No fitness effects of same-sex copulations in male red flour beetles.

Same-sex sexual behavior occurs in diverse animal taxa, yet its evolutionary maintenance is poorly understood as such behavior seems to be costly and does not directly increase reproductive success. We used male Tribolium castaneum beetles, which frequently engage in same-sex copulations, to test if same-sex sexual behavior influences future male mating behavior and reproductive success of males. Furthermore, we tested whether same-sex sexual behavior has benefits via indirect sperm translocation. We conducted a series of mating trials demonstrating that males exposed to same-sex behavior did not sire less offspring compared to control males that did not engage in same-sex behavior. This suggests that same-sex copulations did not lead to fitness costs in subsequent mating interactions. In addition, we found no evidence that indirect sperm translocation via an intermediate male occurs in T. castaneum. Taken together, these results imply that same-sex sexual behavior in males is associated with no costs in terms of lower mating rate and reduced siring success and does not seem to entail benefits. Moreover, our data conform to the hypothesis that sexual indiscrimination is prevalent in this species, which may explain the relatively high frequency of same-sex sexual behavior in T. castaneum.

Five-year results from a prospective, single-arm European trial on decellularized allografts for aortic valve replacement-the ARISE Study and ARISE Registry Data.

OBJECTIVES: Decellularized aortic homografts (DAH) were introduced as a new option for aortic valve replacement for young patients. METHODS: A prospective, EU-funded, single-arm, multicentre study in 8 centres evaluating non-cryopreserved DAH for aortic valve replacement. RESULTS: A total of 144 patients (99 male) were prospectively enrolled in the ARISE Trial between October 2015 and October 2018 with a median age of 30.4 years [interquartile range (IQR) 15.9-55.1]; 45% had undergone previous cardiac operations, with 19% having 2 or more previous procedures. The mean implanted DAH diameter was 22.6 mm (standard deviation 2.4). The median operation duration was 312 min (IQR 234-417), the median cardiopulmonary bypass time was 154 min (IQR 118-212) and the median cross-clamp time 121 min (IQR 93-150). No postoperative bypass grafting or renal replacement therapy were required. Two early deaths occurred, 1 due to a LCA thrombus on day 3 and 1 due ventricular arrhythmia 5 h postoperation. There were 3 late deaths, 1 death due to endocarditis 4 months postoperatively and 2 unrelated deaths after 5 and 7 years due to cancer and Morbus Wegener resulting in a total mortality of 3.47%. After a median follow-up of 5.9 years [IQR 5.1-6.4, mean 5.5 years. (standard deviation 1.3) max. 7.6 years], the primary efficacy end-points peak gradient with median 11.0 mmHg (IQR 7.8-17.6) and regurgitation of median 0.5 (IQR 0-0.5) of grade 0-3 were excellent. At 5 years, freedom from death/reoperation/endocarditis/bleeding/thromboembolism were 97.9%/93.5%/96.4%/99.2%/99.3%, respectively. CONCLUSIONS: The 5-year results of the prospective multicentre ARISE trial continue to show DAH to be safe for aortic valve replacement with excellent haemodynamics.

Propensity score stratified MAP prior and posterior inference for incorporating information across multiple potentially heterogeneous data sources.

Incorporation of external information is becoming increasingly common when designing clinical trials. Availability of multiple sources of information has inspired the development of methodologies that account for potential heterogeneity not only between the prospective trial and the pooled external data sources but also between the different external data sources themselves. Our approach proposes an intuitive way of handling such a scenario for the continuous outcomes setting by using propensity score-based stratification and then utilizing robust meta-analytic predictive priors for each stratum to incorporate the prior data to distinguish among different external data sources in each stratum. Through extensive simulations, our approach proves to be more efficient and less biased than the currently available methods. A real case study using clinical trials that study schizophrenia from multiple different sources is also included.

Duration of and time to response in oncology clinical trials from the perspective of the estimand framework.

Duration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early-stage clinical studies in oncology when efficacy is assessed by the best overall response and presented as the overall response rate. Despite common use of DOR and TTR in particular in single-arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols.

NIMBUS study protocol: a single-centre feasibility study of non-invasive monitoring with bowel ultrasound in paediatric inflammatory bowel disease.

