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Abstract Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA‐binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1‐KO mouse model. Here we show that adeno‐associated viral vector delivery of a modified and FMRP‐independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS‐relevant behavioral phenotypes in the Fmr1‐KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

Abstract KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS‐driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo‐like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS‐mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti‐proliferative effects and cell death in KRAS‐mutant lung and pancreatic but not colon nor KRAS wild‐type cancer cells. Mechanistically, co‐targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress‐activated c‐Jun N‐terminal kinase (JNK)/p38 pathway and E2F1‐induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS‐mutant patient‐derived xenografts and a genetically engineered mouse model of Kras‐induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS‐mutant cancer.

Abstract People rely on data-driven AI technologies nearly every time they go online, whether they are shopping, scrolling through news feeds, or looking for entertainment. Yet despite their ubiquity, personalization algorithms and the associated large-scale collection of personal data have largely escaped public scrutiny. Policy makers who wish to introduce regulations that respect people’s attitudes towards privacy and algorithmic personalization on the Internet would greatly benefit from knowing how people perceive personalization and personal data collection. To contribute to an empirical foundation for this knowledge, we surveyed public attitudes towards key aspects of algorithmic personalization and people’s data privacy concerns and behavior using representative online samples in Germany (N = 1065), Great Britain (N = 1092), and the United States (N = 1059). Our findings show that people object to the collection and use of sensitive personal information and to the personalization of political campaigning and, in Germany and Great Britain, to the personalization of news sources. Encouragingly, attitudes are independent of political preferences: People across the political spectrum share the same concerns about their data privacy and show similar levels of acceptance regarding personalized digital services and the use of private data for personalization. We also found an acceptability gap: People are more accepting of personalized services than of the collection of personal data and information required for these services. A large majority of respondents rated, on average, personalized services as more acceptable than the collection of personal information or data. The acceptability gap can be observed at both the aggregate and the individual level. Across countries, between 64% and 75% of respondents showed an acceptability gap. Our findings suggest a need for transparent algorithmic personalization that minimizes use of personal data, respects people’s preferences on personalization, is easy to adjust, and does not extend to political advertising.

Abstract Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three‐generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co‐segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD. The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency.

Abstract Cancer cell metabolism has received increasing attention. Despite a boost in the application of clinical metabolic profiling (CMP) in cancer patients, a meta‐analysis has not been performed. The primary goal of this study was to assess whether public accessibility of metabolomics data and identification and reporting of metabolites were sufficient to assess which metabolites were consistently altered in cancer patients. We therefore retrospectively curated data from CMP studies in cancer patients published during 5 recent years and used an established vote‐counting method to perform a semiquantitative meta‐analysis of metabolites in tumor tissue and blood. This analysis confirmed well‐known increases in glycolytic metabolites, but also unveiled unprecedented changes in other metabolites such as ketone bodies and amino acids (histidine, tryptophan). However, this study also highlighted that insufficient public accessibility of metabolomics data, and inadequate metabolite identification and reporting hamper the discovery potential of meta‐analyses of CMP studies, calling for improved standardization of metabolomics studies.

Abstract Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell‐free circulating tumor DNA (ctDNA) contains tumor‐specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow‐up. Using an approach combining low‐coverage whole‐genome sequencing of primary tumors and quantification of tumor‐specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA‐based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0–37 months), whereas patients with long‐term disease‐free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.

Abstract Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C‐type lectin Langerin/CD207 are cross‐presented to CD8+ T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin+ dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti‐CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)‐coupled anti‐Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin+ dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8+ T‐cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross‐presentation to CD8+ T cells. Langerin/OVA combined with imiquimod could not prime CD8+ T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin+ dDCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8+ T‐cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.

Abstract The heterotrimeric G‐protein complex is minimally composed of Gα, Gβ, and Gγ subunits. In the classic scenario, the G‐protein complex is the nexus in signaling from the plasma membrane, where the heterotrimeric G‐protein associates with heptahelical G‐protein‐coupled receptors (GPCRs), to cytoplasmic target proteins called effectors. Although a number of effectors are known in metazoans and fungi, none of these are predicted to exist in their canonical forms in plants. To identify ab initio plant G‐protein effectors and scaffold proteins, we screened a set of proteins from the G‐protein complex using two‐hybrid complementation in yeast. After deep and exhaustive interrogation, we detected 544 interactions between 434 proteins, of which 68 highly interconnected proteins form the core G‐protein interactome. Within this core, over half of the interactions comprising two‐thirds of the nodes were retested and validated as genuine in planta. Co‐expression analysis in combination with phenotyping of loss‐of‐function mutations in a set of core interactome genes revealed a novel role for G‐proteins in regulating cell wall modification.

Abstract The ability to analyze and understand the mechanisms by which cells process information is a key question of systems biology research. Such mechanisms critically depend on reversible phosphorylation of cellular proteins, a process that is catalyzed by protein kinases and phosphatases. Here, we present PhosphoPep, a database containing more than 10 000 unique high‐confidence phosphorylation sites mapping to nearly 3500 gene models and 4600 distinct phosphoproteins of the Drosophila melanogaster Kc167 cell line. This constitutes the most comprehensive phosphorylation map of any single source to date. To enhance the utility of PhosphoPep, we also provide an array of software tools that allow users to browse through phosphorylation sites on single proteins or pathways, to easily integrate the data with other, external data types such as protein–protein interactions and to search the database via spectral matching. Finally, all data can be readily exported, for example, for targeted proteomics approaches and the data thus generated can be again validated using PhosphoPep, supporting iterative cycles of experimentation and analysis that are typical for systems biology research.

CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture. Consistent with our in vitro results, in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell density. Finally, WT mice with ischemic fracture that were administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction. [ABSTRACT FROM AUTHOR]

Both the healthcare and education sector suffer from considerable staff shortages. In the healthcare sector, shortages are particularly prominent for nurses, while the education sector experiences significant teacher shortages. In this systematic literature review, we examine the effectiveness of interventions and policies to reduce staff shortages in healthcare and education in high-income countries. We focus our analysis on studies that apply research designs that allow for causal inference to inform policymakers about the effectiveness of interventions. In total, we include 85 studies that meet our inclusion criteria. Out of these studies, 71 studies focus on teachers and 14 on nurses, and 72 of the retrieved studies were conducted in the US. The majority of studies examine the impact of financial incentives and a large share of these studies report positive effects on teacher employment. Moreover, different types of interventions that invest in workers' human capital show predominantly positive effects on employment. Interventions that equip nurses with skills to better cope with the stressors of their profession seem to be particularly effective. The same holds for policies that increase the scope of practice for nurses. Finally, effective school leaders are better capable of retaining (high-quality) teachers. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the impact of venlafaxine and bupropion on the detection of nigrostriatal degeneration by dopamine transporter (DAT)-SPECT. Methods: 43 patients (70.7 ± 8.6y, 44% female) with [123I]FP-CIT-SPECT under venlafaxine (n = 26, 37.5-225 mg/d), bupropion (n = 16, 150 or 300 mg/d) or both (n = 1) were included retrospectively. The striatal specific [123I]FP-CIT binding ratio (SBR), its left–right asymmetry and the putamen-to-caudate ratio were transformed to z-scores and submitted to a cluster analysis for data-driven categorization. Results: Two clusters were identified. The first cluster (37% cases) showed a Parkinson's disease (PD)-like pattern: median striatal SBR/asymmetry/putamen-to-caudate z-score -4.5/4.9/-3.8. The second cluster (63%) showed symmetric reduction with normal intra-striatal gradient: median striatal SBR/asymmetry/putamen-to-caudate z-score -2.7/0.4/0.2. Patients with follow-up clinical reference diagnoses of neurodegenerative (n = 8) and non-neurodegenerative (n = 16) parkinsonism fell exclusively into the former or the latter cluster, respectively (p < 0.001). Conclusion: Venlafaxine and bupropion cause uniform reduction of the striatal [123I]FP-CIT SBR that can be distinguished from PD-like reductions. [ABSTRACT FROM AUTHOR]

Purpose: Deep convolutional neural networks (CNN) hold promise for assisting the interpretation of dopamine transporter (DAT)-SPECT. For improved communication of uncertainty to the user it is crucial to reliably discriminate certain from inconclusive cases that might be misclassified by strict application of a predefined decision threshold on the CNN output. This study tested two methods to incorporate existing label uncertainty during the training to improve the utility of the CNN sigmoid output for this task. Methods: Three datasets were used retrospectively: a "development" dataset (n = 1740) for CNN training, validation and testing, two independent out-of-distribution datasets (n = 640, 645) for testing only. In the development dataset, binary classification based on visual inspection was performed carefully by three well-trained readers. A ResNet-18 architecture was trained for binary classification of DAT-SPECT using either a randomly selected vote ("random vote training", RVT), the proportion of "reduced" votes ("average vote training", AVT) or the majority vote (MVT) across the three readers as reference standard. Balanced accuracy was computed separately for "inconclusive" sigmoid outputs (within a predefined interval around the 0.5 decision threshold) and for "certain" (non-inconclusive) sigmoid outputs. Results: The proportion of "inconclusive" test cases that had to be accepted to achieve a given balanced accuracy in the "certain" test case was lower with RVT and AVT than with MVT in all datasets (e.g., 1.9% and 1.2% versus 2.8% for 98% balanced accuracy in "certain" test cases from the development dataset). In addition, RVT and AVT resulted in slightly higher balanced accuracy in all test cases independent of their certainty (97.3% and 97.5% versus 97.0% in the development dataset). Conclusion: Making between-readers-discrepancy known to CNN during the training improves the utility of their sigmoid output to discriminate certain from inconclusive cases that might be misclassified by the CNN when the predefined decision threshold is strictly applied. This does not compromise on overall accuracy. [ABSTRACT FROM AUTHOR]

The transcription factor SOX10 is a key regulator of myelinated glial cell phenotype and function, with a known role in multiple sclerosis (MS). SOX10 is also expressed in enteric glial cells (EGC) within the gut, yet its regulatory functions in EGC remain poorly understood. This study aimed to identify SOX10 target genes that influence EGC phenotype and may have implications for MS. An EGC cell line was established for doxycycline-inducible SOX10 overexpression. Impact of SOX10 overexpression on EGC phenotype was assessed by genome-wide expression analysis and results were validated via RT-qPCR and western blot. Data were compared with SOX10 ChIP-seq and transcriptomic datasets from MS patients to identify pan-glial SOX10 target genes potentially linked to neuroinflammatory disorders. SOX10 overexpression was associated with ectopic upregulation of genes related to myelin regulation and glial differentiation, as evidenced by increased PLP1 expression at mRNA and protein levels. Comparison to ChIP-seq and MS datasets highlight SOX10 target genes, including PLP1, RNF130, NES and APOD potentially involved in central and peripheral manifestations of MS pathology. Our findings support a cell-specific regulation of EGC phenotype through SOX10 expression level and identify SOX10-regulated genes relevant to EGC function. This research advances the understanding of EGC diversity and provide information about glial cells targeting in neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Prior laser studies have demonstrated that as the temperature of a medium increases, the amount of energy delivered to the target increases. We sought to investigate the role of irrigation fluid temperature on Thulium fiber laser (TFL) urolith ablation. 360 calculi were divided in vitro according to chemical composition: calcium oxalate monohydrate (COM), cystine (CYS), struvite (STR), calcium phosphate (CAP), uric acid (UA), and calcium oxalate dihydrate (COD). A 200 μm TFL was placed directly on each stone, while immersed in 0.9% NaCl at four different temperatures (25 C, 37 C, 44 C, 60 C) and a single laser pulse administered at distinct energy settings (0.1 J, 0.5 J, 1.5 J). Optical coherence tomography assessed the resulting ablation cone volume. Mean stone volume and porosity were evaluated through ANOVA and Tukey post-hoc analysis. A multivariate generalized model for each composition accounted for the impact of fluid temperature and laser energy on stone ablation. Warmer fluid temperatures yielded greater ablation cone volumes for most energy settings, excluding UA stones. When accounting for chemical composition, higher tensile strength stones (COM, CYS) benefited most from warmer fluid in comparison to frangible stones (CAP, STR). The effects of increasing fluid temperature are modest relative to laser pulse energy as a large temperature increase (i.e. 7ºC) is equivalent to a minor energy increase (i.e. 0.1 J). For non-UA stones, TFL ablation efficiency increases with warmer irrigation fluid. The effect, albeit modest compared to laser pulse energy, was most notable for COM and CYS stones. [ABSTRACT FROM AUTHOR]

