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College-level deaf and hard-of-hearing (DHH) students and hearing students of English as a Second Language (L2) along with hearing native speakers (NS) of English were assessed in their knowledge of English resultative and depictive sentences. In "Kevin wiped the table clean," the resultative phrase "clean" indicates that the table became clean as a result of Kevin wiping it. In "Megan drove the car drunk," the depictive phrase "drunk" describes Megan's state throughout the entire event of driving. Findings of a sentence-acceptability rating scale task revealed higher performance by the NS group compared to the DHH and L2 groups, whose near-equivalent performance improved with increasing overall English proficiency. Participants exhibited higher performance on active, passive, and unaccusative resultative sentences than on ungrammatical unergative resultatives and higher performance on grammatical than ungrammatical depictive sentence types. These findings contribute new insights into the comparative study of English acquisition by DHH and L2 learners., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Most patients with unresectable locally advanced cutaneous squamous cell carcinoma (cSCC) benefit from cemiplimab, but some do not respond. Our study aims to identify clinical and histopathological features predicting response to cemiplimab., Patients and Methods: We analyzed 15 patients treated with cemiplimab, assessing clinical, demographic, histopathological, and immunohistochemical characteristics and correlating them with treatment response. Furthermore, effectiveness and safety were evaluated in our cohort., Results: Our cohort included 12 males and 3 females, with a mean age of 78.1 years. The majority of tumors, accounting for 66.7%, were located in the head and neck region. Treatment was well-tolerated, with only one grade 3 colitis. There was no correlation between immune-related adverse events and treatment response. Non-responders were younger (69.4 vs. 82.5 years). A history of hematological malignancy correlated with poorer response. High mitotic rate, poor tumor differentiation, high vimentin and p53, and low E-cadherin expression were associated with worse response. Conversely, higher intratumoral inflammatory infiltrate density, presence of necrotic areas, and lower mismatch repair-protein staining correlated with better response., Conclusions: Cemiplimab is a safe and effective therapy, particularly in elderly patients. Well-differentiated tumors with low proliferative index, intratumoral inflammatory infiltrate, and tumor necrosis may predict better clinical response., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Platinum-black (Pt-B) has been demonstrated to be an excellent electrocatalytic material for the electrochemical oxidation of hydrogen peroxide (H 2 O 2 ). As Pt-B films can be deposited electrochemically, micro- and nano-sized conductive transducers can be modified with Pt-B. Here, we present the potential of Pt-B micro- and sub-micro-sized sensors for the detection and quantification of hydrogen (H 2 ) in solution. Using these microsensors, no sampling step for H 2 determination is required and e.g. , in photocatalysis, the onset of H 2 evolution can be monitored in situ . We present Pt-B-based H 2 micro- and sub-micro-sized sensors based on different electrochemical transducers such as microelectrodes and atomic force microscopy (AFM)-scanning electrochemical microscopy (SECM) probes, which enable local measurements e.g. , at heterogenized photocatalytically active samples. The microsensors are characterized in terms of limits of detection (LOD), which ranges from 4.0 μM to 30 μM depending on the size of the sensors and the experimental conditions such as type of electrolyte and pH. The sensors were tested for the in situ H 2 evolution by light-driven water-splitting, i.e. , using ascorbic acid or triethanolamine solutions, showing a wide linear concentration range, good reproducibility, and high sensitivity. Proof-of-principle experiments using Pt-B-modified cantilever-based sensors were performed using a model sample platinum substrate to map the electrochemical H 2 evolution along with the topography using AFM-SECM.

Per- and polyfluoroalkyl substances (PFAS) may interact with peroxisome proliferator activated receptors (PPARs) and alter lipid homeostasis. Using Xenopus laevis , we investigated the effect of PFAS on (a) lipid homeostasis and whether this correlated to changes in body and hepatic condition; (b) the expression of hepatic genes regulated by PPAR; and (c) the hepatic lipidome. We chronically exposed tadpoles to 0.5 µg/L of either PFOS, PFHxS, PFOA, PFHxA, a binary mixture of PFOS and PFHxS (0.5 µg/L of each), or a control, from NF stage 52 through metamorphic climax. Growth, development, and survival were not affected, but we detected a sex-specific decrease in body condition at NF 66 (6.8%) and in hepatic condition (16.6%) across metamorphic climax for male tadpoles exposed to PFOS. We observed weak evidence for the transient downregulation of apolipoprotein-V ( apoa5 ) at NF 62 in tadpoles exposed to PFHxA. Acyl-CoA oxidase 1 ( acox1 ) was downregulated only in males exposed to PFHxS (Ln(Fold Change) = -0.54). We detected PFAS-specific downregulation of structural glycerophospholipids, while semi-quantitative profiling detected the upregulation in numerous glycerophospholipids, sphingomyelins, and diglycerides. Overall, our findings indicate that PFAS can induce sex-specific effects that change across larval development and metamorphosis. We demonstrate that PFAS alter lipid metabolism at environmentally relevant concentrations through divergent mechanisms that may not be related to PPARs, with an absence of effects on body condition, demonstrating the need for more molecular studies to elucidate mechanisms of PFAS-induced lipid dysregulation in amphibians and in other taxa.

The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech's internal experience for a program intended for use in kidney transplantation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) affects more women than men worldwide, however, men comprise the majority of patients who receive kidney replacement therapy. We aimed to describe the perspectives of patients and their caregivers regarding gender disparities in CKD., Methods: Semi-structured interviews were conducted with 45 patients with CKD (20 women) and 14 caregivers (12 women) from seven clinics in Austria. The interviews were analyzed thematically., Results: Five themes were identified in this study. Participants perceived that women were "disadvantaged and vulnerable" (silent and intimidated, single mother predicament, impeded access to care and support due to socioeconomic disadvantage, had to fend for themselves); "fulfilling gender roles and norms" (primarily responsible for childcare, pressure to perform well as homemakers, put others' needs before their own, encouraging husband's treatment adherence), and "protecting their own health" (self-disciplined, vigilant, confronted health challenges, advocated for their needs). Men were seen to "place the onus of care on others" (expected help from family, relied on others for decisions). Both men and women experienced a "disease-related identity crisis and distress" (women: impaired body image, mental distress; men: denial and self-destruction, emasculated by sickness)., Conclusions: Women with CKD felt vulnerable and were inclined to fulfill gender norms and responsibilities as caregivers but were also vigilant about protecting their own health. Men tended to be reluctant to accept CKD and appeared to depend on others for disease management. Better awareness and addressing these concerns can inform strategies to minimize gender disparities in access to care and outcomes in CKD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Filarial lymphedema (LE) remains a significant global problem despite the progress made toward elimination of lymphatic filariasis (LF). In Ghana, the main approach to LF is preventive chemotherapy, but this has minimal impact on individuals who have already developed LE. In 2018-2020, a 24-month randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of stringent hygiene measures using the Essential Package of Care with or without additional administration of doxycycline (DOX) to improve filarial leg LE. This study enrolled 356 participants with LE stages 1-3 from two districts in the Upper East Region of Ghana. In addition to regular training on appropriate care for their affected legs, participants were randomized to receive 6 weeks of either 200 mg/day DOX (n = 117), 100 mg/day DOX (n = 120), or matching placebo (n = 119). Participants were seen every 2 months, with clinical measurements done at 6, 12, 18, and 24 months to assess the status of affected legs. There was a trend toward later appearance of acute attacks after DOX, but surprisingly, DOX showed no effect on LE stage progression. In all groups, leg LE improvement was more common (DOX 200 mg: n = 23 [20%]; DOX 100 mg: n = 23 [19.5%]; placebo: n = 32 [27.4%]) than LE worsening (DOX 200 mg: n = 2 [1.7%]; DOX 100 mg: n = 3 [2.5%]; placebo: n = 2 [1.7%]). Overall, these data show a strong benefit from adherence to a strict hygiene protocol, with some added potential benefit for DOX in preventing acute attacks.

