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Using a new analytic method ("unique non-overlapping region" (UNOR) analysis), we characterized the genotypes and phenotypes of a large cohort of individuals diagnosed with chromosome 9p deletion syndrome (9PMS) and defined critical genomic regions. We extracted phenotypic information from 48 individuals with 9PMS from medical records and used a guided interview with caregivers to clarify ambiguities. Using high-resolution whole-genome sequencing for breakpoint definition, we aligned deletions and drew virtual breakpoints to obtain UNORs associated with phenotypic characteristics. We next extracted genotype and phenotype data for 57 individuals identified from a systematic review of the 9PMS literature and analyzed these as above. Common phenotypic features included developmental delay/intellectual disability, dysmorphic features, hypotonia, genital defects in XY individuals, psychiatric diagnoses, chronic constipation, atopic disease, vision problems, autism spectrum disorder, gastroesophageal reflux disease, trigonocephaly, congenital heart disease, and neonatal hypoglycemia. Our approach confirmed previous literature reports of an association of FREM1 with trigonocephaly and suggested a possible modifier element for this phenotype. In conclusion, the UNOR approach delineated phenotypic characteristics for 9PMS and confirmed the critical role of FREM1 and a possible long-distance regulatory element in pathogenesis of trigonocephaly that will need to be replicated in future studies., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016)., Methods: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years)., Results: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia)., Conclusion: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Vulsteke reports medical writing support from GSK; consulting fees from Astellas, Atheneum Partners, Bristol Myers Squibb, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, and Roche; advisory board fees from AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; and travel support from Pfizer and Roche. Dr Chambers has nothing to disclose. Dr Rubio Pérez has nothing to disclose. Dr Chan reports research, consulting, and speakers' bureau fees from AbbVie, Acerta, Aravive, AstraZeneca, Clovis, Eisai, GSK, Merck, and Roche. Dr Raaschou-Jensen reports advisory board fees from Eisai. Dr Zhuo has nothing to disclose. Dr Lorusso reports consulting fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, and Seagen; honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, and PharmaMar; payment for expert testimony from Clovis Oncology; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, PharmaMar, and Roche; personal advisory board fees from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Merck Serono, MSD, Oncoinvent, PharmaMar, Seagen, and Sutro; member of board of directors at GCIG (no compensation); medical writing support from Clovis Oncology, GSK, MSD, and PharmaMar; and institutional funding for work in clinical trials from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen. Dr Herzog reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board from Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. Dr de la Motte Rouge reports consulting fees from AstraZeneca, Clovis Oncology, Eisai, Gilead, GSK, MSD, Novartis, Pfizer, and Sanofi; honoraria from AstraZeneca, GSK, MSD, NetCancer, and Pfizer; and travel support from Gilead, MSD, and Pfizer. Dr Thomes Pepin has nothing to disclose. Dr Braicu reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). Dr Chen reports author royalties from UpToDate and serves on the board of directors of the American College of Obstetricians and Gynecologists, on the board of governors of the American College of Surgeons, and as a board member for the NCI PDQ Cancer Genetics Board. Dr Levy has nothing to disclose. Dr Barter has nothing to disclose. Dr Barretina-Ginesta reports consulting or advisory role fees from AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, and Roche; and travel support from AstraZeneca, GSK, MSD, PharmaMar, and Roche. Dr Joosens reports travel fees from MSD. Ms York and Dr Malinowska are current employees of GSK. Dr González-Martín reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis. Dr Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Members of the mammalian gut microbiota metabolize diverse complex carbohydrates that are not digested by the host, which are collectively labeled "dietary fiber." While the enzymes and transporters that each strain uses to establish a nutrient niche in the gut are often exquisitely specific, the relationship between carbohydrate structure and microbial ecology is imperfectly understood. The present study takes advantage of recent advances in complex carbohydrate structure determination to test the effects of fiber monosaccharide composition on microbial fermentation. Fifty-five fibers with varied monosaccharide composition were fermented by a pooled feline fecal inoculum in a modified MiniBioReactor array system over a period of 72 hours. The content of the monosaccharides glucose and xylose was significantly associated with the reduction of pH during fermentation, which was also predictable from the concentrations of the short-chain fatty acids lactic acid, propionic acid, and the signaling molecule indole-3-acetic acid. Microbiome diversity and composition were also predictable from monosaccharide content and SCFA concentration. In particular, the concentrations of lactic acid and propionic acid correlated with final alpha diversity and were significantly associated with the relative abundance of several of the genera, including Lactobacillus and Dubosiella . Our results suggest that monosaccharide composition offers a generalizable method to compare any dietary fiber of interest and uncover links between diet, gut microbiota, and metabolite production., Importance: The survival of a microbial species in the gut depends on the availability of the nutrients necessary for that species to survive. Carbohydrates in the form of non-host digestible fiber are of particular importance, and the set of genes possessed by each species for carbohydrate consumption can vary considerably. Here, differences in the monosaccharides that are the building blocks of fiber are considered for their impact on both the survival of different species of microbes and on the levels of microbial fermentation products produced. This work demonstrates that foods with similar monosaccharide content will have consistent effects on the survival of microbial species and on the production of microbial fermentation products., Competing Interests: D.A.M., J.B.G., and C.B.L. are cofounders of Infinant Health, a probiotic company, and One.Bio, a company advancing novel bioactive glycans. None of these companies had any role in the conceptualization, design, analysis, or preparation of the manuscript.

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross-study analysis of toxicology studies. Cross-study analysis can be used to understand a single compound's toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND datasets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A cross-study analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of 2 different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology.)

Modeling of Multi-Electrode Arrays used in neural stimulation can be computationally challenging since it may involve incredibly dense circuits with millions of interconnected resistors, representing current pathways in an electrolyte (resistance matrix), coupled to nonlinear circuits of the stimulating pixels themselves. Here, we present a method for accelerating the modeling of such circuits while minimizing the error of a simplified simulation by using a sparse plus low-rank approximation of the resistance matrix. Specifically, we prove that thresholding of the resistance matrix elements enables its sparsification with minimized error. This is accomplished with a sorting algorithm implying efficient O (N log (N)) complexity. The eigenvalue-based low-rank compensation then helps achieve greater accuracy without adding significantly to the problem size. Utilizing these matrix techniques, we accelerated the simulation of multi-electrode arrays by an order of magnitude, reducing the computation time by about 10-fold, while maintaining an average error of less than 0.3% in the current injected from each electrode. We also show a case where acceleration reaches at least 133 times with additional error in the range of 4%, demonstrating the ability of this algorithm to perform under extreme conditions. Although the techniques presented here are used for simulations of photovoltaic retinal prostheses, they are also immediately applicable to any circuit involving dense connections between nodes, and, with modifications, more generally to any systems involving non-sparse matrices. This approach promises significant improvements in the efficiency of modeling the next-generation retinal implants having thousands of pixels, enabling iterative design with broad applicability., Competing Interests: Authors declare no financial interest in the subject of this paper.

Many bipolar disorder (BD) patients are non-responsive to lithium. The mechanisms underlying lithium (non-)responsiveness are largely unknown. By using gene-set enrichment analysis methods, we found that core clock gene-sets are significantly associated with lithium response. Among the top hits was BHLHE41 , a modulator of the molecular clock and homeostatic sleep. Since BHLHE41 and its paralog BHLHE40 are functionally redundant, we assessed chronic lithium response in double-knockout mutant mice (DKO). We demonstrated that DKOs are non-responsive to lithium's effect in various behavioral tasks. Cellular assays and patch clamp recordings revealed lowered excitability and reduced lithium-response in prefrontal cortical layer 2/3 DKO neurons and on hippocampal long-term potentiation. Single-cell RNA sequencing identified that lithium deregulated mitochondrial respiration, cation channel and postsynapse associated gene-sets specifically in upper layer excitatory neurons. Our findings show that lithium acts in a highly cell-specific way on neuronal metabolism and excitability and modulates synaptic plasticity depending on BHLHE40/41.

