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Sharon J Parish,1 Rossella E Nappi,2 Michael L Krychman,3 Susan Kellogg-Spadt,4 James A Simon,5 Jeffrey A Goldstein,6 Sheryl A Kingsberg7 1Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Obstetrics and Gynecology, IRCCS Policlinico San Matteo University, University of Pavia, Pavia, Italy; 3Southern California Center for Sexual Health and Survivorship Medicine and Clinical Faculty University of California Irvine, Newport Beach and Irvine, CA, USA; 4Pelvic and Sexual Health Institute, Philadelphia, PA, USA; 5Obstetrics and Gynecology, George Washington University, Washington, DC, USA; 6Novo Nordisk Inc, Princeton, NJ, USA; 7Departments of Reproductive Biology and Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA Abstract: Several recent, large-scale studies have provided valuable insights into patient perspectives on postmenopausal vulvovaginal health. Symptoms of vulvovaginal atrophy, which include dryness, irritation, itching, dysuria, and dyspareunia, can adversely affect interpersonal relationships, quality of life, and sexual function. While approximately half of postmenopausal women report these symptoms, far fewer seek treatment, often because they are uninformed about hypoestrogenic postmenopausal vulvovaginal changes and the availability of safe, effective, and well-tolerated treatments, particularly local vaginal estrogen therapy. Because women hesitate to seek help for symptoms, a proactive approach to conversations about vulvovaginal discomfort would improve diagnosis and treatment. Keywords: health care professional, hypoactive sexual desire disorder, local vaginal estrogen therapy, quality of life, urinary tract infection, vulvovaginal atrophy

Abstract Animal age at maturity can be used as a universal and simple predictor of species extinction risk. At present, methods to estimate age at maturity are typically species-specific, limiting comparisons among species, or are infeasible due to practical constraints. To overcome this, here we develop a universal predictor of species-level age at maturity for vertebrates. We show that modelling the frequency of ‘CG’ sequences (CpG sites) in gene promoter regions yields rapid predictions of vertebrate age at maturity. Our models predict age at maturity with remarkable accuracy and generalisability, with median error rates of 30% (less than 1 year) and are robust to genome assemblies of varying quality. We generate predictions for 1912 vertebrate species for which age at maturity estimates were previously absent from public databases. The predictions can be used to help to inform management decisions for the many species for which more detailed population information is currently unavailable.

Abstract Background Resilience is an essential psychological trait that empowers individuals to adapt and thrive in the face of challenges. Although it is acknowledged that health professionals need to possess high levels of resilience, there has been limited research comparing how different groups of health students, particularly school leaver undergraduates and mature age graduate entry students, develop resilience in their coursework. Methods This study combines both objective (academic grades with validated survey results) and subjective data (interviews) to compare how resilience is related to academic coursework performance for two groups of pharmacy students: the mature age graduate entry (GE, N = 64) learners and school leaver undergraduate (UG, N = 208) learners. We employed a sequential explanatory mixed methods design using surveys, academic performance data and semi-structured interviews. The survey tapped constructs related to resilience (burnout, stressors and coping methods) while the interviews elicited a more nuanced understanding of individual and environmental factors. Results Although there was no statistical difference in burnout experience between the two groups, GE students exhibited more positive resilience attitudes than UG when selecting resilience statements on the survey. Both cohorts indicated in the survey that engaging in distraction activities (physical exercise, sleeping, listening to music, anything other than the stressor) was their most preferred method of relieving stress. Within UG student survey responses, those who indicated support from partners, friends and family had better academic performance, while those who did not report coping methods did worse academically. The three key environmental factors we identified that contributed to both undergraduate and graduate entry resilience were workload, feedback provision and psychosocial support. Conclusions Currently, there is still a need for resilience programs geared at academic success to be implemented in higher education. This study provides objective evidence of academic success coupled with exploration into the nuances of resilience amongst different student groups. It not only highlights the differing resilience development strategies and burnout coping mechanisms in emerging health professionals, but showcases the juxtaposition of two different learner groups (UG and GE students) within a discipline. The cross-cohort facilitation of learning as in the discipline-specific strategies identified can help both groups develop resilience and inform future innovations. By comparing mature-age graduate students and younger-in-age undergraduate students, we identified a wider range of strategies and more positive attitudes to burnout in mature-age students. Health and clinical educators in university health degrees, clinical placements and clinical workplaces can develop effective training materials based on findings from this study to 1) assist undergraduate younger-age health students with developing resilience and 2) further refine mature-age health students’ and practicing health professionals’ resilience in today’s fast-paced clinical workplaces.

