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Introduction: While pedaling, cyclists rest their pelvis on the saddle, generating pressures on it. The pressures generated on the saddle are influenced by several factors. This study aimed to evaluate whether the flexibility of hamstring and lower back muscles could be considered a predictor of pressures in the anterior region (PAR) on the saddle., Methods: For this study, 15 young off-road Italian cyclists (11m, 4f) aged 13-16 (Italian Federation categories: ES1, ES2, AL1, AL2) were recruited. Each participant was administered the V sit-and-reach (VSR) to measure the hamstring and lower back muscles flexibility. Subsequently, after performing a bike fitting, the saddle pressures during pedaling at three different intensities (100, 140, 180 W), with participants on their own bike installed on specific bike roller, were recorded. The parameters considered for statistical analysis were front pressure (%) and back pressure (%)., Results: The hamstring and lower back muscles flexibility, as result of the VSR test, was a predictor of saddle PAR at 100 W (R 2  = 0.362, p  = 0.018), at 140 W (R 2  = 0.291, p  = 0.038), and at 180 W (R 2  = 0.349, p  = 0.020) of pedaling intensity., Conclusion: Higher values of the VSR could predict lower values of the pressures exerted in the front region of the saddle. The hamstring and lower back muscles flexibility may be considered a predictor of PAR on the saddle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Vicari, Patti, Giustino, Belmonte, Alamia, Gervasi, Fernández Peña, Palma, Schena, Bianco and Thomas.)

The reproducibility crisis in bioscience, characterized by inconsistent study results, impedes our understanding of biological processes and global collaborative studies offer a unique solution. This study is the first global collaboration using the zebrafish ( Danio rerio ) novel tank test, a behavioral assay for anxiety-like responses. We analyzed data from 20 laboratories worldwide, focusing on housing conditions and experimental setups. Our study included 488 adult zebrafish, tested for 5 min, focusing on a variety of variables. Key findings show females exhibit more anxiety-like behavior than males, underscoring sex as a critical variable. Housing conditions, including higher stocking densities and specific feed types, influenced anxiety levels. Optimal conditions (5 fish/L) and nutritionally rich feeds (e.g., rotifers), mitigated anxiety-like behaviors. Environmental stressors, like noise and transportation, significantly impacted behavior. We recommend standardizing protocols to account for sex differences, optimal stocking densities, nutritionally rich feeds, and minimizing stressors to improve zebrafish behavioral study reliability., Competing Interests: Competing Interest Statement: The authors declare no competing interests.

Bands of interdendritic porosity and positive macrosegregation are commonly observed in pressure die castings, with previous studies demonstrating their close relation to dilatant shear bands in granular materials. Despite recent technological developments, the micromechanism governing dilatancy in the high-pressure die casting (HPDC) process for alloys between liquid and solid temperature regions is still not fully understood. To investigate the influence of fluid flow and the size of externally solidified crystals (ESCs) on the evolution of dilatant shear bands in HPDC, various filling velocities were trialled to produce HPDC samples of Al8SiMnMg alloys. This study demonstrates that crystal fragmentation is accompanied by a decrease in dilatational concentration, producing an indistinct shear band. Once crystal fragmentation stagnates, the enhanced deformation rate associated with a further increase in filling velocity (from 2.2 ms -1 to 4.6 ms -1 ) localizes dilatancy into a highly concentrated shear band. The optimal piston velocity is 3.6 ms -1 , under which the average ESC size reaches the minimum, and the average yield stress and overall product of strength and elongation reach the maximum values of 144.6 MPa and 3.664 GPa%, respectively. By adopting the concept of force chain buckling in granular media, the evolution of dilatant shear bands in equiaxed solidifying alloys can be adequately explained based on further verification with DEM-type modeling in OpenFOAM. Three mechanisms for ESC-enhanced dilation are presented, elucidating previous reports relating the presence of ESCs to the subsequent shear band characteristics. By applying the physics of granular materials to equiaxed solidifying alloys, unique opportunities are presented for process optimization and microstructural modeling in HPDC.

Background: This study aimed to compare and examine the local and non-local effects of a foam rolling (FR) and static stretching (SS) intervention applied to the plantar flexor (PF)., Methods: Fourteen female participants were investigated. Each participant underwent three conditions in a random order at least 48h apart and at the same time of the day: Control (CC), SS, and FR. Each condition was performed unilaterally in the dominant PF for 4 sets (apart from CC). SS was performed for 30 s. The FR included 30 rolls (15 in each direction) over a period of 30 s. A rest of 30 s was provided between each set for all conditions. Outcome variables were ankle dorsiflexion range of movement (ROM), tissue hardness, localized bioimpedance analysis at 50 kHz (L-BIA), and pain pressure thresholds (PPT). Tissue hardness, L-BIA, and PPT were measured in the lower leg and thigh. Measures were assessed pre (T0), immediately post (T1), and 10-min after (T2) the intervention., Results: No differences were found for time for the CC or between the T0 of each condition. Concerning the lower leg, ROM improved for SS and FR from T0 to T1 while returning to baseline in T2. A significant increase in PPT was observed only for SS in T1. L-BIA showed a significant increase for both phase angle and impedance only for FR in T1. Tissue hardness did not change for any group at any time-point. Concerning the thigh, no measure at any time point showed significant differences., Conclusion: Both, FR and SS were able to acutely improve ankle ROM. The observed changes were probably caused by a change in viscoelastic properties and local pain perception, without any variation in tissue morphology. FR was the only intervention to improve the intracellular-to-extracellular ratio and decrease fluids. Non-local effects were not observed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

We present a case of a patient having cone-beam CT (CBCT)-based online adaptive radiotherapy (oART) on Ethos Therapy after oesophagectomy and gastric pull-up. This case report aims to demonstrate that daily oART is a viable treatment option for post-oesophagectomy patients. The patient's radiotherapy plan was generated on the Ethos system using an eight-field intensity-modulated radiation therapy (IMRT) plan imported from the Eclipse planning system. The patient was prescribed 50.4Gy/28# over 5.5 weeks with concurrent carboplatin and paclitaxel. There were no changes to our department's standard clinical tumour volume (CTV) and planning tumour volume (PTV) margins due to the novel nature of the case. For each fraction of daily oART, the heart, right and left lungs, oesophagus and trachea were Ethos-contoured 'Influencer' structures which were reviewed and edited at the console. Minor edits were required to each structure. The adaptive plan was chosen for each fraction due to showing clear dosimetric benefits to both PTV coverage and organ at risk (OAR) doses. Lung doses were significantly reduced with the course mean lung dose reduction of 8.1% and the Lung-CTV V20 reduction of 4.4%. The treatment duration from the start of CBCT acquisition to the end of beam delivery averaged 19 minutes and 12 seconds. The patient was able to tolerate the time on the bed without incident within the scheduled 30-minute appointment slot. Our case demonstrates that significant inter-fraction anatomy changes occur in patients having radiotherapy after oesophagectomy. Without the use of adaption, we have seen that there would be clinically significant undercoverage of target volumes due to sub-optimal dose distribution. We plan to evaluate the imaging available in Ethos dose monitoring to establish if these margins could be reduced in patients treated with online adaptive radiotherapy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Amy Ward, Siobhan Graham, Ewan Almond, Dom Withers declare(s) Speaker fees from Varian Medical Systems. Have received speaker fees and travel expenses for invited talks in the past 36 months, no financial incentive has been offered for this piece of work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ward et al.)