Objective: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study., Methods: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021)., Results: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1 - and BRCA2 -mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions)., Conclusions: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy., Trial Registration Number: NCT02655016., Competing Interests: Competing interests: WSG reports consulting and speaker fees from GSK. BPB reports honoraria, support for attending meetings and/or travel from AstraZeneca, Clovis, GSK, MSD, and PharmaMar and advisory board fees from AstraZeneca, Clovis, GSK, and MSD. DMO reports personal fees (consulting and/or advisory boards) and funding for clinical research from AbbVie, Amgen, AstraZeneca, Clovis, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance, Janssen/J&J, Merck, Mersana, Novocure, Regeneron, SDP Oncology (BBI), Seagen, and Tesaro/GSK; funding for clinical research from Ajinomoto, Array Biopharma, Bristol-Myers Squibb, Cerulean Pharma, EMD Serono, Ergomed, Genmab, INC Research, inVentiv Health Clinical, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA Intl, Serono, Stemcentrx, TRACON Pharmaceuticals, VentiRx, and Yale University; personal fees from Myriad Genetics, Rubis, and Tarveda; personal fees and funding for clinical research from Agenus; and personal fees (consulting and/or advisory boards) from Ambry, Arquer Diagnostics, Celsion, Corcept Therapeutics, Elevar, InxMed, Novartis, Roche Diagnostics MSA, Sorrento, Takeda, and Toray. IV reports institutional payments for corporate-sponsored research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Octimet Oncology, Oncoinvent AS, Sotio AS, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharma, and Oncoinvent AS; honoraria payment from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Jazz Pharma, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio AS; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; and advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, MSD, Novartis, Novocure, Seagen (2021), and Sotio AS. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. AA reports advisory board fees from GSK and MSD. LJC reports institutional research funding from AbbVie, Advaxis, Agenus, Ajinomoto, Arcus Biosciences, Array BioPharma, AstraZeneca, BeiGene USA, BMS, Cerulean Pharma, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Exelixis, Genentech/Roche, Genmab, GSK, Hoffman–LaRoche, Immunogen, Incyte Corporation, Iovance Biotherapeutics, InVentiv Health Clinical, Jansen R&D, Karyopharm, Leap Therapeutics, Ludwig Institute of Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, OncoQuest, OvaGene, Pfizer, PharmaMar, PRA International, Precision Therapeutics, Regeneron, Sanofi, Seattle Genetics, Serono, Stemcentrx, Sumitomo Dainippon Pharma Oncology, Sutro Biopharma, Tesaro (GSK), TRACON Pharm, and Verastem; personal advisory board fees from A28 Therapeutics, Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, GSK, Immunogen, InxMed, Luzsana Biotechnology, Myriad Genetics, Onconova, Rubius Therapeutics, Sorrento Therapeutics, Toray Industries, and VBL Therapeutics; and member of the data monitoring committee for Corcept Therapeutics. RS reports support for attending meetings from MSD and advisory board fees from Clovis Oncology, GSK, and MSD. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. PF reports payment or honoraria and payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Duality Bio, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Seagen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, BioNtech, Clovis Oncology, Eisai, GOG Foundation, Lily, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Onconova, and Toray; and travel support from GSK and BioNtech. EIB reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). CM reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. AY reports a GEICO grant by GSK. RGM reports personal fees from Fujirebio Diagnostics and research funding from Angle plc. PV reports payment of honoraria to self from MSD, Novartis, and Roche. NR-J reports advisory board fees from Eisai. WY and JH are employees of GSK. AG-M reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Eisai, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

African pastoralists suffer recurrent droughts that cause high livestock mortality and vulnerability to climate change. The index-based livestock insurance (IBLI) program offers protection against drought impacts. However, the current IBLI design relying on the normalized difference vegetation index (NDVI) may pose limitation because it does not consider the mixed composition of rangelands (including herbaceous and woody plants) and the diverse feeding habits of grazers and browsers. To enhance IBLI, we assessed the efficacy of utilizing distinct browse and grazing forage estimates from woody LAI (LAI W ) and herbaceous LAI (LAI H ), respectively, derived from aggregate leaf area index (LAI A ), as an alternative to NDVI for refined IBLI design. Using historical livestock mortality data from northern Kenya as reference ground dataset, our analysis compared two competing models for (1) aggregate forage estimates including sub-models for NDVI, LAI (LAI A ); and (2) partitioned biomass model (LAI P ) comprising LAI H and LAI W . By integrating forage estimates with ancillary environmental variables, we found that LAI P , with separate forage estimates, outperformed the aggregate models. For total livestock mortality, LAI P yielded the lowest RMSE (5.9 TLUs) and higher R 2 (0.83), surpassing NDVI and LAI A models RMSE (9.3 TLUs) and R 2 (0.6). A similar pattern was observed for species-specific livestock mortality. The influence of environmental variables across the models varied, depending on level of mortality aggregation or separation. Overall, forage availability was consistently the most influential variable, with species-specific models showing the different forage preferences in various animal types. These results suggest that deriving distinct browse and grazing forage estimates from LAI P has the potential to reduce basis risk by enhancing IBLI index accuracy., (© 2024. The Author(s).)

Background and Purpose: Volume regression during radiotherapy can indicate patient-specific treatment response. We aimed to identify pre-treatment multimodality imaging (MMI) metrics from positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomography (CT) that predict rapid tumor regression during radiotherapy in human papilloma virus (HPV) associated oropharyngeal carcinoma., Materials and Methods: Pre-treatment FDG PET-CT, diffusion-weighted MRI (DW-MRI), and intra-treatment (at 1, 2, and 3 weeks) MRI were acquired in 72 patients undergoing chemoradiation therapy for HPV+ oropharyngeal carcinoma. Nodal gross tumor volumes were delineated on longitudinal images to measure intra-treatment volume changes. Pre-treatment PET standardized uptake value (SUV), CT Hounsfield Unit (HU), and non-gaussian intravoxel incoherent motion DW-MRI metrics were computed and correlated with volume changes. Intercorrelations between MMI metrics were also assessed using network analysis. Validation was carried out on a separate cohort (N = 64) for FDG PET-CT., Results: Significant correlations with volume loss were observed for baseline FDG SUV mean (Spearman ρ = 0.46, p < 0.001), CT HU mean (ρ = 0.38, p = 0.001), and DW-MRI diffusion coefficient, D mean (ρ = -0.39, p < 0.001). Network analysis revealed 41 intercorrelations between MMI and volume loss metrics, but SUV mean remained a statistically significant predictor of volume loss in multivariate linear regression (p = 0.01). Significant correlations were also observed for SUV mean in the validation cohort in both primary (ρ = 0.30, p = 0.02) and nodal (ρ = 0.31, p = 0.02) tumors., Conclusions: Multiple pre-treatment imaging metrics were correlated with rapid nodal gross tumor volume loss during radiotherapy. FDG-PET SUV in particular exhibited significant correlations with volume regression across the two cohorts and in multivariate analysis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nancy Lee receives consulting fees from Shanghai Joanne Medical Ltd, Yingming Consulting, and Varian, has support from a Varian travel grant, and is on the advisory board for Merck, Merck Serono, Merck EMD, Nanobiotix, and Regeneron. Nadeem Riaz receives research support from Invitae, Pfizer, and Repare Therapuetics., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

G protein-coupled receptors (GPCRs) are relevant targets for health and disease as they regulate various aspects of metabolism, proliferation, differentiation, and immune pathways. They are implicated in several disease areas, including cancer, diabetes, cardiovascular diseases, and mental disorders. It is worth noting that about a third of all marketed drugs target GPCRs, making them prime pharmacological targets for drug discovery. Numerous functional assays have been developed to assess GPCR activity and GPCR signaling in living cells. Here, we review the current literature of genetically encoded cell-based assays to measure GPCR activation and downstream signaling at different hierarchical levels of signaling, from the receptor to transcription, via transducers, effectors, and second messengers. Singleplex assay formats provide one data point per experimental condition. Typical examples are bioluminescence resonance energy transfer (BRET) assays and protease cleavage assays (e.g., Tango or split TEV). By contrast, multiplex assay formats allow for the parallel measurement of multiple receptors and pathways and typically use molecular barcodes as transcriptional reporters in barcoded assays. This enables the efficient identification of desired on-target and on-pathway effects as well as detrimental off-target and off-pathway effects. Multiplex assays are anticipated to accelerate drug discovery for GPCRs as they provide a comprehensive and broad identification of compound effects.

