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Abstract The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p

Abstract H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.

Abstract Resettlement to a third country offers a durable solution for refugees who cannot integrate into their asylum or transit countries. While most studies focus on the experiences of refugees after their arrival in resettlement countries or on the political aspects of resettlement, fewer studies explore refugees’ perspectives prior to resettlement. This paper examines how Rohingyas in Malaysia view their resettlement opportunities. We collected qualitative micronarratives from 56 adult Rohingyas living in Malaysia between March and September 2019, to explore the complexities of their decision-making processes. The findings indicate that most Rohingyas aspire to resettle in another country to gain legal status or citizenship, providing a better future for their children, including access to education and healthcare. However, preferences among Rohingyas vary: while some are eager to resettle, others express a strong desire to return to their home country in Myanmar. Still, others wish to reunite with family in Myanmar or Bangladesh, and a significant minority are reluctant to resettle in non-Islamic countries, reflecting broader concerns about cultural and religious compatibility. This study highlights the varied resettlement preferences among Rohingyas, underscoring the need for resettlement policies to consider these diverse priorities to enhance the effectiveness of resettlement programs.

Abstract Text-matching software (TMS) is a standard part of efforts to prevent and detect plagiarism in upper secondary and higher education. While there are many studies on the potential benefits of using this technology, few studies look into potential unintended side effects. These side effects include students worrying about being accused of plagiarism due to TMS output, even though they did not intentionally plagiarise. Although such worries are frequently mentioned in the literature, little is known about how prevalent they are, why they occur and how students react to them. This paper aims to fill this knowledge gap. The data for the study comprise 36 interviews with upper secondary and Bachelor students from three European countries combined with survey data from 3,424 students from seven European countries representing a broad range of disciplines. The study found that a substantial proportion of the two groups of students – 47% of upper secondary and 55% of Bachelor students – had experienced TMS-related worries during their current studies. Furthermore, there were substantial differences across countries. Students worry partly because they have a poor understanding of how TMS is used in their institution, and partly because they know that plagiarism is taken very seriously. The study shows that TMS-related worries can lead students to become very focused on not being caught plagiarising, to such an extent that some adopt citation practices that they believe are suboptimal. The paper concludes that institutions using TMS should always combine it with training for students and teachers. Students should be clearly informed about how TMS is used and should develop an understanding of plagiarism and good citation practice that goes beyond the narrow focus on any overlap between texts elicited by the software.

The goal of the indoor localization is to determine the position and orientation of people, devices, and mobile robots. With the rise of Industry 4.0, wireless communication technologies have emerged as a rapidly evolving and crucial area for achieving this goal. Various radiocommunication-based technologies, including Bluetooth, Bluetooth Low Energy (BLE), Wi-Fi, Ultra-Wideband (UWB), and ZigBee offer means to indirectly estimate distance. These methods leverage diverse principles such as time-based measurements, signal strength, and angle of arrival. Indoor positioning systems can be categorized into two approaches: distance-based and distance-independent techniques. The Free Space Path Loss (FSPL) model describes the connection between distance and Received Signal Strength Indicator (RSSI). The parameters within this model significantly impact distance estimation and localization accuracy. Therefore, a method that accurately characterizes the model is critical. This work proposes an orientation-based localization technique utilizing RSSI and trilateration. Measurements were conducted between two ESP32 units in various orientations to obtain optimal parameters for each specific scenario. To assess the effectiveness of this approach, two scenarios were evaluated: one considering orientation and another neglecting it. The results show that incorporating orientation information leads to significantly more accurate positioning compared to the orientation-agnostic approach.

This paper addresses accelerometer array calibration, focusing on determining the errors between multiple sensors. Micro-electromechanical system (MEMS) based triaxial accelerometers, key components of Inertial Measurement Units (IMUs), are used in localization, robotics, and navigation systems. The requirements of these applications necessitate low-cost sensors, which makes MEMS IMUs a reasonable choice. However, these low-cost IMUs are significantly affected by systematic (i.e., bias, misalignment, scale-factor) and random errors. Achieving reliable sensor output depends on the precision of the executed calibration method. While traditional laboratory-based sensor calibration using specialized equipment (i.e., three-axis turntable) is accurate, it is time-consuming and costly. In contrast, in-field calibration techniques, which can be performed using a mechatronic actuator or a robotic arm, have gained popularity. These techniques involve comparing sensor measurements to established reference values. The MEMS sensors are increasingly being used in multi-sensor applications, which demands not only individual sensor error calibration but also important to determine the axis misalignment between the used sensors. During calibration process, various optimization algorithms (e.g., GA, PSO) can also be used to find the error parameters. The proposed measurement system allows for individual calibration of misalignment, bias, and scale factor of the sensor array, and eliminates between-sensor misalignment errors.

Abstract ARHGAP25, a crucial molecule in immunological processes, serves as a Rac-specific GTPase-activating protein. Its role in cell migration and phagocyte functions, affecting the outcome of complex immunological diseases such as rheumatoid arthritis, renders it a promising target for drug research. Despite its importance, our knowledge of its intracellular interactions is still limited. This study employed proteomic analysis of glutathione S-transferase (GST)-tag pulldowns and co-immunoprecipitation from neutrophilic granulocyte cell lysate, revealing 76 candidates for potential physical interactions that complement ARHGAP25’s known profile. Notably, four small GTPases (RAC2, RHOG, ARF4, and RAB27A) exhibited high affinity for ARHGAP25. The ARHGAP25–RAC2 and ARHGAP25–RHOG interactions appeared to be affected by the activation state of the small GTPases, suggesting a GTP–GDP cycle-dependent interaction. In silico dimer prediction pinpointed ARHGAP25’s GAP domain as a credible binding interface, suggesting its suitability for GTP hydrolysis. Additionally, a list of Fc receptor-related kinases, phosphatases, and three of the 14-3-3 members were identified as potential partners, with in silico predictions highlighting eight binding sites, presenting novel insight on a potential regulatory mechanism for ARHGAP25.