Photocatalysts can use visible light to convert CO 2 into useful products. However, to date photocatalysts for CO 2 conversion are limited by insufficient long-term stability and low CO 2 conversion rates. Here we report hybrid photocatalysts consisting of conjugated polymers and a ruthenium(ii)-ruthenium(ii) supramolecular photocatalyst which overcome these challenges. The use of conjugated polymers allows for easy fine-tuning of structural and optoelectronic properties through the choice of monomers, and after loading with silver nanoparticles and the ruthenium-based binuclear metal complex, the resulting hybrid systems displayed remarkably enhanced activity for visible light-driven CO 2 conversion to formate. In particular, the hybrid photocatalyst system based on poly(dibenzo[ b , d ]thiophene sulfone) drove the very active, durable and selective photocatalytic CO 2 conversion to formate under visible light irradiation. The turnover number was found to be very high (TON = 349 000) with a similarly high turnover frequency (TOF) of 6.5 s -1 , exceeding the CO 2 fixation activity of ribulose-1,5-bisphosphate carboxylase/oxygenase in natural photosynthesis (TOF = 3.3 s -1 ), and an apparent quantum yield of 11.2% at 440 nm. Remarkably, quantitative conversion of CO 2 (737 μmol, 16.5 mL) to formate was achieved using only 8 mg of the hybrid photocatalyst containing 80 nmol of the supramolecular photocatalyst at standard temperature and pressure. The system sustained photocatalytic activity even after further replenishment of CO 2 , yielding a very high concentration of formate in the reaction solution up to 0.40 M without significant photocatalyst degradation within the timeframe studied. A range of experiments together with density functional theory calculations allowed us to understand the activity in more detail., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Decades of genetic association testing in human cohorts have provided important insights into the genetic architecture and biological underpinnings of complex traits and diseases. However, for certain traits, genome-wide association studies (GWAS) for common SNPs are approaching signal saturation, which underscores the need to explore other types of genetic variation to understand the genetic basis of traits and diseases. Copy number variation (CNV) is an important source of heritability that is well known to functionally affect human traits. Recent technological and computational advances enable the large-scale, genome-wide evaluation of CNVs, with implications for downstream applications such as polygenic risk scoring and drug target identification. Here, we review the current state of CNV-GWAS, discuss current limitations in resource infrastructure that need to be overcome to enable the wider uptake of CNV-GWAS results, highlight emerging opportunities and suggest guidelines and standards for future GWAS for genetic variation beyond SNPs at scale., (© 2024. Springer Nature Limited.)

Background: Namibia, a low malaria transmission country targeting elimination, has made substantial progress in reducing malaria burden through improved case management, widespread indoor residual spraying and distribution of insecticidal nets. The country's diverse landscape includes regions with varying population densities and geographical niches, with the north of the country prone to periodic outbreaks. As Namibia approaches elimination, malaria transmission has clustered into distinct foci, the identification of which is essential for deployment of targeted interventions to attain the southern Africa Elimination Eight Initiative targets by 2030. Geospatial modelling provides an effective mechanism to identify these foci, synthesizing aggregate routinely collected case counts with gridded environmental covariates to downscale case data into high-resolution risk maps., Methods: This study introduces innovative infectious disease mapping techniques to generate high-resolution spatio-temporal risk maps for malaria in Namibia. A two-stage approach is employed to create maps using statistical Bayesian modelling to combine environmental covariates, population data, and clinical malaria case counts gathered from the routine surveillance system between 2018 and 2021., Results: A fine-scale spatial endemicity surface was produced for annual average incidence, followed by a spatio-temporal modelling of seasonal fluctuations in weekly incidence and aggregated further to district level. A seasonal profile was inferred across most districts of the country, where cases rose from late December/early January to a peak around early April and then declined rapidly to a low level from July to December. There was a high degree of spatial heterogeneity in incidence, with much higher rates observed in the northern part and some local epidemic occurrence in specific districts sporadically., Conclusions: While the study acknowledges certain limitations, such as population mobility and incomplete clinical case reporting, it underscores the importance of continuously refining geostatistical techniques to provide timely and accurate support for malaria elimination efforts. The high-resolution spatial risk maps presented in this study have been instrumental in guiding the Namibian Ministry of Health and Social Services in prioritizing and targeting malaria prevention efforts. This two-stage spatio-temporal approach offers a valuable tool for identifying hotspots and monitoring malaria risk patterns, ultimately contributing to the achievement of national and sub-national elimination goals., (© 2024. The Author(s).)

Abstract: The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of Gi/o-coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor potential ankyrin 1 (TRPA1), a mediator of noxious mechanotransduction in the bowel. Building on in silico docking simulations, we confirmed that the mast cell stabiliser, cromolyn (CS), and phosphodiesterase inhibitor, zaprinast, are agonists at mouse GPR35, promoting the activation of different Gi/o subunits. Pretreatment with either CS or zaprinast significantly attenuated TRPA1-mediated colonic nociceptor activation and prevented TRPA1-mediated mechanosensitisation. These effects were lost in tissue from GPR35-/- mice and were shown to be mediated by inhibition of TRPA1-evoked substance P (SP) release. This observation highlights the pronociceptive effect of SP and its contribution to TRPA1-mediated colonic nociceptor activation and sensitisation. Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by CS pretreatment in a GPR35-dependent manner. Our data demonstrate that GPR35 agonists prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential of GPR35 agonists to deliver nonopioid analgesia for the treatment of abdominal pain., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

The analysis of histopathology images with artificial intelligence aims to enable clinical decision support systems and precision medicine. The success of such applications depends on the ability to model the diverse patterns observed in pathology images. To this end, we present Virchow, the largest foundation model for computational pathology to date. In addition to the evaluation of biomarker prediction and cell identification, we demonstrate that a large foundation model enables pan-cancer detection, achieving 0.95 specimen-level area under the (receiver operating characteristic) curve across nine common and seven rare cancers. Furthermore, we show that with less training data, the pan-cancer detector built on Virchow can achieve similar performance to tissue-specific clinical-grade models in production and outperform them on some rare variants of cancer. Virchow's performance gains highlight the value of a foundation model and open possibilities for many high-impact applications with limited amounts of labeled training data., (© 2024. The Author(s).)