Co-occurring heat and drought stresses challenge crop performance. Stomata open to promote evaporative cooling during heat stress, but close to retain water during drought stress, which resulted in complex stomatal regulation under combined heat and drought. We aimed to investigate stomatal regulation in leaves and flowers of perennial, indeterminate cultivars of tomatoes subjected to individual and combined heat and drought stress followed by a recovery period, measuring morphological, physiological, and biochemical factors involved in stomatal regulation. Under stress, stomata of leaves were predominantly affected by drought, with lower stomatal density and stomatal closing, resulting in significantly decreased photosynthesis and higher leaf temperature. Conversely, stomata in sepals seemed affected mainly by heat during stress. The differential patterns in stomatal regulation in leaves and flowers persisted into the recovery phase as contrasting patterns in stomatal density. We show that flower transpiration is regulated by temperature, but leaf transpiration is regulated by soil water availability during stress. Organ-specific patterns of stomatal development and abscisic acid metabolism mediated this phenomenon. Our results throw light on the dual role of stomata in heat and drought tolerance of vegetative and generative organs, and demonstrate the importance of considering flower surfaces in the phenotyping of stomatal reactions to stress., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Metaorganism research contributes substantially to our understanding of the interaction between microbes and their hosts, as well as their co-evolution. Most research is currently focused on the bacterial community, while archaea often remain at the sidelines of metaorganism-related research. Here, we describe the archaeome of a total of eleven classical and emerging multicellular model organisms across the phylogenetic tree of life. To determine the microbial community composition of each host, we utilized a combination of archaea and bacteria-specific 16S rRNA gene amplicons. Members of the two prokaryotic domains were described regarding their community composition, diversity, and richness in each multicellular host. Moreover, association with specific hosts and possible interaction partners between the bacterial and archaeal communities were determined for the marine models. Our data show that the archaeome in marine hosts predominantly consists of Nitrosopumilaceae and Nanoarchaeota , which represent keystone taxa among the porifera. The presence of an archaeome in the terrestrial hosts varies substantially. With respect to abundant archaeal taxa, they harbor a higher proportion of methanoarchaea over the aquatic environment. We find that the archaeal community is much less diverse than its bacterial counterpart. Archaeal amplicon sequence variants are usually host-specific, suggesting adaptation through co-evolution with the host. While bacterial richness was higher in the aquatic than the terrestrial hosts, a significant difference in diversity and richness between these groups could not be observed in the archaeal dataset. Our data show a large proportion of unclassifiable archaeal taxa, highlighting the need for improved cultivation efforts and expanded databases., 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., (Copyright © 2024 von Hoyningen-Huene, Bang, Rausch, Rühlemann, Fokt, He, Jensen, Knop, Petersen, Schmittmann, Zimmer, Baines, Bosch, Hentschel, Reusch, Roeder, Franke, Schulenburg, Stukenbrock and Schmitz.)

ERBB receptor tyrosine kinases are involved in development and diseases like cancer, cardiovascular, neurodevelopmental, and mental disorders. Although existing drugs target ERBB receptors, the next generation of drugs requires enhanced selectivity and understanding of physiological pathway responses to improve efficiency and reduce side effects. To address this, we developed a multilevel barcoded reporter profiling assay, termed 'ERBBprofiler', in living cells to monitor the activity of all ERBB targets and key physiological pathways simultaneously. This assay helps differentiate on-target therapeutic effects from off-target and off-pathway side effects of ERBB antagonists. To challenge the assay, eight established ERBB antagonists were profiled. Known effects were confirmed, and previously uncharacterized properties were discovered, such as pyrotinib's preference for ERBB4 over EGFR. Additionally, two lead compounds selectively targeting ERBB4 were profiled, showing promise for clinical trials. Taken together, this multiparametric profiling approach can guide early-stage drug development and lead to improved future therapeutic interventions., Competing Interests: The authors declare competing financial interest. B.B., S.P.W., M.J.R., and M.C.W. are employees and shareholders of Systasy Bioscience GmbH., (© 2024 The Author(s).)

We address the challenge of acoustic simulations in three-dimensional (3D) virtual rooms with parametric source positions, which have applications in virtual/augmented reality, game audio, and spatial computing. The wave equation can fully describe wave phenomena such as diffraction and interference. However, conventional numerical discretization methods are computationally expensive when simulating hundreds of source and receiver positions, making simulations with parametric source positions impractical. To overcome this limitation, we propose using deep operator networks to approximate linear wave-equation operators. This enables the rapid prediction of sound propagation in realistic 3D acoustic scenes with parametric source positions, achieving millisecond-scale computations. By learning a compact surrogate model, we avoid the offline calculation and storage of impulse responses for all relevant source/listener pairs. Our experiments, including various complex scene geometries, show good agreement with reference solutions, with root mean squared errors ranging from 0.02 to 0.10 Pa. Notably, our method signifies a paradigm shift as-to our knowledge-no prior machine learning approach has achieved precise predictions of complete wave fields within realistic domains., Competing Interests: Competing interests statement:G.E.K. provides technical advice on direction in machine learning to Anailytica, a private startup company developing AI software products for engineering. He has a very small equity for his work. The rest of the authors declare no competing interest.

Chronic low back pain is characterised by multiple and overlapping biological, psychological, social and broader dimensions, affecting individuals' lives. Multidisciplinary pain services have been considered optimal settings to account for the multidimensionality of chronic low back pain but have largely focused on cognitive and behavioural aspects of individuals' pain. Social dimensions are usually underexplored, considered outside or beyond healthcare professionals' scope of practice. Employing Actor Network Theorist Mol's concept multiplicity, our aim in this paper is to explore how a pain service's practices bring to the fore the social dimensions of individuals living with low back pain. Drawing on 32 ethnographic observations and four group exchanges with the service's clinicians, findings suggest that practices produced multiple enactments of an individual with low back pain. Although individuals' social context was present and manifested during consultations at the pain service (first enactment: 'the person'), it was often disconnected from care and overlooked in 'treatment/management' (second enactment: 'the patient'). In contrast, certain practices at the pain service not only provided acknowledgement of, but actions towards enhancing, individuals' social contexts by adapting rules and habits, providing assistance outside the service and shifting power relations during consultations (third enactment: 'the patient-person'). We therefore argue that different practices enact different versions of an individual with low back pain in pain services, and that engagement with individuals' social contexts can be part of a service's agenda., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Fluoride is a naturally occurring substance that is also added to drinking water, dental hygiene products, and food supplements for preventing dental caries. Concerns have been raised about several other potential health risks of fluoride., Objective: To conduct a robust synthesis of evidence regarding human health risks due to exposure to fluoride in drinking water, and to develop a point of departure (POD) for setting a health-based value (HBV) for fluoride in drinking water., Methods: A systematic review of evidence published since recent reviews of human, animal, and in vitro data was carried out. Bradford Hill considerations were used to weigh the evidence for causality. Several key studies were considered for deriving PODs., Results: The current review identified 89 human studies, 199 animal studies, and 10 major in vitro reviews. The weight of evidence on 39 health endpoints was presented. In addition to dental fluorosis, evidence was considered strong for reduction in IQ scores in children, moderate for thyroid dysfunction, weak for kidney dysfunction, and limited for sex hormone disruptions., Conclusion: The current review identified moderate dental fluorosis and reduction in IQ scores in children as the most relevant endpoints for establishing an HBV for fluoride in drinking water. PODs were derived for these two endpoints, although there is still some uncertainty in the causal weight of evidence for causality for reducing IQ scores in children and considerable uncertainty in the derivation of its POD. Given our evaluation of the overall weight of evidence, moderate dental fluorosis is suggested as the key endpoint until more evidence is accumulated on possible reduction of IQ scores effects. A POD of 1.56 mg fluoride/L for moderate dental fluorosis may be preferred as a starting point for setting an HBV for fluoride in drinking water to protect against moderate and severe dental fluorosis. Although outside the scope of the current review, precautionary concerns for potential neurodevelopmental cognitive effects may warrant special consideration in the derivation of the HBV for fluoride in drinking water.

Objectives: Justice and equity-focused practices in health services play a critical but overlooked role in low back pain (LBP) care. Critical reflexivity - the ability to examine and challenge power relations, and broader social issues embedded in everyday life - can be a useful tool to foster practices that are more socially just. No research has yet explored this approach in back pain health services. This study sought to understand how clinicians construct LBP in relation to broader socio-cultural-political aspects of care and explore if those constructions changed when clinicians engaged with critically reflexive dialogues with researchers., Methods: Using critical discourse analysis methods, this qualitative study explored institutionalised patterns of knowledge in the construction of LBP care. We conducted 22 critically reflexive dialogues with 29 clinicians from two health services in Australia - a private physiotherapy clinic and a public multidisciplinary pain clinic., Results: Our analyses suggested that clinicians and services often constructed LBP care at an individual level. This dominant individualistic discourse constrained consideration of justice-oriented practices in the care of people with LBP. Through dialogues, discursive constructions of LBP care expanded to incorporate systems and health service workplace practices. This expansion fostered more equitable clinical and service practices - such as assisting patients to navigate health care systems, considering patients' socioeconomic circumstances when developing treatment plans, encouraging staff discussion of possible systemic changes to enhance justice, and fostering a more inclusive workplace culture. Although such expansions faced challenges, incorporating broader discourses enabled recommendations to address LBP care inequities., Conclusions: Critical reflexivity can be a tool to foster greater social justice within health services. By expanding constructions of LBP care beyond individuals, critical reflexive dialogues can foster discussion and actions towards more equitable workplace cultures, services and systems., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. FundingThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Health and Medical Research Council (NHMRC, JS: APP1157199, PWH: APP1102905), Arthritis Australia (Project Grant), and The University of Queensland (Early Career Research Grant).