INTRODUCTION: Incidence of inflammatory bowel disease (IBD) is increasing in childhood and treatment increasingly targets mucosal healing. Monitoring bowel inflammation requires endoscopy or MRI enterography which are invasive, expensive and have long waiting lists.We aim to examine the feasibility of a non-invasive monitoring tool-bowel ultrasound (BUS)-in children with IBD and explore correlations with inflammatory markers and disease activity measures. Some BUS criteria have been found to correlate with these markers; however, this has not been validated in children.We aim to examine the feasibility of BUS for monitoring inflammation in this population; highlighting useful parameters for this purpose. We aim to inform a larger scale randomised controlled trial using BUS. METHODS AND ANALYSIS: This prospective observational feasibility study will be carried out over 24 months at the Noah's Ark Children's Hospital for Wales, Cardiff; with the endpoint recruitment of 50 participants. Children aged 2-18 years with a modified Porto criteria diagnosis of IBD will be included.Patients without IBD or who have previously undergone IBD-related surgery will be excluded; as will families unable to give informed consent.Ultrasound scan images and reports will be collected, as well as laboratory results and clinical outcomes.The primary aim will assess the feasibility of targeted BUS for disease monitoring; including recruitment statistics. The secondary aims will involve data collection and correlation analysis for targeted ultrasound parameters, biomarkers, disease activity scores and prediction of changes in treatment. The statistical methods will include: feasibility metrics, descriptive statistics, cross-tabulation and χ2 analysis, correlation analysis, regression analysis. ETHICS AND DISSEMINATION: Ethical approval is granted by NHS Research Ethics Committee. The sponsor is Cardiff and Vale University Health Board. We will publish the results in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: NCT05673278.

Pharmacometrics enhanced Bayesian borrowing approach to improve clinical trial efficiency: Case of empagliflozin in type 2 diabetes.

We report use of a pharmacometrics enhanced Bayesian borrowing (PEBB) approach to leverage historical clinical trial data on a drug product to build models, project the outcome of future clinical trials, and borrow information from these projections to improve the efficiency of future target trials. This design takes a two-stage approach. First, a design phase is performed before target trial data are available to determine the operating characteristics and an appropriate tuning parameter that will be used in the subsequent analysis phase of a chosen target trial. Second, once the target trial data are available, the analysis phase is performed with the determined tuning parameter. This step is where borrowing is applied from these projections to inform the results for the target trial. To illustrate how a PEBB could improve the efficiency of clinical trials, we apply our design to trials with empagliflozin for treating patients with type 2 diabetes. We performed a retrospective evaluation applying the method to a phase III target trial and a hypothetical smaller trial. The type I error could be kept below 10% while increasing the trial power and effective sample size. Our findings suggest that a PEBB has the potential to increase the power of clinical trials, while controlling for type I error, by leveraging the information from previous trials through population pharmacokinetic/pharmacodynamic modeling and simulation.

Biodiesel exhaust particle airway toxicity and the role of polycyclic aromatic hydrocarbons.

Renewable alternatives to fossil diesel (FD) including fatty acid methyl ester (FAME) biodiesel have become more prevalent. However, toxicity of exhaust material from their combustion, relative to the fuels they are displacing has not been fully characterised. This study was carried out to examine particle toxicity within the lung epithelium and the role for polycyclic aromatic hydrocarbons (PAHs). Exhaust particles from a 20% (v/v) blend of FAME biodiesel had little impact on primary airway epithelial toxicity compared to FD derived particles but did result in an altered profile of PAHs, including an increase in particle bound carcinogenic B[a]P. Higher blends of biodiesel had significantly increased levels of more carcinogenic PAHs, which was associated with a higher level of stress response gene expression including CYP1A1, NQO1 and IL1B. Removal of semi-volatile material from particulates abolished effects on airway cells. Particle size difference and toxic metals were discounted as causative for biological effects. Finally, combustion of a single component fuel (Methyl decanoate) containing the methyl ester molecular structure found in FAME mixtures, also produced more carcinogenic PAHs at the higher fuel blend levels. These results indicate the use of FAME biodiesel at higher blends may be associated with an increased particle associated carcinogenic and toxicity risk.