In advanced non-squamous non-small-cell lung cancer (NSCLC), routine testing with next-generation sequencing (NGS) is recommended to identify actionable genomic alterations (AGAs). The therapeutic implications of repeated NGS testing on synchronous and metachronous tumors are unclear. Between February 2017 and October 2020, NSCLC samples from a single institution were reflex-tested using a targeted 15-gene NGS panel (TruSight Tumor 15, Illumina). Thirty-eight patients were identified with multiple NGS results from 82 samples: 11% were from single unifocal, 51% were from synchronous, and 38% were from metachronous tumors. Changes in EGFR, KRAS, PI3KCA, and TP53 variants were found in 22 patients’ samples (58%). No changes were seen with longitudinal testing of multiple samples from single unifocal tumors, while changes were observed in 60% of synchronous and 71% of metachronous tumors. Of these, 26% of patients had AGA differences between samples. Acknowledging the limited sample size, a significant difference in overall survival was observed between synchronous separate primaries and metastasis. Repeat NGS testing of synchronous and metachronous NSCLC tumors may identify differing variants in >50% of patients. These changes may reflect separate primary lung carcinomas, tumor heterogeneity among intrapulmonary metastases, and clonal evolution. NGS testing of multiple tumors may enhance the identification of therapeutic targets for treatment decisions.

Abstract Ferroelectric nematic liquid crystals are fluids exhibiting spontaneous electric polarization, which is coupled to their long range orientational order. Due to their inherent property of making bound and surface charges, the free surface of ferroelectric nematics becomes unstable in electric fields. Here we show that ferroelectric liquid bridges between two electrode plates undergo distinct interfacial instabilities. In a specific range of frequency and voltage, the ferroelectric fluid bridges move as active interacting particles resembling living organisms like swarming insects, microbes or microrobots. The motion is accompanied by sound emission, as a consequence of piezoelectricity and electrostriction. Statistical analysis of the active particles reveals that the movement can be controlled by the applied voltage, which implies the possible application of the system in new types of microfluidic devices.

Abstract Epigenetic modifications, such as 5-methylcytosine (5mC), can sometimes be transmitted between generations, provoking speculation that epigenetic changes could play a role in adaptation and evolution. Here, we use experimental evolution to investigate how 5mC levels evolve in populations of biparental insect (Nicrophorus vespilloides) derived from a wild source population and maintained independently under different regimes of parental care in the lab. We show that 5mC levels in the transcribed regions of genes (gene bodies) diverge between populations that have been exposed to different levels of care for 30 generations. These changes in 5mC do not reflect changes in the levels of gene expression. However, the accumulation of 5mC within genes between populations is associated with reduced variability in gene expression within populations. Our results suggest that evolved change in 5mC could contribute to phenotypic evolution by influencing variability in gene expression in invertebrates.

Abstract Tumour-Infiltrating Lymphocytes (TILs) are pivotal in the immune response against cancer cells. Existing deep learning methods for TIL analysis in whole-slide images (WSIs) demand extensive patch-level annotations, often requiring labour-intensive specialist input. To address this, we propose a framework named annotation-efficient segmentation and attention-based classifier (ANSAC). ANSAC requires only slide-level labels to classify WSIs as having high vs. low TIL scores, with the binary classes divided by an expert-defined threshold. ANSAC automatically segments tumour and stroma regions relevant to TIL assessment, eliminating extensive manual annotations. Furthermore, it uses an attention model to generate a map that highlights the most pertinent regions for classification. Evaluating ANSAC on four breast cancer datasets, we demonstrate substantial improvements over three baseline methods in identifying TIL-relevant regions, with up to 8% classification improvement on a held-out test dataset. Additionally, we propose a pre-processing modification to a well-known method, enhancing its performance up to 6%.

Abstract Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Abstract Background Quality smoking data is crucial for assessing smoking-related health risk and eligibility for interventions related to that risk. Smoking information collected in primary care practices (PCPs) is a major data source; however, little is known about the PCP smoking data quality. This project compared PCP smoking data to that collected in the Māori and Pacific Abdominal Aortic Aneurysm (AAA) screening programme. Methods A two stage review was conducted. In Stage 1, data quality was assessed by comparing the PCP smoking data recorded close to AAA screening episodes with the data collected from participants at the AAA screening session. Inter-rater reliability was analysed using Cohen’s kappa scores. In Stage 2, an audit of longitudinal smoking status was conducted, of a subset of participants potentially misclassified in Stage 1. Data were compared in three groups: current smoker (smoke at least monthly), ex-smoker (stopped > 1 month ago) and never smoker (smoked

ObjectiveWe hypothesized that the insulin-sensitizing adipokine adiponectin (ADP) is upregulated in cystic fibrosis (CF) related diabetes (CFRD) and underweight adults with CF. We aimed to assess correlations between glucose metabolism, body composition and ADP in CF.MethodsWe performed a cross-sectional study among adults with CF at the Copenhagen CF Center. The study included a fasting level of ADP, an oral glucose tolerance test (OGTT), and a dual energy-x-ray absorptiometry scan.ResultsIn total, 115 patients were included of whom 104 had an OGTT performed. Glucose intolerance was not correlated with ADP in multivariable analysis, while increased hepatic insulin resistance (i.e., HOMA-IR) was correlated with reduced ADP levels. ADP declined by 4% (eβ 0.96, 95% CI: 0.94, 0.98), 5% (eβ 0.95, 95% CI: 0.93, 0.98), 9% (eβ 0.91, 95% CI: 0.87, 0.95), and 83% (eβ 0.17, 95% CI: 0.08, 0.37) for each one unit (kg/m2) increase in body mass index, fat mass index, muscle mass index, and bone mineral content index, respectively.ConclusionsIn CF, ADP was negatively correlated with hepatic insulin resistance as well as low fat, muscle, and bone mass, but not with glucose intolerance. This suggests that malnutrition leads to higher ADP levels in CF.