The tunable properties of thermoplastic elastomers (TPEs), through polymer chemistry manipulations, enable these technologically critical materials to be employed in a broad range of applications. The need to "dial-in" the mechanical properties and responses of TPEs generally requires the design and synthesis of new macromolecules. In these designs, TPEs with nonlinear macromolecular architectures outperform the mechanical properties of their linear copolymer counterparts, but the differences in the deformation mechanism providing enhanced performance are unknown. Here, in situ small-angle X-ray scattering (SAXS) measurements during uniaxial extension reveal distinct deformation mechanisms between a commercially available linear poly(styrene)-poly(butadiene)-poly(styrene) (SBS) triblock copolymer and the grafted SBS version containing grafted poly(styrene) (PS) chains from the poly(butadiene) (PBD) midblock. The neat SBS (φ SBS = 100%) sample deforms congruently with the macroscopic dimensions, with the domain spacing between spheres increasing and decreasing along and transverse to the stretch direction, respectively. At high extensions, end segment pullout from the PS-rich domains is detected, which is indicated by a disordering of SBS. Conversely, the PS-grafted SBS that is 30 vol % SBS and 70% styrene (φ SBS = 30%) exhibits a lamellar morphology, and in situ SAXS measurements reveal an unexpected deformation mechanism. During deformation, there are two simultaneous processes: significant lamellar domain rearrangement to preferentially orient the lamellae planes parallel to the stretch direction and crazing. The samples whiten at high strains as expected for crazing, which corresponds with the emergence of features in the 2D SAXS pattern during stretching consistent with fibril-like structures that bridge the voids in crazes. The significant domain rearrangement in the grafted copolymers is attributed to the new junctions formed across multiple PS domains by the grafting of a single chain. The in situ SAXS measurements provide insights into the enhanced mechanical properties of grafted copolymers that arise through improved physical cross-linking that leads to nanostructure domain reorientation for self-reinforcement and craze formation where fibrils help to strengthen the polymer.

Objective: The Timeline Followback (TLFB) is a widely used and well-validated interview-based tool for assessing patterns of recent health risk behavior. There is some evidence of the validity of the TLFB as a self-administered online tool for assessing alcohol use, but further research is needed to establish its validity in younger populations and populations outside the United States. Further, it is unknown how self-administered online TLFB formats compare to more timesaving and commonly used single-item alcohol questions. The primary aim of the current study was to validate a new online, self-administered TLFB for alcohol use against the TLFB interview in a sample of European (Danish) adolescents aged 16-18 years ( N = 30)., Methods: Participants completed a TLFB telephone interview, a self-administered online version of the TLFB, and single-item alcohol questions. Assessments were administered using a within-subject, counter-balanced design. Estimates of number of drinking days, binge-drinking days, maximum drinks consumed on one occasion, total drinks, and drinks per drinking day were compared across metrics., Results: All correlations between the drinking outcomes assessed via the TLFB interview and the TLFB online were positive, and statistically significant ( r s s = 0.86-0.94, p < 0.01). Wilcoxon signed-rank tests showed no significant differences between the TLFB interview and the TLFB online on drinking days, binge drinking days, max drinks, and total drinks. Participants reported drinking significantly more drinks per drinking day on the TLFB online (M = 4.66) compared to on the TLFB interview (M = 4.12; p = 0.009)., Conclusion: Overall, the results support the validity of the online, self-administered TLFB in a sample of European (Danish) adolescents., 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., (Copyright © 2023 Hareskov Jensen, Vallentin-Holbech, Dash, Feldstein Ewing and Rømer Thomsen.)

Introduction: Despite dramatic improvements in safety, logging remains one of the most dangerous industries in the United States. The purpose of this study was to explore longitudinal injury trends among Maine logging workers., Methods: Loggers participated in seven quarterly surveys, over the course of 18 months. Categorical and free text data related to traumatic and acute injury, musculoskeletal disorders (MSD), and chronic pain were exported from REDCap into SAS 9.4, Excel, and NVivo, for quantitative and qualitative analysis, respectively. Time to injury was modeled using two different approaches: (1) time to the occurrence of first injury modeled by proportional hazard regression and (2) an intensity model for injury frequency. Two research team members also analyzed qualitative data using a content analysis approach., Results: During the study, 204 injuries were reported. Of the 154 participants, 93 (60.4%) reported musculoskeletal pain on at least one survey. The majority of injuries were traumatic, including fractures, sprains, and strains. Lack of health insurance was found to be related to increased risk of first injury [HR = 1.41, 95% CI = 0.97-2.04, p = 0.069]. Variables found to be related to injury intensity at the univariate level were: (1) a lack of health insurance [HR = 1.51, 95% CI = 1.04-2.20, p = 0.030], (2) age [HR for 10-year age increase;= 1.12, 95% CI = 0.99-1.27, p = 0.082], and (3) years employed in logging industry [HR for 10-year increase = 1.12, 95% CI = 0.99-1.26, p = 0.052]. Seeking medical attention for injury was not a priority for this cohort, and narratives revealed a trend for self-assessment. A variety of barriers, including finances, prevented loggers from seeking medical attention., Discussion: We found that loggers still experience serious, and sometimes disabling, injuries associated with their work. It was unsurprising that many injuries were due to slips, trips, and falls, along with contact with logging equipment and trees/logs. The narratives revealed various obstacles preventing loggers from achieving optimal health. Examples included geographic distance from healthcare, lack of time to access care, and entrenched values that prioritized independence and traditional masculinity. Financial considerations were also consistently cited as a primary barrier to adequate care., Conclusion: There is a continued need to emphasize occupational health and safety in the logging industry. Implementation of relevant safety programs is key, but it is likely that the benefits of these will not be fully realized until a cultural shift takes place within this industry., (© 2023 Wiley Periodicals LLC.)

Purpose: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC)., Methods: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities., Results: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback., Conclusion: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aurelia aurita 's intricate life cycle alternates between benthic polyp and pelagic medusa stages. The strobilation process, a critical asexual reproduction mechanism in this jellyfish, is severely compromised in the absence of the natural polyp microbiome, with limited production and release of ephyrae. Yet, the recolonization of sterile polyps with a native polyp microbiome can correct this defect. Here, we investigated the precise timing necessary for recolonization as well as the host-associated molecular processes involved. We deciphered that a natural microbiota had to be present in polyps prior to the onset of strobilation to ensure normal asexual reproduction and a successful polyp-to-medusa transition. Providing the native microbiota to sterile polyps after the onset of strobilation failed to restore the normal strobilation process. The absence of a microbiome was associated with decreased transcription of developmental and strobilation genes as monitored by reverse transcription-quantitative PCR. Transcription of these genes was exclusively observed for native polyps and sterile polyps that were recolonized before the initiation of strobilation. We further propose that direct cell contact between the host and its associated bacteria is required for the normal production of offspring. Overall, our findings indicate that the presence of a native microbiome at the polyp stage prior to the onset of strobilation is essential to ensure a normal polyp-to-medusa transition. IMPORTANCE All multicellular organisms are associated with microorganisms that play fundamental roles in the health and fitness of the host. Notably, the native microbiome of the Cnidarian Aurelia aurita is crucial for the asexual reproduction by strobilation. Sterile polyps display malformed strobilae and a halt of ephyrae release, which is restored by recolonizing sterile polyps with a native microbiota. Despite that, little is known about the microbial impact on the strobilation process's timing and molecular consequences. The present study shows that A. aurita 's life cycle depends on the presence of the native microbiome at the polyp stage prior to the onset of strobilation to ensure the polyp-to-medusa transition. Moreover, sterile individuals correlate with reduced transcription levels of developmental and strobilation genes, evidencing the microbiome's impact on strobilation on the molecular level. Transcription of strobilation genes was exclusively detected in native polyps and those recolonized before initiating strobilation, suggesting microbiota-dependent gene regulation., Competing Interests: The authors declare no conflict of interest.