Background: Little attention has been paid to the generalizability of cohort studies in bipolar disorder (BD) to patient with BD in everyday clinical practice. Methods: A sample of patients with bipolar I disorder (BD-I) treated at a Dutch outpatient clinic for BD were compared with Dutch participants with BD-I of four clinical cohort studies, and participants with BD-I in a general population study in the Netherlands, on sociodemographic and clinical characteristics. Results: On many variables participants from the outpatient sample matched with those of the included studies. However, compared with participants of several of the clinical cohort studies, these outpatients were significantly younger, had an earlier age of onset of mood symptoms, and had a shorter duration of illness. Compared with participants in the general population study, outpatients had significant higher levels of education and less often lived together or were married. One cohort study reported much lower comorbidity rates of alcohol use disorders, drug use disorders, and anxiety disorders than in the outpatient sample. In contrast, comorbidity rates were higher in the population study. Limitations: Due to methodological differences between studies, comparisons between several variables was limited, and for some variables data was lacking. Conclusions: Our findings suggest that many findings from cohort studies and general population study in BD-I are generalizable to everyday clinical practice, especially mood disorder outpatient centers. However, differences between samples indicate some selection and referral bias. [ABSTRACT FROM AUTHOR]

Background: Timely intensive care unit (ICU) admission for patients with encephalitis is associated with better prognosis. Therefore, our aim was to create a risk score predicting ICU admission in adults with encephalitis, which could aid in optimal management and resource allocation. Methods: We initially identified variables that would be most predictive of ICU admission among 372 patients with encephalitis from two hospital systems in Houston, Texas (cohort 1), who met the International Encephalitis Consortium (IEC) criteria from 2005 to 2023. Subsequently, we used a binary logistic regression model to create a risk score for ICU admission, which we then validated externally using a separate cohort of patients from two hospitals in Baltimore, Maryland (cohort 2), who met the IEC criteria from 2006 to 2022. Results: Of 634 patients with encephalitis, 255 (40%) were admitted to the ICU, including 45 of 113 (39.8%) patients with an autoimmune cause, 100 of 272 (36.7%) with an infectious cause, and 110 of 249 (44.1%) with an unknown cause (p = 0.225). After conducting a multivariate analysis in cohort 1, we found that the presence of focal neurological signs, new-onset seizure, a Full Outline of Unresponsiveness score ≤ 14, leukocytosis, and a history of chronic kidney disease at admission were associated with an increased risk of ICU admission. The resultant clinical score for predicting ICU admission had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval [CI] 0.72–0.82, p < 0.001). Patients were classified into three risk categories for ICU admission: low risk (score 0, 12.5%), intermediate risk (scores 1–5, 49.5%), and high risk (scores 6–8, 87.5%). External validation in cohort 2 yielded an AUROC of 0.76 (95% CI 0.69–0.83, p < 0.001). Conclusions: ICU admission is common in patients with encephalitis, regardless of etiology. Our risk score, encompassing neurologic and systemic factors, may aid physicians in decisions regarding intensity of care for adult patients with encephalitis upon hospital admission. [ABSTRACT FROM AUTHOR]

In this article we study perturbations of local, nonlinear Dirichlet forms on arbitrary topological measure spaces. As a main result, we show that the semigroup generated by a local, regular, nonlinear Dirichlet form E dominates the semigroup generated by another local functional F if, and only if, F is a specific zero order perturbation of E . On the way, we prove a nonlinear version of the Riesz–Markov representation theorem, we define an abstract boundary of a topological measure space, and apply the notion of nonlinear capacity. The main result helps to classify the perturbations that lie between Neumann and Dirichlet boundary conditions. [ABSTRACT FROM AUTHOR]

Fish may have different sensitivity to pollutants present in the water. We analyzed the liver histology, and P-gp expression in six species of fish from the Doce River basin. Fish were caught at six different points in the Doce River, and liver samples were taken for histological analysis. P-gp expression was analyzed using an immunohistochemical technique. In Astyanax lacustris, Hoplias intermedius, Hypostomus affinis, Trachelyopterus striatulus and Oligosarcus acutirostris, a double arrangement of hepatocyte plates was generally observed (tubular-form), while in Deutorodon taeniatus, a single arrangement of hepatocyte plates was frequently observed (cord-like). Histological changes, such as cytoplasmic vacuolation and nuclear alteration, were observed in the livers of all species analyzed, however, the species A. lacustris (34.1%) and H. affinis (33.3%) were those with the fewest individuals with histological changes. The H. intermedius, T. striatulus, and O. acutirostris were the species that presented more than 80% of their individuals with histological changes. The A. lacustris and H. affinis were the species that showed the highest P-pg immunolabeling in the liver, while the T. striatulus and O. acutirostris had the lowest levels. These results support the hypothesis that levels of P-gp expression could respond to the resistance or sensitivity of each species to environmental pollutants. [ABSTRACT FROM AUTHOR]

Molds of the genus Fusarium infect nearly all types of grain, causing significant yield and quality losses. Many species of this genus produce mycotoxins, which pose significant risks to human and animal health. In beer production, the complex interaction between primary fungal metabolites and secondarily modified mycotoxins in barley, malt, and beer complicates the situation, highlighting the need for effective analytical methods to quickly and accurately monitor these toxins. We developed and validated a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method to simultaneously analyze 14 Fusarium toxins, including modified forms (deoxynivalenol (DON), DON-3-glucoside, 3-acetyl-DON, 15-acetyl-DON, nivalenol, fusarenone X, HT-2 toxin, T-2 toxin, the enniatins A, A1, B, B1, beauvericin, and zearalenone) in barley and throughout the malting process. Stable isotope dilution assays (SIDAs) and matrix-matched calibration were used for quantification. A micro-malting setup was established to produce Fusarium-contaminated barley malt under reproducible conditions using targeted inoculation with F. culmorum. Mycotoxins were quantified throughout the malting process and compared to the content of fungal DNA. Further, the impact of various malting parameters was investigated, thus revealing that different malting scenarios exhibited different toxin enrichment patterns. We demonstrated that mycotoxin concentration and the ratio of DON to DON-3-glucoside changed throughout the malting processes, depending on fungal spore concentrations, germination temperature, and malting temperature. The study highlights the complexity of mycotoxin dynamics in malt production and the importance of optimized processing conditions to minimize toxin levels in final malt products. [ABSTRACT FROM AUTHOR]

