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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.

Magnetic nanoparticles (MNPs), particularly iron oxide nanoparticles (IONPs), play a pivotal role in biomedical applications ranging from magnetic resonance imaging (MRI) enhancement and cancer hyperthermia treatments to biosensing. This study focuses on the synthesis, characterization, and application of IONPs with two different size distributions for frequency mixing magnetic detection (FMMD), a technique that leverages the nonlinear magnetization properties of MNPs for sensitive biosensing. IONPs are synthesized through thermal decomposition and subsequent growth steps. Our findings highlight the critical influence of IONP size on the FMMD signal, demonstrating that larger particles contribute dominantly to the FMMD signal. This research advances our understanding of IONP behavior, underscoring the importance of size in their application in advanced diagnostic tools.

Abstract Animal age data are valuable for management of wildlife populations. Yet, for most species, there is no practical method for determining the age of unknown individuals. However, epigenetic clocks, a molecular‐based method, are capable of age prediction by sampling specific tissue types and measuring DNA methylation levels at specific loci. Developing an epigenetic clock requires a large number of samples from animals of known ages. For most species, there are no individuals whose exact ages are known, making epigenetic clock calibration inaccurate or impossible. For many epigenetic clocks, calibration samples with inaccurate age estimates introduce a degree of error to epigenetic clock calibration. In this study, we investigated how much error in the training data set of an epigenetic clock can be tolerated before it resulted in an unacceptable increase in error for age prediction. Using four publicly available data sets, we artificially increased the training data age error by iterations of 1% and then tested the model against an independent set of known ages. A small effect size increase (Cohen's d >0.2) was detected when the error in age was higher than 22%. The effect size increased linearly with age error. This threshold was independent of sample size. Downstream applications for age data may have a more important role in deciding how much error can be tolerated for age prediction. If highly precise age estimates are required, then it may be futile to embark on the development of an epigenetic clock when there is no accurately aged calibration population to work with. However, for other problems, such as determining the relative age order of pairs of individuals, a lower‐quality calibration data set may be adequate.

Abstract Colorectal cancer possesses marked intratumoral heterogeneity. While subclonal interactions between Vogelstein driver mutations have been extensively studied, less is known about competitive or cooperative effects between subclonal populations with other cancer driver mutations. FBXW7 is a cancer driver mutation which is present in close to 17% of colorectal cancer cells. In this study, we generated isogenic FBXW7 mutant cells using CRISPR-Cas9. We identified an upregulation of oxidative phosphorylation and DNA damage in FBXW7 mutant cells, which surprisingly proliferated at a decreased rate compared to wildtype cells. To determine subclonal interactions, wildtype and mutant FBXW7 cells were cocultured using a Transwell system. Wildtype cells cocultured with FBXW7 mutant cells similarly developed DNA damage which was not observed when wildtype cells were co-cultured with other wildtype cells, suggesting that FBXW7 mutant cells were inducing DNA damage in neighbouring wildtype cells. Using mass spectrometry, we identified AKAP8 as being secreted by FBXW7 mutant cells into the coculture media. Furthermore, overexpression of AKAP8 in wildtype cells recapitulated the DNA damage phenotype observed during coculture, while co-culture of wildtype cells with double mutant FBXW7 −/− /AKAP8 −/− cells abrogated the DNA damage phenotype. Here, we describe a hitherto unknown phenomenon of AKAP8-mediated DNA damage from FBXW7 mutant to neighbouring wildtype cells. Our findings demonstrate the importance of elucidating the local effect of cancer driver mutations between subclonal populations.