There is an urgent need for improved and timely health and nutrition data. We developed and tested a smartphone application that caregivers from a pastoral population used to measure, record and submit high-frequency and longitudinal health and nutrition information on themselves and their children. The data were assessed by comparing caregiver-submitted measurements of mid-upper arm circumference (MUAC) to several benchmark data sets, including data collected by community health volunteers from the participating caregivers during the project period and data generated by interpreting photographs of MUAC measurements submitted by all participants. We found that the caregivers participated frequently and consistently over the 12-month period of the project; most of them made several measurements and submissions in at least 48 of the 52 weeks of the project. The evaluation of data quality was sensitive to which data set was used as the benchmark, but the results indicate that the errors in the caregivers' submissions were similar to that of enumerators in other studies. We then compare the costs of this alternative approach to data collection through more conventional methods, concluding that conventional methods can be more cost-effective for large socioeconomic surveys that value the breadth of the survey over the frequency of data, while the alternative we tested is favoured for those with objectives that are better met by high-frequency observations of a smaller number of well-defined outcomes., (© 2023 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Obesity has been linked with numerous health issues as well as an increased risk of breast cancer. Although effects of direct obesity in patient outcomes is widely studied, effects of exposure to obesity-related systemic influences in utero have been overlooked. In this study, we investigated the effect of multigenerational obesity on epithelial cell migration and invasion using decellularized breast tissues explanted from normal female mouse pups from a diet induced multigenerational obesity mouse model. We first studied the effect of multigenerational diet on the mechanical properties, adipocyte size, and collagen structure of these mouse breast tissues, and then, examined the migration and invasion behavior of normal (KTB-21) and cancerous (MDA-MB-231) human mammary epithelial cells on the decellularized matrices from each diet group. Breast tissues of mice whose dams had been fed with high-fat diet exhibited larger adipocytes and thicker and curvier collagen fibers, but only slightly elevated elastic modulus and inflammatory cytokine levels. MDA-MB-231 cancer cell motility and invasion were significantly greater on the decellularized matrices from mice whose dams were fed with high-fat diet. A similar trend was observed with normal KTB-21 cells. Our results showed that the collagen curvature was the dominating factor on this enhanced motility and stretching the matrices to equalize the collagen fiber linearity of the matrices ameliorated the observed increase in cell migration and invasion in the mice that were exposed to a high-fat diet in utero. Previous studies indicated an increase in serum leptin concentration for those children born to an obese mother. We generated extracellular matrices using primary fibroblasts exposed to various concentrations of leptin. This produced curvier ECM and increased breast cancer cell motility for cells seeded on the decellularized ECM generated with increasing leptin concentration. Our study shows that exposure to obesity in utero is influential in determining the extracellular matrix structure, and that the resultant change in collagen curvature is a critical factor in regulating the migration and invasion of breast cancer cells., Competing Interests: Declaration of competing interest The authors declare no financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Necrotizing enterocolitis (NEC) is the leading cause of death caused by gastrointestinal disease in preterm infants. Major risk factors include prematurity, formula feeding, and gut microbial colonization. Microbes have been linked to NEC, yet there is no evidence of causal species, and select probiotics have been shown to reduce NEC incidence in infants. In this study, we evaluated the effect of the probiotic Bifidobacterium longum subsp. infantis ( BL. infantis ), alone and in combination with a human milk oligosaccharide (HMO)-sialylactose (3'SL)-on the microbiome, and the incidence of NEC in preterm piglets fed an infant formula diet. We studied 50 preterm piglets randomized between 5 treatments: (1) Preterm infant formula, (2) Donor human milk (DHM), (3) Infant formula + 3'SL, (4) Infant formula + BL. infantis , and (5) Infant formula and BL. infantis + 3'SL. NEC incidence and severity were assessed through the evaluation of tissue from all the segments of the GI tract. The gut microbiota composition was assessed both daily and terminally through 16S and whole-genome sequencing (WGS) of rectal stool samples and intestinal contents. Dietary BL. infantis and 3'SL supplementation had no effect, yet DHM significantly reduced the incidence of NEC. The abundance of BL. infantis in the gut contents negatively correlated with disease severity. Clostridium sensu stricto 1 and Clostridium perfringens were significantly more abundant in NEC and positively correlated with disease severity. Our results suggest that pre- and probiotics are not sufficient for protection from NEC in an exclusively formula-based diet. The results highlight the differences in microbial species positively associated with both diet and NEC incidence.

Background: Due to the rising concern of inadequate sleep, critical analysis is needed for the presence of sleep problems in diverse populations. Research has shown that college athletes may be one such population at risk for sleep disturbances. Poor sleep may lead to physiological, psychological, and cognitive deficits that can impact college athletes academically and athletically. This investigation was performed to examine the relationship of age, sex, and history of concussion on sleep disturbance in college athletes., Methods: A total of 191 collegiate athletes between the ages of 18-26 from a single academic NCAA institution in the Rocky Mountain region of the USA, consented to participate in the study. Participants completed a demographic questionnaire and the Athlete Sleep Screening Questionnaire (ASSQ). Results were analyzed using SPSS Version 27., Results: Primary results revealed that female athletes reported higher sleep disturbance scores when compared to males (U=3643.0, P=0.016). Self-reported sleep disturbances when traveling for sport were higher for females (X(1) = 23.800, P<0.001). Males were also less likely to report daytime dysfunction when traveling for sport (X(1) =22.988, P<0.001). Sleep disturbance had a significant association with age (X(1) =4.145, P=0.042), with older participants (20+ years of age) reporting greater sleep disturbance. Concussion history did not associate with sleep disturbance in the present study., Conclusions: Results suggest that sophomore or older female may be at higher risk for sleep disturbances. Clarifying sex-specific sleep health and understanding the role of age and academic class is crucial to enhance and personalize interventions.

Purpose: To explore how uncertainty plays out in low back pain (LBP) care and investigate how clinicians manage accompanying emotions/tensions., Materials and Methods: We conducted ethnographic observations of clinical encounters in a private physiotherapy practice and a public multidisciplinary pain clinic. Our qualitative reflexive thematic analysis involved abductive thematic principles informed by Fox and Katz (medical uncertainty) and Ahmed (emotions)., Results: We identified three themes. (1) Sources of uncertainty: both patients and clinicians expressed uncertainty during clinical encounters (e.g., causes of LBP, mismatch between imaging findings and presentation). Such uncertainty was often accompanied by emotions - anger, tiredness, frustration. (2) Neglecting complexity: clinicians often attempted to decrease uncertainty and associated emotions by providing narrow answers to questions about LBP. At times, clinicians' denial of uncertainty also appeared to deny patients the right to make informed decisions about treatments. (3) Attending to uncertainty?: clinicians attended to uncertainty through logical reasoning, reassurance, acknowledgement, personalising care, shifting power, adjusting language and disclosing risks., Conclusions: Uncertainty pervades LBP care and is often accompanied by emotions, emphasising the need for a healthcare culture that recognises the emotional dimensions of patient-clinician interactions and prepares clinicians and patients to be more accepting of, and clearly communicate about, uncertainty.IMPLICATIONS FOR REHABILITATIONUncertainty pervades LBP care and is often accompanied by emotions.Neglecting complexity in LBP care may compromise person-centred care.Acknowledging uncertainty can enhance communication, balance patient-clinician relationships and address human aspects of care.

Professor Labonté's editorial is an important intervention that reiterates the stark socio-economic and health inequities that were exposed and perpetuated during the coronavirus disease 2019 (COVID-19) pandemic to call on the public health community to hold politicians to account for their promises of 'building back better.' The editorial makes present how quickly pandemic promises seem to have become dislodged by an ostensibly endless cycle of political and economic crises. But it also expresses a hope that lessons from the pandemic will eventually serve to challenge prevailing (economic) policy orthodoxy and feed a collective demand for more progressive social, economic and environmental justice-oriented politics., (© 2023 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

G protein-coupled receptors (GPCRs) are major disease-relevant drug targets; robust monitoring of their activities upon drug treatment is key to drug discovery. The split TEV cell-based assay technique monitors the interaction of an activated GPCR with β-arrestin-2 through TEV protein fragment complementation using a luminescent signal as the readout. In this work, split TEV GPCR β-arrestin-2 recruitment assays were optimized to monitor the endogenous ligand-induced activities of six GPCRs (DRD1, DRD2, HTR2A, GCGR, AVPR2, and GLP1R). Each GPCR was tested in four forms; i.e., its wildtype form, a variant with a signal peptide (SP) to facilitate receptor expression, a variant containing the C-terminal tail from the V2 vasopressin receptor (V2R tail) to promote β-arrestin-2 recruitment, and a variant containing both the SP and V2R tail. These 24 GPCR variants were systematically tested for assay performance in four cell lines (HEK-293, PC12 Tet-Off, U-2 OS, and HeLa). We found that the assay performance differed significantly for each GPCR variant and was dependent on the cell line. We found that V2R improved the DRD2 split TEV assays and that HEK-293 cells were the preferred cell line across the GPCRs tested. When taking these considerations into account, the defined selection of assay modifications and conditions may improve the performance of drug development campaigns that apply the split TEV technique as a screening tool.