Intimate partner homicides (IPH) are serious offenses by a heterogeneous group of offenders with diverse risk factors that are too unspecific for the successful prediction of an offense. Recent research suggested several warning signs that may precede IPH and enhance its prevention, but little is still known about "leaking." Leaking comprises all offense-related statements, behaviors, or actions that express the perpetrator's thoughts, fantasies, ideas, interests, feelings, intentions, plans, or positive evaluations of an own violent act or previous similar offenses prior to the own attack. This review aims to identify the forms, recipients, and media of leaking as well as potential subgroup differences in cases of IPH. We identified 47 relevant publications via a systematic search of eight databases and additional methods. We included publications that did not explicitly use the term, but described behaviors that could be interpreted as leaking. Up to now, leaking has not been systematically researched in cases of IPH. Nevertheless, publications described several behaviors that are in line with our definition of leaking and were categorized into five broader categories: (a) homicide announcements, (b) previous severe acts of violence, (c) suicidal behavior, (d) planning activities, and (e) interest in similar offenses/offenders. Information on recipients and media as well as subgroup differences was sparse. Leaking is relevant in IPH, but more systematic research is needed to understand its potential role in future risk analyses procedures and prevention of IPH., 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.

Renal sympathetic denervation (RDN) is an interventional supplement to medical treatment in patients with arterial hypertension. While the first sham-controlled trial, SYMPLICITY HTN‑3 was neutral, with improved procedural details, patient selection and follow-up, recent randomized sham-controlled trials of second-generation devices show a consistent blood pressure lowering effect of RDN, as compared to sham controls. These new data and the recent U.S. Food and Drug Administration (FDA) premarket approval of two RDN devices are the basis for the present recommendations update.This joint position paper from the Austrian Society of Hypertension, together with the Austrian Society of Nephrology and the Working Group of Interventional Cardiology from the Austrian Society of Cardiology includes an overview about the available evidence on RDN and gives specific recommendations for the work-up, patient selection, pretreatment, procedural management and follow-up in patients undergoing RDN in Austria. Specifically, RDN may be used in clinical routine care, together with lifestyle measures and antihypertensive drugs, in patients with resistant hypertension (i.e. uncontrolled blood pressure on 3 antihypertensive drugs) and in those with uncontrolled hypertension, after adequate work-up, if institutional, patient-related and procedural conditions are fulfilled., (© 2024. The Author(s).)

Biomethanation represents a promising approach for biomethane production, with biofilm-based processes like trickle bed reactors (TBRs) being among the most efficient solutions. However, maintaining stable performance can be challenging, and both pure and mixed culture approaches have been applied to address this. In this study, inocula enriched with hydrogenotrophic methanogens were introduced to to TBRs as bioaugmentation strategy to assess their impacts on the process performance and microbial community dynamics. Metagenomic analysis revealed a metagenome-assembled genome belonging to the hydrogenotrophic genus Methanobacterium, which became dominant during enrichment and successfully colonized the TBR biofilm after bioaugmentation. The TBRs achieved a biogas production with > 96 % methane. The bioaugmented reactor consumed additional H 2. This may be due to microbial species utilizing CO 2 and H 2 via various CO 2 reduction pathways. Overall, implementing bioaugmentation in TBRs showed potential for establishing targeted species, although challenges remain in managing H 2 consumption and optimizing microbial interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In breast cancer, over one third of all patients harbor a somatic mutation in the PIK3CA gene, encoding the p110α catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) in their tumor cells. Circulating tumor cells (CTCs) are cells shed from the primary tumor into the blood stream. Recently, the long-term stable breast cancer CTC-ITB-01 cell line with tumorigenic and metastatic capacity was established from liquid biopsy derived cells. The oncogenic hotspot PIK3CA mutation H1047R (kinase domain) was detected in the primary tumor, CTCs and metastasis of the same patient. Other PIK3CA mutations located within the C2 domain (E418K and E453K) were detected in the CTCs and the vaginal metastasis but not in the primary tumor. The goal of our study was to functionally characterize the impact of the rare E418K and E453K mutations within the C2 domain that were not detected in the primary tumor., Methods: PIK3CA mutations E418K, E453K, H1047R were generated by site-directed mutagenesis and stably overexpressed in breast cancer cells by lentiviral transduction. Subsequent signaling pathway activation was examined by western blot analysis. The impact of PIK3CA mutations on biological processes was studied by live cell imaging using the Incucyte Zoom system. Structural modeling was conducted in Pymol. The membrane localization of the mutants was evaluated by separating the cytosolic and membrane fraction using ultracentrifugation. Drug susceptibility of CTC-ITB-01 cells was analyzed by live cell imaging., Results: Western blot analysis of human MDA-MB-231, MCF-7 and T47D breast cancer cells stably overexpressing either the PIK3CA wildtype (WT) or one of the E418K, E453K or H1047R mutants revealed a significant increase in AKT phosphorylation in both C2 mutants (E418K and E453K) and the kinase domain mutant H1047R. Functional analysis showed a significantly increased proliferation of MDA-MB-231 cells overexpressing the E453K and H1047R mutants. Migration was increased in all cells overexpressing WT and each of the mutants. Interestingly, invasion and chemotaxis were only enhanced in the MDA-MB-231 cells overexpressing the C2 domain mutants, i.e. E418K and E453K. In addition, membrane localization of the two C2 domain mutants was increased. Structural modeling of the E453K mutation suggests a disruption of the interaction between the negative regulatory domain of the p85α subunit and the p110α catalytic subunit as a potential mechanism leading to the observed activation of PI3K/AKT/mTOR signaling. Dual targeting of AKT/mTOR pathway by MK2206 and RAD001 leads to very strong synergistic effects (IC 50 MK2206: 148 nM, IC 50 RAD001: 15 nM) with respect to proliferation in the CTC-ITB-01 line through apoptosis induction., Conclusions: Our results demonstrate that PIK3CA C2 domain mutations activate PI3K downstream AKT signaling and can increase proliferation, migration and invasion after stable lentiviral transduction. Although both investigated mutations - E418K and E453K - are located within the C2 domain, a different molecular mechanism can be proposed. The PIK3CA mutated CTC-ITB-01 shows a high susceptibility against dual inhibition of AKT/mTOR. Further studies are required to fully elucidate the oncogenic potential of rare PIK3CA mutations., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pathogenic variants in the leucine zipper-like transcriptional regulator 1 gene ( LZTR1 ) have been identified in schwannomatosis and Noonan syndrome. Here, we expand the phenotype spectrum of LZTR1 variants. We identified four loss-of-function heterozygous LZTR1 variants in five children with multiple café au lait macules and one adult with multiple café au lait macules and axillar freckling, by applying gene panel analysis in four families. The three LZTR1 variants, namely, c.184del/p.Glu62Ser fs *39, c.1927C < T/p.Gln643*, and c.857&#95;858delinsT/p.Gly286Val fs *65, were novel, whereas the variant c.1018C > T/ p.Arg340* had been previously reported in a patient with schwannomatosis. Similar to what is known from other LZTR1 -associated conditions, penetrance of the skin manifestations was reduced in two carriers of the familial variants. Our study expands the LZTR1 phenotype to the presence of isolated café au lait macules with or without freckling. Thus, variants in the LZTR1 gene should be considered in patients with multiple café au lait macules., 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 Horn, Neuhann, Hennig, Abad-Perez, Prott, Cardellini, Potratz, Leubner, Eichhorn, Merkel, Abicht and Kaindl.)