Recent developments in condition-based maintenance (CBM) have helped make it a promising approach to maintenance cost avoidance in engineering systems. By performing maintenance based on conditions of the component with regards to failure or time, there is potential to avoid the large costs of system shutdown and maintenance delays. However, CBM requires a large investment cost compared to other available maintenance strategies. The investment cost is required for research, development, and implementation. Despite the potential to avoid significant maintenance costs, the large investment cost of CBM makes decision makers hesitant to implement. This study is the first in the literature that attempts to address the problem of conducting a cost-benefit analysis (CBA) for implementing CBM concepts for unmanned systems. This paper proposes a method for conducting a CBA to determine the return on investment (ROI) of potential CBM strategies. The CBA seeks to compare different CBM strategies based on the differences in the various maintenance requirements associated with maintaining a multi-component, unmanned system. The proposed method uses modular dynamic fault tree analysis (MDFTA) with Monte Carlo simulations (MCS) to assess the various maintenance requirements. The proposed method is demonstrated on an unmanned surface vessel (USV) example taken from the literature that consists of 5 subsystems and 71 components. Following this USV example, it is found that selecting different combinations of components for a CBM strategy can have a significant impact on maintenance requirements and ROI by impacting cost avoidances and investment costs.

Satellite altimetry water level measurements are valuable in episodic and climate change related hydrodynamic impact studies, despite their sparse temporal distribution over the global ocean. This study presents the spatiotemporal characteristics of the open-ocean satellite derived water level measurements globally for the period 31/12/1992-15/10/2019 and evaluates their efficacy to represent the water level even during intense atmospheric conditions. Water level measurements from 23 different satellite missions are compared with tide gauge records and hydrodynamic simulations. The satellite measurements reproduce the water-level variations with good to excellent skill for ~60% of the areas considered. Additionally, satellite measurements and local atmospheric conditions are utilized in order to examine whether statistical data driven models can contribute to decreasing the temporal sparseness of the water level data over the global ocean. The suitability of this low computational-cost method is demonstrated by deriving a 63-year hindcast of the daily maximum water level for the global ocean, and for a medium-term 15-day ensemble forecast. The publicly available long-term water-level hindcast and the parameters of the data-driven statistical model derived can serve as a tool for designing and facilitating local and global coastal risk-assessment studies.

Nove funkcionalnosti na mobilni platformi za učenje glasbene teorije so usmerjene v prima vista izvajanje ritmičnih in melodičnih vzorcev ter so integrirane v celostno zasnovo platforme, saj ohranjajo enotne poigritvene elemente. Evalvacija uporabniške izkušnje novih igrificiranih pripomočkov je ponudila pozitivne povratne informacije, ki so spodbudni za popularizacijo in nadaljnji razvoj aplikacije.

Ovarian cancer is the leading cause of death among gynecological cancers in most developed countries, with many patients developing chemotherapy resistance leaving them with a 5-year survival rate of

Grey wolf (Canis lupus Linnaeus 1758) is the largest representative of the Canidae family in Bulgaria. It inhabits almost the whole territory, most frequently the mountainous and hilly areas. The grey wolf is a hunting species in the country. Despite this, there is little information in the literature on its size. The aim of this work was to provide the first systematized data of the somatometric characteristics (weight – P; total body length – L; length of the body to the base of the tail – Lb; tail length – Lo and height at the withers – Hb) of the grey wolf in Bulgaria and to establish what is the degree of their sexual dimorphism. We found that the adult males are 24.3% heavier than the females (t=4.46; p

Abstract Cariprazine—the only single antipsychotic drug in the market which can handle all symptoms of bipolar I disorder—involves trans-4-substituted cyclohexane-1-amine as a key structural element. In this work, production of trans-4-substituted cyclohexane-1-amines was investigated applying transaminases either in diastereotope selective amination starting from the corresponding ketone or in diastereomer selective deamination of their diasteromeric mixtures. Transaminases were identified enabling the conversion of the cis-diastereomer of four selected cis/trans-amines with different 4-substituents to the corresponding ketones. In the continuous-flow experiments aiming the cis diastereomer conversion to ketone, highly diastereopure trans-amine could be produced (de > 99%). The yield of pure trans-isomers exceeding their original amount in the starting mixture could be explained by dynamic isomerization through ketone intermediates. The single transaminase-catalyzed process—exploiting the cis-diastereomer selectivity of the deamination and thermodynamic control favoring the trans-amines due to reversibility of the steps—allows enhancement of the productivity of industrial cariprazine synthesis.

Abstract Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. Methods We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. Results DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo. Conclusions Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.

Abstract Introduction Herpes zoster (HZ) can cause substantial patient morbidity and lead to large healthcare costs. However, the disease burden of HZ in Southeast Asia may be underestimated. This study aimed to estimate the public health burden of HZ and the impact of vaccinating adults aged ≥ 50 years old in five Southeast Asian countries (Indonesia, Malaysia, Philippines, Thailand, and Vietnam), with adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination. Methods For each country, we adapted a static multicohort Markov model developed with a 1-year cycle length and lifetime horizon. Demographics were obtained from the World Health Organization, HZ incidence from a worldwide meta-regression reporting Asian-specific values, proportions of postherpetic neuralgia (PHN) and non-PHN complications from local/regional studies, and vaccine efficacy from a long-term follow-up trial. First-dose coverage and second-dose compliance were assumed to be 30% and 70%, respectively. A one-way deterministic sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness and uncertainty of inputs for each country. Results Without RZV, it was estimated that there would be a total of approximately 10 million HZ cases, 2.1 million PHN cases, and 1.4 million non-PHN complications in individuals aged ≥ 50 years included in the model. Introducing RZV under 30% coverage could avoid approximately 2.2 million (22%) HZ cases, almost 500,000 (21%) PHN cases, and around 300,000 (22%) non-PHN complications. OWSA showed that first-dose coverage and initial HZ incidence had the largest impact on the estimated number of HZ cases avoided. The number needed to vaccinate ranged from 15 to 21 to prevent one case of HZ and from 68 to 104 to prevent one case of PHN across each country. Conclusions This study demonstrated that there is substantial HZ disease burden in older adults for the five selected countries in Southeast Asia, negatively impacting national healthcare systems. Introducing RZV could potentially reduce this burden. A graphical abstract is available with this article. Graphical Abstract