Reversibly photoswitchable fluorescent proteins are essential markers for advanced biological imaging, and optimization of their photophysical properties underlies improved performance and novel applications. Here we establish a link between photoswitching contrast, one of the key parameters that dictate the achievable resolution in nanoscopy applications, and chromophore conformation in the non-fluorescent state of rsEGFP2, a widely employed label in REversible Saturable OpticaL Fluorescence Transitions (RESOLFT) microscopy. Upon illumination, the cis chromophore of rsEGFP2 isomerizes to two distinct off-state conformations, trans1 and trans2, located on either side of the V151 side chain. Reducing or enlarging the side chain at this position (V151A and V151L variants) leads to single off-state conformations that exhibit higher and lower switching contrast, respectively, compared to the rsEGFP2 parent. The combination of structural information obtained by serial femtosecond crystallography with high-level quantum chemical calculations and with spectroscopic and photophysical data determined in vitro suggests that the changes in switching contrast arise from blue- and red-shifts of the absorption bands associated to trans1 and trans2, respectively. Thus, due to elimination of trans2, the V151A variants of rsEGFP2 and its superfolding variant rsFolder2 display a more than two-fold higher switching contrast than their respective parent proteins, both in vitro and in E. coli cells. The application of the rsFolder2-V151A variant is demonstrated in RESOLFT nanoscopy. Our study rationalizes the connection between structural and photophysical chromophore properties and suggests a means to rationally improve fluorescent proteins for nanoscopy applications., (© 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Objectives: Pancreatic exocrine insufficiency (PEI) is a common complication in patients with chronic pancreatitis (CP), leading to increased morbidity and mortality if not treated adequately. Pancreatic enzyme replacement therapy|pancreas enzyme replacement therapy (PERT) is the cornerstone in treatment of patients with PEI. In the present study, we use data from the Scandinavian Baltic Pancreatic Club database to examine adherence of PERT according to United European Gastroenterology evidence-based guidelines treatment of CP., Patients and Methods: Patients with definitive or probable CP according to M-ANNHEIM diagnostic criteria were included. We collected information on exposures, exocrine function, intake of pancreatic enzymes, and markers of nutrition. Fecal elastase &lt;200 μg/g was defined as a marker for PEI. Enzyme replacement therapy of 100,000 lipase units or more was defined as adequate treatment., Results: We included 1006 patients from 8 centers in five countries. Sixty-four percent of the patients were correctly treated. Twenty-five per cent of PEI patients were not taking enzymes at all, and 20% of PEI patients were undertreated with insufficient PERT doses according to the guidelines. Fourteen percent of patients with sufficient pancreatic function were receiving enzymes despite normal exocrine pancreatic function. There were center differences. Current smoking was associated with lack of treatment and alcohol abuse was associated with under-treatment. There were no associations between "no treatment" or "under-treatment" for underweight or vitamin D deficiency., Conclusion: In our CP expert centers, the adherence to guidelines for enzyme treatment is insufficient. Both patient factors and center differences have influence on treatment adherence., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Chlorosphaerolactylate B, a newly discovered antimicrobial halometabolite from the cyanobacterium Sphaerospermopsis sp. LEGE 00249 has been synthesized in three steps by using 12-bromododecanoic acid as starting material. A total of 0.5 g was produced for in vitro and in vivo antimicrobial efficacy testing. In vitro , the minimal inhibitory concentration (MIC) was estimated to be 256 mg/L for Staphylococcus aureus , while the minimal biofilm inhibitory concentration (MBIC) was estimated to be 74 mg/L. The in vivo study utilized a porcine model of implant-associated osteomyelitis. In total, 12 female pigs were allocated into 3 groups based on inoculum ( n = 4 in each group). An implant cavity (IC) was drilled in the right tibia and followed by inoculation and insertion of a steel implant. All pigs were inoculated with 10 μL containing either: 11.79 mg synthetic Chlorosphaerolactylate B + 10 4 CFU of S. aureus (Group A), 10 4 CFU of S. aureus (Group B), or pure saline (Group C), respectively. Pigs were euthanized five days after inoculation. All Group B animals showed macroscopic and microscopic signs of bone infection and both tissue and implant harbored S. aureus bacteria (mean CFU on implants = 1.9 × 10 5 ). In contrast, S. aureus could not be isolated from animals inoculated with saline. In Group A, two animals had a low number of S. aureus (CFU = 6.7 × 10 1 and 3.8 × 10 1 , respectively) on the implants, otherwise all Group A animals were similar to Group C animals. In conclusion, synthetic Chlorosphaerolactylate B holds potential to be a novel antimicrobial and antibiofilm compound., 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., (Copyright © 2022 Jensen, Jensen, Aalbaek, Blirup-Plum, Soto, Cepas, López, Gabasa, Gutiérrez-del-Río, Villar, Lombó, Iglesias, Soengas, López Ortiz and Jensen.)

Cognitive deficits are a hallmark of schizophrenia, for which no convincing pharmacological treatment option is currently available. Here, we tested spironolactone as a repurposed compound in Tcf4 transgenic mice subjected to psychosocial stress. In this '2-hit' gene by environment mouse (GxE) model, the animals showed schizophrenia-related cognitive deficits. We had previously shown that spironolactone ameliorates working memory deficits and hyperactivity in a mouse model of cortical excitatory/inhibitory (E/I) dysbalance caused by an overactive NRG1-ERBB4 signaling pathway. In an add-on clinical study design, we used spironolactone as adjuvant medication to the standard antipsychotic drug aripiprazole. We characterized the compound effects using our previously established Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP). PsyCoP is a widely applicable analysis pipeline based on the Research Domain Criteria (RDoC) framework aiming at facilitating translation into the clinic. In addition, we use dimensional reduction to analyze and visualize overall treatment effect profiles. We found that spironolactone and aripiprazole improve deficits of several cognitive domains in Tcf4tg x SD mice but partially interfere with each other's effect in the combination therapy. A similar interaction was detected for the modulation of novelty-induced activity. In addition to its strong activity-dampening effects, we found an increase in negative valence measures as a side effect of aripiprazole treatment in mice. We suggest that repurposed drug candidates should first be tested in an adequate preclinical setting before initiating clinical trials. In addition, a more specific and effective NRG1-ERBB4 pathway inhibitor or more potent E/I balancing drug might enhance the ameliorating effect on cognition even further., (© 2022. The Author(s).)

Long-term inhalation exposure to manganese (Mn) metal or its inorganic compounds can result in manganism or subclinical neurofunctional deficits. Studies have described affected workers in Mn dioxide mining, Mn-containing ore crushing and milling facilities, manufacturing of dry-cell batteries, Mn steel and alloy production plants, and in welders. The objective of this study was to critically review existing evidence on the reliability of potential biomarkers of Mn exposure, specifically the relationship between inhalation exposure to Mn particulates in different occupational settings and Mn concentrations in blood and other biological fluids and tissues, with a particular focus on whole blood as a potentially useful medium for measuring internal tissue dose. We also examined available evidence on the relationship between Mn levels in blood and adverse clinical and subclinical neurotoxic outcomes. Three bibliographic databases were searched for relevant studies and identified references were screened by two independent reviewers. Of the 6338 unique references identified, 76 articles were retained for data abstraction. Findings indicate that the relationships between Mn in blood and both external Mn exposure indices and neurofunctional impairments are limited and inconsistent. Different sources of exposure to Mn compounds, heterogeneity in the methodological approaches, and inadequate reporting of essential information limited direct comparison of the reported findings. Among the Mn-exposure biomarkers considered in this review - including biomarkers in blood, plasma, serum, erythrocytes, urine, bone, toenails, fingernails, hair, saliva - biomarkers in whole blood may provide to be most useful in Mn biomonitoring and risk assessment.