Lymphedema, hydrocele, and acute adenolymphangitis (ADL) are chronically disabling consequences in patients with lymphatic filariasis (LF). Provision of morbidity management and disability prevention and concurrent mass drug administration of anthelmintics are two pillars for elimination of LF. This study assessed the impact of strict hygiene protocols with or without doxycycline on the progression of filarial lymphedema. A randomized, placebo-controlled, double-blind trial was conducted in two regions in Tanzania. We enrolled 362 participants with lymphedema stages 1-3 assigned into three treatment groups of doxycycline 200 mg once daily, doxycycline 100 mg once daily, or matching placebo for 42 days in addition to hygiene measures. The participants were followed every 2 months for 2 years. Twenty-four months after treatment onset, 17.7% of participants displayed improved limb conditions, including 15/104 (14.4%) in the doxycycline 200 mg group, 16/105 (15.2%) in the doxycycline 100 mg group, and 25/107 (23.4%) in the placebo group. During the first 6 months after treatment, the number of participants experiencing an ADL attack was significantly lower in the doxycycline groups than in the placebo group. The study also found that hygiene was one of the factors associated with preventing the occurrence of acute attacks over the whole study period. Doxycycline 100 mg was a significant factor for the halt of progression (odds ratio: 0.53, P = 0.0239) when both legs if affected at baseline were considered. These findings emphasize the importance of practicing hygiene in reducing the occurrence of ADL attacks and the benefits of doxycycline with regards to acute attacks and halt of progression.

Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 cis -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these cis - and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies., Competing Interests: Disclosures J.B.M is an academic associate for Quest Diagnostics Inc. Endocrine R&D. MIMcC is now an employee of Genentech and a holder of Roche stock.

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection., (© 2024. The Author(s).)

Phosphorescence-based oxygen-sensing hydrogels are a promising platform technology for an upcoming generation of insertable biosensors that are smaller, softer, and potentially more biocompatible than earlier designs. However, much remains unknown about their long-term performance and biocompatibility in vivo . In this paper, we design and evaluate a range of hydrogel sensors that contain oxygen-sensitive phosphors stabilized by micro- and nanocarrier systems. These devices demonstrated consistently good performance and biocompatibility in young adult rats for over three months. This study thoroughly establishes the biocompatibility and long-term suitability of phosphorescence lifetime sensors in vivo , providing the groundwork for expansion of this platform technology into a family of small, unobtrusive biosensors for a range of clinically relevant metabolites.

Background: Duchenne muscular dystrophy (DMD) is a severe monogenic hereditary disease with early manifestation and a progressive course. Treatment options have so far been limited. Gene therapy opens up new options for DMD patients., Objectives: Against the background of a further death following DMD gene therapy, the side effects and risks of the gene therapeutics already approved or undergoing clinical trials will be evaluated and alternative gene therapeutics will be described. Based thereon, the future of DMD gene therapy will be discussed., Current Data: For the first time, in June 2023, delandistrogene moxeparvovec (SRP-9001), a gene replacement therapy based on an adeno-associated virus (AAV) vector, was approved in the USA for children aged 4-5 years with DMD. Other promising gene therapies are in preclinical development or clinical trials, including CRISPR/Cas9-mediated strategies to restore dystrophin expression. Two deaths following DMD gene therapy with high-dose AAV vectors were attributed to AAV-mediated immune responses. The pre-existing disease underlying the therapy is most likely involved in the fatal AAV toxicity., Conclusions: Although gene therapy applications of AAV vectors are generally considered safe, the systemic administration of high vector doses can lead to severe side effects with a potentially fatal outcome in individual patients, especially after activation of the immune system. In the future, new methods for immunosuppression, reduction of AAV dose and alternative vectors will therefore increasingly come to the fore., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

There is a rapid spread of antibiotic resistance in the environment. However, the impact of antibiotic resistance in drinking water is relatively underexplored. Thus, this study aimed to quantify antibiotic resistance genes (ARGs) and antibiotic residues in two drinking water production facilities (NW-E and NW-C) in North West Province, South Africa and link these parameters to bacterial communities. Physicochemical and ARG levels were determined using standard procedures. Residues (antibiotics and fluconazole) and ARGs were quantified using ultra-high performance liquid chromatography (UHPLC) chemical analysis and real-time PCR, respectively. Bacterial community compositions were determined by high-throughput 16S rRNA sequencing. Data were analysed using redundancy analysis and pairwise correlation. Although some physicochemical levels were higher in treated than in raw water, drinking water in NW-E and NW-C was safe for human consumption using the South African Water Quality Guideline (SAWQG). ARGs were detected in raw and treated water. In NW-E, the concentrations of ARGs (sul1, intl1, EBC, FOX, ACC and DHA) were higher in treated water than in raw water. Regarding antimicrobial agents, antibiotic and fluconazole concentrations were higher in raw than in treated water. However, in NW-C, trimethoprim concentrations were higher in raw than in treated water. Redundancy analysis showed that bacterial communities were not significantly correlated (Monte Carlo simulations, p-value >0.05) with environmental factors. However, pairwise correlation showed significant differences (p-value <0.05) for Armatimonas, CL500-29 marine group, Clade III, Dickeya and Zymomonas genera with environmental factors. The presence of ARGs and antibiotic residues in the current study indicated that antibiotic resistance is not only a clinical phenomenon but also in environmental settings, particularly in drinking water niches. Consumption of NW-E and NW-C treated water may facilitate the spread of antibiotic resistance among consumers. Thus, regulating and monitoring ARGs and antibiotic residues in drinking water production facilities should be regarded as paramount., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tsholo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The novelty-seeking model (NSM) does not offer a compelling unifying framework for understanding creativity and curiosity. It fails to explain important manifestations and features of curiosity. Moreover, the arguments offered to support a curiosity-creativity link - a shared association with a common core process and various superficial associations between them - are neither convincing nor do they yield useful predictions.