Abstract: Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Aims/hypothesis: Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes., Methods: We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose., Results: We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone., Conclusions/interpretation: Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models., (© 2024. The Author(s).)

Although rare genetic conditions are mostly caused by DNA sequence alterations that functionally disrupt individual genes, large-scale studies using genome sequencing have started to unmask additional complexity. Understanding how combinations of variants in different genes shape human phenotypes is expected to provide important insights into the clinical and genetic heterogeneity of rare disorders. Here, we use albinism, an archetypal rare condition associated with hypopigmentation, as an exemplar for the study of genetic interactions. We analyse data from the Genomics England 100,000 Genomes Project alongside a cohort of 1120 individuals with albinism, and investigate the effect of dual heterozygosity for the combination of two established albinism-related variants: TYR:c.1205 G > A (p.Arg402Gln) [rs1126809] and OCA2:c.1327 G > A (p.Val443Ile) [rs74653330]. As each of these changes alone is insufficient to cause disease when present in the heterozygous state, we sought evidence of synergistic effects. We show that, when both variants are present, the probability of receiving a diagnosis of albinism is significantly increased (odds ratio 12.8; 95% confidence interval 6.0 - 24.7; p-value 2.1 ×10 -8 ). Further analyses in an independent cohort, the UK Biobank, support this finding and highlight that heterozygosity for the TYR:c.1205 G > A and OCA2:c.1327 G > A variant combination is associated with statistically significant alterations in visual acuity and central retinal thickness (traits that are considered albinism endophenotypes). The approach discussed in this report opens up new avenues for the investigation of oligogenic patterns in apparently Mendelian disorders., (© 2024. The Author(s).)

Practicing physical activities or sports that involve frequent jumping and landing can strain the muscles and joints of the lower limbs, especially in those who do not have adequate physical preparation. The objective of this study was to (a) determine the correlation between ankle range of motion (ROM) and landing stability following jumps; (b) assess the association between the jump height in a counter-movement jump (CMJ) test and ankle ROM; and (c) examine the connection between stabilometry during specific jumps movements present in many sports and in ankle stabilization. Sixty-two healthy amateur volleyball players participated in the study (age: thirty-seven females and twenty-five males; age (years): 16.5 ± 4.25; height (cm): 166 ± 11.4; weight (Kg): 61.6 ± 13.7). Participants were recruited for the study in collaboration with student sports associations. The evaluations encompassed the measurement of ankle joint mobility for both lower limbs using an inertial sensor, a static baropodometric and stabilometric analysis using a pressure platform, and the CMJ test using the Microgate system. After the assessments, participants performed a "specific jump landing task". Significant correlations were found between foot range of motion (ROM) and counter-movement jump (CMJ) performance. Specifically, the ROM of the right foot had a strong correlation with the CMJ (r = 0.81, p < 0.001), while the left foot ROM showed a moderate correlation (r = 0.46, p < 0.001). The specific jump task revealed substantial changes in stabilometry parameters, particularly during forward hops compared to lateral jumps. Dorsiflexion ROM significantly impacts jumping ability. Evaluating landing patterns and stabilometry during targeted activities can help optimize training, improve dynamic balance, and reduce ankle injury risk.

Background: Food loss and waste estimates are highly inconsistent as a result of methodological and systemic differences. Additionally, the absence of in-depth evidence surrounding the biological drivers of food loss and waste precludes targeted mitigation action. To address this challenge, we undertook a metanalysis utilising a systematic literature review combined with industry stakeholder surveys to examine the incidence of food loss and waste in the UK fruit and vegetable supply chain between primary production and retail., Results: We estimated that 37% of fruit and vegetables, equivalent to 2.4 Mt of produce, is lost between production and sale. In the UK, primary production is the main stage responsible for these losses (58%), and is dominated by four crops (apple, onion, carrot and potato), which contribute 71% of total food loss and waste. Quality and supply/demand mismatch are the core drivers, combined with limited ability to control postharvest quality decline as a result of technical or economic barriers., Conclusions: Innate biological mechanisms contribute to, and detract from, marketable quality generating food loss risks where these cannot be adequately modified or controlled. Through climate change effects, reduced pesticide availability, changing consumer behaviour and increased pressure to reduce resource/energy inputs during pre- and postharvest handling, food loss and waste risk is likely to increase in the short term unless targeted, coordinated action is taken to actively promote its mitigation. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

The demand for an efficient and reliable ultrasonic phased array imaging system is not unique to a single industry. Today's imaging systems can be enhanced in a number of areas including; improving scanning and processing times, reducing data storage requirements, simplifying hardware, and prolonging probe lifespan. In this work, it is shown that by combining the use of coded excitation with single-bit data capture, a number of these areas can be improved. Despite using single-bit receive data, resolution can be recovered through the coded excitation pulse compression process, and shown to produce high signal-to-noise ratio (SNR) images of phase coherence imaging (PCI) and total focusing method (TFM) of tip diffraction in a carbon steel sample. Comparison with conventional single-cycle transmission pulses has shown that little imaging performance degradation is seen despite a significant reduction in data resolution and size. This has also been shown to be effective at low excitation voltages with gain compensation due to the obsolescence of signal saturation concerns when considering single-bit receive data. The ability to compute high-resolution ultrasonic images from low-resolution input data at low transmission voltages has important implications for data compression, acquisition and imaging performance, operator safety, and hardware simplification for ultrasonic imaging systems across industrial and medical fields.

How the timing of development is linked to organismal size is a longstanding question. Although numerous studies have reported a correlation of temporal and spatial traits, the developmental or selective constraints underlying this link remain largely unexplored. We address this question by studying the periodic process of embryonic axis segmentation in-vivo in Oryzias fish. Interspecies comparisons reveal that the timing of segmentation correlates to segment, tissue and organismal size. Segment size in turn scales according to tissue and organism size. To probe for underlying causes, we genetically hybridised two closely related species. Quantitative analysis in ~600 phenotypically diverse F2 embryos reveals a decoupling of timing from size control, while spatial scaling is preserved. Using developmental quantitative trait loci (devQTL) mapping we identify distinct genetic loci linked to either the control of segmentation timing or tissue size. This study demonstrates that a developmental constraint mechanism underlies spatial scaling of axis segmentation, while its spatial and temporal control are dissociable modules., (© 2024. The Author(s).)