In spite of forecasts for anomalous dryness based on the canonical La Niña signal, Water Years 2011, 2017, and 2023 brought copious precipitation to California and the Southwestern United States (SWUS). Although El Niño–Southern Oscillation (ENSO) is the main source of seasonal precipitation predictability for the region, outstanding Atmospheric River (AR) activity produced the unexpected regional wetness in each of these heretical water years (WYs). We define heretical WYs as those that result in precipitation anomalies that oppose those expected based on ENSO canon. We assess the contribution of ARs and other storms to these WYs, finding that heretical La Niña/El Niño WYs were characterized by anomalously robust/deficient AR activity. In California, precipitation accumulation during the heretical La Niña WYs was comparable to or even exceeded that observed during the exceedingly wet WY1998—the textbook canonical El Niño year. Our findings indicate a weaker/stronger relationship between ENSO and AR/non-AR precipitation, primarily driven by storm frequency. Although ARs can disrupt the ENSO-precipitation signal, ENSO still influences the frequency of AR precipitation in the southwestern U.S. desert, the region influenced by ARs that make landfall in Baja California, Mexico. These results highlight the complexity of ENSO's impact on precipitation in the Western US and underscore the need for a nuanced understanding of ENSO’s influence on ARs to improve seasonal precipitation prediction. [ABSTRACT FROM AUTHOR]

The adult electric organ in weakly electric mormyrid fish consists of action-potential-generating electrocytes, structurally and functionally modified skeletal muscle cells. The electrocytes have a disc-shaped portion and, on one of its sides, numerous thin processes, termed stalklets. These unite to stalks leading to a single main stalk that carries the innervation site. Here, we describe the 3-dimensional layout of the stalklet/stalk system in adult Campylomormyrus compressirostris by differential interference contrast microscopy and confocal fluorescence microscopy. Using antibodies against Na+/K+-ATPase α-subunit and plasma membrane Ca2+-ATPase, we show that these ion pumps are differentially distributed over the stalklet/stalk system, with plasma membrane Ca2+-ATPase being enriched on the stalklet membrane. Stalklets are distributed and organized in a quite uniform pattern on the posterior face of the electrocyte disc and fuse to terminal stalks. The latter then unite in a mostly dichotomic mode to stalks of increasing thickness, with the main stalk measuring about 100 µm in diameter. We further analyse the structural organization of stalklets and stalks, with a characteristic cytoskeletal system of bundled actin filaments in the centre and nuclei in subsurface position. These results suggest that the stalklet/stalk system is adapted in its structural layout to generate an action potential highly synchronized over the entire disc-portion of the electrocyte, accounting for the short electric organ discharge in this species. Our results suggest that actin-related proteins overexpressed in electrocytes, as shown previously by transcriptome analysis, may be involved in the organization of the unique F-actin system in stalklets and stalks. [ABSTRACT FROM AUTHOR]

Background: Multidisciplinary care is paramount in patient-specific decision making, especially as pertaining to oral cavity squamous cell cancer (OCSCC) treatment. Protracted surgery-postoperative-radiation (S-PORT) has a detrimental impact on OCSCC patients' outcomes. This study examined the impact of surgeon-radiation oncologist dyads on the treatment of OCSCC, focusing on S-PORT interval and disease specific outcomes. Methods: All OCSCC patients treated in a tertiary cancer center between 2009 to 2017 were included. Patients were categorized into "dyad" and "nondyad" groups defined as whether they were treated by a paired surgeon–radiation oncology team with joint multidisciplinary clinic or shared >30% patient volumes. Univariate and multivariate logistic regression were performed to identify factors associated with a prolonged S-PORT time interval (≥8 weeks). Overall survival and locoregional recurrence were estimated and compared. Results: A total of 444 OCSCC were eligible. Treatment by a dyad was significantly less likely associated with S-PORT ≥ 8 weeks (odds ratio [OR]unadjusted: 0.65; 95% confidence interval [CI] 0.44–0.96; p = 0.03). Obtaining pre-operative radiation oncology consultation also decreased the S-PORT interval. Advanced T-category and the need for free tissue flap reconstruction increased the likelihood of prolonged S-PORT on univariate but not multivariate analysis. No significant differences were observed in overall survival or locoregional recurrence by dyad status nor S-PORT (p > 0.05). Conclusions: Surgeon-radiation oncology dyads significantly minimized time from surgery to postoperative radiation in OCSCC. While improvement in overall survival or locoregional recurrence was not observed, these findings support close knit collaborative multidisciplinary treatment care models, including dyad-based care. [ABSTRACT FROM AUTHOR]

Background: Anastomotic ulcers (AU) at the gastroenterostomy are a common postoperative complication after laparoscopic Roux-en-Y gastric bypass (LRYGB). Possible risk factors for ulcer formation include active smoking, the use of non-steroidal anti-inflammatory drugs, increased tension or ischemia at the anastomosis, or factors that increase the acid secretion of the gastric pouch. Therefore, a longer gastric pouch may increase risk of AU formation after LRYGB. Methods: This study is a retrospective analysis of prospective collected data from patients undergoing LRYGB between 2009 and 2019 with a minimum follow-up of 2 years. In 2018, we changed the operative technique from short to long gastric pouch LRYGB. We analyzed AU formation, dumping syndrome, age, weight evolution, obesity-associated medical problems, and NSAID in two groups: long (LP-GP) vs. short pouch (SP-GP) LRYGB. Results: A total of 1058 patients were included in the analysis (178 with LP-GP and 880 with SP-GP). A long gastric pouch significantly increased the rate of AU (LP-GP 12.4% vs. SP-GP 2.6%, p ≤ 0.01, OR 5.3). In contrast, the appearance of dumping syndrome improved in patients undergoing LP-GP (LP-GP 49% vs. SP-GP 60%, P ≤ 0.01, OR 1.5). However, no difference was observed between the groups in terms of weight loss in the first 2 years postoperative. Conclusion: LRYGB with a long compared to a short gastric pouch increases the rate of AU while decreasing the appearance of dumping syndrome. These findings influence the postoperative course of patients undergoing LRYGB, particularly concerning prolonged proton pump inhibitor prophylaxis and a possible tailored surgical approach. [ABSTRACT FROM AUTHOR]