Photoswitchable fluorophores─proteins and synthetic dyes─whose emission is reversibly switched on and off upon illumination, are powerful probes for bioimaging, protein tracking, and super-resolution microscopy. Compared to proteins, synthetic dyes are smaller and brighter, but their photostability and the number of achievable switching cycles in aqueous solutions are lower. Inspired by the robust photoswitching system of natural proteins, we designed a supramolecular system based on a fluorescent diarylethene ( DAE ) and cucurbit[7]uril (CB7) (denoted as DAE @CB7). In this assembly, the photoswitchable DAE molecule is encapsulated by CB7 according to the host-guest principle, so that DAE is protected from the environment and its fluorescence brightness and fatigue resistance in pure water improved. The fluorescence quantum yield (Φ fl ) increased from 0.40 to 0.63 upon CB7 complexation. The photoswitching of the DAE @CB7 complex, upon alternating UV and visible light irradiations, can be repeated 2560 times in aqueous solution before half-bleaching occurs (comparable to fatigue resistance of the reversibly photoswitchable proteins), while free DAE can be switched on and off only 80 times. By incorporation of reactive groups [maleimide and N -hydroxysuccinimidyl (NHS) ester], we prepared bioconjugates of DAE @CB7 with antibodies and demonstrated both specific labeling of intracellular proteins in cells and the reversible on/off switching of the probes in cellular environments under irradiations with 355 nm/485 nm light. The bright emission and robust photoswitching of DAE-Male3 @CB7 and DAE-NHS @CB7 complexes (without exclusion of air oxygen and addition of any stabilizing/antifading reagents) enabled confocal and super-resolution RESOLFT (reversible saturable optical fluorescence transitions) imaging with apparent 70-90 nm optical resolution.

This study validates a VR supermarket as a research tool by studying the influence of the food shopping setting on consumers' price memory-an important antecedent for price comparisons in the purchase situation. In a quasi-experiment, two groups of consumers were given a shopping task in either a physical supermarket or a virtual reality supermarket setting. Upon task completion, participants' explicit and implicit price memory was measured across three food product categories (pizza sauce, pasta, and dark chocolate). Results revealed no significant difference between the two settings, supporting the comparability between the VR shopping experience and the experience in the physical supermarket. The VR supermarket can therefore be a valid tool for studying consumer food choice behaviour in a shopping context. Further results show that explicit price memory is weaker compared to implicit price memory, that even prices are remembered better than odd prices, and that price memory follows the expected pattern in a VR supermarket as well. Finally, exploratory findings indicate that the feeling of physical presence and self-presence is relatively high for this particular VR supermarket, whereas social presence is weaker.

Background: There is a need for effective and cost-effective interprofessional care models that support older people to maintain their quality of life (QoL) and physical performance to live longer independently in their own homes., Objectives: The objectives were to evaluate effectiveness, QoL and physical performance, and cost-utility of a people-centred care model (PCCM), including the contribution of clinically trained pharmacists, compared with that of usual care in primary care., Methods: A randomised controlled trial (RCT) with a two-year follow-up was conducted. The participants were multimorbid community-living older people, aged ≥75 years. The intervention comprised an at-home patient interview, health review, pharmacist-led clinical medication review, an interprofessional team meeting, and nurse-led care coordination and health support. At the baseline and at the 1-year and 2-year follow-ups, QoL (SF-36, 36-Item Short-Form Health Survey) and physical performance (SPPB, Short Performance Physical Battery) were measured. Additionally, a physical dimension component summary in the SF-36 was calculated. The SF-36 data were transformed into SF-6D scores to calculate quality-adjusted life-years (QALYs). Healthcare resource use were collected and transformed into costs. A healthcare payer perspective was adopted. Incremental cost-effectiveness ratio (ICER) was calculated, and one-way sensitivity analysis was performed., Results: No statistically or clinically significant differences were observed between the usual care (n = 126) and intervention group (n = 151) patients in their QoL; at the 2-year follow-up the mean difference was -0.02, (95 % CI -0.07; 0.04,p = 0.56). While the mean difference between the groups in physical performance at the 2-year follow-up was -1.02, (-1.94;-0.10,p = 0.03), between the physical component summary scores it was -7.3, (-15.2; 0.6,p = 0.07). The ICER was -73 638€/QALY, hence, the developed PCCM dominated usual care, since it was more effective and less costly., Conclusions: The cost-utility analysis showed that the PCCM including pharmacist-led medication review dominated usual care. However, it had no effect on QoL and the effect towards physical performance remained unclear., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate if using a hip bandage is more effective than standard care in the prevention of total hip arthroplasty re-dislocation in patients with a previous total hip arthroplasty dislocation., Design: randomized controlled trial., Setting: Holstebro Regional Hospital and Viborg Regional Hospital., Subjects: A total of 99 patients, 51 women, mean 70.7 (SD 9.9) years were enrolled in an un-blinded, clinical randomized controlled trial., Interventions: Participants with at least one previous total hip arthroplasty dislocation were randomized to either wearing a bandage reducing flexion, adduction, and internal rotation of the hip (intervention group) or to standard care (control group). The participants were followed for 12 weeks. Main follow-up measures were as follows: number of re-dislocations (primary outcome), hip disability measured with the Oxford Hip Score (0-48, 48 best), quality of life measured with the 36-Item Short Form Survey (0-100, 100 best), satisfaction with treatment and serious adverse events. Statistical analyses followed the intention-to-treat principle., Results: No significant group differences were observed for the primary outcome re-dislocations (9 versus 15, P  = 0.143) or for disability (11.3 versus 14.4, P  = 0.161), quality of life (57.7 versus 48.3, P  = 0.050) or satisfaction with treatment ( P  = 0.562). There were 3 serious adverse events leading to total hip arthroplasty revision in the intervention group and 4 in the control group., Conclusion: We found that a hip bandage is not superior to standard care in the prevention of total hip arthroplasty re-dislocation in those with a previous total hip arthroplasty dislocation.

Background: Although endemic to much of the global population, few studies have examined Helicobacter pylori (H. pylori) in US refugee populations. This study investigates the prevalence of H. pylori infection and barriers to treatment in the International Family Medicine Clinic (IFMC), a primary care refugee clinic, in central Virginia., Materials and Methods: We conducted a chart review of 188 refugee patients of the IFMC who were referred for an H. pylori test between January 1, 2019, and December 31, 2020. Recorded measures included patient demographics, H. pylori test result, treatment of initial infection, completion of test of cure (TOC), TOC results, salvage therapy, and barriers to treatment. Binary logistic regression was performed to examine the association between demographic factors and H. pylori test results., Results: Of the 171 patients who completed an H. pylori test, 94 tested positive (54.9%). Of the 93 patients that were subsequently treated, 76 were treated with clarithromycin triple therapy (82%). Forty-eight patients (52%) completed a TOC after completing treatment, and 21 (43%) of these patients remained positive, indicating persistent infection. Eighteen patients (90%) who remained positive for H. pylori were subsequently treated with quadruple therapy. Patients under 18 (OR = 0.25, p < 0.01) and patients with a history of previous H. pylori (OR = 0.44, p < 0.05) were less likely to have positive results on initial H. pylori testing. Common barriers to treatment included pregnancy, religious observance (e.g., fasting), and health system complications (e.g., prior authorization for medications, cost of treatment)., Conclusions: The prevalence of H. pylori among refugees at the IFMC was higher than the overall prevalence estimate for the United States, which is consistent with previous studies. This work represents an updated picture of H. pylori prevalence among refugees in the United States and contributes to the identification of treatment barriers., (© 2022 The Authors. Helicobacter published by John Wiley & Sons Ltd.)

Excessive exposure to manganese (Mn) is linked to its accumulation in the brain and adverse neurological effects. Paramagnetic properties of Mn allow the use of magnetic resonance imaging (MRI) techniques to identify it in biological tissues. A critical review was conducted to evaluate whether MRI techniques could be used as a diagnostic tool to detect brain Mn accumulation as a quantitative biomarker of inhaled exposure. A comprehensive search was conducted in MEDLINE, EMBASE, and PubMed to identify potentially relevant studies published prior to 9 May 2022. Two reviewers independently screened identified references using a two-stage process. Of the 6452 unique references identified, 36 articles were retained for data abstraction. Eligible studies used T1-weighted MRI techniques and reported direct or indirect T1 measures to characterize Mn accumulation in the brain. Findings demonstrate that, in subjects exposed to high levels of Mn, deposition in the brain is widespread, accumulating both within and outside the basal ganglia. Available evidence indicates that T1 MRI techniques can be used to distinguish Mn-exposed individuals from unexposed. Additionally, T1 MRI may be useful for semi-quantitative evaluation of inhaled Mn exposure, particularly when interpreted along with other exposure indices. T1 MRI measures appear to have a nonlinear relationship to Mn exposure duration, with R1 signal only increasing after critical thresholds. The strength of the association varied depending on the regions of interest imaged and the method of exposure measurement. Overall, available evidence suggests potential for future clinical and risk assessment applications of MRI as a diagnostic tool.