Although Eucalyptus is widely planted outside its native range for timber and pulp production, the effects of these exotic plantations on biodiversity relative to native semi-natural forests or plantations of native tree species remain incompletely understood. Here, we compare the diversity of saproxylic beetles (Coleoptera) and true bugs (Hemiptera) between non-native Eucalyptus benthamii Maiden and Cambage (Camden white gum) and native Pinus taeda L. (loblolly pine) stands on the upper Coastal Plain of South Carolina, U.S.A. We sampled insects emerging from logs of both species placed in both stand types after 1, 2, 6, and 12 months in the field. Beetle and true bug richness and diversity were both significantly lower from eucalypt than from pine wood. Moreover, the two communities were compositionally distinct. Whereas pine supported many species of host-specific phloeoxylophagous beetles, most species collected from eucalypts were mycophagous or predatory taxa capable of utilizing a wide range of hosts. Species richness did not differ between logs placed in eucalypt vs. pine stands but Shannon's diversity was significantly higher in the eucalypt stands, possibly due to greater sun exposure in the latter. Contrary to a previous study, we found no support for the idea that eucalypt litter reduces the diversity of saproxylic insects. Our findings add to the growing body of evidence that non-native plantations are less favorable to biodiversity than those consisting of native tree species., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org)., Methods: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023., Results: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAF V600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date., Conclusion: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gael Roth declares consulting or advisory role or invitation as a speaker for Servier, AstraZeneca, Bristol-Myers Squibb, MSD, Amgen, Ipsen, Accord Healthcare, Pierre Fabre, Incyte, Netris Pharma and Alpha Tau, as well as travel accommodations, or expenses from Servier, AstraZeneca, Bristol Myers Squibb, MSD, Roche, Amgen, Viatris, Pierre Fabre and Ipsen. Research funding by Genoscience Pharma, Netris Pharma. Matthieu Sarabi declares consultancy/honoraria AstraZeneca, Servier, Roche and accommodations or expenses from Ipsen. Jean-Frédéric Blanc declares honoraria from incyte, servier, AZ, Roche, Tahio oncology, MSD. Anne-Laure Bretagne-Bignon declares consulting for Astra Zeneca, Servier, Ipsen and accommodations or congress registration support for Merck and Ipsen. Romain Coriat declares honoraria for lectures and Advisory board for: BAYER, Servier, Pierre Fabre, AAA, Merck, Amgen. Christelle de la Fouchardière declares holding an advisory role with Amgen, Bayer, BMS, Daichi-Sankyo, Eisai, Imescia, Incyte, Lilly, Merck, MSD, Pierre Fabre Oncologie, Roche, and Servier; receiving grants from Pierre Fabre and Servier outside of the submitted work; receiving fees from Ipsen, Eisai, Pierre Fabre, Servier, being an invited speaker outside of the submitted work. Julien Edeline declares consulting or advisory role for BTG, Bristol Myers Squibb, AstraZeneca, Bayer, Ipsen, AstraZeneca, MSD, Eisai, Boston Scientific, Roche, Basilea, Merck Serono, Servier; research Funding from Bristol Myers Squibb (Inst), BeiGene (Inst); travel, accommodations or expenses from Amgen, Bristol Myers Squibb, Roche. Astrid Lièvre declares honoraria for lectures from Amgen, Astellas, Astra-Zeneca, Bayer, BMS, Incyte, Ipsen, Leo-pharma, Mylan, Novartis, Pierre Fabre, Roche, Servier and Viatris; consulting/advisory relationship from AAA, Astellas, Bayer, BMS, Incyte, Pierre Fabre and Servier; travel, accommodations or congress registration support from Bayer, Boehringer, Ipsen, Mylan, MSD, Pierre Fabre, Roche and Servier; research funding from Bayer (Inst), Lilly (Inst). Sylvain Manfredi declares travel accommodation from MSD, AMGEN. Cindy Neuzillet declares Honoraria and consulting from Amgen, AstraZeneca, Baxter, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, Mundipharma, Novartis, Nutricia, OSE Immunotherapeutics, Pierre Fabre, Roche, Sanofi, Servier, Viatris, as well as research funding AstraZeneca, Bristol-Myers Squibb, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, Viatris. Valérie Paradis declares honoraria for lectures from Incyte. Anthony Turpin declares personal fees from Servier, Viatris, Incyte Bioscience, BMS, Merck and grants and personal fees from AstraZeneca and MSD. Olivier Bouché declares consulting or advisory role for Pierre Fabre, Amgen, Bayer, Servier, MSD, Deciphera, Apmonia Therapeutics and Merck outside the submitted work. David Malka declares honoraria for Roche, Amgen, Bayer, Merck Serono, Servier, Sanofi, Pierre Fabre, Viatris, Bristol Myers Squibb, MSD Oncology, LEO Pharma, Incyte, AstraZeneca; consulting or advisory role: Roche, Sanofi, Merck Serono, MSD, Servier, Bayer, Incyte, Amgen, Bristol Myers Squib, Taiho Oncology, AbbVie, AstraZeneca, Pierre Fabre; travel, accommodations or expenses from Roche, Bayer, Sanofi, Merck Serono, Amgen, Servier, Pierre Fabre, Bristol Myers Squibb/Pfizer, MSD, Viatris. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The medical development in the previous 15 years and the changes in treatment reality of the comprehensive elective treatment of abdominal aortic aneurysms necessitate a re-evaluation of the quality assurance guidelines of the Federal Joint Committee in Germany (QBAA-RL). In the current version this requires a specialist further training quota for nursing personnel in intensive care wards of 50%. The quota was determined in 2008 based on expert opinions, although a direct empirical evidence base for this does not exist., Methods: Representatives from the fields of patient representation, physicians, nursing personnel and other relevant interface areas were invited to participate in a modified Delphi procedure. Following a comprehensive narrative literature search, a survey and focus group discussions with national and international experts, a total of three anonymized online-based voting rounds were carried out for which previously determined key statements were assessed with a 4‑point Likert scale (totally disagree up to totally agree). In addition, the expert panel had also defined a recommendation for a minimum quota for the specialist training of nursing personnel on intensive care wards in the treatment of abdominal aortic aneurysms, whereby an a priori agreement of 80% of the participants was defined as the consensus limit., Results: Overall, 37 experts participated in the discussions and three successive voting rounds (participation rate 89%). The panel confirmed the necessity of a re-evaluation of the guideline recommendations and recommended the introduction of a shift-related minimum quota of 30% of the full-time equivalent of nursing personnel on intensive care wards and the introduction of structured promotional programs for long-term elevation of the quota., Conclusion: In this national Delphi procedure with medical and nursing experts as well as representatives of patients, the fundamental benefits and needs of professional specialist qualifications in the field of intensive care medicine were confirmed. The corresponding minimum quota for specialist further training of intensive care nursing personnel should generally apply without limitations to specific groups. The expert panel stipulates a shift-related minimum quota for intensive care nursing personnel with specialist training of 30% of the nursing personnel on intensive care wards and the obligatory introduction of structured and transparent promotion programs for the long-term enhancement., (© 2024. The Author(s).)

Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence. Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity. G protein-coupled receptors (GPCRs) are among the main modulators of metabolism and energy balance. They, for instance, regulate appetite and satiety in certain hypothalamic neurons, as well as glucose and lipid metabolism and hormone secretion from adipocytes. Mutations in some GPCRs, such as the melanocortin receptor type 4 (MC4R), have been associated with early-onset obesity. Here, we identified the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) as a member of the regulating network governing food intake and the maintenance of energy balance. Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity, accompanied by dysregulation of glucose homeostasis. Consistently, we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity. Therefore, we propose that LPHN1 dysfunction is a risk factor for obesity development., (© 2024. The Author(s).)

Escalating wildfire frequency and severity, exacerbated by shifting climate patterns, pose significant ecological and economic challenges. Prescribed burns, a common forest management tool, aim to mitigate wildfire risks and protect biodiversity. Nevertheless, understanding the impact of prescribed burns on soil and microbial communities in temperate mixed forests, considering temporal dynamics and slash fuel types, remains crucial. Our study, conducted at the University of Tennessee Forest Resources AgResearch and Education Center in Oak Ridge, TN, employed controlled burns across various treatments, and the findings indicate that low-intensity prescribed burns have none or minimal short-term effects on soil parameters but may alter soil nutrient concentrations, as evidenced by significant changes in porewater acetate, formate, and nitrate concentrations. These burns also induce shifts in microbial community structure and diversity, with Proteobacteria and Acidobacteria increasing significantly post-fire, possibly aiding soil recovery. In contrast, Verrucomicrobia showed a notable decrease over time, and other specific microbial taxa correlated with soil pH, porewater nitrate, ammonium , and phosphate concentrations. Our research contributes to understanding the intricate relationships between prescribed fire, soil dynamics, and microbial responses in temperate mixed forests in the Southern Appalachian Region, which is valuable for informed land management practices in the face of evolving environmental challenges., 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 Rafie, Blentlinger, Putt, Williams, Joyner, Campa, Schubert, Hoyt, Horn, Franklin and Hazen.)