Calcitonin gene-related peptide (CGRP) and adrenomedullin 2/intermedin (AM2/IMD) play important roles in several pathologies, including cardiovascular disease, migraine and cancer. The efficacy of drugs targeting CGRP signalling axis for the treatment of migraine patients is sometimes offset by side effects (e.g. inflammation and microvascular complications, including aberrant neovascularisation in the skin). Recent studies using animal models implicate CGRP in lymphangiogenesis and lymphatic vessel function. However, whether CGRP or AM2/IMD can act directly on lymphatic endothelial cells is unknown. Here, we found that CGRP and AM2/IMD induced p44/42 MAPK phosphorylation in a time- and dose-dependent manner in primary human dermal lymphatic endothelial cells (HDLEC) in vitro, and thus directly affected these cells. These new findings reveal CGRP and AM2/IMD as novel regulators of LEC biology and warrant further investigation of their roles in the context of pathologies associated with lymphatic function in the skin and other organs, and therapies targeting CGRP signalling axis., Competing Interests: Declaration of competing interest Leonid Nikitenko reports financial support was provided by Welcome Trust Biomedical Vacation Scholarship. Dimitrios Manolis reports financial support was provided by Welcome Trust Biomedical Vacation Scholarship. Leonid Nikitenko reports financial support was provided by Biochemical Society UK Summer Vacation Studentship. Oktawia A. Ryskiewicz-Sokalska reports financial support was provided by Biochemical Society UK Summer Vacation Studentship. Leonid Nikitenko reports financial support was provided by Castle Hill Hospital Melanoma Charitable Fund. Shirin Hasan reports financial support was provided by Castle Hill Hospital Melanoma Charitable Fund. Anthony Maraveyas reports financial support was provided by Castle Hill Hospital Melanoma Charitable Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The movement of populations between locations and activities can result in complex transmission dynamics, posing significant challenges in controlling infectious diseases like COVID-19. Notably, networks of care homes create an ecosystem where staff and visitor movement acts as a vector for disease transmission, contributing to the heightened risk for their vulnerable communities. Care homes in the UK were disproportionately affected by the first wave of the COVID-19 pandemic, accounting for almost half of COVID-19 deaths during the period of 6th March - 15th June 2020 and so there is a pressing need to explore modelling approaches suitable for such systems. We develop a generic compartmental Susceptible - Exposed - Infectious - Recovered - Dead (SEIRD) metapopulation model, with care home residents, care home workers, and the general population modelled as subpopulations, interacting on a network describing their mixing habits. We illustrate the model application by analysing the spread of COVID-19 over the first wave of the COVID-19 pandemic in the NHS Lothian health board, Scotland. We explicitly model the outbreak's reproduction rate and care home visitation level over time for each subpopulation and execute a data fit and sensitivity analysis, focusing on parameters responsible for inter-subpopulation mixing: staff-sharing, staff shift patterns and visitation. The results from our sensitivity analysis show that restricting staff sharing between homes and staff interaction with the general public would significantly mitigate the disease burden. Our findings indicate that protecting care home staff from disease, coupled with reductions in staff-sharing across care homes and expedient cancellations of visitations, can significantly reduce the size of outbreaks in care home settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Immune-mediated hemolytic anemia (IMHA) is defined as an immune-mediated destruction of erythrocytes. Relapses are recognized, but risk factors are poorly defined. We hypothesized that a lower packed cell volume (PCV) on presentation, more transfusions during hospitalization, or a higher total bilirubin would be associated with an increased risk of relapse. IMHA was defined as a PCV less than 30% at diagnosis with two of the following identified: spherocytes, positive Coombs test, elevated total bilirubin, hemoglobinemia, or positive slide agglutination. This was a retrospective study evaluating 163 dogs between January 2005 and December 2019 from one specialty hospital. There were 13 relapses. The probability (95% confidence interval [CI]) of relapse by 3 and 12 mo was 0.05 (0.02-0.13) and 0.11 (0.06-0.22). The probability (95% CI) of relapse by 12 mo in patients who required two or more transfusions was 0.20 (0.09-0.42) compared with 0.07 (0.02-0.19) in patients who did not (P = .191). A lower PCV at diagnosis was not associated with an increased risk of relapse (hazard ratio [95% CI] 0.95 [0.86-1.04], P = .238). A higher total bilirubin was associated with a significantly increased risk of relapse (P = .003). With each increase of 1 mg/dL of total bilirubin, there was a 0.17 (95% CI 0.06-0.28) increase in the probability of relapse. These patients would likely need closer monitoring., (© 2024 by American Animal Hospital Association.)

Purpose: Dose-escalated radiation therapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiation therapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease while limiting toxicity. This study evaluated the toxicity and quality of life (QoL) with CyberKnife-based SBRT and simultaneous integrated boost in localized prostate cancer., Methods and Materials: Eligible participants included newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least 1 of the following: Gleason ≥4+3, magnetic resonance imaging(MRI)-defined T3a N0, prostate-specific antigen ≥20) with up to 2 MRI-identified DILs. Participants received 36.25 Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5 Gy as allowed by organ-at-risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2+ genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using Radiation Therapy Oncology Group scoring, biochemical parameters, International Prostate Symptom Score, International Index of Erectile Function 5, and EQ-5D QoL outcomes were assessed., Results: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43 Gy. Cumulative acute grade 2+ genitourinary and gastrointestinal toxicity were 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. International Prostate Symptom Score and urinary QoL scores recovered to baseline by 6 months. Patient-reported outcomes showed no significant change in EQ-5D QoL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date., Conclusions: CyberKnife SBRT-delivered dose of 36.25 Gy to the prostate with a simultaneous integrated boost up to 47.5 Gy is well tolerated. Acute and late genitourinary and gastrointestinal toxicity rates are comparable to other contemporary SBRT trials and series with focal boost., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In recent decades, the field of statistical linguistics has made significant strides, which have been fueled by the availability of data. Leveraging Twitter data, this paper explores the English and Spanish languages, investigating their rank diversity across different scales: temporal intervals (ranging from 3 to 96 h), spatial radii (spanning 3 km to over 3000 km), and grammatical word ngrams (ranging from 1-grams to 5-grams). The analysis focuses on word ngrams, examining a time period of 1 year (2014) and eight different countries. Our findings highlight the relevance of all three scales with the most substantial changes observed at the grammatical level. Specifically, at the monogram level, rank diversity curves exhibit remarkable similarity across languages, countries, and temporal or spatial scales. However, as the grammatical scale expands, variations in rank diversity become more pronounced and influenced by temporal, spatial, linguistic, and national factors. Additionally, we investigate the statistical characteristics of Twitter-specific tokens, including emojis, hashtags, and user mentions, revealing a sigmoid pattern in their rank diversity function. These insights contribute to quantifying universal language statistics while also identifying potential sources of variation.

Quantifying the contribution of genetics and environmental effects on disease initiation and progression, as well as the shared genetics of different diseases, is vital for the understanding of the disease etiology of multimorbidities. In this study, we leverage nationwide Danish registries to provide a granular atlas of the genetic origin of disease phenotypes for a cohort of all Danes 1978-2018 with partially known pedigree (n = 6.3 million). We estimate the heritability and genetic correlation between thousands of disease phenotypes using a novel approach that can be scaled to nationwide data. Our findings confirm the importance of genetics for a number of known associations and increase the resolution of heritability by adding numerous associations, some of which point to shared biologically origin of different phenotypes. We also establish the heritability of disease trajectories and the importance of sex-specific genetic contributions. Results can be accessed at https://h2.cpr.ku.dk/ ., (© 2024. The Author(s).)

