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

A continuum description of the energetics and evolution of stepped surfaces in strained nanostructures

As a departure from existing continuum approaches for describing the stability and evolution of surfaces of crystalline materials, this article provides a description of surface evolution based on the physics of the main feature imposed by the discrete nature of the material, namely, crystallographic surface steps. It is shown that the formation energy of surface steps depends on the sign of extensional strain of the crystal surface, and this behavior plays a crucial role in surface evolution. The nature of this dependence implies that there is no energetic barrier to nucleation of islands on the growth surface during deposition, and that island faces tend toward natural orientations which have no counterpart in unstrained materials. This behavior is expressed in terms of a small number of parameters that can be estimated through atomistic analysis of stepped surfaces. The continuum framework developed is then applied to study the time evolution of surface shape of an epitaxial film being deposited onto a substrate. The kinetic equation for mass transport is enforced in a weak form by means of a variational formulation [...].Comment: 25 pages, 7 figs, KEYWORDS=surface diffusion, surface energy, morphology evolution, semiconductor material, stability and bifurcatio

A Population-Based Serologic Survey of Immunity to Tetanus in the United States

Background. Vaccination rates are frequently considered a surrogate measure of protection. To provide more accurate estimates, serum levels of antibody against tetanus were measured as part of the third National Health and Nutrition Examination Survey (NHANES III), which studied a representative sample of the civilian, noninstitutionalized population of the United States. Methods. We measured tetanus antitoxin using a solid- phase enzyme immunoassay in serum samples from 10,618 persons six years of age and older who were examined during phase 1 of NHANES III in 1988 to 1991. Results. Overall, 69.7 percent of Americans six years of age and older had protective levels of tetanus antibodies (0.15 IU per milliliter). The rate decreased from 87.7 percent among those 6 to 11 years of age to 27.8 percent among those 70 years of age or older. Among children 6 to 16 years of age, 82.2 percent had protective levels of tetanus antibodies, with little variation according to race or ethnicity. More men than women were immune (79.0percent vs. 62.4 percent). Mexican Americans had a significantly lower rate of immunity (57.9 percent, P 0.05) than either non-Hispanic whites (72.7 percent) or non-Hispanic blacks (68.1 percent). Those with a history of military service, higher levels of education, or incomes above the poverty level were more likely to have protective antibody levels. Although the prevalence of immunity declined rapidly starting at the age of 40 years, most of the 107 cases of tetanus (with 20 deaths) reported in 1989 and 1990 occurred in persons 60 years of age or older. Conclusions. Despite the fact that effective vaccines against tetanus have been available since the 1940s, many Americans do not have immunity to tetanus, and the rates are lowest among the elderly. There is an excellent correlation between vaccination rates (96 percent) and immunity (96 percent) among six-year-olds. However, antibody levels decline over time, and one fifth of older children (10 to 16 years of age) do not have protective antibody levels

Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization.

A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette-Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities

Prolonged Excretion of Poliovirus among Individuals with Primary Immunodeficiency Disorder: An Analysis of the World Health Organization Registry.

Individuals with primary immunodeficiency disorder may excrete poliovirus for extended periods and will constitute the only remaining reservoir of virus after eradication and withdrawal of oral poliovirus vaccine. Here, we analyzed the epidemiology of prolonged and chronic immunodeficiency-related vaccine-derived poliovirus cases in a registry maintained by the World Health Organization, to identify risk factors and determine the length of excretion. Between 1962 and 2016, there were 101 cases, with 94/101 (93%) prolonged excretors and 7/101 (7%) chronic excretors. We documented an increase in incidence in recent decades, with a shift toward middle-income countries, and a predominance of poliovirus type 2 in 73/101 (72%) cases. The median length of excretion was 1.3 years (95% confidence interval: 1.0, 1.4) and 90% of individuals stopped excreting after 3.7 years. Common variable immunodeficiency syndrome and residence in high-income countries were risk factors for long-term excretion. The changing epidemiology of cases, manifested by the greater incidence in recent decades and a shift to from high- to middle-income countries, highlights the expanding risk of poliovirus transmission after oral poliovirus vaccine cessation. To better quantify and reduce this risk, more sensitive surveillance and effective antiviral therapies are needed

First-Response ABCDE Management of Status Epilepticus: A Prospective High-Fidelity Simulation Study