The European Union’s Green Deal emphasizes life science and biotechnology as key drivers for achieving a circular economy. However, the prevalent use of non-sustainable single-use plastics derived from petrochemical sources in life science research and development contradicts this ecological goal. This study presents a viable alternative through on-site sterile 3D printing of single-use plastics using poly(lactic acid) (PLA). The sterile printing of PLA demonstrates a substantial reduction in CO2eqemissions per shake flask, decreasing from 260 g CO2eqto 145 g CO2eq. Suitability for cell culture was demonstrated for sterile printed PLA, autoclaved high-temperature PLA and for suspension cell cultures in shake flasks using CHO and insect cells as well as adherent Vero cell cultures in cell culture wells. Further optimization of sustainable shake flasks is achieved by utilizing recycled PLA, resulting in a remarkable reduction to 73 g CO2eq, constituting a 72% decrease in CO2eqemissions compared to conventional single-use plastics. Moreover, by employing geometric optimization to minimize material usage, emissions can be further reduced to 44 g CO2eq, representing an 83% reduction in CO2eqemissions. Anticipated advancements in PLA production suggest future carbon net negative PLA production, potentially achieving zero carbon emissions for single-use plastics using PLA. The exceptionally cost-effective nature of 3D printed single-use plastics, coupled with negligible capital costs for implementation, positions sterile 3D printing as a practical solution aligned with the 2030 Green Deal goals. Moreover, ongoing improvements in bioplastic production underscore the feasibility of meeting the 2050 targets of carbon neutrality for single-use plastics in life science research and development.

Participation in a paediatric, complex randomized controlled trial (RCT) might add to the family burden when a child is diagnosed with a severe disease. Although important, there are only a limited number of papers describing this aspect of research from the family point of view. This study explored parents’ and children’s experiences of participation in a research study shortly after the child had been diagnosed with type 1 diabetes. Sixteen parents (nine mothers, seven fathers) and nine children were interviewed by an independent researcher about their inducement, the decision-making process within the family which led to their participation, and their experience of having done so. The result showed that the parents wanted to contribute to improve treatment for children with diabetes in general but also specifically for their own child. Older children were more involved in the decision making than the younger children. Study information needs to be communicated clearly and effectively since decision-making based on information of a clinical trial directly after the child’s diabetes onset proved difficult. Being randomized to the intervention group in this specific study was considered somewhat burdensome. However, parental participants in both intervention and control group claimed that they would recommend participation in research studies to other parents in a similar situation, and so did the children. There was no difference between the mothers’ and fathers’ experiences.

The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society).

AbstractHollow-core precast prestressed reinforced concrete (HCPPRC) slabs have been widely available since the 1980s in different structures due to many advantages. Since no shear reinforcement is arranged in HCPPRC slabs before casting, concrete itself provides the shear resistance, especially in the zones close to the supports, which are the most popular regions for shear failure. This experimental study aims to investigate some shear strengthening techniques for HCPPRC slabs, including using carbon fiber reinforced polymer (CFRP) sheets, concrete topping, filling 50% of the slab voids in shear zones with concrete, filling all shear zone voids with concrete, steel through anchors in shear zones, and mixing between filling 50% of the slab shear zone voids in addition to using steel anchors. The experimental program consists of two control specimens and six shear-strengthened specimens that were tested using two-line loads up to failure. Cracking load, cracking deflection, ultimate load, maximum deflection, and failure mode are recorded and discussed for all specimens. The results show that filling 50% and 100% of shear voids with concrete increases slab concrete strength by about 79% and 61.45%, respectively, while using steel through anchors decreases slab concrete strength. Moreover, filling 50% of the shear voids is the best technique for strengthening the shear capacity of HCPPRC slabs due to increasing the cross-section area of the slab’s shear strength. In contrast, using screws with nuts only is not preferred for shear strengthening of HCPPRC slabs.

The evolutionary origins of Bilateria remain enigmatic. One of the more enduring proposals highlights similarities between a cnidarian-like planula larva and simple acoel-like flatworms. This idea is based in part on the view of the Xenacoelomorpha as an outgroup to all other bilaterians which are themselves designated the Nephrozoa (protostomes and deuterostomes). Genome data can provide important comparative data and help understand the evolution and biology of enigmatic species better. Here, we assemble and analyze the genome of the simple, marine xenacoelomorph Xenoturbella bocki, a key species for our understanding of early bilaterian evolution. Our highly contiguous genome assembly of X. bocki has a size of ~111 Mbp in 18 chromosome-like scaffolds, with repeat content and intron, exon, and intergenic space comparable to other bilaterian invertebrates. We find X. bocki to have a similar number of genes to other bilaterians and to have retained ancestral metazoan synteny. Key bilaterian signaling pathways are also largely complete and most bilaterian miRNAs are present. Overall, we conclude that X. bocki has a complex genome typical of bilaterians, which does not reflect the apparent simplicity of its body plan that has been so important to proposals that the Xenacoelomorpha are the simple sister group of the rest of the Bilateria.

Correlated Multimodal Imaging (CMI) gathers information about the same specimen with two or more modalities that–combined–create a composite and complementary view of the sample (including insights into structure, function, dynamics and molecular composition). CMI allows one to reach beyond what is possible with a single modality and describe biomedical processes within their overall spatio-temporal context and gain a mechanistic understanding of cells, tissues, and organisms in health and disease by untangling their molecular mechanisms within their native environment. The field of CMI has grown substantially over the last decade and previously unanswerable biological questions have been solved by applying novel CMI workflows. To disseminate these workflows and comprehensively share the scattered knowledge present within the CMI community, an initiative was started to bring together imaging, image analysis, and biomedical scientists and work towards an open community that promotes and disseminates the field of CMI. This community project was funded for the last 4 years by an EU COST Action called COMULIS (COrrelated MUltimodal imaging in the LIfe Sciences). In this review we share some of the showcases and lessons learnt from the action. We also briefly look ahead at how we anticipate building on this initial initiative.

The international scientific community puts an ever-growing emphasis on research excellence and performance evaluation. So does the European Union with its flagship research excellence grant scheme organised by the European Research Council. This paper aims to provide an in-depth analysis of one of the ERC's thematic panels within the social sciences, namely the SH2 “Political Science” panel. The analysis is based on empirical, statistical methods, and network analysis tools to gain insights about the grant winners' publication patterns and their coauthor networks. The results draw up an academic career track of the grantees based on quantitative publication patterns and performance. Besides, a change in authorship can be observed, which is proven by the formation of new groups and intensifying intra-group collaboration patterns in the case of all three grant types. However, the ERC grant serves different functions for the winners of three different categories: for the Starting Grant winners, it offers the possibility to kick off and establish their research group, for the Consolidator Grant winners, it opens up new opportunities to extend their co-authorship network, and for the Advanced Grant winners, it offers the chance to start a new collaboration.

