveys suggested a global community prevalence of 1.8%. This was further updated to 3.9% with eight additional surveys (Van Meter et al. 2019a). A narrative analysis (Parry et al. 2018) of the original 12 surveys concluded rates of PBD were substantially lower than 1.8% and led to a nine-article debate on the validity, overdiagnosis and iatrogenic aspects of the PBD diagnosis (e.g. Carlson and Dubicka 2019). This article extends the narrative analysis to include the eight newer community surveys.Methods: In terms of the Cochrane Handbook for Systematic Reviews of Interventions, the heterogenous community surveys were arguably unsuitable for statistical meta-analysis and warranted a narrative analysis.Results: Across all twenty surveys there was significant variation in methodologies and reported prevalence rates. Of the eight newer surveys, five (two Brazilian, one English, one Turkish, one United States) provided information of pre-adolescent rates of bipolar spectrum disorder. These pre-adolescent rates were zero or close to zero. Rates of adolescent hypomania/mania were higher, but follow-up data suggested most hypomania did not progress to adult bipolar disorder.Limitations: Methods in the original surveys vary and criteria used for various bipolar diagnoses were not always fully described. This limitation applies to a narrative analysis but also to a statistical meta-analysis.Conclusion: Bipolar disorder is very rare in childhood and rare in adolescence. PBD as a diagnostic construct fails to correlate with adult bipolar disorder and the term should be abandoned. Hypomanic syndromes in adolescence may not progress to adult bipolar disorder. Early diagnosis of bipolar disorder is important, but over-diagnosis risks adverse iatrogenic consequences.

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