Case report: Eighteen nails gun shots in the head, thorax and abdomen but still conscious at admission: A challenging patient for the cardiac surgeon!

We report an unusual case of multiple penetrating cerebral, cardiac and abdominal injuries following a suicidal attempt using a nail gun. Successful treatment required several emergency procedures and resulted from a wise interdisciplinary management and timing of surgery.

Percutaneous large-bore aspiration embolectomy with veno-arterial extracorporal membrane oxygenation support or standby in patients with high-risk pulmonary embolism and contraindications to thrombolysis: a preliminary single centre experience.

AIMS: Large-bore catheter aspiration embolectomy reduces thrombus burden and right ventricle strain and improves haemodynamics after pulmonary embolism (PE). Sparse data are available for patients with high-risk PE and contraindications to thrombolysis or thrombolysis failure, particularly if veno-arterial extracorporal membrane oxygenation (VA-ECMO) is required. METHODS AND RESULTS: All patients with acute high-risk PE and contraindications to thrombolysis undergoing FlowTriever® percutaneous embolectomy and VA-ECMO circulatory support (or standby) at the University Hospital Zurich between April 2021 and August 2022 were retrospectively analysed. The primary outcome was the combination of recurrent PE, heart failure hospitalization, and all-cause death at 30 days. The analysis included 15 patients: mean age was 63.1 years and 14 (93%) were men. Overall, four (27%) patients presented with cardiac arrest, eight (53%) with ongoing obstructive shock, and three (20%) with persistent arterial hypotension. Veno-arterial extracorporal membrane oxygenation was implanted prior to aspiration embolectomy in eight (53%) patients. Three of seven patients without initial VA-ECMO support experienced periprocedural cardiac arrest, of whom two received ECMO support before completion of embolectomy. Veno-arterial extracorporal membrane oxygenation weaning was successful in all patients after a mean of 5.4 days. There was one periprocedural death in a patient who did not receive VA-ECMO support following a periprocedural cardiac arrest. The primary outcome at 30 days occurred in five (33.3%; 95% confidence interval 13.0-61.3%) patients. CONCLUSION: This study provides preliminary evidence for the feasibility of percutaneous large-bore aspiration embolectomy in combination with VA-ECMO support (or standby) in patients with high-risk PE and contraindications to thrombolysis.

Inmunogenicidad y capacidad protectora de variantes de la nueva vacuna antialérgica PROLINEM DS / mmunogeni city and protective efficacy of variants of a novel PROLINEM DS anti - allergic vaccine

Introducción: La vacuna antialérgica de segunda generación PROLINEM-DS está compuesta por alérgenos del ácaro Dermatophagoides siboney y la combinación de adyuvantes: proteoliposoma de N. meningitidis B y gel de hidróxido de aluminio. La adsorción del alérgeno es relevante para la seguridad y eficacia clínica de las vacunas adsorbidas en gel de hidróxido de aluminio en estudios previos se demostró la influencia negativa de los iones fosfato en la adsorción del alérgeno. Objetivo: Evaluar la inmunogenicidad y capacidad protectora de cuatro variantes de formulación obtenidas dentro del espacio de diseño de la vacuna PROLINEM DS. Métodos: Se emplearon 4 variantes de formulación con diferentes contenidos de tampón fosfato salino y gel de hidróxido de aluminio. Se administraron a ratones BALB/c 3 dosis subcutáneas una por semana. Luego, los ratones fueron sometidos a reto alergénico por aerosol. Resultados: Todas las variantes indujeron anticuerpos IgG1 e IgG2a alérgeno específico. Este efecto se correlacionó con el balance de citoquinas proinflamatorias Th1/Th2 en los pulmones y en los ganglios. La variante con reducción de tampón fosfato salino y gel de hidróxido de aluminio fue la de mayor índice IgG/IgE después de la vacunación. Esta relación muestra, en una variable, el equilibrio entre los componentes potencialmente bloqueadores y efectores. La tolerancia local en el lugar de la inyección mostró una reducción de los granulomas en los ratones vacunados con menos gel de hidróxido de aluminio. Conclusiones: La reducción del contenido de gel de hidróxido de aluminio y fosfatos se consideran mejoras farmacéuticas sin inconvenientes en cuanto a la inmunogenicidad de esta vacuna con un perfil de seguridad satisfactorio para futuros ensayos clínicos en humanos.