Modern dog and cat owners increasingly use internet resources to obtain information on pet health issues. While access to online information can improve owners’ knowledge of patient care and inform conversations with their veterinarian during consultations, there is also a risk that owners will misinterpret online information or gain a false impression of current standards in veterinary medicine. This in turn can cause problems or tensions, for example if the owner delays consulting their veterinarian about necessary treatment, or questions the veterinarian’s medical advice. Based on an online questionnaire aimed at dog and cat owners in Austria, Denmark and the United Kingdom (N = 2117) we investigated the use of internet resources to find veterinary medical information, the type of internet resources that were used, and whether owner beliefs explain how often they used the internet to find medical information about their pet. Approximately one in three owners reported that they never used internet resources prior to (31.7%) or after (37.0%) a consultation with their veterinarian. However, when owners do make use of the internet, our results show that they were more likely to use it before than after the consultation. The most common internet resources used by owners were practice websites (35.0%), veterinary association websites (24.0%), or ‘other’ websites providing veterinary information (55.2%). Owners who believe that the use of internet resources enables them to have a more informed discussion with their veterinarians more often use internet resources prior to a consultation, whereas owners who believed that internet resources help them to make the right decision for their animal more often use internet resources after a consultation. The results suggest that veterinarians should actively ask pet owners if they use internet resources, and what resources they use, in order to facilitate open discussion about information obtained from the internet. Given that more than a third of pet owners use practice websites, the findings also suggest that veterinarians should actively curate their own websites where they can post information that they consider accurate and trustworthy.

Water-related issues such as scarcity and pollution have become increasingly pressing in sub-Saharan Africa, especially Nigeria, highlighting the need for an effective environmental education (EE) programme. The relationship between EE and water pollution prevention and conservation in Nigeria remains an open question. Therefore, this study aimed to assess the role of EE in water pollution prevention and conservation in Nigeria. A simple random sampling was used to select 766 respondents from the southwest geo-political zone of Nigeria. Data were analyzed using simple descriptive statistics and analysis of variance. Results show a high level of awareness of water pollution and conservation strategies. However, people's attitude towards preventing water pollution and conservation was poor. Age does not significantly (at p < 0.05) affect awareness and attitude towards water pollution prevention and conservation. However, the level of education significantly (at p < 0.05) influences the level of awareness and attitude of people towards water pollution prevention and conservation. EE increases awareness and attitude towards water pollution prevention and conservation. Therefore, the Federal Ministries of Water Resources and Education should endeavour to make EE a compulsory programme in the school curriculum across all levels of education. HIGHLIGHTS The level of awareness of water pollution prevention and conservation was very high.; Attitude towards water pollution prevention and water conservation was very poor.; Environmental education increases awareness and promotes a positive attitude towards water conservation.; Age of respondents affects the level of awareness or attitude towards water pollution prevention and conservation.;

Abstract Controlled release formulation (CRF) of herbicide is an effective weed management technique with less eco-toxicity than other available commercial formulations. To maximise the effectiveness of CRFs however, it is crucial to understand the herbicide-releasing behaviour at play, which predominately depends on the interaction mechanisms between active ingredients and carrier materials during adsorption. In this study, we investigated and modelled the adsorption characteristics of model herbicide 2,4-D onto two organo-montmorillonites (octadecylamine- and aminopropyltriethoxysilane-modified) to synthesise polymer-based CRFs. Herbicide-releasing behaviour of the synthesised CRF microbeads was then analysed under various experimental conditions, and weed control efficacy determined under glasshouse conditions. Results revealed that adsorption of 2,4-D onto both organo-montmorillonites follows the pseudo-second-order kinetics model and is predominately controlled by the chemisorption process. However, multi-step mechanisms were detected in the adsorption on both organoclays, hence intra-particle diffusion is not the sole rate-limiting step for the adsorption process. Both organoclays followed the Elovich model, suggesting they have energetically heterogeneous surfaces. Herbicide-releasing behaviours of synthesised beads were investigated at various pH temperatures and ionic strengths under laboratory and glasshouse conditions. Furthermore, weed control efficacy of synthesised beads were investigated using pot studies under glasshouse condition. Desorption studies revealed that both synthesised microbeads have slow releasing behaviour at a wide range of pHs (5–9), temperatures (25–45 °C), and ionic strengths. The results also revealed that synthesised microbeads have excellent weed control efficacy on different broad-leaf weed species under glasshouse conditions.

Abstract Background One of the stranger phenomena that can occur during gene translation is where, as a ribosome reads along the mRNA, various cellular and molecular properties contribute to stalling the ribosome on a slippery sequence and shifting the ribosome into one of the other two alternate reading frames. The alternate frame has different codons, so different amino acids are added to the peptide chain. More importantly, the original stop codon is no longer in-frame, so the ribosome can bypass the stop codon and continue to translate the codons past it. This produces a longer version of the protein, a fusion of the original in-frame amino acids, followed by all the alternate frame amino acids. There is currently no automated software to predict the occurrence of these programmed ribosomal frameshifts (PRF), and they are currently only identified by manual curation. Results Here we present PRFect, an innovative machine-learning method for the detection and prediction of PRFs in coding genes of various types. PRFect combines advanced machine learning techniques with the integration of multiple complex cellular properties, such as secondary structure, codon usage, ribosomal binding site interference, direction, and slippery site motif. Calculating and incorporating these diverse properties posed significant challenges, but through extensive research and development, we have achieved a user-friendly approach. The code for PRFect is freely available, open-source, and can be easily installed via a single command in the terminal. Our comprehensive evaluations on diverse organisms, including bacteria, archaea, and phages, demonstrate PRFect’s strong performance, achieving high sensitivity, specificity, and an accuracy exceeding 90%. The code for PRFect is freely available and installs with a single terminal command. Conclusion PRFect represents a significant advancement in the field of PRF detection and prediction, offering a powerful tool for researchers and scientists to unravel the intricacies of programmed ribosomal frameshifting in coding genes.