Alternative splicing and multiple transcription start and termination sites can produce a diverse repertoire of mRNA transcript variants from a given gene. While the full picture of the human transcriptome is still incomplete, publicly available RNA datasets have enabled the assembly of transcripts. Using publicly available deep sequencing data from 927 human samples across 48 tissues, we quantified known and new transcript variants, provide an interactive, browser-based application Splice-O-Mat and demonstrate its relevance using adhesion G protein-coupled receptors (aGPCRs) as an example. On average, 24 different transcript variants were detected for each of the 33 human aGPCR genes, and several dominant transcript variants were not yet annotated. Variable transcription starts and complex exon-intron structures encode a flexible protein domain architecture of the N- and C termini and the seven-transmembrane helix domain (7TMD). Notably, we discovered the first GPCR (ADGRG7/GPR128) with eight transmembrane helices. Both the N- and C terminus of this aGPCR were intracellularly oriented, anchoring the N terminus in the plasma membrane. Moreover, the assessment of tissue-specific transcript variants, also for other gene classes, in our application may change the evaluation of disease-causing mutations, as their position in different transcript variants may explain tissue-specific phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Marine organisms are currently, and will continue to be, exposed to the simultaneous effects of multiple environmental changes. Plankton organisms form the base of pelagic marine food webs and are particularly sensitive to ecosystem changes. Thus, warming, acidification, and changes in dissolved nutrient concentrations have the potential to alter these assemblages, with consequences for the entire ecosystem. Despite the growing number of studies addressing the potential influence of multiple drivers on plankton, global change may also cause less obvious alterations to the networks of interactions among species. Using inverse analyses applied to data collected during a mesocosm experiment, we aimed to compare the ecological functioning of coastal plankton assemblages and the interactions within their food web under different global change scenarios. The experimental treatments were based on the RCP 6.0 and 8.5 scenarios developed by the IPCC, which were extended (ERCP) to integrate the future predicted changes in coastal water nutrient concentrations. Overall, we identified that the functioning of the plankton food web was rather similar in the Ambient and ERCP 6.0 scenarios, but substantially altered in the ERCP 8.5 scenario. Using food web modelling and ecological network analysis, we identified that global change strengthens the microbial loop, with a decrease of energy transfer efficiency to higher trophic levels. Microzooplankton responded as well by an increased degree of herbivory in their diet and represented, compared to mesozooplankton, by far the main top-down pressure on primary producers. We also observed that the organisation of the food web and its capacity to recycle carbon was higher under the ERCP 8.5 scenario, but flow diversity and carbon path length were significantly reduced, illustrating an increased food web stability at the expense of diversity. Here, we provide evidence that if global change goes beyond the ERCP 6.0 scenario, coastal ecosystem functioning will be subjected to dramatic changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Erectile function preservation is an important quality of life factor in patients treated for prostate cancer. A dose-optimization approach on sexual structures was developed and evaluated to limit erectile dysfunction after radiotherapy., Materials and Methods: Twenty-three men with localized prostate cancer and no erectile dysfunction were enrolled in the study. All patients received a prescription dose between 76 and 78Gy. Computed tomography/magnetic resonance image registration was used to delineate the prostatic volume and the sexual structures: internal pudendal arteries (IPA), penile bulb and corpus cavernosum. Erectile function was evaluated using the 5-items International Index of Erectile Function (IIEF-5) score every 6 months during the 2 years after radiotherapy and once a year afterwards. No erectile dysfunction, mild erectile dysfunction and severe erectile dysfunction were defined if the IIEF-5 scores were 20-25, 17-19 and < 17, respectively., Results: The mean follow-up was 4.5 years. The mean age of the patients was 66.3 years. At 2 years, 67% of the patients had no erectile dysfunction, 11% had mild erectile dysfunction and 22% had severe erectile dysfunction. No significant difference was found between the patients with and without erectile dysfunction (IIEF-5≥20 and IIEF-5<20, respectively) for any of the parameters: dosimetric values (internal pudendal arteries, penile bulb, corpus cavernosum), age, comorbidity and smoking status. The biochemical-relapse free survival was 100% at 2 years., Conclusion: This approach with dose-optimization on sexual structures for localized prostate cancer found excellent results on erectile function preservation after radiotherapy, with 78% of the patients with no or mild erectile dysfunction at 2 years., (Copyright © 2024. Published by Elsevier Masson SAS.)

The extracellular matrix (ECM) is a network of macromolecules that presents a vital scaffold for cells and enables multiple ways of cellular communication. Thus, it is essential for many physiological processes such as development, tissue morphogenesis, homeostasis, the shape and partially the size of the body and its organs. To ensure these, the composition of the ECM is tissue-specific and highly dynamic. ECM homeostasis is therefore tightly controlled by several mechanisms. Here, we show that FMI-1, the homolog of the Adhesion GPCR Flamingo/CELSR/ADGRC in the nematode Caenorhabditis elegans, modulates the composition of the ECM by controlling the production both of ECM molecules such as collagens and also of ECM modifying enzymes. Thereby, FMI-1 affects the morphology and functionality of the nematode´s cuticle, which is mainly composed of ECM, and also modulates the body size. Mechanistic analyses highlight the fact that FMI-1 exerts its function from neurons non-cell autonomously (trans) solely via its extracellular N terminus. Our data support a model, by which the activity of the receptor, which has a well-described role in the planar cell polarity (PCP) pathway, involves the PCP molecule VANG-1, but seems to be independent of the DBL-1/BMP pathway., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

This study addressed the critical gap in research on the academic English vocabulary knowledge of deaf and hard-of-hearing (DHH) students at the college level, with a specific focus on academic English verbs. An English vocabulary test was developed to assess knowledge of academic verbs at three distinct corpus-defined lexical frequency ranges. The test was administered to the DHH students along with two comparison groups of college peers-students of English as an Additional Language (EAL)1 and hearing native-English-speaking students. Results revealed near-ceiling performance by hearing native speakers but significant vocabulary challenges in the DHH and EAL learner groups, who exhibited parallel lexical knowledge. Learner group performance increased as verb frequency range increased and as overall English proficiency level increased. The findings demonstrate that lexical frequency effects guide English verb acquisition in the targeted populations.2., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Instrumental behavior can reflect the influence of goal-directed and habitual systems. Contemporary research suggests that stress may facilitate control by the habitual system under conditions where the behavior would otherwise reflect control by the goal-directed system. However, it is unclear how stress modulates the influence of these systems on instrumental responding to achieve this effect, particularly in females. Here, we examine whether a mild psychogenic stressor experienced before acquisition training (Experiment 1), or prior to the test of expression (Experiment 2) would influence goal-directed and habitual control of instrumental responding in female rats. In both experiments, rats acquired an instrumental nose-poke response for a sucrose reward. This was followed by a reinforcer devaluation phase in which half the rats in Stressed and Non-Stressed conditions received pairings of the sucrose pellet with illness induced by lithium chloride until they rejected the pellet when offered. The remaining rats received a control treatment consisting of pellets and illness on separate days (Unpaired). Control by goal-directed and habitual systems was evaluated in a subsequent nonreinforced test of nose poking. The results of Experiment 1 indicated that the Non-Stressed Paired group reduced nose-poking compared to the Unpaired controls, identifying the response as goal directed, whereas the Stressed Paired and Unpaired groups made a similar number of nose pokes identifying the response as habitual despite a similar amount of training. Results from Experiment 2 indicated habitual control of nose-poke responding was present when stress was experienced just prior to the test. Collectively, these data suggest that stress may facilitate habitual control by altering the relative influence of goal-directed and habitual processes underpinning instrumental behavior. These results may be clinically relevant for understanding the contributions of stress to dysregulated instrumental behavior in compulsive pathologies., (Copyright © 2024. Published by Elsevier Inc.)