Abstract Background Traditionally managed semi-natural pastures are recognised for their high biodiversity. One drawback is that these pastures are often low in fodder production and hence rather unprofitable, which may lead to abandonment. Two ways to increase production and profitability and maintain grazing are to (i) offer the grazers supplementary feed, or (ii) co-enclose the semi-natural pasture with an improved pasture. Both practices may transfer nutrients to the semi-natural pasture, with potential negative effects on biodiversity. This systematic review aimed to analyse the available evidence concerning the following primary question: “What is the effect of giving grazers access to additional nutrient sources on biodiversity in semi-natural pastures?” (Q1). We also used two supporting questions: “What is the effect of giving grazers access to additional nutrient sources on nutrient status of the soils of semi-natural pastures?” (Q2) and “How do the grazers of semi-natural pastures behave while having access to additional nutrient sources?” (Q3). Methods Searches for peer-reviewed and grey literature were made using bibliographic databases, search engines, specialist websites, and stakeholder contacts. Literature was screened for relevance according to predefined eligibility criteria, and critical appraisal was performed using the tool CEECAT. A database of the relevant studies was compiled. Descriptive information about the evidence base is presented in tables and an interactive evidence atlas. Because of absent study setup replication, Q1 and Q2 were not analysed quantitatively. However, sample size allowed the use of mixed modelling to quantitatively analyse Q3 regarding the effects of (i) co-enclosing an improved pasture on grazers’ electivity for the improved area, and (ii) supplementary feed on the forage intake of grazers. Review findings A total of 12 articles on the effects of supplementary feeding and 19 on the effects of co-enclosing an improved pasture were included, of which some targeted multiple review questions. Because of the limited literature, it is not possible to draw any conclusions concerning the effects on biodiversity (Q1) or nutritional status (Q2) in semi-natural pastures. For Q3, 28 studies fulfilled our criteria, of which 18 investigated the behaviour of grazers related to co-enclosing an improved pasture, and 10 investigated their forage intake while having access to supplementary fodder. The results show that all grazer species except goats preferred grazing in the improved areas regardless of whether they were grazing together with other grazer species or not. We found no effect of supplementary feeding on forage intake of the grazers. Conclusions We detected a knowledge gap concerning the effects of the two additional nutrient sources on semi-natural pasture biodiversity (Q1) and nutrient status (Q2), which points toward further research needs. Analysis of Q3 showed that grazers prefer to graze improved compared to semi-natural pasture areas. However, how this behaviour subsequently affects nutrient transport and biodiversity is unclear and cannot be translated into management recommendations. To gain better knowledge about the primary question of our review, research focusing specifically on this question is needed. We provide suggestions for how such studies could be designed, including spatio-temporal setup, and key management and environmental conditions to consider.

Abstract Securing a sustainable global food supply for a growing population requires a shift toward a more plant-based diet. The application of plant-based proteins is therefore increasing, but unpleasant off-flavors complicate their use. Here, we screened 97 microorganisms for their potential to remove off-flavors in a process with limiting amounts of fermentable sugar. This allowed the production of a more neutral-tasting, purified food ingredient while limiting microbial growth and the production of typical fermentation end products. We demonstrate that various lactic acid bacteria (LAB) and yeasts remove “green” aldehydes and ketones. This conversion can be carried out in less than one hour in almond, pea, potato, and oat proteins. Heterofermentative LAB was best at aldehyde and ketone neutralization with minimum de novo formation of microbial volatiles such as ethylacetate (sweet, fruity) or alpha-diketones (butter- and cheese-like). While sensory properties were improved, changes in protein solubility, emulsification, foaming, and in vitro digestibility were limited.