Abstract Background Given the strikingly high diagnostic error rate in hospitals, and the recent development of Large Language Models (LLMs), we set out to measure the diagnostic sensitivity of two popular LLMs: GPT‐4 and PaLM2. Small‐scale studies to evaluate the diagnostic ability of LLMs have shown promising results, with GPT‐4 demonstrating high accuracy in diagnosing test cases. However, larger evaluations on real electronic patient data are needed to provide more reliable estimates. Methods To fill this gap in the literature, we used a deidentified Electronic Health Record (EHR) data set of about 300,000 patients admitted to the Beth Israel Deaconess Medical Center in Boston. This data set contained blood, imaging, microbiology and vital sign information as well as the patients' medical diagnostic codes. Based on the available EHR data, doctors curated a set of diagnoses for each patient, which we will refer to as ground truth diagnoses. We then designed carefully‐written prompts to get patient diagnostic predictions from the LLMs and compared this to the ground truth diagnoses in a random sample of 1000 patients. Results Based on the proportion of correctly predicted ground truth diagnoses, we estimated the diagnostic hit rate of GPT‐4 to be 93.9%. PaLM2 achieved 84.7% on the same data set. On these 1000 randomly selected EHRs, GPT‐4 correctly identified 1116 unique diagnoses. Conclusion The results suggest that artificial intelligence (AI) has the potential when working alongside clinicians to reduce cognitive errors which lead to hundreds of thousands of misdiagnoses every year. However, human oversight of AI remains essential: LLMs cannot replace clinicians, especially when it comes to human understanding and empathy. Furthermore, a significant number of challenges in incorporating AI into health care exist, including ethical, liability and regulatory barriers.

Cestodes of the family Anoplocephalidae parasitize a wide range of usually herbivorous hosts including e.g. rodents, ungulates, primates, elephants and hyraxes. While in some hosts, the epidemiology of the infection is well studied, information is lacking in others. In this study of mountain gorillas in the Virunga Massif, an extensive sample set comprising adult cestodes collected via necropsies, proglottids shed in feces, and finally, fecal samples from both night nests and identified individuals were analysed. Anoplocephala gorillae was the dominant cestode species detected in night nest samples and individually known gorillas, of which only 1 individual hosted a Bertiella sp. It was shown that the 2 species can be distinguished through microscopy based on egg morphology and polymerase chain reaction (PCR) assays for diagnostics of both species were provided. Sequences of mitochondrial (cox 1) and nuclear (ITS1, 18S rDNA, 28S rDNA) markers were used to evaluate the phylogenetic position of the 2 cestodes detected in mountain gorillas. Both types of fecal samples, from night nests and from identified individuals, provided comparable information about the prevalence of anoplocephalid cestodes, although the analysis of samples collected from identified gorilla individuals showed significant intra-individual fluctuation of A. gorillae egg shedding within a short period. Therefore, multiple samples should be examined to obtain reliable data for wildlife health management programmes, especially when application of anthelmintic treatment is considered. However, while A. gorillae is apparently a common symbiont of mountain gorillas, it does not seem to impair the health of its host.

Abstract Background Body shape, an intuitive health indicator, is deterministically driven by body composition. We developed and validated a deep learning model that generates accurate dual-energy X-ray absorptiometry (DXA) scans from three-dimensional optical body scans (3DO), enabling compositional analysis of the whole body and specified subregions. Previous works on generative medical imaging models lack quantitative validation and only report quality metrics. Methods Our model was self-supervised pretrained on two large clinical DXA datasets and fine-tuned using the Shape Up! Adults study dataset. Model-predicted scans from a holdout test set were evaluated using clinical commercial DXA software for compositional accuracy. Results Predicted DXA scans achieve R 2 of 0.73, 0.89, and 0.99 and RMSEs of 5.32, 6.56, and 4.15 kg for total fat mass (FM), fat-free mass (FFM), and total mass, respectively. Custom subregion analysis results in R 2s of 0.70–0.89 for left and right thigh composition. We demonstrate the ability of models to produce quantitatively accurate visualizations of soft tissue and bone, confirming a strong relationship between body shape and composition. Conclusions This work highlights the potential of generative models in medical imaging and reinforces the importance of quantitative validation for assessing their clinical utility.

This study examines the publication performance of the Czech Republic, Poland, Hungary, and Slovakia across 24 social science disciplines indexed by Scopus from 2019 to 2023. Using data from Scopus, SciVal, and Scimago, we analyzed regional journal statuses, disciplinary backlogs, journal biases, and publication excellence. Our results show that Poland and the Czech Republic lead in journal and publication counts, whereas Hungary and Slovakia lag behind significantly. Four disciplines—e-learning, human factors and ergonomics, life-span and life-course studies, and social work—had minimal or no publications, highlighting their marginalization. We found a high internal bias in publication practices, notably in Poland and Hungary, which raises concerns considering the Norwegian list standards. While Poland and the Czech Republic show a higher proportion of excellent publications, the overall number of high-quality articles remains low, and publications by the Big Five publishers are exceedingly limited. This analysis underscores the need for strategic policy interventions to enhance research quality and international collaboration to improve the scientific standing of the Visegrad countries.

IntroductionRheumatoid arthritis (RA) is commonly characterized by joint space narrowing. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization and quantification of joint space in extremity joints commonly affected by RA, such as the 2nd and 3rd metacarpophalangeal joints. However, age, sex, and obesity can also influence joint space narrowing. Thus, this study aimed to determine whether HR-pQCT joint space metrics could distinguish between RA patients and controls, and determine the effects of age, sex and body mass index (BMI) on these joint space metrics.MethodsHR-pQCT joint space metrics (volume, width, standard deviation of width, maximum/minimum width, and asymmetry) were acquired from RA patients and age-and sex-matched healthy control participants 2nd and 3rd MCP joints. Joint health and functionality were assessed with ultrasound (i.e., effusion and inflammation), hand function tests, and questionnaires.ResultsHR-pQCT-derived 3D joint space metrics were not significantly different between RA and control groups (p > 0.05), despite significant differences in inflammation and joint function (p