Abstract Background Benefit of early awake prone positioning for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether prone position plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared to usual care alone. Methods In this multicentre randomised clinical trial, 268 patients were randomly assigned to awake prone position plus usual care (N = 135) or usual care alone (N = 132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Main secondary outcomes included the rates of NIV, of intubation or death, within 28 days. Results Median time spent each day in the prone position within 72 h of randomisation was 90 min (IQR 30–133). The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the prone position group and 12.9% (17/132) in the usual care group [odds ratio adjusted for stratification (aOR) 0.43; 95% confidence interval (CI) 0.14–1.35]. The probability of intubation, or intubation or death (secondary outcomes) was lower in the prone position group than in the usual care group (aOR 0.11; 95% CI 0.01–0.89 and aOR 0.09; 95% CI 0.01–0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2 ≥ 95% on inclusion (aOR 0.11; 95% CI 0.01–0.90, and aOR 0.09; 95% CI 0.03–0.27, respectively). Conclusions Awake prone position plus usual care in COVID-19 patients in medical wards did not decrease the composite outcome of need for NIV or intubation or death. Trial registration ClinicalTrials.gov Identifier: NCT04363463 . Registered 27 April 2020.

Artificial intelligence (AI) has shown its effectiveness in helping clinical users meet evolving challenges. Recently, ChatGPT, a newly launched AI chatbot with exceptional text comprehension capabilities, has triggered a global wave of AI popularization and application in seeking answers through human‒machine dialogues. Gastric cancer, as a globally prevalent disease, has a five-year survival rate of up to 90% when detected early and treated promptly. This research aims to explore ChatGPT's potential in disseminating gastric cancer knowledge, providing consultation recommendations, and interpreting endoscopy reports. Through experimentation, the GPT-4 model of ChatGPT achieved an appropriateness of 91.3% and a consistency of 95.7% in a gastric cancer knowledge test. Furthermore, GPT-4 has demonstrated considerable potential in consultation recommendations and endoscopy report analysis.

Abstract Age at sexual maturity is a key life history trait that can be used to predict population growth rates and develop life history models. In many wild animal species, the age at sexual maturity is not accurately quantified. This results in a reduced ability to accurately model demography of wild populations. Recent studies have indicated the potential for CpG density within gene promoters to be predictive of other life history traits, specifically maximum lifespan. Here, we have developed a machine learning model using gene promoter CpG density to predict the mean age at sexual maturity in mammalian species. In total, 91 genomes were used to identify 101 unique gene promoters predictive of age at sexual maturity across males and females. We found these gene promoters to be most predictive of age at sexual maturity in females (R2 = 0.881) compared to males (R2 = 0.758). The median absolute error rate was also found to be lower in females (0.427 years) compared to males (0.785 years). This model provides a novel method for species‐level age at sexual maturity prediction without the need for long‐term monitoring. This study also highlights a potential epigenetic mechanism for the onset of sexual maturity, indicating the possibility of using epigenetic biomarkers for this important life history trait.

Over the last 30 years, high-resolution site documentation has rapidly developed, with analogue drawings and film photography being replaced with high-precision digital recordings. Today, most archaeological field data sets are produced using digital tools that store spatial and visual information in various digital formats directly, i.e., born-digital. A fully digital workflow makes the process of combining, comparing, and integrating field datasets quicker, easier, and potentially more analytically powerful. However, at sites where both analogue and born-digital data sets have been produced, additional procedural digitization steps are required before full data interoperability is achieved. In cases where the archaeological sites have a long excavation history, multiple generations of analogue and digital site documentation techniques have often been used, making it particularly challenging to physically reconstruct an excavated site based on its archival material. The Middle Stone Age site of Blombos Cave, South Africa, is a prime example of this type of challenging situation. This site features a more than 3-meter-deep and well-preserved archaeological sequence dated to between 300 and 100 000 years ago. Since it was initially excavated in 1991, multiple archaeological campaigns have been carried out (>15), and the excavations are still ongoing. The field documentation from Blombos Cave has, over the years, produced varied but rich datasets that have never been integrated into a single, coherent, and accessible archive. In this paper we evaluate the changes in excavation protocol at Blombos Cave over time, and we use this knowledge to digitally integrate and map the various stages of excavation within a three-dimensional framework using digital photogrammetry and archival photographs. The archaeological and analytical value of this approach is exemplified through multiple case studies, in which we demonstrate how and why the merging of old and new archaeological field data can lead to new results, specifically by offering more complete mapping and more accurate and analytically dynamic visualisations. The research history at Blombos Cave is not unique or site-specific. Our approach would be applicable to a wide variety of sites and contexts where long-running excavations have produced a mix of analogue and digital field data.