Respiratory infections following status epilepticus (SE) are frequent, and associated with higher mortality, prolonged ICU stay, and higher rates of refractory SE. Lack of airway protection may contribute to respiratory infectious complications. This study investigates the order and frequency of physicians treating a simulated SE following a systematic Airways-Breathing-Circulation-Disability-Exposure (ABCDE) approach, identifies risk factors for non-adherence, and analyzes the compliance of an ABCDE guided approach to SE with current guidelines. We conducted a prospective single-blinded high-fidelity trial at a Swiss academic simulator training center. Physicians of different affiliations were confronted with a simulated SE. Physicians (; n; = 74) recognized SE and performed a median of four of the five ABCDE checks (interquartile range 3-4). Thereof, 5% performed a complete assessment. Airways were checked within the recommended timeframe in 46%, breathing in 66%, circulation in 92%, and disability in 96%. Head-to-toe (exposure) examination was performed in 15%. Airways were protected in a timely manner in 14%, oxygen supplied in 69%, and antiseizure drugs (ASDs) administered in 99%. Participants' neurologic affiliation was associated with performance of fewer checks (regression coefficient -0.49;; p; = 0.015). We conclude that adherence to the ABCDE approach in a simulated SE was infrequent, but, if followed, resulted in adherence to treatment steps and more frequent protection of airways

Identification of microorganisms by a rapid PCR panel from positive blood cultures leads to faster optimal antimicrobial therapy - a before-after study

BACKGROUND The BioFire® FilmArray® Blood Culture Identification Panel 1 (BF-FA-BCIP) detects microorganisms with high accuracy in positive blood cultures (BC) - a key step in the management of patients with suspected bacteraemia. We aimed to compare the time to optimal antimicrobial therapy (OAT) for the BF-FA-BCIP vs. standard culture-based identification. METHODS In this retrospective single-centre study with a before-after design, 386 positive BC cases with identification by BF-FA-BCIP were compared to 414 controls with culture-based identification. The primary endpoint was the time from BC sampling to OAT. Secondary endpoints were time to effective therapy, length of stay, (re-)admission to ICU, in-hospital and 30-day mortality. Outcomes were assessed using Cox proportional hazard models and logistic regressions. RESULTS Baseline characteristics of included adult inpatients were comparable. Main sources of bacteraemia were urinary tract and intra-abdominal infection (19.2% vs. 22.0% and 16.8% vs. 15.7%, for cases and controls, respectively). Median (95%CI) time to OAT was 25.5 (21.0-31.2) hours with BF-FA-BCIP compared to 45.7 (37.7-51.4) hours with culture-based identification. We observed no significant difference for secondary outcomes. CONCLUSIONS Rapid microorganism identification by BF-FA-BCIP was associated with a median 20-h earlier initiation of OAT in patients with positive BC. No impact on length of stay and mortality was noted. TRIAL REGISTRATION Clinicaltrials.gov, NCT04156633, registered on November 5, 2019

Effect of COVID-19 on acute treatment of ST-segment elevation and Non-ST-segment elevation acute coronary syndrome in northwestern Switzerland

To investigate the effect of the corona virus disease 2019 (COVID-19) pandemic on the acute treatment of patients with ST-segment elevation (STEMI) and Non-ST-segment elevation acute coronary syndrome (NSTE-ACS).; We retrospectively identified patients presenting to the emergency department (ED) with suspected ACS. We evaluated the number of percutaneous coronary interventions (PCIs) for STEMI, NSTE-ACS, and elective PCI cases. In STEMI patients, we assessed the time from chest pain onset (cpo) to ED presentation, post-infarction left ventricular ejection fraction (LVEF), and time from ED presentation to PCI. We directly compared cases from two time intervals: January/February 2020 versus March/April 2020 (defined as 2 months before and after the COVID-19 outbreak). In a secondary analysis, we directly compared cases from March/April 2020 with patients from the same time interval in 2019.; From January to April 2020, 765 patients presented with acute chest pain to the ED. A dramatic reduction of ED presentations after compared to before the COVID-19 outbreak (31% relative reduction) was observed. Overall, 398 PCIs were performed, 220/398 PCIs (55.3%) before versus 178/398 PCIs (44.7%) after the outbreak. While numbers for NSTE-ACS and elective interventions declined by 21% and 31%, respectively, the number of STEMI cases remained stable. Time from cpo to ED presentation, post-infarction LVEF, and median door-to-balloon time remained unchanged.; In contrast to previous reports, our findings do not confirm the dramatic drop in STEMI cases and interventions in northwestern Switzerland as observed in other regions and hospitals around the world

Vaccine schedules and the effect on humoral and intestinal immunity against poliovirus: a systematic review and network meta-analysis.