Background and Aims: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1β has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1β, in the treatment of patients with AH., Methods: Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle., Results: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04)., Conclusions: CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: This study investigated sustainability and multimorbidity alongside barriers to employment including health and policy to demonstrate intersectional impact on return-to-work success within a UK welfare-to-work programme., Design: Cohort study design: The study calculated the proportion of time spent employed after experiencing a job start and the proportion retaining work over 6 months. Employment/unemployment periods were calculated, sequence-index plots were produced and visualisations were explored by benefit type and age., Setting: This study used confidential access to deidentified data from unemployed Work Programme clients operated by Ingeus on behalf of the UK Government in Scotland between 1 April 2013 and 31 July 2014., Participants: 13 318 unemployed clients aged 18-64 years were randomly allocated to a Work Programme provider and monitored over 2 years., Results: This study has two distinct groupings. 'Employment and Support Allowance (ESA)' corresponding to those with work-limiting disability in receipt of related state financial support, and 'Jobseeker's Allowance (JSA)' corresponding to unemployment claimants. Despite fewer and later job starts for ESA clients, those that gained employment spend relatively more subsequent time in employment when compared with individuals without work-limiting conditions (ESA clients under 50, 0.73; ESA clients over 50, 0.79; JSA clients under 50, 0.67 and JSA clients over 50, 0.68). Proportion in permanent jobs was higher among ESA than JSA clients (JSA under 50, 92%; JSA over 50, 92%; ESA under 50, 95% and ESA over 50, 97%)., Conclusion: The research demonstrated that returning to paid employment after a reliance on welfare benefits is challenging for people aged over 50 and those with disability. The study found that although fewer older ESA claimants entered employment, they typically remained in employment more than JSA clients who did not leave the Work Programme early. This indicates the importance of identifying risk factors for job loss in ageing workers and the development of interventions for extension of working lives., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: Previous reports showed enhanced graft function in both healthy and injured porcine lungs after preservation at 10 °C. The objective of the study is to elucidate the mechanism of lung protection by 10 °C and identify potential therapeutic targets to improve organ preservation., Methods: Metabolomics data were analyzed from healthy and injured porcine lungs that underwent extended hypothermic preservation on ice and at 10 °C. Tissue sampled before and after preservation were subjected to untargeted metabolic profiling. Principal component analysis was performed to test for the separability of the paired samples. Significantly changed metabolites between the 2 time points were identified and analyzed to determine the underlying metabolic pathways. The levels of respiratory activity of lung tissue at hypothermic temperatures were confirmed using high resolution respirometry., Results: In both healthy and injured lungs (n = 5 per intervention), principal component analysis suggested minimal change in metabolites after ice preservation but significant change of metabolites after 10 °C preservation, which was associated with significantly improved lung function as assessed by ex vivo lung perfusion and lung transplantation. For healthy lungs, lipid energy pathway was found primarily active at 10 °C. For injured lungs, additional carbohydrate energy pathway and anti-ferroptosis pathways aiding organ repair were identified. These metabolic features are also key features involved in mammal hibernation., Conclusions: Untargeted metabolomics revealed a dynamic metabolic gradient for lungs stored at 10 °C. Elucidating the underlying mechanisms behind this pathway regulation may lead to strategies that will allow organs "hibernate" for days, potentially making organ banking a reality., Competing Interests: Conflict of Interest Statement M.C., M.L., and S.K. are shareholders of Traferox Technologies Inc. S.K. serves as Chief Medical Officer of Traferox Technologies Inc, receives personal fees from Traferox Technologies Inc, and is an inventor of IP licensed to Traferox Technologies Inc. M.C. serves as Chief Scientific Officer of Traferox Technologies Inc, receives personal fees from Traferox Technologies Inc, and is an inventor of IP licensed to Traferox Technologies Inc. Traferox devices were not used in any part of the study. M.C. and S.K. are consultants for Lung Bioengineering Inc. S.K. is a consultant for Abbott, CareDx, and United Therapeutics. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Photocatalyst systems combining donor polymers with acceptor molecules have shown the highest evolution rates for sacrificial hydrogen production from water for organic systems to date. Here, new donor molecules have been designed and synthesised taking inspiration from the structure-performance relationships which have been established in the development of non-fullerene acceptors. While a conventional bulk heterojunction (BHJ) pairing consists of a donor polymer and acceptor small molecule, here we have successfully reversed this approach by using new p-type small molecules in combination with a n-type conjugated polymer to produce non-conventional BHJ (ncBHJ) nanoparticles. We have applied these ncBHJs as photocatalysts in the sacrificial hydrogen evolution from water, and the best performing heterojunction displayed high activity for sacrificial hydrogen production from water with a hydrogen evolution rate of 22 321 μmol h -1 g -1 which compares well with the state-of-the-art for conventional BHJ photocatalyst systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption., (© 2024. The Author(s).)