BackgroundIndividuals reporting self-injury are at greater risk of several adverse outcomes, including suicide. There is reason to be concerned how these individuals cope when stressful life events increase. This study aimed to investigate the trajectories of anxiety and depressive symptoms and the predictive value of self-injury history in individuals with psychiatric symptoms during the unique and stressful conditions of the COVID-19 pandemic.MethodsIn a longitudinal population cohort study (N = 1810) ranging from 2020 to 2022, anxiety (measured by Generalized Anxiety Disorder, GAD-7) and depressive symptoms (measured by Patient Health Questionnaire, PHQ-9) were self-reported monthly during 12 months. Latent growth curve models with and without self-reported self-injury history as predictors were conducted.ResultsOverall, anxiety and depressive symptoms decreased from baseline, but remained at moderate severity at follow-up. Individuals reporting suicidal or nonsuicidal self-injury reported significantly higher symptom severity at baseline. In addition, individuals reporting suicidal self-injury demonstrated a slower rate of decline in the symptom load over the course of 12 months.ConclusionsOver the course of 12 months, anxiety and depressive symptoms decreased in individuals with psychiatric symptoms, but still indicate a psychiatric burden. Individuals with a history of self-injury could be more vulnerable in face of stressful conditions such as those experienced during the COVID-19 pandemic.

AbstractConservation translocations require robust post‐release monitoring to evaluate their success, which can be challenging to implement and maintain. Monitoring techniques that can account for the dispersal and cryptic nature of translocated animals are necessary to provide critical information on persistence and distribution. In this study, we developed a highly sensitive environmental DNA (eDNA) assay specific to the critically endangered western swamp turtle (Pseudemydura umbrina), a species currently undergoing trials of assisted colonization. Actively filtering sufficient volumes of water in lentic systems is difficult due to high concentrations of clogging particulates, therefore we assessed the viability of passive sampling in a controlled environment by submerging filter membranes and directly extracting DNA. Active sampling detected P. umbrina with a 97.6% detection rate, whereas passive sampling resulted in an 8.3% detection rate. We then used a fine‐scale eDNA sampling design and radio‐tracked translocated P. umbrina at the assisted colonization wetland to investigate eDNA dispersal and spatial monitoring resolution. We detected P. umbrina at 42% (7/17) of eDNA sample sites, and the probability of a positive eDNA detection was negatively associated with the distance of P. umbrina from the sampling site, indicating limited eDNA dispersal from the source. Systems with low natural mixing and limited eDNA dispersal provide an opportunity for high‐resolution spatial and temporal monitoring via targeted eDNA approaches. This is beneficial for monitoring rare species in these systems, as such high‐resolution results can provide insights into species presence, distribution, and microhabitat use.

ABSTRACTThe human Epstein–Barr virus (EBV), as a member of the human γ herpes viruses (HHV), is known to be linked with distinct tumor types. It is a double-stranded DNA virus and its genome encodes among others for 48 different microRNAs (miRs). Current research demonstrated a strong involvement of certain EBV-miRs in molecular immune evasion mechanisms of infected cells by, e.g., the disruption of human leukocyte antigen (HLA) class Ia and NKG2D functions. To determine novel targets of EBV-miRs involved in immune surveillance, ebv-miR-BART7-3p, an EBV-encoded miR with high expression levels during the different lytic and latent EBV life cycle phases, was overexpressed in human HEK293T cells. Using a cDNA microarray-based comparative analysis, 234 (229 downregulated and 5 upregulated) deregulated human transcripts were identified in ebv-miR-BART7-3p transfectants, which were mainly involved in cellular processes and molecular binding. A statistically significant downregulation of the anti-proliferative and tumor-suppressive hsa-miR-34A and the anti-viral interferon lambda (IFNL)3 mRNA was found. The ebv-miR-BART7-3p-mediated downregulation of IFNL3 expression was due to a direct interaction with the IFNL3 3’-untranslated region (UTR) as determined by luciferase reporter gene assays including the identification of the accurate ebv-miR-BART7-3p binding site. The effect of ebv-miR-BART7-3p on the IFNL3 expression was validated both in human cell lines in vitro and in human tissue specimen with known EBV status. These results expand the current knowledge of EBV-encoded miRs and their role in immune evasion, pathogenesis and malignant transformation.