Introduction: The second generation anti allergic vaccine named PROLINEM DS is based on allergens from D. siboney house dust mite and a combination adjuvant containing PL and Alum. Allergen adsorption is relevant both safety and clinical efficacy in alum-adsorbed vaccines. Negative influence of phosphate ions on allergen adsorption was demonstrated in previous researches. Objective: To evaluate immunogenicity and protective efficacy of four variants obtained within design space of PROLINEM DS vaccine. Methods: Four variants were differentiated from each other by both phosphate and alum contents. Balb/c mice were administered with 3 doses by subcutaneous route. Further, mice were subjected to allergen aerosol challenge. Results: Specific IgG1 and IgG2a antibodies were induced by four vaccine variants. It was correlated with pro inflammatory cytokines balance Th1/Th2 both in lungs and lymphatic nodes. Formulation with lower PBS and Alum levels showed the highest IgG/IgE ratio at the end of vaccination schedule. This ratio shows in one variable the balance between potentially blocking and effector components. Mice injected with lower level of Alum showed a reduction of granuloma size in the site of vaccine administration. Conclusion: Decrease both alum and phosphate contents were a pharmaceutical improvement for antiallergic vaccines formulation. Safety and efficacy in this vaccine are crucial for future human clinical trials.

Comportamiento de la IgE y las subclases de IgG en las infecciones por Staphylococcus aureus / Manifestation of IgE and IgG subclasses in Staphylococcus aureus infections

RESUMEN Introducción: Las infecciones cutáneas por Staphylococcus aureus, se presentan con alta frecuencia en la comunidad. La forma superficial de esta es la foliculitis. Una extensión hacia el tejido subcutáneo da como resultado la formación de una lesión supurativa local llamada forúnculo. Aproximadamente el 20 % de los pacientes con forúnculo presentan una o más recidivas durante el año siguiente, y cierto número presenta forunculosis recidivante crónica durante meses o años. Objetivo: Conocer el comportamiento de los niveles de IgE y las subclases de IgG expresadas en pacientes y controles, para inferir el patrón de la respuesta inmune a la infección. Métodos: Se realizó un estudio prospectivo donde se determinaron las subclases de inmunoglobulina G (IgG) y los niveles de inmunoglobulina E (IgE) en suero de 25 enfermos con lesiones cutáneas por Staphylococcus aureus, y 25 controles sanos, provenientes del banco de sangre. Se elaboró un antígeno (Bacterina de Staphylococcus aureus) y en su enfrentamiento se procedió con la metodología de normalización y validación de ensayos inmunoenzimáticos para cuantificar IgG humana. Los resultados se expresaron en densidades ópticas y gráficamente como la relación matemática (IgG1/3) para Th1 e (IgE/IgG4) para Th2, en el suero de los pacientes. Resultados: Se obtuvo respuesta IgG1 e IgG4 en pacientes y controles y respuesta IgE anti Staphylococcus aureus en pacientes. Conclusiones: Como Staphylococcus aureus es flora normal de la piel, los controles ya han tenido contacto con él, lo que provoca el desarrollo de respuesta Th1 (IgG1) y anticuerpos bloqueadores (IgG4). Contrariamente, los enfermos desarrollan respuesta Th2 (IgE) y la infección.

ABSTRACT Introduction: Staphylococcus aureus skin infections occur with high frequency in the community. Folliculitis is its superficial form. An extension into the subcutaneous tissue results in the formation of a local suppurative lesion known as a furunculosis. Approximately 20% of patients with a furuncle have one or more recurrences over the next year, and a certain number have chronic relapsing furunculosis for months or years. Objective: to know the manifestation of IgE levels and IgG subclasses expressed in patients and controls, to infer the pattern of the immune response to infection. Methods: we conducted a prospective study where immunoglobulin G (IgG) subclasses and immunoglobulin E (IgE) levels were determined in serum of 25 ill patients with Staphylococcus aureus skin lesions, and 25 healthy controls, from the blood bank. An antigen (Staphylococcus aureus bacterin) was elaborated and in its confrontation, the normalization and validation methodology of immunoenzymatic assays to quantify human IgG was carried out. The results were expressed in optical densities and graphically as the mathematical ratio (IgG1/3) for Th1 and (IgE/IgG4) for Th2, in the serum of the patients. Results: IgG1 and IgG4 responses were obtained in patients and controls, and anti-Staphylococcus aureus IgE responses in patients. Conclusions: the controls have already had contact with Staphylococcus aureus, as it is normal flora of the skin, which causes the development of Th1 response (IgG1) and antibodies blockers (IgG4). On the contrary, ill patients develop a Th2 response (IgE) and the infection.