Current methods for testing water for faecal contamination rely on the culture of faecal indicator bacteria (FIB; Escherichia coli and Enterococci) that take 24–48 h, which leads to delays in taking proactive measures and poses a risk to public health. More rapid methods are therefore required. Here, we have tested a rapid, portable assay (Bacterisk) that detects the bacterial biomarker endotoxin in 30 min to quantify the bacterial biomass present, to evaluate 159 coastal water samples and to compare the results with the traditional culture of FIB. There was a significant correlation between the Bacterisk data given in endotoxin risk (ER) units and FIB culture that could accurately distinguish between poor and sufficient or good quality bathing water using the EU bathing directive values. Receiver operating characteristic analysis was used to determine the optimal ER threshold for coastal water samples, and the area under the curve was 0.9176 with a p-value of

Abstract Two distemper paint samples taken from decorative boards in Uvdal stave church, Norway, were analysed using palaeoproteomics, with an aim of identifying their binder and possible contaminants. The results point at the use of calfskin to produce hide glue as the original paint binder, and are consistent with the instructions of binder production and resource allocation in the historical records of Norway. Although we did not observe any evidence of prior restoration treatments using protein-based materials, we found abundant traces of human saliva proteins, as well as a few oats and barley peptides, likely deposited together on the boards during their discovery in the 1970s. This work illustrates the need to fully consider contamination sources in palaeoproteomics and to inform those working with such objects about the potential for their contamination.

Background information: Inappropriate disposal of unused antimicrobials can push the environment out of balance, and increase the likelihood of antimicrobial-resistant organisms to grow. We aimed to investigate the recommendations for the disposal of unwanted antibiotics given as advice to consumers by community pharmacists practising in Australia. Methods: A cross-sectional study using mystery shopping explored pharmacists' recommendations for disposing of unwanted antibiotics. Simulated patients called community pharmacies across Australia for advice on disposing of leftover antibiotic mixtures. Findings: Of 1577 pharmacists called across Australia, over 59 % recommended incorrect disposal methods, i.e., putting the leftover antibiotic syrup in the home rubbish bin or down the sink or toilet, 28.4 % recommended putting the unused antibiotic straight into the rubbish bin, and 10 pharmacists recommended throwing the leftover syrup on the grass, soil, or in a street drain. There were 19 pharmacists who did not want to recommend disposal at all; some recommended calling the prescriber to ask. Of the pharmacists who advised consumers to return unwanted antibiotic liquid to their pharmacy, 21 (1.3 % overall) indicated that they would pour it down the sink at the pharmacy upon being returned. Interpretation: Pharmacists' advice on antibiotic disposal varied despite the availability of a national scheme enabling consumers to return unwanted medicines to pharmacies for this purpose. Enhanced education and policies could help pharmacists guide the public on proper disposal.

Background: Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that usually mimics type 1 or 2A von Willebrand disease (VWD). Key Clinical Question: Can AVWS mimic the phenotype of type 2B VWD? Clinical Approach: A 64-year-old male patient presented with thrombocytopenia, normal routine hemostasis results, and normal VWF antigen and factor VIII levels but reduced von Willebrand factor (VWF) activity (31 IU/dL). The ristocetin-induced platelet aggregation test showed paradoxical aggregation at low doses of ristocetin, suggesting type 2B VWD, but no deleterious sequence variation was found in either the VWF or GP1BA genes, compatible with AVWS. Serum protein electrophoresis revealed a monoclonal immunoglobulin G antibody. Conclusion: This AVWS with a 2B phenotype VWD was probably related to a monoclonal immunoglobulin G antibody causing a VWF conformational change, resulting in increased affinity to platelet glycoprotein-Ib. In the event of surgery or bleeding, treatment with vonicog alfa seems to be the best option for this patient.

