Tag: pubmed

Proteins. 2022 Apr 10. doi: 10.1002/prot.26343. Online ahead of print.

ABSTRACT

The startling diversity in αβ T cell receptor (TCR) sequences and structures complicates molecular-level analyses of the specificity and sensitivity determining T cell immunogenicity. A number of 3D structures are now available of ternary complexes between TCRs and peptide:major histocompatibility complexes (pMHC). Here, to glean molecular-level insights we analyze structures of TCRs bound to human class I nonamer peptide-MHC complexes. Residues at peptide positions 4 to 8 are found to be particularly important for TCR binding. About 90% of the TCRs hydrogen bond with one or both of the peptide residues at positions 4 and 8 presented by MHC allele HLA-A2, and this number is still ~79% for peptides presented by other MHC alleles. Residue 8, which lies outside the previously-identified central peptide region, is crucial for TCR recognition of class I MHC-presented nonamer peptides. The statistics of the interactions also sheds light on the MHC residues important for TCR binding. The present analysis will aid in the structural modeling of TCR:pMHC complexes and has implications for the rational design of peptide-based vaccines and T cell-based immunotherapies.

PMID:35403257 | DOI:10.1002/prot.26343

Stat Med. 2022 Apr 10. doi: 10.1002/sim.9397. Online ahead of print.

ABSTRACT

We propose a test for multisample comparison studies that can be applied without strict assumptions, especially when the underlying population distributions are far from normal. The new test can detect differences not only in location or scale but also in shape parameters among parent population distributions. We are motivated by numerous medical studies, where the variables are not normally distributed and may present in the various groups more complex differences than simple differences in a particular aspect of underlying distributions, such as location or scale. In these situations, traditional ANOVA and Kruskal-Wallis tests are unreliable since the underlying assumptions are not valid. The proposed procedure also allows the researcher to determine which aspects are more responsible for a significant result. This is an important practical advantage over procedures that test for general differences among the distribution functions but cannot identify which aspects lead to significant results. The asymptotic distribution of the test statistic is analyzed along with its small sample behavior against several competing tests. The practical advantages of the proposed procedure are illustrated with a multisample comparison study of a biomarker for liver damage in patients with hepatitis C.

PMID:35403240 | DOI:10.1002/sim.9397

Stat Med. 2022 Apr 10. doi: 10.1002/sim.9393. Online ahead of print.

ABSTRACT

The development of a new diagnostic test ideally follows a sequence of stages which, among other aims, evaluate technical performance. This includes an analytical validity study, a diagnostic accuracy study, and an interventional clinical utility study. In this article, we propose a novel Bayesian approach to sample size determination for the diagnostic accuracy study, which takes advantage of information available from the analytical validity stage. We utilize assurance to calculate the required sample size based on the target width of a posterior probability interval and can choose to use or disregard the data from the analytical validity study when subsequently inferring measures of test accuracy. Sensitivity analyses are performed to assess the robustness of the proposed sample size to the choice of prior, and prior-data conflict is evaluated by comparing the data to the prior predictive distributions. We illustrate the proposed approach using a motivating real-life application involving a diagnostic test for ventilator associated pneumonia. Finally, we compare the properties of the approach against commonly used alternatives. The results show that, when suitable prior information is available, the assurance-based approach can reduce the required sample size when compared to alternative approaches.

PMID:35403239 | DOI:10.1002/sim.9393

Prenat Diagn. 2022 Apr 11. doi: 10.1002/pd.6143. Online ahead of print.

ABSTRACT

OBJECTIVE: Viral infections during pregnancy are a major health concern to mother and fetus. By repurposing cell-free Non Invasive Prenatal Testing (NIPT) sequencing data, we investigated prevalence and abundance of viral DNA in a cohort of 108,349 pregnant women.

METHOD: Cell-free DNA sequencing reads that did not map to any of the human chromosomes or mitochondrial DNA of the human reference genome build GRCh38 were aligned to 224 DNA viruses selected from the NCBI refseq viral database.

RESULTS: In total 443,665 reads of viral origin were detected across 42,273 samples representing 165 viral species. Several are known to be potentially harmful during pregnancy and/or childbirth, including Cytomegalovirus, Parvovirus B19 and Hepatitis B. Viral sequences were mostly detected at very low abundance. However, several cases had exceptionally high viral loads for Parvovirus B19, Hepatitis B and others. We found statistically significant associations between presence of viral DNA and gestational age, maternal age, fetal fraction, cfDNA concentration and others.

CONCLUSION: We demonstrate the feasibility to detect viral DNA from typical genome-wide NIPT cfDNA sequencing and describe the main characteristics of the viral DNA in our cohort. Our dataset of detected viral sequence reads is made publicly available to guide future clinical implementations. This article is protected by copyright. All rights reserved.

PMID:35403226 | DOI:10.1002/pd.6143

Clin Exp Metastasis. 2022 Apr 11. doi: 10.1007/s10585-022-10161-y. Online ahead of print.