Infection by dsRNA viruses is associated with enhanced sporulation efficiency in Saccharomyces cerevisiae.

Upon starvation diploid cells of the facultative sexual yeast Saccharomyces cerevisiae undergo sporulation, forming four metabolically quiescent and robust haploid spores encased in a degradable ascus. All endosymbionts, whether they provide net benefits or costs, utilize host resources; in yeast, this should induce an earlier onset of sporulation. Here, we tested whether the presence of endosymbiotic dsRNA viruses (M satellite and L-A helper) correspond with higher sporulation rate of their host, S. cerevisiae. We find that S. cerevisiae hosting both the M and L-A viruses (so-called "killer yeasts") have significantly higher sporulation efficiency than those without. We also found that the removal of the M virus did not reduce sporulation frequency, possibly because the L-A virus still utilizes host resources with and without the M virus. Our findings indicate that either virulent resource use by endosymbionts induces sporulation, or that viruses are spread more frequently to sporulating strains. Further exploration is required to distinguish cause from effect.

Serological responses to COVID-19 Comirnaty booster vaccine, London, United Kingdom, September to December 2021.

Serum samples were collected pre- and post-booster vaccination with Comirnaty in 626 participants (aged ≥ 50 years) who had received two Comirnaty doses < 30 days apart, two Comirnaty doses ≥ 30 days apart or two Vaxzevria doses ≥ 30 days apart. Irrespective of primary vaccine type or schedule, spike antibody GMTs peaked 2-4 weeks after second dose, fell significantly ≤ 38 weeks later and rose above primary immunisation GMTs 2-4 weeks post-booster. Higher post-booster responses were observed with a longer interval between primary immunisation and boosting.

Small Airway Susceptibility to Chemical and Particle Injury.

Small airways (SA) in humans are commonly defined as those conducting airways <2 mm in diameter. They are susceptible to particle- and chemical-induced injury and play a major role in the development of airway disease such as COPD and asthma. Susceptibility to injury can be attributed in part to structural features including airflow dynamics and tissue architecture, but recent evidence may indicate a more prominent role for cellular composition in directing toxicological responses. Animal studies support the hypothesis that inherent cellular differences across the tracheobronchial tree, including metabolic CYP450 expression in the distal conducting airways, can influence SA susceptibility to injury. Currently, there is insufficient information in humans to make similar conclusions, prompting further necessary work in this area. An understanding of why the SA are more susceptible to certain chemical and particle exposures than other airway regions is fundamental to our ability to identify hazardous materials, their properties, and accompanying exposure scenarios that compromise lung function. It is also important for the ability to develop appropriate models for toxicity testing. Moreover, it is central to our understanding of SA disease aetiology and how interventional strategies for treatment may be developed. In this review, we will document the structural and cellular airway regional differences that are likely to influence airway susceptibility to injury, including the role of secretory club cells. We will also describe recent advances in single-cell sequencing of human airways, which have provided unprecedented details of cell phenotype, likely to impact airway chemical and particle injury.

Sexual selection moderates heat stress response in males and females.