IntroductionBradykinesia is an essential diagnostic criterion for Parkinson’s disease (PD) but is frequently observed in many non-parkinsonian movement disorders, complicating differential diagnosis, particularly in disorders featuring tremors. The presence of bradykinetic features in the subset of dystonic tremors (DT), either “pure” dystonic tremors or tremors associated with dystonia, remains currently unexplored. The aim of the current study was to evaluate upper limb bradykinesia in DT patients, comparing them with healthy controls (HC) and patients with PD by observing repetitive finger tapping (FT).MethodsThe protocol consisted of two main parts. Initially, the kinematic recording of repetitive FT was performed using optical hand tracking system (Leap Motion Controller). The values of amplitude, amplitude decrement, frequency, frequency decrement, speed, acceleration and number of halts of FT were calculated. Subsequently, three independent movement disorder specialists from different movement disorders centres, blinded to the diagnosis, rated the presence of FT bradykinesia based on video recordings.ResultsThirty-six subjects participated in the study (12 DT, 12 HC and 12 early-stage PD). Kinematic analysis revealed no significant difference in the selected parameters of FT bradykinesia between DT patients and HC. In comparisons between DT and PD patients, PD patients exhibited bigger amplitude decrement and slower FT performance. In the blinded clinical assessment, bradykinesia was rated, on average, as being present in 41.6% of DT patients, 27.7% of HC, and 91.7% of PD patients. While overall inter-rater agreement was moderate, weak agreement was noted within the DT group.DiscussionClinical ratings indicated signs of bradykinesia in almost half of DT patients. The objective kinematic analysis confirmed comparable parameters between DT and HC individuals, with more pronounced abnormalities in PD across various kinematic parameters. Interpretation of bradykinesia signs in tremor patients with DT should be approached cautiously and objective motion analysis might complement the diagnostic process and serve as a decision support system in the choice of clinical entities.

Alternative splicing (AS) is an important molecular biological mechanism regulated by complex mechanisms involving a plethora of cis and trans-acting elements. Furthermore, AS is tissue specific and altered in various pathologies, including infectious, inflammatory, and neoplastic diseases. Recently developed immuno-oncological therapies include monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells targeting, among others, immune checkpoint (ICP) molecules. Despite therapeutic successes have been demonstrated, only a limited number of patients showed long-term benefit from these therapies with tumor entity-related differential response rates were observed. Interestingly, splice variants of common immunotherapeutic targets generated by AS are able to completely escape and/or reduce the efficacy of mAb- and/or CAR-based tumor immunotherapies. Therefore, the analyses of splicing patterns of targeted molecules in tumor specimens prior to therapy might help correct stratification, thereby increasing therapy success by antibody panel selection and antibody dosages. In addition, the expression of certain splicing factors has been linked with the patients’ outcome, thereby highlighting their putative prognostic potential. Outstanding questions are addressed to translate the findings into clinical application. This review article provides an overview of the role of AS in (tumor) diseases, its molecular mechanisms, clinical relevance, and therapy response.

This paper analyses a series of websites of language institutions in Japan and highlights the consistent contradictions between the language policies advertised and the recruitment of non-native English-speaking teachers (NNESTs) conducted. I did a qualitative website study that involved an analysis of the most in-demand ELT companies and organizations in Japan. The websites were of ELT institutions, which were a mix of private institutions that teach for profit, and organisations that are mediators in supplying teachers (Assistant Language Teachers–ALTs) for schools around the country. The aim of this was to compare and contrast the discourse in language ideology with recruitment policies at these companies regarding NNESTs. Conducting a study of these companies’ websites enabled me to find and highlight trends in recruitment and language ideologies where I found a series of inconsistencies but also some encouraging trends in moves towards a more global outlook in teacher recruitment and discourse ideology. At the heart of the analysis was the question of whether a move towards more NNEST recruitment was due to changes in language ideology or economic necessity. The increase in non-native English-speaking teacher recruitment in Japan would be an encouraging development in attitudes and policy if it was related to a recognition of how the linguistic landscape in the 21st century is evolving but it seems apparent that economic factors are the motivating factor.

Abstract Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram’s anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.