Exposure to xenobiotics can increase the production of reactive oxygen species (ROS). When detoxification organs such as the intestines and liver cannot neutralise these xenobiotics, it can induce oxidative stress and cause damage to tissues. Therefore, cell-based bioassays that indicate intracellular ROS production are a useful screening tool to evaluate the effect of these chemicals. Although flow cytometry is commonly used to measure ROS in cells, many research laboratories in the Global South do not always have access to such specialised instrumentation. Therefore, we describe a sensitive but low-cost method that can easily be used to determine ROS production in vitro . This method employs the fluorogenic dye, 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCF-DA), which emits fluorescence after being oxidised to a fluorescent derivative. Since the H 2 DCF-DA bioassay indicates non-specific ROS production it can be used as a marker of overall oxidative stress. This method was validated by exposing human duodenum epithelial adenocarcinoma (HuTu-80) and rat liver epithelial hepatoma (H4IIE- luc ) cells to agricultural soil samples.•Production of ROS can be determined in vitro in intestinal and liver cells.•This method is inexpensive and can be easily performed in standard laboratories.•The method provides a tool for the high-throughput screening of environmental samples., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The Erythropoietin-producing hepatocellular receptor tyrosine kinase member EphB6 is a pseudokinase which has not attracted an equivalent amount of interest as its enzymatically-active counterparts. The aim of this study was to assess the expression of EphB6 in pituitary tumors., Methods and Results: Human normal pituitaries and pituitary tumors were examined for EphB6 mRNA expression using real-time PCR and for EphB6 protein by immunohistochemistry and Western blotting. EphB6 was highly expressed in non-functioning pituitary neuroendocrine tumors (NF-PitNETs) versus the normal pituitary and GH-secreting PitNETs. EphB6 mRNA expression was correlated with tumor size., Conclusions: Our results suggest EphB6 aberrant expression in NF-PitNETs. Future studies are warranted to determine the role and significance of EphB6 in NF-PitNETs tumorigenesis., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is related to risk factors such as viral hepatitis, alcohol intake, and non-alcoholic fatty liver disease (NAFLD). The constitutive activation of the PI3K/AKT signaling pathway is common in HCC and has essential involvement in tumor progression. The serine/threonine kinase AKT has several downstream substrates, which have been implicated in the regulation of cellular metabolism. However, the contribution of each of the three AKT isoforms, i.e., AKT1, AKT2 and AKT3, to HCC metabolism has not been comprehensively investigated. In this study, we analyzed the functional role of AKT1, AKT2 and AKT3 in HCC metabolism. The overexpression of activated AKT1, AKT2 and AKT3 isoforms in the human HCC cell lines Hep3B and Huh7 resulted in higher oxygen consumption rate (OCR), ATP production, maximal respiration and spare respiratory capacity in comparison to vector-transduced cells. Vice versa, lentiviral vector-mediated knockdowns of each AKT isoform reduced OCR in both cell lines. Reduced OCR rates observed in the three AKT isoform knockdowns were associated with reduced extracellular acidification rates (ECAR) and reduced lactate production in both analyzed cell lines. Mechanistically, the downregulation of OCR by AKT isoform knockdowns correlated with an increased phosphorylation of the pyruvate dehydrogenase on Ser232, which negatively regulates the activity of this crucial gatekeeper of mitochondrial respiration. In summary, our data indicate that each of the three AKT isoforms is able to upregulate OCR, ECAR and lactate production independently of each other in human HCC cells through the regulation of the pyruvate dehydrogenase.

Introduction: Tissue Na + overload is present in patients receiving hemodialysis (HD) and is associated with cardiovascular mortality. Strategies to actively modify tissue Na + amount in these patients by adjusting the HD regimen have not been evaluated., Methods: In several substudies, including cross-sectional analyses ( n  = 75 patients on HD), a cohort study and a cross-over interventional study ( n  = 10 patients each), we assessed the impact of ultrafiltration (UF) volume, prolongation of dialysis treatment time, and modification of dialysate Na + concentration on tissue Na + content using 23 Na magnetic resonance imaging ( 23 Na-MRI)., Results: In the cross-sectional analysis of our patients on HD, differences in dialysate sodium concentration ([Na + ]) were associated with changes in tissue Na + content, whereas neither UF volume nor HD treatment time affected tissue Na + amount. Skin Na + content was lower in 17 patients on HD, with dialysate [Na + ] of <138 mmol/l compared to 58 patients dialyzing at ≥138 mmol/l (20.7 ± 7.3 vs. 26.0 ± 8.8 arbitrary units [a.u.], P  < 0.05). In the cohort study, intraindividual prolongation of HD treatment time was not associated with a reduction in tissue Na + content. Corresponding to the observational data, intraindividual modification of dialysate [Na + ] from 138 to 142 to 135 mmol/l resulted in concordant changes in skin Na + (24.3 ± 7.6 vs. 26.3 ± 8.0 vs. 20.8 ± 5.6 a.u, P  < 0.05 each), whereas no significant change in muscle Na + occurred., Conclusion: Solely adjustment of dialysate [Na + ] had a reproducible impact on tissue Na + content. 23 Na-MRI could be utilized to monitor the effectiveness of dialysate [Na + ] modifications in randomized-controlled outcome trials., (© 2024 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Background: Vaccines are essential in disease prevention among patients on chronic hemodialysis (HD). However, during the coronavirus disease 2019 pandemic, there has been an increased rate of vaccination hesitancy. A better understanding of patients' opinions may help identify a more targeted approach to increase vaccination rates., Materials and Methods: Questionnaires with 43 questions based on the recommendations of the Strategic Advisory Group of Experts (SAGE) on Immunization Working Group on Vaccine Hesitancy were administered to patients during routine HD sessions at different dialysis centers in Austria., Results: In total, 347 patients participated in this study. Approximately 81% of the patients were aged > 54 years, and 65% were men. Further, 53% of patients were receiving HD from private units. In ~ 72% of patients, the dialysis physicians were the source of vaccination information. Meanwhile, the source of information in 28% of patients was the primary care physician (28%), and 18% of patients obtained vaccination details from the internet. The number of younger (aged < 55 years) patients who were more likely to use online content as the main source of information was significantly higher than that of older patients (32 vs. 15%, p = 0.001). Furthermore, the number of older patients who wanted to receive more information from the dialysis physician was significantly higher than that of younger patients (57 vs. 38%, p = 0.009). Only 65% of patients had a good understanding of the mechanisms of action of vaccines. The younger population (aged 18 - 54 years) had a higher number of individuals with a good understanding of vaccine mechanisms than the older population (78 vs. 62%, p = 0.016). Moreover, 86% of the whole population wanted to complete the recommended vaccinations. However, only 39% of respondents had sufficient information about the vaccination plan in Austrian., Conclusion: Numerous patients receiving HD wanted to obtain more information from their dialysis physicians. Increased awareness among providers and targeted communication might increase vaccination rates.

Goal and Aims: To pilot the feasibility and evaluate the performance of an EEG wearable for measuring sleep in individuals with Parkinson's disease., Focus Technology: Dreem Headband, Version 2., Reference Technology: Polysomnography., Sample: Ten individuals with Parkinson's disease., Design: Individuals wore Dreem Headband during a single night of polysomnography., Core Analytics: Comparison of summary metrics, bias, and epoch-by-epoch analysis., Additional Analytics and Exploratory Analyses: Correlation of summary metrics with demographic and Parkinson's disease characteristics., Core Outcomes: Summary statistics showed Dreem Headband overestimated several sleep metrics, including total sleep, efficiency, deep sleep, and rapid eye movement sleep, with an exception in light sleep. Epoch-by-epoch analysis showed greater specificity than sensitivity, with adequate accuracy across sleep stages (0.55-0.82)., Important Supplemental Outcomes: Greater Parkinson's disease duration and rapid eye movement behavior were associated with more wakefulness, and worse Parkinson's disease motor symptoms were associated with less deep sleep., Core Conclusion: The Dreem Headband performs similarly in Parkinson's disease as it did in non-Parkinson's disease samples and shows promise for improving access to sleep assessment in people with Parkinson's disease., Competing Interests: Declaration of conflicts of interest Dr. Gonzales reports grants from the Alzheimer’s Association Part the Cloud Gates, the Alzheimer’s Drug Discovery Foundation, the Texas Alzheimer’s Research and Care Consortium, Institutional Pilot Awards, and the National Institutes of Health, as well as personal stock in Abbie. Ms. Pollet and her spouse are employed by and receive income from Academy Diagnostics Sleep and EEG Center. Dr. Seshadri has consulted for Eisai and Biogen outside of the current work. Ms. Wang, Mr. Verlarde, Dr. Horn, Dr. Coss, Dr. Vaou, Dr. Wang, Dr. Li, Dr. Miao, and Dr. Gonzalez report no conflicts., (Copyright © 2023 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

A better understanding of age-related differences in judgment and decision making is important from both theoretical and applied perspectives. In this review, we focus on value-based decisions across adulthood and specifically on how loss aversion (a relatively stronger weight of losses than gains on decisions) and the relative motivational impact of gains and losses may change with aging. In doing so, we will also cover recent findings about the effects of gain or loss incentives on performance in cognitive tasks that involve attention, learning, and remembering. We point out open questions and critical moderating variables for future theorizing and research., 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 Author. Published by Elsevier Ltd.. All rights reserved.)