Interest in bile acids (BAs) is growing due to their emerging role as signaling molecules and their association with various diseases such as colon cancer and metabolic syndrome. Analyzing BAs requires chromatographic separation of isomers, often with long run times, which hinders BA analysis in large studies. Here, we present a high-throughput method based on liquid chromatography-tandem mass spectrometry to quantify BAs in mouse samples. After acidic protein precipitation in the presence of a comprehensive mixture of stable isotope-labeled internal standards (SIL-ISs), BAs are separated on a biphenyl column by gradient elution at basic pH. Quantification is performed using a six-point calibration curve. Except for the separation of β- and ω-muricholic acid (MCA) species, a rapid separation of 27 BA species was achieved in a run time of 6.5 min. Plasma quality controls (QCs) were used to evaluate intra- and inter-day precision. The CV was less than 10% for most BA species and exceeded 20% only for glycohyodeoxycholic (GHDCA) and taurohyodeoxycholic acid (THDCA) due to the lack of a corresponding SIL-IS. The limit of quantification (LoQ) was tested using diluted QCs and was found to be compromised for some BA species as a result of insufficient isotopic purity of the SIL-IS, leading to significant interference with the respective analyte. Finally, we tested the mouse sample material requirements for plasma, bile, and liver samples and determined BA concentrations in C57/BL6N wild-type mice. In conclusion, the LC–MS/MS method presented here permits a rapid and reproducible quantification of the major murine BAs. [ABSTRACT FROM AUTHOR]

EPR applications have evolved continuously with the development of the EPR technique. Since 1967, Bruker EPR is constantly developing its products to keep pace with these constantly changing demands. This article presents commercial EPR solutions in perspective of the past, present, and future. [ABSTRACT FROM AUTHOR]

In this paper we give an explanation of a number of observations relating to degree growth of birational mappings of the plane and their deautonomisation by singularity confinement. These observations are of a link between two a priori unrelated notions: firstly the dynamical degree of the mapping and secondly the evolution of parameters required for its singularity structure to remain unchanged under a sufficiently general deautonomisation. We explain this correspondence for a large class of birational mappings of the plane via the spaces of initial conditions for their deautonomised versions. We show that even for non-integrable mappings in this class, the surfaces forming these spaces have effective anticanonical divisors and one can define a period map parametrising them, similar to that in the theory of rational surfaces associated with discrete Painlevé equations. This provides a bridge between the evolution of coefficients in the deautonomised mapping and the induced dynamics on the Picard lattice which encode the dynamical degree. [ABSTRACT FROM AUTHOR]

Purpose: Dopamine transporter imaging is routinely used in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) diagnosis. While [11C]CFT PET is prevalent in Asia with a large APS database, Europe relies on [123I]FP-CIT SPECT with limited APS data. Our aim was to develop a deep learning-based method to convert [11C]CFT PET images to [123I]FP-CIT SPECT images, facilitating multicenter studies and overcoming data scarcity to promote Artificial Intelligence (AI) advancements. Methods: A CycleGAN was trained on [11C]CFT PET (n = 602, 72%PD) and [123I]FP-CIT SPECT (n = 1152, 85%PD) images from PD and non-parkinsonian control (NC) subjects. The model generated synthetic SPECT images from a real PET test set (n = 67, 75%PD). Synthetic images were quantitatively and visually evaluated. Results: Fréchet Inception Distance indicated higher similarity between synthetic and real SPECT than between synthetic SPECT and real PET. A deep learning classification model trained on synthetic SPECT achieved sensitivity of 97.2% and specificity of 90.0% on real SPECT images. Striatal specific binding ratios of synthetic SPECT were not significantly different from real SPECT. The striatal left-right differences and putamen binding ratio were significantly different only in the PD cohort. Real PET and real SPECT had higher contrast-to-noise ratio compared to synthetic SPECT. Visual grading analysis scores showed no significant differences between real and synthetic SPECT, although reduced diagnostic performance on synthetic images was observed. Conclusion: CycleGAN generated synthetic SPECT images visually indistinguishable from real ones and retained disease-specific information, demonstrating the feasibility of translating [11C]CFT PET to [123I]FP-CIT SPECT. This cross-modality synthesis could enhance further AI classification accuracy, supporting the diagnosis of PD and APS. [ABSTRACT FROM AUTHOR]

Purpose: Radioligand therapy is an increasingly important option for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Radiohybrid ligands targeting prostate-specific membrane antigen (PSMA) are a novel group of theranostic radioligand therapy agents for which higher tumour absorbed radiation doses have been demonstrated compared to established PSMA ligands. Here, we report data from ten patients who were treated within a compassionate use program with the radiohybrid PSMA-ligand [177Lu]Lu-rhPSMA-10.1 after experiencing disease progression under treatment with [177Lu]Lu-PSMA-I&T. Methods: Ten patients with advanced PSMA-positive prostate cancer who showed progression under treatment with [177Lu]Lu-PSMA-I&T received up to three cycles of rescue therapy with [177Lu]Lu-rhPSMA-10.1 (7.4–8.1 GBq per cycle). Efficacy (PSA response according to PCWG3 and RECIP) and overall survival were evaluated. Adverse events were recorded from first application. Results: Despite progression with [177Lu]Lu-PSMA-I&T, after the first cycle of [177Lu]Lu-rhPSMA-10.1 rescue therapy, five patients (50%) showed a decrease in serum PSA level. In imaging, three of the ten patients (30%) showed a partial radiologic response. Four of the five patients with a decrease of serum PSA under [177Lu]Lu-rhPSMA-10.1 had initially responded to treatment with [177Lu]Lu-PSMA-I&T but had become resistant. However, the remaining patient had shown continuous disease progression during [177Lu]Lu-PSMA-I&T therapy but showed an immediate response to [177Lu]Lu-rhPSMA-10.1. The additional treatment with [177Lu]Lu-rhPSMA-10.1 was generally well tolerated by all patients. Conclusions: Patients showing tumour progression while receiving [177Lu]Lu-PSMA-I&T radioligand therapy may benefit from rescue therapy with the novel radiohybrid PSMA ligand, [177Lu]Lu-rhPSMA-10.1. Higher tumour absorbed radiation doses with [177Lu]Lu-rhPSMA-10.1 may overcome primary and acquired radiation resistance. [ABSTRACT FROM AUTHOR]