Abstract The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.

Nowadays, the increasing number of medical diagnostic data and clinical data provide more complementary references for doctors to make diagnosis to patients. For example, with medical data, such as electrocardiography (ECG), machine learning algorithms can be used to identify and diagnose heart disease to reduce the workload of doctors. However, ECG data is always exposed to various kinds of noise and interference in reality, and medical diagnostics only based on one-dimensional ECG data is not trustable enough. By extracting new features from other types of medical data, we can implement enhanced recognition methods, called multimodal learning. Multimodal learning helps models to process data from a range of different sources, eliminate the requirement for training each single learning modality, and improve the robustness of models with the diversity of data. Growing number of articles in recent years have been devoted to investigating how to extract data from different sources and build accurate multimodal machine learning models, or deep learning models for medical diagnostics. This paper reviews and summarizes several recent papers that dealing with multimodal machine learning in disease detection, and identify topics for future research.

Objectives: Image-based sarcopenia has been the subject of recent studies, hypothesized as a prognostic factor for patients with thoracoabdominal aortic aneurysms. Methods and Materials: We conducted a single-center retrospective analysis of patients who underwent complex endovascular repair for thoracoabdominal aortic aneurysms between 2008 and 2016. CT image assessment was performed and patients were classified as sarcopenic and non-sarcopenic using two stratification methods: skeletal mass index (SMI) and total psoas muscle index (TPMI). According to sex, each patient was defined as sarcopenic if their SMI or TPMI was in the lowest third of the study group. The primary endpoint was impact of sarcopenia on perioperative mortality and long-term survival. Secondary endpoints were perioperative complications. Results: From a total of 155 patients, 135 were eligible for study. Overall, in-hospital mortality was 5.9% (8/135). The 30-day, 1-year, 3-year and 5-year mortality was 10.4% (14/135), 20% (27/135), 28.1% (38/135) and 31.1% (42/135), respectively. There was no difference in the long-term mortality rates between sarcopenic and non-sarcopenic patients regardless of the stratification method used (p = 0.4 for SMI and p = 0.2 for TPMI). According to SMI, 30-day mortality of sarcopenic patients was significantly lower in comparison to non-sarcopenic patients (1/45, 2.2% vs. 13/90, 14.4%, p = 0.028). Based on the total psoas muscle index, sarcopenic patients were at higher risk for development of pulmonary complications in comparison to non-sarcopenic patients postoperatively (p = 0.03). Conclusion: Using SMI and TPMI, sarcopenia was not associated with reduced long-term survival in patients undergoing complex endovascular repair for thoracoabdominal aortic aneurysms.

Abstract Insect declines are a global issue with significant ecological and economic ramifications. Yet, we have a poor understanding of the genomic impact these losses can have. Genome‐wide data from historical specimens have the potential to provide baselines of population genetic measures to study population change, with natural history collections representing large repositories of such specimens. However, an initial challenge in conducting historical DNA data analyses is to understand how molecular preservation varies between specimens. Here, we highlight how Next‐Generation Sequencing methods developed for studying archaeological samples can be applied to determine DNA preservation from only a single leg taken from entomological museum specimens, some of which are more than a century old. An analysis of genome‐wide data from a set of 113 red‐tailed bumblebee Bombus lapidarius specimens, from five British museum collections, was used to quantify DNA preservation over time. Additionally, to improve our analysis and further enable future research, we generated a novel assembly of the red‐tailed bumblebee genome. Our approach shows that museum entomological specimens are comprised of short DNA fragments with mean lengths below 100 base pairs (BP), suggesting a rapid and large‐scale post‐mortem reduction in DNA fragment size. After this initial decline, however, we find a relatively consistent rate of DNA decay in our dataset, and estimate a mean reduction in fragment length of 1.9 bp per decade. The proportion of quality filtered reads mapping to our assembled reference genome was around 50%, and decreased by 1.1% per decade. We demonstrate that historical insects have significant potential to act as sources of DNA to create valuable genetic baselines. The relatively consistent rate of DNA degradation, both across collections and through time, mean that population‐level analyses—for example for conservation or evolutionary studies—are entirely feasible, as long as the degraded nature of DNA is accounted for.