NO ABSTRACT

PMID:35403206 | DOI:10.1007/s10585-022-10161-y

Int J Cardiol Cardiovasc Risk Prev. 2022 Mar 25;13:200129. doi: 10.1016/j.ijcrp.2022.200129. eCollection 2022 Jun.

ABSTRACT

BACKGROUND: Patients diagnosed with atrial fibrillation (AF) are at increased risk of stroke. Several guidelines to assess the risk of ischemic stroke and major bleeding in AF patients have been published. The CHA ₂DS ₂-VASc score has been adopted widely for predicting stroke within one year of the index AF diagnosis and is used to guide the prescription of anticoagulants. Anticoagulation therapy increases the risk of bleeding and scoring systems such as HAS-BLED assess the risk of major bleeding in anticoagulated patients. Despite these advances, no study has examined the risks of the two outcomes simultaneously. How patients’ fear of particular outcomes affects these risks also remains unknown.

METHODS: We incorporated the risks of ischemic stroke and major bleeding within one year of the index AF admission as well as the fear of stroke and bleeding of each individual patient. The patients enrolled in this retrospective observational study were identified using hospital admission data from the Myocardial Infarction Data Acquisition System (MIDAS), a statewide database including all hospitalizations for cardiovascular disease in New Jersey. Probabilities of the outcomes (ischemic stroke, major bleeding, both, or neither within one year of the index AF admission) were estimated using multinomial regression with patient demographics and comorbidities (heart failure [HF], hypertension [HTN], diabetes mellitus [DM], anemia, chronic obstructive pulmonary disease [COPD], kidney disease [KD], prior stroke or transient ischemic attack [TIA]) as predictors. These estimates were used in a Deming regression to model the association of ischemic stroke and major bleeding in grouped patients. The assessment of the importance of each outcome was superimposed on the final model to arrive at a recommendation for anticoagulation therapy.

RESULTS: The results of the Deming regression indicated a positive relationship between ischemic stroke and major bleeding (slope = 1.67, 95% confidence interval [CI] 1.37 to 1.97). Estimates of the risks of the two outcomes and the lines of best fit from Deming regression were determined. This model for risk assessment of stroke and major bleeding within one year of the index AF hospital admission combined objective data and subjective assessment of the relative fear of stroke versus bleeding by each hypothetical patient on 0-100 scale. Examples with the fears of stroke versus major bleeding being equal (50-50) and a higher fear of stroke (80-20) are presented.

CONCLUSIONS: The new model for risk assessment of ischemic stroke and major bleeding within one year of the index AF hospital admission proposed in this work used objective, empirically driven measures, and subjective assessment of the outcomes’ importance for individual patients. Such models may assist physicians in their decision making regarding anticoagulation therapy.

PMID:35403171 | PMC:PMC8991313 | DOI:10.1016/j.ijcrp.2022.200129

Neurotrauma Rep. 2022 Mar 15;3(1):129-138. doi: 10.1089/neur.2021.0026. eCollection 2022.

ABSTRACT

Football exposes its players to traumatic brain, neck, and spinal injury. It is unknown whether the adolescent football player develops imaging abnormalities of the brain and spine that are detectable on magnetic resonance imaging (MRI). The objective of this observational study was to identify potential MRI signatures of early brain and cervical spine (c-spine) injury in high school football players. Eighteen football players (mean age, 17.0 ± 1.5 years; mean career length, 6.3 ± 4.0 years) had a baseline brain MRI, and 7 had a follow-up scan 9-42 months later. C-spine MRIs were performed on 11 of the 18 subjects, and 5 had a follow-up scan. C-spine MRIs from 12 age-matched hospital controls were also retrospectively retrieved. Brain MRIs were reviewed by a neuroradiologist, and no cerebral microbleeds were detected. Three readers (a neuroradiologist, a neurosurgeon, and an orthopedic spine surgeon) studied the cervical intervertebral discs at six different cervical levels and graded degeneration using an established five-grade scoring system. We observed no statistically significant difference in disc degeneration or any trend toward increased disc degeneration in the c-spine of football players as compared with age-matched controls. Further research is needed to validate our findings and better understand the true impact of contact sports on young athletes.

PMID:35403100 | PMC:PMC8985528 | DOI:10.1089/neur.2021.0026

Cancer Diagn Progn. 2021 Nov 3;1(5):393-398. doi: 10.21873/cdp.10052. eCollection 2021 Nov-Dec.

ABSTRACT

BACKGROUND/AIM: Advanced understanding of screening and therapeutic modalities acts as provision for increased survival in patients diagnosed with optic nerve gliomas. Secondary primary malignancies (SPMs) in patients diagnosed with primary optic nerve glioma (OPG) are currently an uncharacterized frontier. This US national database analysis highlights the incidences of SPMs in patients diagnosed with primary OPG.

MATERIALS AND METHODS: Standardized incidence ratios (SIR) and excess absolute risk (EAR) for SPMs were calculated using the SEER-specific multiple outcome analysis. 95% SIR confidence intervals were calculated with statistical significance achieved at p<0.05.