Objective: Fatty infiltration of skeletal muscle (Myosteatosis) is associated with increased frailty, decreased muscle and mobility function, which seems fairly prevalent in multiple myeloma (MM) patients. This study aimed to determine the prognostic value of myosteatosis assessed by CT for progression-free survival (PFS) and overall survival (OS). Materials and methods: This IRB-approved cohort study included patients with newly diagnosed MM who were treated at a single university hospital and received CT at baseline. Geriatric assessment was performed via International Myeloma Working Group frailty score and Revised Myeloma Comorbidity Index. Myosteatosis was determined through measurement of paravertebral muscle radiodensity. Statistical analyses included uni- and multivariable Cox proportional hazard models and the Kaplan–Meier-method. Results: A total of 226 newly diagnosed MM patients (median age: 65 years [range: 29–89], 63% males, mean BMI: 25 [14–42]) were analyzed. The prevalence of myosteatosis was 51%. Muscle radiodensity was significantly decreased in individuals with International Staging System stage III vs. I (p < 0.001), indicating higher fatty muscle infiltration in patients with advanced disease. Both PFS and OS were significantly decreased in patients with myosteatosis (PFS: median 32.0 months (95% CI 20.5.5–42.2) vs. 66.4 months without myosteatosis (95% CI 42.5-not reached), p <.001); OS: median 58.6 (95% CI 51.3—90.2) vs. not reached, p <.001). Myosteatosis remained an independent predictor of OS in multivariable analyses (HR: 1.98; 95%-CI: 1.20–3.27). Conclusion: Myosteatosis seems fairly prevalent in patients with newly diagnosed MM and associated with impaired overall survival. Prospective clinical trials are required to better understand the role of myosteatosis in MM patients. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of the prognostic significance of four different scoring systems in a real-world cohort of patients with metastatic urothelial carcinoma (mUC) or renal cell carcinoma (mRCC) undergoing immunotherapy (IO). Methods: For 120 patients with mUC (n = 67) and mRCC (n = 53) who received IO between July 2016 and December 2020 at the tertiary Urological University Medical Centre Mannheim, the following scores were recorded at pre-treatment baseline: modified Glasgow prognostic score (mGPS), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER). Overall survival (time between the beginning of IO until the patients' death or last contact) was determined for every patient. Results: Kaplan-Meier analyses revealed that high baseline mGPS, SII (> 979) and NLR (> 3) were associated with poor overall survival (OS) (p < 0.05). Cox proportional hazards regression analyses showed that baseline mGPS and NLR had a significant independent prognostic influence on OS (p < 0.05), of which mGPS had a greater significance (p < 0.001, mGPS Score 2 vs. Score 0: HR 4.1, 95% CI 1.9–8.8). Although a high baseline NER (63.9) was associated with poor OS, it did not reach statistical significance. Baseline NER was also not identified as a significant score in the regression analyses. Conclusion: mGPS, SII and NLR are scoring systems that are easy to record in routine clinical practice. As they provide good prediction of OS in patients with mUC and mRCC under IO, they may allow identification of patients at high-risk and monitor them more cautiously in addition to imaging. [ABSTRACT FROM AUTHOR]

Loss of kidney function is a substantial personal and public health burden. Kidney function is typically assessed as estimated glomerular filtration rate (eGFR) based on serum creatinine. UK Biobank provides serum creatinine measurements from study center assessments (SC, n = 425,147 baseline, n = 15,314 with follow-up) and emerging electronic Medical Records (eMR, "GP-clinical") present a promising resource to augment this data longitudinally. However, it is unclear whether eMR-based and SC-based creatinine values can be used jointly for research on eGFR decline. When comparing eMR-based with SC-based creatinine by calendar year (n = 70,231), we found a year-specific multiplicative bias for eMR-based creatinine that decreased over time (factor 0.84 for 2007, 0.97 for 2013). Deriving eGFR based on SC- and bias-corrected eMR-creatinine yielded 454,907 individuals with ≥ 1eGFR assessment (2,102,174 assessments). This included 206,063 individuals with ≥ 2 assessments over up to 60.2 years (median 6.00 assessments, median time = 8.7 years), where we also obtained eMR-based information on kidney disease or renal replacement therapy. We found an annual eGFR decline of 0.11 (95%-CI = 0.10–0.12) versus 1.04 mL/min/1.73m2/year (95%-CI = 1.03–1.05) without and with bias-correction, the latter being in line with literature. In summary, our bias-corrected eMR-based creatinine values enabled a 4-fold increased number of eGFR assessments in UK Biobank suitable for kidney function research. [ABSTRACT FROM AUTHOR]

While all native tRNAs undergo extensive post-transcriptional modifications as a mechanism to regulate gene expression, mapping these modifications remains challenging. The critical barrier is the difficulty of readthrough of modifications by reverse transcriptases (RTs). Here we use Induro—a new group-II intron-encoded RT—to map and quantify genome-wide tRNA modifications in Induro-tRNAseq. We show that Induro progressively increases readthrough over time by selectively overcoming RT stops without altering the misincorporation frequency. In a parallel analysis of Induro vs. a related RT, we provide comparative datasets to facilitate the prediction of each modification. We assess tRNA modifications across five human cell lines and three mouse tissues and show that, while the landscape of modifications is highly variable throughout the tRNA sequence framework, it is stabilized for modifications that are required for reading of the genetic code. The coordinated changes have fundamental importance for development of tRNA modifications in protein homeostasis. Here the authors report genome-wide profiling of tRNA modifications using Induro-tRNAseq and uncover coordinated changes across cell types and tissues that underlie the basis of protein homeostasis. [ABSTRACT FROM AUTHOR]