Hormonal contraceptives are utilized by millions of women worldwide. However, it remains unclear if these powerful endocrine modulators may alter cognitive function. Habit formation involves the progression of instrumental learning as it goes from being a conscious goal-directed process to a cue-driven automatic habitual motor response. Dysregulated goal and/or habit is implicated in numerous psychopathologies, underscoring the relevance of examining the effect of hormonal contraceptives on goal-directed and habitual behavior. This study examined the effect of levonorgestrel (LNG), a widely used progestin-type contraceptive, on the development of habit in intact female rats. Rats were implanted with subcutaneous capsules that slowly released LNG over the course of the experiment or cholesterol-filled capsules. All female rats underwent operant training followed by reward devaluation to test for habit. One group of females was trained at a level that is sub-threshold to habit, while another group of females was trained to a level well over the habit threshold observed in intact females. The results reveal that all sub-threshold trained rats remained goal-directed irrespective of LGN treatment, suggesting LNG is not advancing habit formation in female rats at this level of reinforcement. However, in rats that were overtrained well above the threshold, cholesterol females showed habitual behavior, thus replicating a portion of our original studies. In contrast, LNG-treated habit-trained rats remained goal-directed, indicating that LNG impedes the development and/or expression of habit following this level of supra-threshold to habit training. Thus, LNG may offset habit formation by sustaining attentional or motivational processes during learning in intact female rats. These results may be clinically relevant to women using this type of hormonal contraceptive as well as in other progestin-based hormone therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Time-based prospective memory (TBPM) involves remembering to perform actions at specific times in the future. Several studies suggest that monetary consequences improve prospective remembering; however, the effect of monetary consequences on strategic time monitoring (i.e., clock-checking behaviour) in TBPM is still unknown. The present study investigated how the monetary costs on clock-checking affected TBPM accuracy and strategic time monitoring. Participants performed an ongoing lexical decision task while carrying out a TBPM task every two minutes. Motivational incentives were manipulated across three experimental conditions: a single-cost condition in which missed TBPM responses led to monetary deductions, a double-cost condition in which both missed responses and time monitoring led to monetary deductions, and a control condition with no monetary deductions. Overall, the findings indicated that monetary costs on clock-checking prompted more parsimonious strategic time monitoring behaviour, which negatively impacted TBPM accuracy. These results emphasize the importance of weighing the motivational aspects involved in strategic monitoring, shedding light on the complex relationship between clock-checking behaviour, its consequences, and TBPM performance., (© 2024. The Author(s).)

Background: CAR-T cell therapy has shown impressive results and is now part of standard-of-care treatment of B-lineage malignancies, whereas the treatment of myeloid diseases has been limited by the lack of suitable targets. CD45 is expressed on almost all types of blood cells including myeloid leukemia cells, but not on non-hematopoietic tissue, making it a potential target for CAR-directed therapy. Because of its high expression on T and NK cells, fratricide is expected to hinder CD45CAR-mediated therapy. Due to its important roles in effector cell activation, signal transduction and cytotoxicity, CD45 knockout aimed at preventing fratricide in T and NK cells has been expected to lead to considerable functional impairment., Methods: CD45 knockout was established on T and NK cell lines using CRISPR/Cas9-RNPs and electroporation, and the successful protocol was transferred to primary T cells. A combined protocol was developed enabling CD45 knockout and retroviral transduction with a third-generation CAR targeting CD45 or CD19. The functionality of CD45 ko effector cells, CD45 ko /CD45CAR-T and CD45 ko /CD19CAR-T cells was studied using proliferation as well as short- and long-term cytotoxicity assays., Results: As expected, the introduction of a CD45-CAR into T cells resulted in potent fratricide that can be avoided by CD45 knockout. Unexpectedly, the latter had no negative impact on T- and NK-cell proliferation in vitro. Moreover, CD45 ko /CD45CAR-T cells showed potent cytotoxicity against CD45-expressing AML and lymphoma cell lines in short-term and long-term co-culture assays. A pronounced cytotoxicity of CD45 ko /CD45CAR-T cells was maintained even after four weeks of culture. In a further setup, we confirmed the conserved functionality of CD45 ko cells using a CD19-CAR. Again, the proliferation and cytotoxicity of CD45 ko /CD19CAR-T cells showed no differences from those of their CD45-positive counterparts in vitro., Conclusions: We report the efficient production of highly and durably active CD45 ko /CAR-T cells. CD45 knockout did not impair the functionality of CAR-T cells in vitro, irrespective of the target antigen. If their activity can be confirmed in vivo, CD45 ko /CD45CAR-T cells might, for example, be useful as part of conditioning regimens prior to stem cell transplantation.

Introduction: Chronic kidney disease (CKD) in stages 3-5 without albuminuria occurs more often in women than in men; however, most patients initiating and receiving kidney replacement therapy are men. Sex-determined biological factors and gender-related aspects both likely account for this discrepancy. Patient opinions on gender-related discrepancies in kidney care have not been investigated., Methods: Building upon the findings of semi-structured interviews previously conducted with CKD patients and their caregivers, two questionnaires were developed to investigate patient behavior and opinions relating to gender and CKD. These questionnaires containing 39 items were distributed to eight outpatient clinics in Austria. Responses were descriptively analyzed and compared between genders, as well as between age-groups and CKD stages., Results: Questionnaires from 783 patients and 98 caregivers were included in the analysis and covered health awareness and self-management of disease, the impact of gender roles and gender equality, and patient autonomy and trust in the health-care system. A total of 56.1% of men patients and 63.1% of women patients found that women were better at looking after their health compared to men (41.1%/34.3% no difference, 2.8%/2.6% men better). A total of 95.4% of men patients, 95.0% of women patients, 100% of men caregivers, and 95.5% of women caregivers stated that all patients with kidney disease were treated completely equally, irrespective of gender., Conclusion: Neither the patients nor the caregivers stated gender-determined treatment decisions in CKD care. Both men and women however agreed that women are better at maintaining their own health and excel in disease self-management., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: Information that is beneficial for health decision-making is often ignored or actively avoided. Countering information avoidance can increase knowledge of disease risk factors and symptoms, aiding early diagnoses and reducing disease transmission. We examine whether curiosity can be a useful tool in increasing demand for, and engagement with, potentially aversive but useful health information., Methods: Four pre-registered randomized online studies were conducted with 5795 participants recruited from online survey platforms. Curiosity for aversive health information was manipulated by providing a 'curiosity incentive' - identity-related information alongside aversive information - (Study 1), obscuring information (Studies 2 and 3), and eliciting guesses about the information (Studies 2 and 4). Willingness to view four types of aversive health information was elicited: alcohol consumption screening scores (Study 1), colon cancer risk scores (Study 2), cancer risk factors (Study 3), and the sugar content of drinks (Study 4)., Results: In Study 1, the curiosity manipulation increased the likelihood that participants viewed information about the riskiness of their drinking. Studies 2 and 3 show that curiosity prompts can counter people's reluctance to learn about and assess their cancer risk. And Study 4 shows that using curiosity prompts to encourage engagement with aversive information (sugar content of drinks) also improves health-related choices (opting for a sugar-free drink alternative)., Conclusion: Curiosity prompts provide an effective and simple way to increase engagement with aversive health information., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Caregivers of children with chronic illness, such as hematology-oncology conditions, face numerous stressors, and a subset experience persistent distress and poor psychological outcomes. Many logistical and ethical barriers complicate the provision of mental health care to caregivers in children's hospital settings. Telemental health (TMH) is one method to increase access and reduce barriers. Methods: A partnership was established with an outside TMH agency to provide mental health care to caregivers of children with hematology-oncology conditions. Development and implementation strategies are described, and feasibility was measured on four dimensions. Results: One hundred twenty-seven ( n  = 127) caregivers were referred for TMH services in the first 28 months of program implementation. Of the total, 63/127 (49%) received TMH services for at least one session. Most caregivers had a child in active medical treatment (89%). A small portion (11%) of caregivers were bereaved or had a child in hospice care. Program feasibility was enhanced by hospital leadership support and availability of staffing, financial, and technology resources. Available resources also contributed to the practicality of program development and swift implementation and integration within the defined hospital system. Discussion: Partnership with an outside TMH agency increased access to care and reduced barriers to treating caregivers in a children's hospital setting. Offering mental health interventions to caregivers aligns with evidence-based standards of care. Future research will elucidate caregiver satisfaction with this modality of treatment and whether use of TMH reduces disparities in caregiver receipt of mental health care in children's hospital settings.