RESULTS: SPMs originating from soft tissues (including the heart) (SIR=33.23, CI=6.85-97.11; EAR=5.07), breast (SIR=4.99, CI=1.36-12.77; EAR=5.57), female breast (SIR=5.03, CI=1.37-12.89; EAR=5.58), brain (SIR=105.38, CI=65.23-161.08; EAR=36.23), cranial nerves (SIR=103.29, CI=12.51-373.12; EAR=3.45), non-lymphocytic leukemia (SIR=15.05, CI=1.82-54.37; EAR=3.25), myeloid and monocytic leukemia (SIR=16.26, CI=1.97-58.75; EAR=3.27), and Kaposi’s sarcoma (SIR=79.88, CI=2.02-445.08; EAR=1.72) demonstrated significantly increased SIR. Overall, the values for cumulative SPM (SIR=6.04, CI=4.33-8.19; EAR=59.60) highlight the overall significance in incidence of SPM in patients diagnosed with OPG.

CONCLUSION: Clinical decision-making should reconcile enhanced propensities for development of SPM.

PMID:35403153 | PMC:PMC8962871 | DOI:10.21873/cdp.10052

Biophys Rep (N Y). 2022 Apr 4:100056. doi: 10.1016/j.bpr.2022.100056. Online ahead of print.

ABSTRACT

The identification of viral mutations that confer escape from antibodies is crucial for understanding the interplay between immunity and viral evolution. We describe a molecular dynamics (MD) based approach that goes beyond contact mapping, scales well to a desktop computer with a modern graphics processor, and enables the user to identify functional protein sites that are prone to vaccine escape in a viral antigen. We first implement our MD pipeline to employ site-wise calculation of Kullback-Leibler divergence in atom fluctuation over replicate sets of short-term MD production runs thus enabling a statistical comparison of the rapid motion of influenza hemagglutinin (HA) in both the presence and absence of three well-known neutralizing antibodies. Using this simple comparative method applied to motions of viral proteins, we successfully identified in silico all previously empirically confirmed sites of escape in influenza HA, predetermined via selection experiments and neutralization assays. Upon the validation of our computational approach, we then surveyed potential hot spot residues in the receptor binding domain of the SARS-CoV-2 virus in the presence of COVOX-222 and S2H97 antibodies. We identified many single sites in the antigen-antibody interface that are similarly prone to potential antibody escape and that match many of the known sites of mutations arising in the SARS-CoV-2 variants of concern. In the omicron variant, we find only minimal adaptive evolutionary shifts in the functional binding profiles of both antibodies. In summary, we provide an inexpensive and accurate computational method to monitor hot spots of functional evolution in antibody binding footprints.

PMID:35403093 | PMC:PMC8978532 | DOI:10.1016/j.bpr.2022.100056

Phytomed Plus. 2022 May;2(2):100233. doi: 10.1016/j.phyplu.2022.100233. Epub 2022 Jan 31.

ABSTRACT

BACKGROUND: In the absence of a specific drug for COVID 19, treatment with plant extracts could be an option worthy of further investigation and has motivated to evaluate the safety and anti-SARS-CoV-2 activity of plant extracts.

PURPOSE: To screen the phytochemicals for anti-SARS-CoV-2 in silico and evaluate their safety and efficacy in vitro and in vivo.

METHOD: The phytochemicals for anti-SARS-CoV-2 were screened in silico using molecular docking. The hits generated from in silico screening were subjected for extraction, isolation and purification. The anti-SARS-CoV-2 activity of Zanthoxylum piperitum (E1), Withania somnifera (E2), Calophyllum inophyllum (E3), Andrographis paniculata (E4), Centella asiatica (E5) ethanol extracts. The aerial parts were used for E1, E3, E4, E5 and root was used for E2. The in vitro safety and anti-SARS-CoV-2 activity of plant methanol extracts were performed in VeroE6 cells using Remdesivir as positive control. The acute and sub-acute toxicity study was performed in Wistar male and female rats.

RESULTS: The percentage of cell viability for E4, E5 and E2 treated VeroE6 cells were remarkably good on the 24th and 48th hour of treatment. The in vitro anti-SARS-CoV-2 activity of E4, E5 and E2 were significant for both E gene and N gene. The percentage of SARS-CoV-2 inhibition for E4 was better than Remdesivir. For E gene and N gene, Remdesivir showed IC₅₀ of 0.15 µM and 0.11 µM respectively, For E gene and N gene, E4 showed IC₅₀ of 1.18 µg and 1.16 µg respectively. Taking the clue from in vitro findings, the E4, E5 and E2 were combined (E 4.5.2) and evaluated for acute and sub-acute toxicity in Wistar male and female rats. No statistically significant difference in haematological, biochemical and histopathological parameters were noticed.

CONCLUSION: The study demonstrated the anti-SARS-CoV-2 activity in vitro and safety of plant extracts in both in vitro and in vivo experimental conditions.

PMID:35403091 | PMC:PMC8801592 | DOI:10.1016/j.phyplu.2022.100233