BACKGROUND: The eradication of wild and vaccine-derived poliovirus requires the global withdrawal of oral poliovirus vaccines (OPVs) and replacement with inactivated poliovirus vaccines (IPVs). The first phase of this effort was the withdrawal of the serotype 2 vaccine in April 2016, with a switch from trivalent OPVs to bivalent OPVs. The aim of our study was to produce comparative estimates of humoral and intestinal mucosal immunity associated with different routine immunisation schedules. METHODS: We did a random-effect meta-analysis with single proportions and a network meta-analysis in a Bayesian framework to synthesise direct and indirect data. We searched MEDLINE and the Cochrane Library Central Register of Controlled Trials for randomised controlled trials published from Jan 1, 1980, to Nov 1, 2018, comparing poliovirus immunisation schedules in a primary series. Only trials done outside western Europe or North America and without variation in age schedules (ie, age at administration of the vaccine) between study groups were included in the analyses, because trials in high-income settings differ in vaccine immunogenicity and schedules from other settings and to ensure consistency within the network of trials. Data were extracted directly from the published reports. We assessed seroconversion against poliovirus serotypes 1, 2, and 3, and intestinal immunity against serotype 2, measured by absence of shedding poliovirus after a challenge OPV dose. FINDINGS: We identified 437 unique studies; of them, 17 studies with a maximum of 8279 evaluable infants were eligible for assessment of humoral immunity, and eight studies with 4254 infants were eligible for intestinal immunity. For serotype 2, there was low between-trial heterogeneity in the data (τ=0·05, 95% credible interval [CrI] 0·009-0·15) and the risk ratio (RR) of seroconversion after three doses of bivalent OPVs was 0·14 (95% CrI 0·11-0·17) compared with three doses of trivalent OPVs. The addition of one or two full doses of an IPV after a bivalent OPV schedule increased the RR to 0·85 (0·75-1·0) and 1·1 (0·98-1·4). However, the addition of an IPV to bivalent OPV schedules did not significantly increase intestinal immunity (0·33, 0·18-0·61), compared with trivalent OPVs alone. For serotypes 1 and 3, there was susbstantial inconsistency and between-trial heterogeneity between direct and indirect effects, so we only present pooled estmates on seroconversion, which were at least 80% for serotype 1 and at least 88% for serotype 3 for all vaccine schedules. INTERPRETATION: For WHO's polio eradication programme, the addition of one IPV dose for all birth cohorts should be prioritised to protect against paralysis caused by type 2 poliovirus; however, this inclusion will not prevent transmission or circulation in areas with faecal-oral transmission. FUNDING: UK Medical Research Council

Immunogenicity of Reduced-Dose Monovalent Type 2 Oral Poliovirus Vaccine in Mocuba, Mozambique

Funding Information: This work was supported by Rotary International, through a grant from the World Health Organization (grant 2019/889177-2). Publisher Copyright: © The Author(s) 2020.Background. The monovalent type 2 oral poliovirus vaccine (mOPV2) stockpile is low. One potential strategy to stretch the existing mOPV2 supply is to administer a reduced dose: 1 drop instead of 2. Methods. We conducted a randomized, controlled, open-label, noninferiority trial (10% margin) to compared immunogenicity after administration of 1 versus 2 drops of mOPV2. We enrolled 9–22-month-old infants from Mocuba district of Mozambique. Poliovirus neutralizing antibodies were measured in serum samples collected before and 1 month after mOPV2 administration. Immune response was defined as seroconversion from seronegative (<1:8) at baseline to seropositive (≥1:8) after vaccination or boosting titers by ≥4-fold for those with titers between 1:8 and 1:362 at baseline. The trial was registered at anzctr.org.au (no. ACTRN12619000184178p). Results. We enrolled 378 children, and 262 (69%) completed per-protocol requirements. The immune response of mOPV2 was 53.6% (95% confidence interval, 44.9%–62.1%) and 60.6% (52.2%–68.4%) in 1-drop and 2-drop recipients, respectively. The noninferiority margin of the 10% was not reached (difference, 7.0%; 95% confidence interval, −5.0% to 19.0%). Conclusion. A small loss of immunogenicity of reduced mOPV2 was observed. Although the noninferiority target was not achieved, the Strategic Advisory Group of Experts on Immunization recommended the 1-drop strategy as a dose-sparing measure if mOPV2 supplies deteriorate further.publishersversionpublishe