This study presents an approach to structure, analyze and evaluate corporate standardization processes using the example of pre-standardization for the reduction of environmental impacts in product design and development. For this purpose, we give a detailed description of the evolution of the European Standard EN 16524 entitled “Mechanical products—Methodology for reduction of environmental impacts in product design and development”. The standardization strategy behind the evolution of EN 16524 is analyzed using the approach of a Business Model Canvas combined with an evaluation using pre-defined success factors. Moreover, we derive general recommendations for corporate standardization professionals in checklists for each field of the underlying Business Model Canvas. With regard to the case study depicted here, we come to the conclusion that pre-standards are especially suited for innovation transfer in the field of emerging and rapidly evolving scientific and technical results.

Genes encode risk for coronary disease, identifying how they function is critical to developing new therapies. In work reported the authors have identified one culprit gene, PDGFD, and studied how it functions to promote disease risk.

Measurement(s) terrestrial mining Technology Type(s) Data Collection Sample Characteristic - Environment land Sample Characteristic - Location global

Abstract Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.

A Re(I) complex of 3,3′-diamino-2,2′-bipyridine reacts irreversibly with aldehydes and unhindered ketones in water to form bis-aminal cyclised derivatives with the solid-state structure of the reaction with benzaldehyde reported. This reaction produces a Re(I) complex which is significantly more emissive than the starting compound. [ABSTRACT FROM AUTHOR]

Abstract Prior laboratory research has suggested that humans may become more prosocial in stressful or threatening situations, but it is unknown whether the link between prosociality and defense generalizes to real-life. Here, we examined the association between defensive responses to a real-world threat (the COVID-19 pandemic) and everyday altruism. Four independent samples of 150 (N = 600) US residents were recruited online at 4 different timepoints, and self-report measures of perceived COVID-19 threat, defensive emotions (e.g., stress and anxiety), and everyday altruism were collected. Our operationalization of defensive emotions was inspired by the threat imminence framework, an ecological model of how humans and animals respond to varying levels of threat. We found that perceived COVID-19 threat was associated with higher levels of everyday altruism (assessed by the Self-report Altruism scale). Importantly, there was a robust association between experiencing acute anxiety and high physiological arousal during the pandemic (responses typically characteristic of higher perceived threat imminence), and propensity to engage in everyday altruism. Non-significant or negative associations were found with less acute defensive responses like stress. These findings support a real-life relation between defensive and altruistic motivation in humans, which may be modulated by perceived threat imminence.

Colobomas of the globe and microphthalmia are congenital conditions that can strongly affect vision. Etiologies are varied and include embryonic and hereditary origins. We report what is, to the best of our knowledge, the first case of a SIX6 gene pathogenic variant associated with a phenotype of both bilateral microphthalmia and extensive colobomas of the globes. A 3-week-old boy presented with bilateral microphthalmia and iris, optic nerve, and chorioretinal colobomas. Genetic analysis was performed on a panel of 78 genes (microphthalmia, anophthalmia, and coloboma panel), and a homozygous likely pathogenic variant was identified in the SIX6 gene, resulting in the loss of the initiator methionine. Thus, our report expands the phenotypic spectrum of SIX6-related disorders.

Abstract Background To evaluate the rate and risk factors of epiretinal membrane (ERM) formation and need for ERM peeling after pars plana vitrectomy (PPV) for uncomplicated primary rhegmatogenous retinal detachment (RRD). Methods Retrospective, single-center, cohort study of 119 consecutive patients (119 eyes) that underwent RRD repair using PPV. The primary outcomes were ERM formation, classified using an optical coherence tomography grading system, and the rate of ERM peeling. Visual acuity, postoperative complications, and risk factors for ERM formation and peeling were also identified. Results Postoperative ERM formation occurred in 69 eyes (58.0%); 56 (47.1%) were stage 1, 9 (7.6%) stage 2, 3 (2.5%) stage 3, and 1 (0.8%) stage 4. Only 6 (5.0%) eyes required secondary PPV for a visually significant ERM, with a mean time to reoperation of 488 ± 351 days. Risk factors for ERM formation included intraoperative cryotherapy, more than 1000 laser shots, 360° laser photocoagulation, and choroidal detachment (p