Cyanogenic glycosides form part of a binary plant defense system that, upon catabolism, detonates a toxic hydrogen cyanide bomb. In seed plants, the initial step of cyanogenic glycoside biosynthesis—the conversion of an amino acid to the corresponding aldoxime—is catalyzed by a cytochrome P450 from the CYP79 family. An evolutionary conundrum arises, as no CYP79s have been identified in ferns, despite cyanogenic glycoside occurrence in several fern species. Here, we report that a flavin-dependent monooxygenase (fern oxime synthase; FOS1), catalyzes the first step of cyanogenic glycoside biosynthesis in two fern species (Phlebodium aureum and Pteridium aquilinum), demonstrating convergent evolution of biosynthesis across the plant kingdom. The FOS1 sequence from the two species is near identical (98%), despite diversifying 140 MYA. Recombinant FOS1 was isolated as a catalytic active dimer, and in planta, catalyzes formation of an N-hydroxylated primary amino acid; a class of metabolite not previously observed in plants. Thodberg et al. report the first step of the synthesis of cyanogenic glycosides, a plant defense mechanism, by a Flavin-dependent monooxygenase (FOS1) in ferns, revealing convergent evolution of biosynthesis across the plant kingdom. The authors isolate FOS1 as a catalytically active dimer and demonstrate that it catalyzes the formation of N-hydroxylated amino acids. [ABSTRACT FROM AUTHOR]

Background: Societies under duress may selectively increase the reporting of disordered persons from vulnerable communities to law enforcement. Mentally ill African American males reportedly are perceived as more threatening relative to females and other race/ethnicities. We examine whether law enforcement/court order-requested involuntary psychiatric hospitalizations increased among African American males shortly after ambient economic decline—a widely characterized population stressor. Methods: We identified psychiatric inpatient admissions requested by law enforcement/court orders from 2006 to 2011 across four US states (Arizona, California, New York, North Carolina). Our analytic sample comprises 13.1 million psychiatric inpatient admissions across 95 counties over 72 months. We operationalized exposure to economic downturns as percent change in monthly employment in a metropolitan statistical area (MSA). We used zero inflated negative binomial and linear fixed effects regression analyses to examine psychiatric inpatient admissions requested by law enforcement/court orders following regional employment decline over a time period that includes the Great Recession of 2008. Findings. Declines in monthly employment precede by one month a 6% increase in psychiatric hospitalizations requested by law enforcement/court order among African American males (p < 0.05), but not among other race/sex groups. Estimates amount to an excess of 2554 involuntary admissions among African American males statistically attributable to aggregate-level employment decline. Conclusions: Economic downturns may increase involuntary psychiatric commitments among African American males. Our findings underscore the unique vulnerability of racial/ethnic minorities during economic contractions. [ABSTRACT FROM AUTHOR]

Multiple Myeloma (MM) is a hematological disease predominantly affecting elderly patients. The complexity of current treatment necessitates individualized approaches. Therein, functional assessment (FA) tools, such as the Revised Comorbidity Index (R-MCI) at our University- and Comprehensive Cancer Center Freiburg, play a crucial role. This study aimed to determine (a) the implementation of the R-MCI in our MM-tumor board (MM-TB), (b) its impact on treatment guidance at baseline and (c) potential changes during follow-up. This exploratory study investigated R-MCI coverage and distribution in a cohort of patients with multiple TB presentations. Among them, a follow-up patient cohort undergoing subsequent MM-therapy was analyzed to determine treatment adjustments and changes in patients' condition measured by R-MCI alterations. During our 3-year assessment period, 565 patients were presented in our MM-TB, totaling 1256 TB-presentations. In the multiple TB presentation cohort, the median number of TB presentations was 3 (range: 2–12). R-MCI scores within the MM-TB were available in 94%, whereas in 6%, the R-MCI had not been integrated. Among these, potential failure to identify the need for treatment modifications was determined. In the follow-up cohort, patient characteristics were typical for referral/university centers. Dose reductions were performed in 55% and were more prevalent among patients with ≥ 4 vs. lesser TB presentations. Most patients (55%) showed a fitness stabilization or improvement via follow-up R-MCI. R-MCI integration in MM-TB exceeded > 90%, indicating its successful integration for treatment support. Our results underscore its value in guiding therapy decisions, providing a comprehensive assessment beyond age considerations. [ABSTRACT FROM AUTHOR]

The Social Misfit Theory, which states that some individuals deviate from what is normative in a community and may therefore be more likely to be victimized, has mostly been studied in Western countries. The current study addresses in a longitudinal sample whether socio-economic minorities (SES) in the classroom (a contextual SES minority) are more likely to become victims of bullying in India, and whether the relation between minority status and victimization is mediated by perception of oneself as a minority. The current study used three waves separated by three month intervals. A sample of youth from Indore India (grades 7 to 9; N = 1238; M-ageT1 = 13.15, SD = 1.16, 24 percent girls) was used. It was found that being a contextual SES minority was related to more victimization, but only when the contextual status was corroborated by the perceived minority status. However, over time, being part of a contextual minority predicted decreased victimization, possibly pointing to normative beliefs and values in the Indian context. The results of this study are in contrast to the Social Misfit Theory, but do support self-perception as a mediator. [ABSTRACT FROM AUTHOR]

Objective: We investigated diagnostic utility of phosphorylated tau 217 and 181 (ptau217, ptau181), glial fibrillary acidic protein (GFAP), amyloid beta 42 and 40 (Aβ42, Aβ40), and neurofilament light (NfL) to distinguish biomarker-defined Alzheimer disease (AD) from non-AD conditions, in a heterogenous clinical cohort of younger people. Methods: Plasma biomarkers were analysed using ultrasensitive technology, and compared in patients with CSF Alzheimer disease profiles (A+T+) to other CSF profiles (Other). Results: Seventy-nine patients were included, median age 60.8 years: 16 A+T+, 63 Other. Ptau217, ptau181, GFAP were significantly elevated in A+T+ compared to Other (3.67 vs 1.12 pg/mL, 3.87 vs 1.79 pg/mL, 189 vs 80 pg/mL, respectively). ptau217 distinguished AD from Other with 90% accuracy (88% specificity, 100% sensitivity). ptau217 also demonstrated strong diagnostic performance for clinically diagnosed AD. Conclusions: Plasma ptau217 has strong diagnostic performance in distinguishing CSF biomarker-defined AD in a clinically relevant, younger cohort of people with symptoms, adding further weight for a simple diagnostic blood test for AD as a cause of a patient’s symptoms. [ABSTRACT FROM AUTHOR]