In animals, reproductive performance typically improves over time early in life. Several ultimate and proximate mechanisms may contribute to such an age-related improvement and these mechanisms can act in a relative or in an absolute sense. Low performance of young individuals may be the consequence of a comparison or competition with older individuals (relative), or it may be due to specific traits of young individuals and be unrelated to the presence of older competitors (absolute). Here, we perform a test to disentangle whether the effect of age class (yearling or older) on male extra-pair siring success is relative or absolute. Male age is the most consistent predictor of male extra-pair siring success across bird species, yet the mechanisms underlying this pattern are not well understood. Low extra-pair siring success of yearling males may be a consequence of the presence of older ("adult") males (hypothesis 1), because adult males are more successful in intra- and intersexual interactions or because females prefer to copulate with adult males when available (relative preference). Alternatively, low extra-pair siring success of yearlings may be independent of the presence of adult males (hypothesis 2), for example, if yearling males on average invest less in extra-pair behavior or if females avoid them as extra-pair mates, independent of the availability of older males (absolute preference). To distinguish between these 2 hypotheses, we experimentally manipulated the age structure of a nest-box-breeding population of blue tits (Cyanistes caeruleus) by removing almost all adult males, and compared patterns of extra-pair paternity in the experimental year with those from the preceding 15 "control" years. Removal of adult males resulted in a substantial increase in the extra-pair siring success of yearling males compared to the "control" years, but did not affect the population-level frequency of extra-pair paternity or its spatial patterns. Our results provide clear evidence that extra-pair siring success of yearlings can increase and that it depends on the presence of older males in the population, indicating a relative effect of age on reproductive performance. These results suggest that older males outcompete yearling males in direct or indirect interactions, in sperm competition or as a result of differences in attractiveness to females.

Abstract When host nests are scarce, avian brood parasites would benefit from behaviours that increase the availability of suitable nests. Several studies reported ejection of host nestlings from nests by brood parasites; however, whether brood parasites do so to induce the host to re‐nest and thus increase opportunities for future parasitism (i.e. ‘farming’ behaviour) remains unclear. Here, we report observational evidence of farming behaviour by a common cuckoo Cuculus canorus female in a Daurian redstart Phoenicurus auroreus population: (1) the cuckoo destroyed a host nest by ejecting all nestlings, (2) the host then produced a new nest and (3) the cuckoo successfully parasitized the replacement nest. We suggest that farming behaviour may be more common, but often goes undetected because it requires intense nest monitoring.

Abstract Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low‐volume optimization experiments are reported. A Buchwald–Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self‐optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using

Abstract Global hydrological reanalyses are modelled datasets providing information on river discharge evolution everywhere in the world. With multi‐decadal daily timeseries, they provide long‐term context to identify extreme hydrological events such as floods and droughts. By covering the majority of the world's land masses, they can fill the many gaps in river discharge in‐situ observational data, especially in the global South. These gaps impede knowledge of both hydrological status and future evolution and hamper the development of reliable early warning systems for hydrological‐related disaster reduction. River discharge is a natural integrator of the water cycle over land. Global hydrological reanalysis datasets offer an understanding of its spatio‐temporal variability and are therefore critical for addressing the water–energy–food–environment nexus. This paper describes how global hydrological reanalyses can fill the lack of ground measurements by using earth system or hydrological models to provide river discharge time series. Following an inventory of alternative sources of river discharge datasets, reviewing their advantages and limitations, the paper introduces the Copernicus Emergency Management Service (CEMS) Global Flood Awareness System (GloFAS) modelling chain and its reanalysis dataset as an example of a global hydrological reanalysis dataset. It then reviews examples of downstream applications for global hydrological reanalyses, including monitoring of land water resources and ocean dynamics, understanding large‐scale hydrological extreme fluctuations, early warning systems, earth system model diagnostics and the calibration and training of models, with examples from three Copernicus Services (Emergency Management, Marine and Climate Change).

The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production via a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO–sGC–cGMP pathway, with a focus on PH.

Abstract Freestanding slender fluid filaments of room‐temperature ferroelectric nematic liquid crystals are described. They are stabilized either by internal electric fields of bound charges formed due to polarization splay or by external voltage applied between suspending wires. The phenomenon is similar to those observed in dielectric fluids, such as deionized water, except that in ferroelectric nematic materials the voltages required are three orders of magnitudes smaller and the aspect ratio is much higher. The observed ferroelectric fluid threads are not only unique and novel but also offer measurements of basic physical quantities, such as the ferroelectric polarization and viscosity. Ferroelectric nematic fluid threads may have practical applications in nano‐fluidic micron‐size logic devices, switches, and relays.

Summary: Background: To date, economic analyses of tissue-based next generation sequencing genomic profiling (NGS) for advanced solid tumors have typically required models with assumptions, with little real-world evidence on overall survival (OS), clinical trial enrollment or end-of-life quality of care. Methods: Cost consequence analysis of NGS testing (555 or 161-gene panels) for advanced solid tumors through the OCTANE clinical trial (NCT02906943). This is a longitudinal, propensity score-matched retrospective cohort study in Ontario, Canada using linked administrative data. Patients enrolled in OCTANE at Princess Margaret Cancer Centre from August 2016 until March 2019 were matched with contemporary patients without large gene panel testing from across Ontario not enrolled in OCTANE. Patients were matched according to 19 patient, disease and treatment variables. Full 2-year follow-up data was available. Sensitivity analyses considered alternative matched cohorts. Main Outcomes were mean per capita costs (2019 Canadian dollars) from a public payer's perspective, OS, clinical trial enrollment and end-of-life quality metrics. Findings: There were 782 OCTANE patients with 782 matched controls. Variables were balanced after matching (standardized difference 0.40), and greater in two (ovary, biliary, both p

Epigenetics has been a buzzword in science for many years, but 20 years ago, the idea that epigenetic gene regulation could be a driver in evolutionary processes was only a mischievous glint in a Lamarckian eye. Now, however, theoretical and experimental studies have illuminated the possible roles that epigenetic information could play in evolution and we are on the cusp of testing this concept in ecologically relevant settings.

