The Bovine Seminal Plasma Protein PDC-109 Possesses Pan-Antiviral Activity

Mammalian seminal plasma contains a multitude of bioactive components, including lipids, glucose, mineral elements, metabolites, proteins, cytokines, and growth factors, with various functions during insemination and fertilization. The seminal plasma protein PDC-109 is one of the major soluble components of the bovine ejaculate and is crucially important for sperm motility, capacitation, and acrosome reaction. A hitherto underappreciated function of seminal plasma is its anti-microbial and antiviral activity, which may limit the sexual transmission of infectious diseases during intercourse. We have recently discovered that PDC-109 inhibits the membrane fusion activity of influenza virus particles and significantly impairs viral infections at micromolar concentrations. Here we investigated whether the antiviral activity of PDC-109 is restricted to Influenza or if other mammalian viruses are similarly affected. We focused on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 19 (COVID-19), thoroughly assessing PDC-109 inhibition with SARS-CoV-2 Spike (S)-pseudotyped reporter virus particles, but also live-virus infections. Consistent with our previous publications, we found significant virus inhibition, albeit accompanied by substantial cytotoxicity. However, using time-of-addition experiments we discovered a treatment regimen that enables virus suppression without affecting cell viability. We furthermore demonstrated that PDC-109 is also able to impair infections mediated by the VSV glycoprotein (VSVg), thus indicating a broad pan-antiviral activity against multiple virus species and families.Open Access Publication Fund of the University of Duisburg-EssenPeer Reviewe

Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection.

The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NFκB, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts

Characterization of Hantavirus N Protein Intracellular Dynamics and Localization

Hantaviruses are enveloped viruses that possess a tri-segmented, negative-sense RNA genome. The viral S-segment encodes the multifunctional nucleocapsid protein (N), which is involved in genome packaging, intracellular protein transport, immunoregulation, and several other crucial processes during hantavirus infection. In this study, we generated fluorescently tagged N protein constructs derived from Puumalavirus (PUUV), the dominant hantavirus species in Central, Northern, and Eastern Europe. We comprehensively characterized this protein in the rodent cell line CHO-K1, monitoring the dynamics of N protein complex formation and investigating co-localization with host proteins as well as the viral glycoproteins Gc and Gn. We observed formation of large, fibrillar PUUV N protein aggregates, rapidly coalescing from early punctate and spike-like assemblies. Moreover, we found significant spatial correlation of N with vimentin, actin, and P-bodies but not with microtubules. N constructs also co-localized with Gn and Gc albeit not as strongly as the glycoproteins associated with each other. Finally, we assessed oligomerization of N constructs, observing efficient and concentration-dependent multimerization, with complexes comprising more than 10 individual proteins

Zygapophysial joint blocks in chronic low back pain: a test of Revel's model as a screening test

BACKGROUND: Only controlled blocks are capable of confirming the zygapophysial joints (ZJ) as the pain generator in LBP patients. However, previous workers have found that a cluster of clinical signs ("Revel's criteria"), may be valuable in predicting the results of an initial screening ZJ block. It was suggested that these clinical findings are unsuitable for diagnosis, but may be of value in selecting patients for diagnostic blocks of the lumbar ZJ's. To constitute evidence in favour of a clinical management strategy, these results need confirmation. This study evaluates the utility of 'Revel's criteria' as a screening tool for selection of chronic low back pain patients for controlled ZJ diagnostic blocks. METHODS: This study utilized a prospective blinded concurrent reference standard related validity design. Consecutive chronic LBP patients completed pain drawings, psychosocial distress and disability questionnaires, received a clinical examination and lumbar zygapophysial blocks. Two reference standards were evaluated simultaneously: 1. 75% reduction of pain on a visual analogue scale (replication of previous work), and 2. abolition of the dominant or primary pain. Using "Revel's criteria" as predictors, logistic regression analyses were used to test the model. Estimates of sensitivity, specificity, predictive values and likelihood ratios for selected variables were calculated for the two proposed clinical strategies. RESULTS: Earlier results were not replicated. Sensitivity of "Revel's criteria" was low sensitivity (<17%), and specificity high (approximately 90%). Absence of pain with cough or sneeze just reached significance (p = 0.05) within one model. CONCLUSIONS: "Revel's criteria" are unsuitable as a clinical screening test to select chronic LBP patients for initial ZJ blocks. However, the criteria may have use in identifying a small subset (11%) of patients likely to respond to the initial block (specificity 93%)

Technical Aspects of Flow Cytometry-based Measurable Residual Disease Quantification in Acute Myeloid Leukemia: Experience of the European LeukemiaNet MRD Working Party

Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization

Randomised controlled trial of a theoretically grounded tailored intervention to diffuse evidence-based public health practice [ISRCTN23257060]