Objectives: Temporomandibular disorders (TMD) are musculoskeletal conditions with a multifactorial aetiology. The predictive role of direct orofacial macrotrauma in the development of TMD is considered controversial. This systematic review aims to elucidate the association between direct orofacial macrotrauma and TMD, and to identify potential factors involved in this relationship. Materials and methods: A comprehensive literature search of PubMed, Embase, and Web of Science databases up to November 1, 2023, was performed in collaboration with a medical information specialist, identifying 2,047 unique studies. Of these, 139 met the inclusion criteria of this investigation. Results: Our synthesis of the literature indicates a consistent association between TMD and direct orofacial macrotrauma in adults, while this relationship appears less defined in paediatric and adolescent populations. The association shows robustness across various TMD diagnoses and trauma locations, remaining not only immediately following the direct orofacial macrotrauma but also after long time, despite other interventions. These outcomes could be due to the physical effect of the trauma, but they might be associated with the psychosocial effect of the trauma as well. Conclusions: The evidence supports a robust, but complex, association between direct orofacial macrotrauma and TMD. Clinical relevance: This finding underscores the importance of considering both physical and psychosocial sequelae of trauma in the clinical management of direct orofacial macrotrauma and TMD. [ABSTRACT FROM AUTHOR]

Freshwater organisms are among the most vulnerable species being impaired by global climate change. Freshwater Pearl Mussel (Margaritifera margaritifera) is a keystone species that facilitates a number of important ecosystem functions in cold water oligotrophic streams, while is currently facing habitat alteration and degradation due to human activities. Global climate change is amplifying these negative impacts. Population decline is directly connected with transformation of population genetic structure and may result in significant loss of genetic diversity. In this study, we identified populations of M. margaritifera for conservation prioritization in the north-eastern part of the species' range and investigated the potential impact of future climate scenarios on its conservation genetics. We used nine microsatellite loci to examine genetic diversity and differentiation in 17 populations of the species from rivers of the Barents, White, and Baltic Sea basins. To forecast the effects of climatic changes on the dynamics of genetic structure, we applied the Bayesian clustering algorithm. Genetic simulations were conditioned to mean summer temperatures estimated under future carbon emission projections, i.e., representative concentration pathway (RCP) scenarios 4.5 and 8.5. High genetic diversity and low genetic differentiation were found in the studied populations, with individuals being assigned to three genetic clusters. Future climate change will significantly rearrange cluster distribution resulting in lower population differentiation. The only exception were populations of the Baltic Sea basin that keep their genetic uniqueness under current and future climatic conditions. Obtained data allowed us to delineate three conservation units that play critical roles in securing the genetic diversity of the species currently and in the future: (1) populations of the Barents Sea basin with the highest contribution to the overall genetic diversity; (2) populations of northern Karelia which will lose significant part of their diversity under the climate change; and (3) populations of the Baltic Sea basin, with a unique gene pool which is threatened by climate change and other anthropogenic pressures. [ABSTRACT FROM AUTHOR]

Introduction: Preoperative diagnostic protocols vary worldwide, some prioritizing safety while others question routine procedures. Building on prior research, this study explores the impact of diverse preoperative findings on bariatric management and procedure selection. Methods: In a retrospective analysis of prospective data of over 1000 bariatric surgery patients from January 2017 to December 2022 undergoing primary laparoscopic Roux-en-Y gastric bypass (LRYGB) or sleeve gastrectomy (LSG) were analyzed. Preoperative assessment included upper endoscopy, upper GI series, and esophageal manometry. Sonography data were excluded. The primary endpoint examined the influence of preoperative exams on procedure selection, the secondary endpoint evaluated their therapeutic impact. Results: 897 patients (741 RYGB, 156 SG) were included. All underwent upper endoscopy, revealing common findings such as type C gastritis and reflux esophagitis. Upper endoscopy prompted a therapeutic consequence in 216 patients (24.3%), resulting in a number needed to screen (NNS) of 4.1. Upper GI series and manometry were more frequently performed before LSG. Upper GI series detected hiatal hernias and motility disorders but did not result in any change of procedures. Esophageal manometry found pathologies in 37 (25.3%) patients rising to 41.5% if symptoms were present. Overall, 16 (1.8%) patients experienced a change in the planned procedure, with 14 changes prompted by preoperative findings and two by technical difficulties. Conclusion: We advise routine upper endoscopies for all patients undergoing LRYGB or LSG, while reserving upper GI series only for selected cases. Manometry should be exclusively performed on symptomatic patients undergoing LSG, ensuring a balanced and individualized preoperative assessment. [ABSTRACT FROM AUTHOR]

Context: Land-use intensification can alter small mammal community composition and induce loss of genetic variation in remaining populations. Fragmented landscapes favor generalist and synanthropic species, which are potential reservoirs of pathogens and pose risks to agriculture and forestry. Objectives: This study aimed to evaluate the effects of land-use intensity on small mammal diversity in grassland and forest habitats, as well as on genetic variation patterns driven by geographic (isolation by distance) and environmental distance (isolation by resistance) factors. Methods: We analysed differences in small mammal community diversity on grassland and forest plots with varying land-use intensities. Genetic analyses were conducted on Myodes glareolus and Microtus arvalis populations from each habitat, using microsatellites. Maximum Likelihood Population Effects models were employed to elucidate gene flow patterns and significant differences in genetic structure based on land-use intensity. Results: Small mammal communities in grasslands were significantly less diverse than in forests. Land-use intensity had a significant effect on diversity within grassland but not within forest habitats. M. glareolus showed three genetic groups, while M. arvalis displayed no discernible population structure or landscape-related pattern. Land-use intensity did not significantly influence the genetic structure of either species. Gene flow in M. glareolus is best described by the IBR model. Conclusion: Land-use intensity significantly affects small mammal community composition, particularly in grasslands. Neither species' genetics is directly impacted by land-use intensity but rather by landscape connectivity and distance. Risk assessments for rodent-borne zoonotic pathogens and crop damage should be framed within a habitat connectivity context. [ABSTRACT FROM AUTHOR]