Abstract Background The individual lifestyle and environment of an organism can influence its phenotype and potentially the phenotype of its offspring. The different genetic and non-genetic components of the inheritance system and their mutual interactions are key mechanisms to generate inherited phenotypic changes. Epigenetic changes can be transmitted between generations independently from changes in DNA sequence. In Caenorhabditis elegans, epigenetic differences, i.e. epimutations, mediated by small non-coding RNAs, particularly 22G-RNAs, as well as chromatin have been identified, and their average persistence is three to five generations. In addition, previous research showed that some epimutations had a longer duration and concerned genes that were enriched for multiple components of xenobiotic response pathways. These results raise the possibility that environmental stresses might change the rate at which epimutations occur, with potential significance for adaptation. Results In this work, we explore this question by propagating C. elegans lines either in control conditions or in moderate or high doses of cisplatin, which introduces genotoxic stress by damaging DNA. Our results show that cisplatin has a limited effect on global small non-coding RNA epimutations and epimutations in gene expression levels. However, cisplatin exposure leads to increased fluctuations in the levels of small non-coding RNAs derived from tRNA cleavage. We show that changes in tRNA-derived small RNAs may be associated with gene expression changes. Conclusions Our work shows that epimutations are not substantially altered by cisplatin exposure but identifies transient changes in tRNA-derived small RNAs as a potential source of variation induced by genotoxic stress.

Abstract Hurricanes can trigger widespread landslides and flooding creating compound hazards and multiple risks for vulnerable populations. An example is the island of Dominica in the Caribbean, where the population lives predominantly along the coast close to sea level and is subject to storm surge, with steep topography rising behind, with a propensity for landslides and flash river flooding. The simultaneous occurrence of the multiple hazards amplifies their impacts and couples with physical and social vulnerabilities to threaten lives, livelihoods, and the environment. Neglecting compound hazards underestimates overall risk. Using a whole island macroscale, (level-I) analysis, susceptibility scenarios for hurricanes, triggered landslides, and floods were developed by incorporating physical process parameters. The susceptibilities were combined with vulnerability indicators to map spatial patterns of hurricane multi-risks in Dominica. The analysis adopted a coupled approach involving the frequency ratio (FR), analytic hierarchy process (AHP), and geographic information system (GIS). Detailed hazard modelling was done at selected sites (level-II), incorporating storm surge estimates, landslide runout simulations, and steady flow analysis for floods. High-resolution terrain data and simulation models, the Rapid Mass Movement Simulation (RAMMS) and the hydrologic engineering center’s river analysis system (HEC-RAS), were employed. Ground validation confirmed reasonable agreement between projected and observed scenarios across different spatial scales. Following the United Nations Office for disaster risk reduction (UNDRR) call for the inclusion of local, traditional, and indigenous knowledge, feedback, and expert opinion to improve understanding of disaster risk, 17 interviews with local experts and 4 participatory workshops with residents were conducted, and findings were incorporated into the analysis, so as to gain insights into risk perceptions. The study’s outcomes encompass projections and quantification of hurricane compound hazards, vulnerabilities, accumulated risks, and an understanding of local priorities. These findings will inform decision-making processes for risk mitigation choices and community actions by providing a new framework for multi-hazard risk assessment that is easy to implement in combining different data forms.

Abstract Evidence-based assessment (EBA) in mental health is a critical aspect of improving patient outcomes and addressing the gaps in mental health care. EBA involves the use of psychometric instruments to gather data that can inform clinical decision-making, inform policymakers, and serve as a basis for research and quality management. Despite its potential, EBA is often hindered by barriers such as workload and cost, leading to its underutilization. Regarding low- and middle-income countries (LMIC), the implementation of EBA is recognized as a key strategy to address and close the prevalent mental health treatment gap. To simplify the application of EBA including in LMIC, an international team of researchers and practitioners from Tanzania, Kosovo, Chile, and Switzerland developed the Mental Health Information Reporting Assistant (MHIRA). MHIRA is an open-source electronic health record that streamlines EBA by digitising psychometric instruments and organising patient data in a user-friendly manner. It provides immediate and convenient reports to inform clinical decision-making. The current article provides a comprehensive overview of the features and technical details of MHIRA, as well as insights from four implementation scenarios. The experience gained during the implementations as well as the user-feedback suggests that MHIRA has the potential to be successfully implemented in a variety of clinical contexts and simplify the use of EBA. However, further research is necessary to establish its potential to sustainably transform healthcare services and impact patient outcomes. In conclusion, MHIRA represents an important step in promoting the widespread adoption of EBA in mental health. It offers a promising solution to the barriers that have limited the use of EBA in the past and holds the potential to improve patient outcomes and support the ongoing efforts to address gaps in mental health care.

Landslides pose a serious risk to life and property in the mountainous regions around the globe. Understanding the interplay of landslide conditioning and triggering factors is essential for lessening the impacts caused by the hazard. Cox's Bazar — a coastal mountainous district in Bangladesh is recurrently affected by rainfall-triggered landslides. Based on analysis of 14 experiential landslides and combination of gauged and satellite rainfall estimates for the period from 2003 to 2019, the present study determines three landslide-triggering rainfall thresholds for the Cox's Bazar District (CBD): 1. Intensity-Duration (ID) threshold derived in this study revealed that any rainfall event with an intensity of ≥4.04 ​mm/h if prolonging for ≥12h can cause slope failures; 2. Event-Duration (ED) threshold suggested that a normalized cumulative event rainfall (EMAP) of 0.15 for one day is expected to trigger landslides; and 3. threshold calculated using randomly chosen antecedent rainfall expressed best distinction on 30-day rainfall and the equation of the threshold came out as Rth ​= ​64–0.02 Ra30. The recurrence probability of the derived antecedent rainfall threshold and likely landslides was determined through the Poisson distribution. Moreover, we assess the landslide susceptibility of the district with a coupled use of Frequency Ratio (FR) statistical measure and Geographic Information System (GIS). Considering the combined role of selected conditioning factors, the landslide susceptibility status of the CBD was quantified and classified into probability intervals. The accuracy of the susceptibility maps was assessed through the Relative Landslide Density Index (R-Index) that used a field landslide inventory, comprising well distributed 891 events. Moreover, gridded population data was superimposed on the derived susceptibility maps to understand the risk levels of people. The derivation of landslide-triggering rainfall thresholds and spatial susceptibility assessment has been useful to propose a low-cost Landslide Early Warning System (LEWS) which can contribute in alleviating the adverse effects of landslide hazard in the CBD.