This narrative review aimed to identify young cancer survivors' behaviours, experiences, and perspectives concerning physical activity, and identify useful strategies for promoting a healthy lifestyle. A manual search on the following databases was conducted: PubMed, Scopus, and Web of Science. The search was conducted between June 1, 2023, and April 12, 2024. Articles published from database inception up to April 12, 2024, were retrieved. Articles published in any language were considered. Perspectives including ideas, perceived barriers, and facilitators have been identified. Young cancer survivors seem to engage in physical activity as a useful coping strategy to regain normality and keep healthy after the cancer diagnosis. Although emotional and social support seems fundamental to increase participation, several other factors, including physical limitations, fatigue, sex, cancer type, and socio-economic status can influence physical activity participation. For those engaged in physical activity, the preferred activities are walking, biking, going to the gym, and exercising at home, while the least preferred are exercising at the hospital or boot camp-based exercises. Yoga is more frequently chosen by those still under treatment. Young cancer survivors appear to have unique needs different from those of adult cancer survivors. Mode of treatment delivery, increased awareness concerning the effects of physical activity, including families and friends, connecting survivors, and providing social support together with increasing motivation are key strategies for the promotion of physical activity in young cancer survivors. Fitness and healthcare professionals should consider these aspects to increase young cancer survivors' involvement in physical activities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Prior studies of muscle blood flow and muscle-specific oxygen consumption have required invasive injection of dye and magnetic resonance imaging, respectively. Such measures have limited utility for continuous monitoring of the respiratory muscles. Frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy (FD-NIRS & DCS) can provide continuous surrogate measures of blood flow index (BF i ) and metabolic rate of oxygen consumption (MRO 2 ). This study aimed to validate sternocleidomastoid FD-NIRS & DCS outcomes against electromyography (EMG) and mouth pressure (Pm) during incremental inspiratory threshold loading (ITL). Six female and six male healthy adults (means ± SD; 30 ± 7 yr, maximum inspiratory pressure 118 ± 61 cmH 2 O) performed incremental ITL starting at low loads (8 ± 2 cmH 2 O) followed by 50-g increments every 2 min until task failure. FD-NIRS & DCS continuously measured sternocleidomastoid oxygenated and deoxygenated hemoglobin + myoglobin (oxy/deoxy[Hb + Mb]), tissue saturation of oxygen (StO 2 ), BF i , and MRO 2 . Ventilatory parameters including inspiratory Pm were also evaluated. Pm increased during incremental ITL ( P < 0.05), reaching -47[-74 to -34] cmH 2 O (median [IQR: 25%-75%]) at task failure. Ventilatory parameters were constant throughout ITL (all P > 0.05). Sternocleidomastoid BF i and MRO 2 increased from the start of the ITL (both P < 0.05). Deoxy[Hb + Mb] increased close to task failure, concomitantly with a constant increase in MRO 2 , and decreased StO 2 . Sternocleidomastoid deoxy[Hb + Mb], BF i , StO 2 , and MRO 2 obtained during ITL via FD-NIRS & DCS correlated with sternocleidomastoid EMG (all P < 0.05). In healthy adults, FD-NIRS & DCS can provide continuous surrogate measures of respiratory BF i and MRO 2 . Increasing sternocleidomastoid oxygen consumption near task failure was associated with increased oxygen extraction and reduced tissue saturation. NEW & NOTEWORTHY This study introduces a novel approach, frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy (FD-NIRS & DCS), for noninvasive continuous monitoring of respiratory muscle blood flow and metabolic rate of oxygen consumption. Unlike prior methods involving invasive dye injection and magnetic resonance imaging, FD-NIRS & DCS offers the advantage of continuous measurement without the need for invasive procedures. It holds promise for advancing muscle physiology understanding and opens avenues for real-time monitoring of respiratory muscles.

Selection of nursery habitats by marine fish, such as European sea bass (Dicentrarchus labrax), is poorly understood. Identifying and protecting the full range of juvenile nursery habitats is vital to supporting resilient fish populations and economically important fisheries. We examined how the condition, stomach fullness, and diet of juvenile European sea bass, along with their abundance, differ at high or low tide between the following estuarine habitats: saltmarsh, oyster reefs, shingle, sand, and mud edge habitats. Using a combination of fyke and seine netting we found no difference in sea bass abundance or condition across high-tide habitats, suggesting that rather than differentially selecting between them, juvenile sea bass use all available shallow habitats at high tide. Stomach fullness was significantly higher on saltmarsh and sand compared to mud, and thus these habitats may support better foraging. Dietary DNA metabarcoding revealed that sand and saltmarsh diets mostly comprised Hediste polychaetes, whereas zooplanktonic taxa dominated diets over mud. At low tide, sea bass abundance was highest in shingle and oyster reefs, where stomach fullness and condition were lowest. This may indicate a potential trade-off between using habitats for foraging and refuge. Although sea bass abundance alone does not capture productivity, the high abundance across all estuarine habitats at high tide suggests that it is important to consider the protection of a mosaic of interconnected habitats to support nursery functions rather than focus on individual habitat types., (© 2024 The Author(s). Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

Background: Long-standing health inequalities in Australian society that were exposed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic were described as "fault lines" in a recent call to action by a consortium of philanthropic organizations. With asthma a major contributor to childhood disease burden, studies of its spatial epidemiology can provide valuable insights into the emergence of health inequalities early in life., Objective: The aims of this study were to characterize the spatial variation of asthma prevalence among children living within Australia's 4 largest cities and quantify the relative contributions of climatic and environmental factors, outdoor air pollution, and socioeconomic status in determining this variation., Methods: A Bayesian model with spatial smoothing was developed to regress ecologic health status data from the 2021 Australian Census against groups of explanatory covariates intended to represent mechanistic pathways., Results: The prevalence of asthma in children aged 5 to 14 years averages 7.9%, 8.2%, 8.5%, and 7.6% in Sydney, Melbourne, Brisbane, and Perth, respectively. This small inter-city variation contrasts against marked intracity variation at the small-area level, which ranges from 6% to 12% between the least and most affected locations in each. Statistical variance decomposition on a subsample of Australian-born, nonindigenous children attributes 66% of the intracity spatial variation to the assembled covariates. Of these covariates, climatic and environmental factors contribute 30%, outdoor air pollution contributes 19%, and areal socioeconomic status contributes the remaining 51%., Conclusion: Geographic health inequalities in the prevalence of childhood asthma within Australia's largest cities reflect a complex interplay of factors, among which socioeconomic status is a principal determinant., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The PAX6 gene encodes a highly-conserved transcription factor involved in eye development. Heterozygous loss-of-function variants in PAX6 can cause a range of ophthalmic disorders including aniridia. A key molecular diagnostic challenge is that many PAX6 missense changes are presently classified as variants of uncertain significance. While computational tools can be used to assess the effect of genetic alterations, the accuracy of their predictions varies. Here, we evaluated and optimised the performance of computational prediction tools in relation to PAX6 missense variants. Through inspection of publicly available resources (including HGMD, ClinVar, LOVD and gnomAD), we identified 241 PAX6 missense variants that were used for model training and evaluation. The performance of ten commonly used computational tools was assessed and a threshold optimization approach was utilized to determine optimal cut-off values. Validation studies were subsequently undertaken using PAX6 variants from a local database. AlphaMissense, SIFT4G and REVEL emerged as the best-performing predictors; the optimized thresholds of these tools were 0.967, 0.025, and 0.772, respectively. Combining the prediction from these top-three tools resulted in lower performance compared to using AlphaMissense alone. Tailoring the use of computational tools by employing optimized thresholds specific to PAX6 can enhance algorithmic performance. Our findings have implications for PAX6 variant interpretation in clinical settings., (© 2024. The Author(s).)

The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC], without amplification). Although this trial applied the 2018 Americal Society of Clinial Oncology (ASCO)/College of American Pathologists (CAP) HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients' treatment may be misaligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO/CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitized whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to establish consensus scores for each case and determine the percentage of HER2 expressing tumor cells. Consensus was reached on all cases, with 40 classified as 1+ and 3 as 2+ (not amplified), totaling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% of cases (56/60), the consensus score matched with the majority opinion of pathologists' independent scores. Seven (41.2%) of the 17 cases reported locally as HER2 0 were classified as HER2 low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists' accuracy in matching the consensus scores ranged from 73.3% to 91.67% (mean, 80.74%). Among HER2-low cancers those in which <20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen's κ coefficients for concordance were excellent for 4, good in 1, and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls improved pathologists' accuracy and concordance., (Copyright © 2024 United States & Canadian Academy of Pathology. All rights reserved.)