Summary: Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p

Background: Intraoperative hypotension is associated with organ injury. Current intraoperative arterial pressure management is mainly reactive. Predictive haemodynamic monitoring may help clinicians reduce intraoperative hypotension. The Acumen™ Hypotension Prediction Index software (HPI-software) (Edwards Lifesciences, Irvine, CA, USA) was developed to predict hypotension. We built up the European multicentre, prospective, observational EU HYPROTECT Registry to describe the incidence, duration, and severity of intraoperative hypotension when using HPI-software monitoring in patients having noncardiac surgery. Methods: We enrolled 749 patients having elective major noncardiac surgery in 12 medical centres in five European countries. Patients were monitored using the HPI-software. We quantified hypotension using the time-weighted average MAP

The medical cyclotrons intended for the production of medical isotopes are relatively widespread. The most common radioisotope product of these facilities is 18F which origins from 18O(p, n)18F reaction. Due to relatively large amounts of produced nuclei, the leakage neutron and gamma flux is a big issue in radiation safety in such cyclotron labs. Due to relatively high energies of accelerated protons, high energy gammas and neutrons are produced with energies above 10 MeV with high penetration properties. Neutron and gamma spectra around cyclotron IBA Cyclone 18/9 intended for production of 18F was measured with stilbene detector. It was compared to simulated neutron spectra with various Monte Carlo codes and with spectral indices calculated from reaction rates in activation detectors. Strong disagreement in simulation of spectra in backward angles was found for MC codes Geant4 and MCNP6.2.

This paper deals with the measurement of Spectrum Averaged Cross Sections in two different neutron fields formed in zero power reactors. The first was Benchmark Neutron Reference Field in the LR-0 reactor, and the second field was in the center of the vertical channel touching the fuel in the VR-1 reactor. The spectrum averaged cross section differs for both cases as the spectra differ, but after normalization to 235U PFNS using calculated correction, both results are in good agreement, thus confirming the spectra in both cases are similar in the 1 – 14 MeV region. A good agreement between lower threshold reactions averaged in actual reactor spectra and prompt fission neutron spectrum of 235U is reported as well.

Summary: While readily achieved in cell lines, the application of CRISPR-Cas9 gene editing in human-derived organoids suffers from limited efficacy and complex protocols. Here, we describe a multi-guide RNA CRISPR-Cas9 gene-editing protocol which efficiently achieves complete gene knockout in adult human colonic organoids. This protocol also describes crucial steps including how to harvest patient tissue to maximize gene-editing efficacy and a technique to validate gene knockout following editing with immunofluorescent staining of the organoids against the target protein. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Luffa is a genus of tropical and subtropical vines belonging to the Cucurbitaceae family. Sponge gourd (Luffa cylindrica) and ridge gourd (Luffa acutangula) are two important species of the genus Luffa and are good sources of human nutrition and herbal medicines. As a vegetable, aromatic luffa is more preferred by consumers than nonaromatic luffa. While the aroma trait is present in the sponge gourd, the trait is not present in the ridge gourd. In this study, we identified Luffa cylindrica’s betaine aldehyde dehydrogenase (LcBADH) as a gene associated with aroma in the sponge gourd based on a de novo assembly of public transcriptome data. A single nucleotide polymorphism (SNP: A > G) was identified in exon 5 of LcBADH, causing an amino acid change from tyrosine to cysteine at position 163, which is important for the formation of the substrate binding pocket of the BADH enzyme. Based on the identified SNP, a TaqMan marker, named AroLuff, was developed and validated in 370 F2 progenies of the sponge gourd. The marker genotypes were perfectly associated with the aroma phenotypes, and the segregation ratios supported Mendelian’s simple recessive inheritance. In addition, we demonstrated the use of the AroLuff marker in the introgression of LcBADH from the aromatic sponge gourd to the ridge gourd to improve aroma through interspecific hybridization. The marker proved to be useful in improving the aroma characteristics of both Luffa species.