Background and study aims  The majority of patients with 10 or more cumulative colorectal adenomas have uninformative genetic testing and meet criteria for colonic adenomatous polyposis of unknown etiology (CPUE). The yield of upper gastrointestinal screening in patients with CPUE after multi-gene panel testing is unknown and our objective was to characterize this. Patient and methods  A multicenter, retrospective analysis of screening upper endoscopies in adults with CPUE after multi-gene panel testing was performed. Those with a history of gastroduodenal neoplasia prior to CPUE diagnosis were excluded. Demographic and clinical variables were collected and compared. Results  One hundred and twenty-eight patients with CPUE were included from five participating centers. Nine (7.0 %) had gastroduodenal neoplasia on initial screening upper endoscopy. Those with over 100 colorectal adenomas had a significantly higher rate of gastroduodenal neoplasia than those with 20-99 or 10-19 colorectal adenomas (44.4 % vs 4.1 % vs 4.4 %, P  = 0.002). Similar results were seen when the analysis was restricted to only duodenal or ampullary adenomas. The only malignancy was a gastric cancer in a patient with 20 to 99 colorectal adenomas. When comparing patients with gastroduodenal neoplasia to those without, the only significantly different characteristic was the cumulative number of colorectal adenomas. Conclusions  We found a 7 % rate of gastroduodenal neoplasia in patients with CPUE after multi-gene panel testing. Although patients with ≥ 100 colorectal adenomas had a significantly higher risk, over 4 % of patients with 10 to 99 colorectal adenomas had gastroduodenal neoplasia. Given this, we recommend a screening upper endoscopy at the time of a colonoscopy after CPUE diagnosis., Competing Interests: Competing interests Dr. Stanich receives research support from Emtora Biosciences, Janssen Pharmaceuticals Inc., Pfizer Inc., and the PTEN Research Foundation. Dr. Katona receives research support from Epigenomics, Freenome, Guardant Health, Immunovia, and Janssen Pharmaceuticals Inc., and has consulted for Exact Sciences. Dr. Kupfer receives research support from Immunovia and Invitae., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Hospital discharge of older people in need of both medical and social care following their hospital stay requires extensive coordination. This study aims to examine and compare the views of nurses in three Nordic cities on the influence of sociodemographic factors and having close relatives, for the hospital discharge and post hospital care of older people with complex health and social care needs. Thirty-five semi-structured interviews (Copenhagen n  = 11, Tampere n  = 8, Stockholm n  = 16) with nurses were conducted. The nurses were identified through the researchers' networks, invitation and snowball sampling, and recruited from hospitals, primary care practices, home care units, home nursing units, and geriatric departments. The interviews were transcribed and analysed using thematic analysis. Interpretations were discussed and agreed within the team. Four main themes and 13 sub-themes were identified. Across the cities, informants reported that the patient's health status, rather than their gender or ethnicity, steered the discharge date and further care. Care costs, commonly reported in Tampere but also in Copenhagen and Stockholm including costs for medications and home help, were considered barriers for disadvantaged older people. Home situation, local arrangements and differences in collaboration between healthcare professionals at different sites also influenced the hospital discharge. Generally, the patient's health status steered the hospital discharge and post-hospital care. Close relatives were regarded important and a potential advantage. Some informants tried to compensate for the absence of close relatives, highlighting the importance of care systems that can compensate for this to minimise avoidable inequity., Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00701-6., Competing Interests: Conflicts of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2022.)

We conducted a critical review on biomarkers of environmental manganese (Mn) exposure to answer the following questions: 1) are there reliable biomarkers of internal Mn exposure (Mn in biological matrices) associated with external metrics of Mn exposure (Mn in environmental media)? and 2) are there accurate reference values (RVs) for Mn in biological matrices? Three bibliographic databases were searched for relevant references and identified references were screened by two independent reviewers. Of the 6342 unique references identified, 86 articles were retained for data abstraction. Our analysis of currently available evidence suggests that Mn levels in blood and urine are not useful biomarkers of Mn exposure in non-occupational settings. The strength of the association between Mn in environmental media and saliva was variable. Findings regarding the utility of hair Mn as a biomarker of environmental Mn exposure are inconsistent. Measurements of Mn in teeth are technically challenging and findings on Mn in tooth components are scarce. In non-occupationally exposed individuals, bone Mn measurements using in vivo neutron activation analysis (IVNAA) are associated with large uncertainties. Findings suggest that Mn in nails may reflect Mn in environmental media and discriminate between groups of individuals exposed to different environmental Mn levels, although more research is needed. Currently, there is no strong evidence for any biological matrix as a valid biomarker of Mn exposure in non-occupational settings. Because of methodological limitations in studies aimed at derivation of RVs for Mn in biological materials, accurate RVs are scarce.

Background: In the context of a growing appreciation for the wellbeing of the health workforce as the foundation of high-quality, sustainable health systems, this paper presents findings from two complementary studies to explore occupational stress and professional quality of life among health workers that were conducted in preparation for a task-shifting intervention to improve antenatal mental health services in Cape Town., Methods: This mixed-methods, cross-sectional study was conducted in public sector Midwife Obstetric Units and associated Non-Profit Organisations in Cape Town. Semi-structured interviews and a quantitative survey were conducted among facility-and community-based professional and lay health workers. The survey included demographic as well as effort-reward imbalance (ERI) and professional quality of life (PROQOL) questionnaires to examine overall levels of work-related psychosocial stress and professional quality of life, as well as differences between lay and professional health workers. Qualitative data was analysed using a thematic content analysis approach. Quantitative data was analysed using STATA 12., Results: Findings from 37 qualitative interviews highlighted the difficult working conditions and often limited reward and support structures experienced by health workers. Corroborating these findings, our quantitative survey of 165 professional and lay health workers revealed that most health workers experienced a mismatch between efforts spent and rewards gained at work (61.1% of professional and 70.2% of lay health workers; p = 0.302). There were few statistically significant differences in ERI and PROQOL scores between professional and lay health workers. Although Compassion Satisfaction was high for all health worker groups, lay health workers also showed elevated levels of burnout and compassion fatigue, with community-based health workers particularly affected., Conclusions: Findings of this study add to the existing evidence base on adverse working conditions faced by South African public-sector health workers that should be taken into consideration as national and local governments seek to 're-engineer' South Africa's Primary Health Care system. Furthermore, they also highlight the importance of taking into consideration the wellbeing of health workers themselves to develop interventions that can sustainably foster resilient and high-quality health systems., (© 2022. The Author(s).)

Purpose: To compare corneal endothelial damage from longitudinal and torsional ultrasound during phacoemulsification., Setting: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA., Design: Experimental study., Methods: 9 New Zealand white rabbits underwent bilateral surgery. After incision, the Intrepid Balanced Tip of the Centurion Ozil handpiece was inserted into the anterior chamber, and the following settings were used: 50 mL/min flow, 70 mm Hg intraocular pressure, 600 mm Hg vacuum, and 60% longitudinal (1 eye) or torsional (contralateral eye) ultrasound for 30 seconds. Cumulative dissipated energy (CDE) was noted. After euthanasia and enucleation, the corneas were removed, stained with trypan blue/alizarin red, and photographed (400× photographs from 5 specific areas and 1 overview photograph from each corneal button). The ImageJ program was used to evaluate cell damage and loss in the photographs obtained from each cornea., Results: Cavitation bubbles around the phacoemulsification tip were generally observed in the longitudinal group. CDE was 17.4 ± 0.58 and 6.93 ± 0.15 in the longitudinal and torsional groups, respectively (P = .003). The percentage of intact cells was statistically higher in the torsional group (94.22% ± 5.99% vs 56.85% ± 22.29%), and the percentage of lost cells was statistically higher in the longitudinal group (42.10% ± 22.02% vs 4.97% ± 6.23%) (P = .003). This was observed in the analysis of the 400× photographs and the overview photographs., Conclusions: This study suggests that torsional ultrasound was associated with significantly less corneal endothelial cell damage than classical longitudinal tip motion, providing further insight on mechanisms of corneal endothelial damage during phacoemulsification., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

The pursuit of health equity is foundational to the global health enterprise. But while moral concerns over health inequities can galvanise political commitment, how such concerns can or should translate into practice remains less clear. This paper reviews evolving ways that equity goals have featured in key World Health Organization (WHO)-related policy documents, before discussing the heuristic value and empirical traction that the concept of equity can bring to the health system strengthening (HSS) agenda. We argue that while health equity is often presented as the overarching goal of HSS, in practice this is typically circumscribed to the provision of healthcare services. Although health care equity is important, we suggest that this narrow focus risks losing sight of the structural political, social and economic drivers of health and health inequities, as well as the broader contexts of care and complex socio-political mechanisms through which health systems are strengthened. Drawing on new lines of empirical inquiry, we propose that broadening the equity lens for HSS -offers exciting opportunities to put health systems at the heart of a more ambitious equity agenda in global health.