Paleopathology, the study of diseases and injuries from the fossil record, allows for a unique view into the life of prehistoric animals. Pathologies have nowadays been described in nearly all groups of fossil vertebrates, especially dinosaurs. Despite the large number of skeletons, pathologies had never been reported in the sauropodomorph Plateosaurus trossingensis. Here we describe the first pathologies of Plateosaurus using two individuals with pathologies in the chevrons of the tail, from the Upper Triassic of Trossingen, SW Germany. The two specimens each contain three consecutive pathological chevrons. Our results show that the pathologies were caused by external trauma in one individual and potentially tendinous trauma in the other. Healing of the lesions allowed survival of both animals. Using additional pathological specimens found in other collections and from multiple localities, we observe that 14.8% of all individuals of Plateosaurus contain pathologies within their chevrons, suggesting it was a vulnerable bone., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schaeffer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Motivation: Crosses among inbred lines are a fundamental tool for the discovery of genetic loci associated with phenotypes of interest. In organisms for which large reference panels or SNP chips are not available, imputation from low-pass whole-genome sequencing is an effective method for obtaining genotype data from a large number of individuals. To date, a structured analysis of the conditions required for optimal genotype imputation has not been performed., Results: We report a systematic exploration of the effect of several design variables on imputation performance in F2 crosses of inbred medaka lines using the imputation software STITCH. We determined that, depending on the number of samples, imputation performance reaches a plateau when increasing the per-sample sequencing coverage. We also systematically explored the trade-offs between cost, imputation accuracy, and sample numbers. We developed a computational pipeline to streamline the process, enabling other researchers to perform a similar cost-benefit analysis on their population of interest., Availability and Implementation: The source code for the pipeline is available at https://github.com/birneylab/stitchimpute. While our pipeline has been developed and tested for an F2 population, the software can also be used to analyse populations with a different structure., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

The epigenome is the suite of interacting chemical marks and molecules that helps to shape patterns of development, phenotypic plasticity and gene regulation, in part due to its responsiveness to environmental stimuli. There is increasing interest in understanding the functional and evolutionary importance of this sensitivity under ecologically realistic conditions. Observations that epigenetic variation abounds in natural populations have prompted speculation that it may facilitate evolutionary responses to rapid environmental perturbations, such as those occurring under climate change. A frequent point of contention is whether epigenetic variants reflect genetic variation or are independent of it. The genome and epigenome often appear tightly linked and interdependent. While many epigenetic changes are genetically determined, the converse is also true, with DNA sequence changes influenced by the presence of epigenetic marks. Understanding how the epigenome, genome and environment interact with one another is therefore an essential step in explaining the broader evolutionary consequences of epigenomic variation. Drawing on results from experimental and comparative studies carried out in diverse plant and animal species, we synthesize our current understanding of how these factors interact to shape phenotypic variation in natural populations, with a focus on identifying similarities and differences between taxonomic groups. We describe the main components of the epigenome and how they vary within and between taxa. We review how variation in the epigenome interacts with genetic features and environmental determinants, with a focus on the role of transposable elements (TEs) in integrating the epigenome, genome and environment. And we look at recent studies investigating the functional and evolutionary consequences of these interactions. Although epigenetic differentiation in nature is likely often a result of drift or selection on stochastic epimutations, there is growing evidence that a significant fraction of it can be stably inherited and could therefore contribute to evolution independently of genetic change., Competing Interests: The authors have no conflict of interest to declare., (© 2024 The Author(s). Evolutionary Applications published by John Wiley & Sons Ltd.)

In late summer and autumn, the passage of intense tropical cyclones can profoundly perturb oceanic and coastal ecosystems. Direct negative effects on individuals and marine communities can be dramatic, especially in the coastal zone, 1 , 2 , 3 , 4 but cyclones can also enhance pelagic primary and secondary production. 5 , 6 , 7 , 8 , 9 However, cyclone impacts on open ocean marine life remain poorly understood. Here, we investigate their effects on the foraging movements of a wide-ranging higher predator, the Desertas petrel (Pterodroma deserta), in the mid-latitude North Atlantic during hurricane season. Contrary to previously studied pelagic seabirds in tropical and mid-latitude regions, 10 , 11 Desertas petrels did not avoid cyclones by altering course, nor did they seek calmer conditions within the cyclone eye. Approximately one-third of petrels tracked from their breeding colony interacted with approaching cyclones. Upon encountering strong winds, the birds reduced ground speed, likely by spending less time in flight. A quarter of birds followed cyclone wakes for days and over thousands of kilometers, a behavior documented here for the first time. Within these wakes, tailwind support was higher than along alternative routes. Furthermore, at the mesoscale (hours-weeks and hundreds of kilometers), sea surface temperature dropped and surface chlorophyll sharply increased, suggesting direct effects on ocean stratification, primary production, and therefore presumably prey abundance and accessibility for surface-feeding petrels. We therefore hypothesize that cyclone wakes provide both predictably favorable wind conditions and foraging opportunities. As such, cyclones may have positive net effects on the demography of many mid-latitude pelagic seabirds and, likely, other marine top-predators., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Phototherapy clinics administer ultraviolet (UV) light to patients using phototherapy cabinets. The UV radiation from these cabinets is reflected on the white ceiling tiles of the clinic and is then redirected toward both staff and patients in the area. This is particularly problematic for clinical technologists who must undertake dosimetry in these areas and have a specific time (often as low as 30 min) before they reach their maximum exposure limit. By replacing white tiles with black ones, which absorb any stray radiation, we were able to reduce stray reflection by almost 90%, prolonging the time to maximum exposure by nearly 10 times. We present these findings to encourage other similar clinics to undertake the simple protocols outlined in this article, which will significantly improve staff and patient safety., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

New particle formation in the free troposphere is a major source of cloud condensation nuclei globally. The prevailing view is that in the free troposphere, new particles are formed predominantly in convective cloud outflows. We present another mechanism using global observations. We find that during stratospheric air intrusion events, the mixing of descending ozone-rich stratospheric air with more moist free tropospheric background results in elevated hydroxyl radical (OH) concentrations. Such mixing is most prevalent near the tropopause where the sulfur dioxide (SO 2 ) mixing ratios are high. The combination of elevated SO 2 and OH levels leads to enhanced sulfuric acid concentrations, promoting particle formation. Such new particle formation occurs frequently and over large geographic regions, representing an important particle source in the midlatitude free troposphere.

Context: Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation., Objective: To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor., Methods: Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index., Results: SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65)., Conclusion: Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via stem cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs and progenitor populations at the expense of naive LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34 +ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal and in vivo reconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders., (© 2024. The Author(s).)