A widespread effect of climate change is the displacement of organisms from their thermal optima. The associated thermal stress imposed by climate change has been argued to have a particularly strong impact on male reproduction but evidence for this postulated sex-specific stress response is equivocal.One important factor that may explain intra- and interspecific variation in stress responses is sexual selection, which is predicted to magnify negative effects of stress. Nevertheless, empirical studies exploring the interplay of sexual selection and heat stress are still scarce.We tested experimentally for an interaction between sexual selection and thermal stress in the red flour beetle Tribolium castaneum by contrasting heat responses in male and female reproductive success between enforced monogamy and polygamy.We found that polygamy magnifies detrimental effects of heat stress in males but relaxes the observed negative effects in females. Our results suggest that sexual selection can reverse sex differences in thermal sensitivity, and may therefore alter sex-specific selection on alleles associated with heat tolerance.Assuming that sexual selection and natural selection are aligned to favour the same genetic variants under environmental stress, our findings support the idea that sexual selection on males may promote the adaptation to current global warming. Read the free Plain Language Summary for this article on the Journal blog.

Precisión de las referencias bibliográficas de los Trabajos de Fin de Grado en Enfermería / Accuracy of the bibliographic references used for Final Nursing Degree Projects

Objetivo: identificar la calidad de la bibliografía empleada por los estudiantes de 4º curso del Grado de Enfermería de la Facultad de Enfermería, Fisioterapia y Podología de la Universidad Complutense de Madrid.Método: se realizó el estudio mediante la selección y evaluación de las fuentes de información y referencias de artículos de revista de 26 Trabajos de Fin de Grado (TFG) para determinar su concordancia con las normas de Vancouver, al ser estas el sistema de citación más utilizado en las publicaciones de Ciencias de la Salud y el recomendado por el profesorado encargado de la docencia y el seguimiento de los grupos de TFG.Resultados: de un total de 957 referencias se seleccionaron 604 (63,11%) artículos de revistas, identificando y categorizando 1.545 errores (2,55 por referencia). El grupo de los mejor calificados presentó un 17,05% de referencias correctas, frente al 9,13% de los peor calificados.Conclusiones: se encontró una baja precisión de las referencias en ambos grupos. Sin embargo, los trabajos con mayor calificación aportaron más referencias, mayor uso de revistas científicas, mayor concordancia con las normas de Vancouver y menor número de errores.(AU)

Objective: to identify the quality of the bibliography used by students in their 4th year of the Nursing Degree at the School of Nursing, Physiotherapy and Chiropody of the Universidad Complutense de Madrid.Method: the study was conducted through the selection and evaluation of information sources and references from journal articles in 26 Final Degree Projects (FDPs), in order to determine their conformity with the Vancouver Standards, because this is the quotation system more widely used in Health Sciences publications, and recommended by the professors responsible for education and follow-up of FDP groups.Results: out of 957 references in total, there was a selection of 604 (63.11%) journal articles, and 1.545 errors (2.55 per reference) were detected and classified. The group of those with the best scores presented 17.05% of correct references, vs. 9.13% for the group with the worst score.Conclusions: low accuracy in references was found in both groups. However, the projects with higher scores provided more references, higher use of scientific journals, higher agreement with Vancouver Standards, and lower number of errors.(AU)

Scent of a killer: How could killer yeast boost its dispersal?

Vector-borne parasites often manipulate hosts to attract uninfected vectors. For example, parasites causing malaria alter host odor to attract mosquitoes. Here, we discuss the ecology and evolution of fruit-colonizing yeast in a tripartite symbiosis-the so-called "killer yeast" system. "Killer yeast" consists of Saccharomyces cerevisiae yeast hosting two double-stranded RNA viruses (M satellite dsRNAs, L-A dsRNA helper virus). When both dsRNA viruses occur in a yeast cell, the yeast converts to lethal toxin­producing "killer yeast" phenotype that kills uninfected yeasts. Yeasts on ephemeral fruits attract insect vectors to colonize new habitats. As the viruses have no extracellular stage, they depend on the same insect vectors as yeast for their dispersal. Viruses also benefit from yeast dispersal as this promotes yeast to reproduce sexually, which is how viruses can transmit to uninfected yeast strains. We tested whether insect vectors are more attracted to killer yeasts than to non­killer yeasts. In our field experiment, we found that killer yeasts were more attractive to Drosophila than non-killer yeasts. This suggests that vectors foraging on yeast are more likely to transmit yeast with a killer phenotype, allowing the viruses to colonize those uninfected yeast strains that engage in sexual reproduction with the killer yeast. Beyond insights into the basic ecology of the killer yeast system, our results suggest that viruses could increase transmission success by manipulating the insect vectors of their host.