BACKGROUND: Previous studies have shown that Norwegian public health physicians do not systematically and explicitly use scientific evidence in their practice. They work in an environment that does not encourage the integration of this information in decision-making. In this study we investigate whether a theoretically grounded tailored intervention to diffuse evidence-based public health practice increases the physicians' use of research information. METHODS: 148 self-selected public health physicians were randomised to an intervention group (n = 73) and a control group (n = 75). The intervention group received a multifaceted intervention while the control group received a letter declaring that they had access to library services. Baseline assessments before the intervention and post-testing immediately at the end of a 1.5-year intervention period were conducted. The intervention was theoretically based and consisted of a workshop in evidence-based public health, a newsletter, access to a specially designed information service, to relevant databases, and to an electronic discussion list. The main outcome measure was behaviour as measured by the use of research in different documents. RESULTS: The intervention did not demonstrate any evidence of effects on the objective behaviour outcomes. We found, however, a statistical significant difference between the two groups for both knowledge scores: Mean difference of 0.4 (95% CI: 0.2–0.6) in the score for knowledge about EBM-resources and mean difference of 0.2 (95% CI: 0.0–0.3) in the score for conceptual knowledge of importance for critical appraisal. There were no statistical significant differences in attitude-, self-efficacy-, decision-to-adopt- or job-satisfaction scales. There were no significant differences in Cochrane library searching after controlling for baseline values and characteristics. CONCLUSION: Though demonstrating effect on knowledge the study failed to provide support for the hypothesis that a theory-based multifaceted intervention targeted at identified barriers will change professional behaviour

Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) Trial)

<p>Abstract</p> <p>Background</p> <p>Evidence supports the use of exercise for chronic low back pain (CLBP); however, adherence is often poor due to ongoing pain. Auricular acupuncture is a form of pain relief involving the stimulation of points on the outer ear corresponding with specific body parts. It may be a useful adjunct to exercise in managing CLBP; however, there is only limited evidence to support its use with this patient group.</p> <p>Methods/Design</p> <p>This study was designed to test the feasibility of an assessor-blind randomised controlled trial which assess the effects on clinical outcomes and exercise adherence of adding manual auricular acupuncture to a personalised and supervised exercise programme (PEP) for CLBP. No sample size calculation has been carried out as this study aims to identify CLBP referral rates within the catchment area of the study site. The researchers aim to recruit four cohorts of n = 20 participants to facilitate a power analysis for a future randomised controlled trial. A computer generated random allocation sequence will be prepared centrally and used to allocate participants by cohort to one of the following interventions: 1) six weeks of PEP <it>plus </it>manual auricular acupuncture; 2) six weeks of PEP alone. Both groups will also complete a further six weeks of self-paced exercise with telephone follow-up support. In addition to a baseline and exit questionnaire at the beginning and end of the study, the following outcomes will be collected at baseline, and after 7, 13 and 25 weeks: pain frequency and bothersomeness, back-specific function, objective assessment and recall of physical activity, use of analgesia, perceived self-efficacy, fear avoidance beliefs, and beliefs about the consequences of back pain. Since this is a feasibility study, significance tests will not be presented, and treatment effects will be represented by point estimates and confidence intervals. For each outcome variable, analysis of covariance will be performed on the data, conditioning on the baseline value.</p> <p>Discussion</p> <p>The results of this study investigating the adjuvant effects of auricular acupuncture to exercise in managing CLBP will be used to inform the design of a future multi-centre randomised controlled trial.</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN94142364.</p

A decision support tool for predicting patients at risk of readmission : a comparison of classification trees, logistic regression, generalized additive models, and multivariate adaptive regression splines

This is the peer reviewed version of the following article: Eren Demir, “Classification Trees, Logistic Regression, Generalized Additive Models, and Multivariate Adaptive Regression Splines” Decision Sciences, Vol 45(5): 849-880, October 2014, which has been published in final form at doi: 10.1111/deci.12094. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. © 2014 Decision Sciences InstituteThe number of emergency (or unplanned) readmissions in the United Kingdom National Health Service (NHS) has been rising for many years. This trend, which is possibly related to poor patient care, places financial pressures on hospitals and on national healthcare budgets. As a result, clinicians and key decision makers (e.g. managers and commissioners) are interested in predicting patients at high risk of readmission. Logistic regression is the most popular method of predicting patient-specific probabilities. However, these studies have produced conflicting results with poor prediction accuracies. We compared the predictive accuracy of logistic regression with that of regression trees for predicting emergency readmissions within forty five days after been discharged from hospital. We also examined the predictive ability of two other types of data-driven models: generalized additive models (GAMs) and multivariate adaptive regression splines (MARS). We used data on 963 patients readmitted to hospitals with chronic obstructive pulmonary disease and asthma. We used repeated split-sample validation: the data were divided into derivation and validation samples. Predictive models were estimated using the derivation sample and the predictive accuracy of the resultant model was assessed using a number of performance measures, such as area under the receiver operating characteristic (ROC) curve in the validation sample. This process was repeated 1000 times—the initial data set was divided into derivation and validation samples 1000 times, and the predictive accuracy of each method was assessed each time. The mean ROC curve area for the regression tree models in the 1000 derivation samples was 0.928, while the mean ROC curve area of a logistic regression model was 0.924. Our study shows that logistic regression model and regression trees had performance comparable to that of more flexible, data-driven models such as GAMs and MARS. Given that the models have produced excellent predictive accuracies, this could be a valuable decision support tool for clinicians (health care managers, policy makers, etc.) for informed decision making in the management of diseases, which ultimately contributes to improved measures for hospital performance management.Peer reviewedFinal Accepted Versio