Background: Decision-makers require knowledge of the strengths and weaknesses of decision-analytic models used to evaluate healthcare interventions to be able to confidently use the results of such models to inform policy. A number of aspects of model validity have previously been described, but no systematic approach to assessing the validity of a model has been proposed. This study aimed to consolidate the different aspects of model validity into a step-by-step approach to assessing the strengths and weaknesses of a decision-analytic model., Methods: A pre-defined set of steps were used to conduct the validation process of an exemplar early decision-analytic-model-based cost-effectiveness analysis of a risk-stratified national breast cancer screening programme [UK healthcare perspective; lifetime horizon; costs (£; 2021)]. Internal validation was assessed in terms of descriptive validity, technical validity and face validity. External validation was assessed in terms of operational validation, convergent validity (or corroboration) and predictive validity., Results: The results outline the findings of each step of internal and external validation of the early decision-analytic-model and present the validated model (called 'MANC-RISK-SCREEN'). The positive aspects in terms of meeting internal validation requirements are shown together with the remaining limitations of MANC-RISK-SCREEN., Conclusion: Following a transparent and structured validation process, MANC-RISK-SCREEN has been shown to have satisfactory internal and external validity for use in informing resource allocation decision-making. We suggest that MANC-RISK-SCREEN can be used to assess the cost-effectiveness of exemplars of risk-stratified national breast cancer screening programmes (NBSP) from the UK perspective., Implications: A step-by-step process for conducting the validation of a decision-analytic model was developed for future use by health economists. Using this approach may help researchers to fully demonstrate the strengths and limitations of their model to decision-makers., (© 2024. The Author(s).)

Objective: To map existing literature about concussion management in older people, identifying and analyzing gaps in our understanding., Context: Concussion injuries affect older people, yet little guidance is available about how to approach concussion management with older people. Research does not always include older populations, and it is unclear to what extent standard concussion management is appropriate for older people., Design: Scoping review., Method: A structured literature search was conducted using 4 databases to identify existing literature relating to concussion management in older people. Studies that assessed outcomes relating to the management of concussion/mild traumatic brain injury in those 65 years or older were included and mapped according to the main themes addressed., Results: The search yielded a total of 18 articles. Three themes related to early management (use of anticoagulants n = 6, intracranial lesions n = 3, and service delivery for older people n = 5), and 1 theme related to general management (cognitive issues n = 4). A lack of articles exploring general management in older people was observed., Conclusion: Existing literature indicates that specific management strategies are needed for older people with concussion, especially in early management. This review highlights that good evidence is available about early management and this is reflected in some guidelines, yet little evidence about general management is available and this gap is not acknowledged in guidelines. Distinct approaches to early management in older people are clearly recommended to mitigate the risk of poor outcomes. In contrast, general concussion management for older people is poorly understood, with older people poorly represented in research. A better understanding is needed because-as observed in early management-older people have distinct characteristics that may render standard management approaches unsuitable., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The detection of lymph node metastases is essential for breast cancer staging, although it is a tedious and time-consuming task where the sensitivity of pathologists is suboptimal. Artificial intelligence (AI) can help pathologists detect lymph node metastases, which could help alleviate workload issues. We studied how pathologists' performance varied when aided by AI. An AI algorithm was trained using more than 32 000 breast sentinel lymph node whole slide images (WSIs) matched with their corresponding pathology reports from more than 8000 patients. The algorithm highlighted areas suspicious of harboring metastasis. Three pathologists were asked to review a dataset comprising 167 breast sentinel lymph node WSIs, of which 69 harbored cancer metastases of different sizes, enriched for challenging cases. Ninety-eight slides were benign. The pathologists read the dataset twice, both digitally, with and without AI assistance, randomized for slide and reading orders to reduce bias, separated by a 3-week washout period. Their slide-level diagnosis was recorded, and they were timed during their reads. The average reading time per slide was 129 seconds during the unassisted phase versus 58 seconds during the AI-assisted phase, resulting in an overall efficiency gain of 55% ( P <0.001). These efficiency gains are applied to both benign and malignant WSIs. Two of the 3 reading pathologists experienced significant sensitivity improvements, from 74.5% to 93.5% ( P ≤0.006). This study highlights that AI can help pathologists shorten their reading times by more than half and also improve their metastasis detection rate., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

We report the design and characterization of a femtosecond optical parametric oscillator containing an intracavity Herriott cell. Pumped by a 49.16-MHz Yb:fiber laser, the signal wavelength could be tuned over 1440-1530 nm, with the Herriott cell containing 81% of the free-space cavity length required for synchronous operation. We also report a 12.29-MHz OPO using a sub-harmonic pumping approach, extending the Herriott cell OPO concept to low-repetition-rate cavities.

Background: Adaptive trials usually require simulations to determine values for design parameters, demonstrate error rates, and establish the sample size. We designed a Bayesian adaptive trial comparing ventilation strategies for patients with acute hypoxemic respiratory failure using simulations. The complexity of the analysis would usually require computationally expensive Markov Chain Monte Carlo methods but this barrier to simulation was overcome using the Integrated Nested Laplace Approximations (INLA) algorithm to provide fast, approximate Bayesian inference., Methods: We simulated two-arm Bayesian adaptive trials with equal randomization that stratified participants into two disease severity states. The analysis used a proportional odds model, fit using INLA. Trials were stopped based on pre-specified posterior probability thresholds for superiority or futility, separately for each state. We calculated the type I error and power across 64 scenarios that varied the probability thresholds and the initial minimum sample size before commencing adaptive analyses. Two designs that maintained a type I error below 5%, a power above 80%, and a feasible mean sample size were evaluated further to determine the optimal design., Results: Power generally increased as the initial sample size and the futility threshold increased. The chosen design had an initial recruitment of 500 and a superiority threshold of 0.9925, and futility threshold of 0.95. It maintained high power and was likely to reach a conclusion before exceeding a feasible sample size., Conclusions: We designed a Bayesian adaptive trial to evaluate novel strategies for ventilation using the INLA algorithm to efficiently evaluate a wide range of designs through simulation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fluids are drugs used in veterinary patients capable of producing beneficial therapeutic or inadvertent harmful effects within the body's intravascular, interstitial, and intracellular fluid spaces. The individualized design of a fluid therapy plan requires careful patient assessment and targeted selection of proper fluid types, administration routes, and rates, along with adjustments during therapy tailored specifically as per the individual patient's fluid requirement and therapeutic response. Personalized fluid prescriptions and vigilant patient monitoring help avoid patient morbidity from body fluid deficiencies, fluid excess, and electrolyte derangements and support better patient outcomes. These guidelines provide an overview of fluid dynamics within the fluid spaces of the body, describe various types of fluids and their uses, and outline recommendations for fluid administration for resuscitation, rehydration, and maintenance purposes. The guidelines also outline approaches to fluid therapy for anesthetized patients and reiterate the recommendations of reduced fluid rates in this population of patients. Additionally, the guidelines include practical fluid therapy strategies for patients with various common disorders. The goal of these guidelines is to help veterinary professionals safely and effectively prescribe and administer fluid therapy for canine and feline patients., (© 2024 by American Animal Hospital Association.)