Low-cost Particulate Matter (PM) sensors offer an excellent opportunity to improve our knowledge about this type of pollution. Their size and cost, which support multi-node network deployment, along with their temporal resolution, enable them to report fine spatio-temporal resolution for a given area. These sensors have known issues across performance metrics. Generally, the literature focuses on the PM mass concentration reported by these sensors, but some models of sensors also report Particle Number Concentrations (PNCs) segregated into different PM size ranges. In this study, eight units each of Alphasense OPC-R1, Plantower PMS5003 and Sensirion SPS30 have been exposed, under controlled conditions, to short-lived peaks of PM generated using two different combustion sources of PM, exposing the sensors’ to different particle size distributions to quantify and better understand the low-cost sensors performance across a range of relevant environmental ranges. The PNCs reported by the sensors were analysed to characterise sensor-reported particle size distribution, to determine whether sensor-reported PNCs can follow the transient variations of PM observed by the reference instruments and to determine the relative impact of different variables on the performances of the sensors. This study shows that the Alphasense OPC-R1 reported at least five size ranges independently from each other, that the Sensirion SPS30 reported two size ranges independently from each other and that all the size ranges reported by the Plantower PMS5003 were not independent of each other. It demonstrates that all sensors tested here could track the fine temporal variation of PNCs, that the Alphasense OPC-R1 could closely follow the variations of size distribution between the two sources of PM, and it shows that particle size distribution and composition are more impactful on sensor measurements than relative humidity.

Abstract The need for efficient and more accurate ways of monitoring threatened ecosystems is becoming increasingly urgent as climate change intensifies. Coral reefs are an example of an ecosystem in crisis, with widespread declines in coral cover and diversity documented over recent decades. Novel molecular approaches such as biomonitoring using environmental DNA (eDNA) from seawater samples show great potential to complement future coral reef monitoring programs, especially when used in combination with conventional methods. However, eDNA metabarcoding studies often rely on public databases (e.g., GenBank) for assigning taxonomy, which generally limits the number of sequences that can be taxonomically identified. The extent to which building reference tissue sequences improves taxonomic resolution has yet to be fully examined. Here, we combined traditional coral reef monitoring data with eDNA assessments derived from seawater collected at the highly diverse Rowley Shoals in Western Australia. Using two ITS2 assays developed to target basal metazoan DNA and a reference database spiked with 70 local coral specimens, we identified 37 genera and 40 species from 56 1 L seawater samples. We identified considerable overlap of taxa with visual survey data and showed that assignment of amplicon sequence variants was significantly improved when “spiking” the taxonomic classifier with curated sequences of locally collected species. Our findings showcase the potential of eDNA metabarcoding for monitoring the biodiversity of reef corals and highlight the importance of custom reference sequence databases for improving taxonomic resolution in metabarcoding studies.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

The full exploitation of advanced light sources in the terahertz (THz) frequency range requires versatile experimental tools to fully characterize the spatial, temporal, and spectral shapes of the THz electric field. Several techniques for passive THz beam profiling exist that offer information about the temporally integrated intensity. Thus, any information about the electric field itself is lost. Here, we show that a UV–visible light emission produced via a lightwave-driven field emission from single-layer metasurfaces can be used to visualize the peak electric field distribution of THz beams in real time. Our technique is scalable up to frequencies approaching the plasma frequency of the metal used for the metasurface. Uniquely, our device is sensitive to the absolute polarity of the THz lightwave. These findings demonstrate a general pathway to designing metamaterial-based field-sensitive optical detectors suitable for the entire THz and IR spectral region.

Abstract This year’s Nobel Prize in Economics honoured David Card of the University of California, Berkeley “for his empirical contributions to labour economics”, and Joshua Angrist of MIT and Guido Imbens of Stanford University “for their methodological contributions to the analysis of causal relationships”. We explain how the laureates revolutionised the analysis of causal relationships in empirical economics through the methodology of natural experiments. Three examples from the German labour market on the effects of minimum wages, code-termination and unemployment insurance illustrate how natural experiments yield new insights, which can form the foundation for evidence-based policy advice.