A novel distraction technique is described for total hip arthroplasty in symptomatic high hip dislocation (Crowe IV) combining an intramedullary motorized lengthening nail with a pelvic support plate to gradually stretch hip soft tissues (distalization) and performing total hip arthroplasty with the cup in the primary acetabulum. Twelve patients (15 hips) were identified in a retrospective study via chart review. Medical records and radiographs were reviewed for details of the initial case parameters, surgical details, magnitude of distalization, duration of treatment, outcomes, and complications. Followed by an average of 67.4 mm of distalization, nearly anatomical cup placement, and equal leg length were achieved in all patients. During distalization, pain level was low with acceptable range of motion. One unplanned surgery and no complications with long-term sequelae occurred., (© 2023 The Authors.)

Background: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit., Methods: Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed., Results: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols., Conclusions: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Drylands comprise one-third of Earth's terrestrial surface area and support over two billion people. Most drylands are projected to experience altered rainfall regimes, including changes in total amounts and fewer but larger rainfall events interspersed by longer periods without rain. This transition will have ecosystem-wide impacts but the long-term effects on microbial communities remain poorly quantified. We assessed belowground effects of altered rainfall regimes (+ 65% and -65% relative to ambient) at six sites in arid and semi-arid Australia over a period of three years (2016-2019) coinciding with a significant natural drought event (2017-2019). Microbial communities differed significantly among semi-arid and arid sites and across years associated with variation in abiotic factors, such as pH and carbon content, along with rainfall. Rainfall treatments induced shifts in microbial community composition only at a subset of the sites (Milparinka and Quilpie). However, differential abundance analyses revealed that several taxa, including Acidobacteria, TM7, Gemmatimonadates and Chytridiomycota, were more abundant in the wettest year (2016) and that their relative abundance decreased in drier years. By contrast, the relative abundance of oligotrophic taxa such as Actinobacteria, Alpha-proteobacteria, Planctomycetes, and Ascomycota and Basidiomycota, increased during the prolonged drought. Interestingly, fungi were shown to be more sensitive to the prolonged drought and to rainfall treatment than bacteria with Basidiomycota mostly dominant in the reduced rainfall treatment. Moreover, correlation network analyses showed more positive associations among stress-tolerant dominant taxa following the drought (i.e., 2019 compared with 2016). Our result indicates that such stress-tolerant taxa play an important role in how whole communities respond to changes in aridity. Such knowledge provides a better understanding of microbial responses to predicted increases in rainfall variability and the impact on the functioning of semi-arid and arid ecosystems., (© 2023. The Author(s).)

Introduction: In epithelial cancers, truncated O-glycans, such as the Thomson-nouveau antigen (Tn) and its sialylated form (STn), are upregulated on the cell surface and associated with poor prognosis and immunological escape. Recent studies have shown that these carbohydrate epitopes facilitate cancer development and can be targeted therapeutically; however, the mechanism underpinning their expression remains unclear., Methods: To identify genes directly influencing the expression of cancer-associated O-glycans, we conducted an unbiased, positive-selection, whole-genome CRISPR knockout-screen using monoclonal antibodies against Tn and STn., Results and Conclusions: We show that knockout of the Zn2+-transporter SLC39A9 (ZIP9), alongside the well-described targets C1GALT1 (C1GalT1) and its molecular chaperone, C1GALT1C1 (COSMC), results in surface-expression of cancer-associated O-glycans. No other gene perturbations were found to reliably induce O-glycan truncation. We furthermore show that ZIP9 knockout affects N-linked glycosylation, resulting in upregulation of oligo-mannose, hybrid-type, and α2,6-sialylated structures as well as downregulation of tri- and tetra-antennary structures. Finally, we demonstrate that accumulation of Zn2+ in the secretory pathway coincides with cell-surface presentation of truncated O-glycans in cancer tissue, and that over-expression of COSMC mitigates such changes. Collectively, the findings show that dysregulation of ZIP9 and Zn2+ induces cancer-like glycosylation on the cell surface by affecting the glycosylation machinery., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Prospective memory is important for our health and independence but declines with age. Hence, interventions to enhance prospective memory, for example by providing an incentive, may promote healthy ageing. The neuroanatomical correlates of prospective memory and the processing of incentive-related prospective memory changes in older adults are not fully understood. In an fMRI study, we will therefore test whether incentives improve prospective memory in older adults and how prospective memory is processed in the brain in general, and when incentives are provided. Since goals and interests change across adulthood, avoiding losses is becoming more important for older adults than achieving gains. We therefore posit that loss-related incentives will enhance prospective memory, which will be subserved by increased prefrontal and midbrain activity., Methods: We will include n = 60 healthy older adults (60-75 years of age) in a randomized, single-blind, and parallel-group study. We will acquire 7T fMRI data in an incentive group and a control group (n = 30 each, stratified by education, age, and sex). Before and after fMRI, all participants will complete questionnaires and cognitive tests to assess possible confounders (e.g., income, personality traits, sensitivity to reward or punishment)., Discussion: The results of this study will clarify whether loss-related incentives can enhance prospective memory and how any enhancement is processed in the brain. In addition, we will determine how prospective memory is processed in the brain in general. The results of our study will be an important step towards a better understanding of how prospective memory changes when we get older and for developing interventions to counteract cognitive decline., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Traditional methods for determining superoxide dismutase (SOD) content and catalase (CAT) activity rely on measuring the absorbance of individual tissue (biological) samples using a cuvette and spectrophotometer, rather than cell cultures. Although there are kits available for SOD and CAT assays, these allow for high-throughput analysis of samples and might be too expensive for research laboratories in countries from the Global South, such as South Africa. This paper describes a simple and cost-effective method to determine SOD content and CAT activity in mammalian cell cultures following exposure to environmental chemical mixtures by measuring absorbance in 96-well microplates. Moreover, the equipment used for this method is considered standard for cell culture laboratories, while the reagents and consumables are easily obtainable.•Antioxidant enzyme levels can be measured in vitro in cell cultures.•The supernatant obtained can be used to determine protein concentration, SOD content, and CAT activity.•This method is simple and affordable, allowing for the analysis of multiple samples (up to 32 samples per microplate)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

G protein-coupled receptors (GPCRs) modulate the function of adipose tissue (AT) in general and of adipocytes, specifically. Although it is well-established that GPCRs are widely expressed in AT, their repertoire as well as their regulation and function in (patho)physiological conditions (e.g., obesity) is not fully resolved. Here, we established FATTLAS, an interactive public database, for improved access and analysis of RNA-seq data of mouse and human AT. After extracting the GPCRome of non-obese and obese individuals, highly expressed and differentially regulated GPCRs were identified. Exemplarily, we describe four receptors (GPR146, MRGPRF, FZD5, PTGER2) and analyzed their functions in a (pre)adipocyte cell model. Besides all receptors being involved in adipogenesis, MRGPRF is essential for adipocyte viability and regulates cAMP levels, while GPR146 modulates adipocyte lipolysis via constitutive activation of Gi proteins. Taken together, by implementing and using FATTLAS we describe four hitherto unrecognized GPCRs associated with AT function and adipogenesis., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)