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The Frizzled family (FZD 1-10 ) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD 7 and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD 7 for cancer treatment. Structure-based virtual screening has identified compound 28, which inhibited WNT/β-catenin signaling based on the luciferase-based reporter gene TOPFlash assay. However, upon pharmacological validation, compound 28 rather acts as a potent Firefly luciferase (Fluc) inhibitor (IC 50 = 30 nM), matching the reported IC 50 for compound 28-mediated inhibition in the TOPFlash assay. Moreover, we employed Fluc-independent assays, a FZD 7 -focused bioluminescence resonance energy transfer biosensor and quantitative PCR, to emphasize the inability of compound 28 to inhibit the WNT-3A-induced conformational dynamics in FZD 7 and transcription of Axin2, a WNT target gene. Thus, we underline the importance of counter screens to validate compounds that interfere with the detection technology used for compound screening.

Objective: To systematically explore vulvar pathology diagnosed prior to vulvar squamous cell carcinoma (VSCC), as well as the association with tumor characteristics, stage and survival outcome, with the aim of improving vulvar cancer prevention strategies., Methods: VSCC diagnosed between 2005 and 2019 were identified from a population-based cohort provided by the Dutch Nationwide Pathology Databank. Pathology reports were reviewed to identify vulvar pathology diagnosed before primary VSCC. Data on treatment, tumor stage and survival were collected from the Netherlands Cancer Registry. Prior vulvar pathology was correlated to tumor characteristics and stage. Cox's proportional hazards model was used to assess the impact of clinicopathological variables on survival., Results: A total of 1036 VSCC patients were identified, of whom most (73 %) had no prior biopsy-confirmed vulvar pathology. High-grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN) were diagnosed prior to VSCC in only 8 % and 2 % of cancer patients, respectively, while adjacent HSIL and adjacent dVIN were reported in 35 % and 22 % of surgical VSCC resection specimens, respectively. The remaining 17 % had a benign vulvar pathology diagnosis prior to cancer. Patients showed advanced staged tumors in 15 % and 9 % of patients with prior HSIL and dVIN, respectively, as compared to 32 % in patients without prior vulvar pathology (p < 0.001). There was no independent association between prior vulvar pathology and survival outcomes., Conclusion: The vast majority of VSCC patients were not preceded by a pre-malignant lesion or other benign vulvar pathology, although such lesions were frequently identified adjacent to VSCC in resection specimens. Patients without prior vulvar pathology showed more advanced-stage tumors, which may contribute to less favorable outcomes., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Secondary malignancies are potential complications after high-dose therapy and autologous stem cell transplantation (ASCT). Information on the detailed course of such events is scarce, yet may be essential to minimize the impact of these sequelae., Patients and Methods: We regularly monitored 877 patients for up to 31 years after ASCT in our outpatient department., Results: Four-hundred and five patients with malignant lymphoma and 472 patients with multiple myeloma were analysed with a median follow-up from the initial malignant diagnosis of 7.0 years (0.5-35.5), from ASCT of 4.8 years (range 0.2-31.3). Eighty-nine of these patients suffered from 94 invasive secondary malignancies (30 haematologic malignancies, 64 solid tumours). In 29 patients a non-melanoma skin cancer was observed. 31/64 (48%) patients with solid tumours were diagnosed in an early stage of the disease (UICC 0-2) and had a chance of cure. 5% of the patients developed an invasive malignancy within 5 years, 12% within 10 years, 21% within 20 years. Risk factors were advanced age, the diagnosis lymphoma and in lymphoma patients additionally male sex., Conclusions: Secondary malignancies after ASCT are relatively frequent complications. Our findings suggest that systematic life-long cancer screening after ASCT is essential to improve the prognosis of these adverse events., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The TRK inhibitor larotrectinib is US Food and Drug Administration approved for NTRK fusion-positive solid tumors that lack a satisfactory alternative or have progressed after treatment but has not been systematically studied as a frontline therapy with a defined duration of treatment. ADVL1823 evaluated larotrectinib in patients with newly diagnosed NTRK fusion-positive solid tumors with response-adapted duration of therapy and local control., Methods: Patients received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and surgical resectability. The primary end point was the objective response rate (ORR) within six cycles in patients with infantile fibrosarcoma (IFS); patients with other histologic diagnoses were analyzed in a separate cohort. Secondary objectives included event-free survival (EFS) and overall survival (OS)., Results: Thirty-three patients were enrolled: 18 with IFS and 15 with other solid tumors. The ORR within six cycles was 94% (17/18; 95% adjusted CI, 72.7 to 98.6) among children with IFS and 60% (9/15; 95% CI, 32.3 to 83.7) among children with other solid tumors. Six percent (2/33; 95% CI, 0.7 to 22.2) patients developed progressive disease while on therapy. Two-year EFS and OS among these groups were 82.2% (95% CI, 54.3 to 93.9) and 93.8% (95% CI, 63.2 to 99.1) for IFS and 80% (95% CI, 50.0 to 93.1) and 93.3% (95% CI, 61.3 to 99.0) for other solid tumors, respectively. Patients undergoing surgical resection of their tumor had prolonged EFS, with only 1 of 16 such patients experiencing disease progression. Four of 33 patients had dose-limiting toxicities., Conclusion: Larotrectinib is highly active in patients with newly diagnosed NTRK fusion-positive solid tumors. Larotrectinib should be a frontline option for patients with IFS and other NTRK fusion-positive solid tumors. Local control with surgical resection remains important in the treatment of patients with IFS.

Aims: SPARCL1 was recently identified as a biomarker of right ventricular (RV) maladaptation in patients with pulmonary hypertension (PH), and N-terminal pro-brain natriuretic protein (NT-proBNP) is an established biomarker of RV failure in PH. The present study investigated whether NT-proBNP and SPARCL1 concentrations are associated with load-independent parameters of RV function and RV-to-pulmonary artery (RV-PA) coupling as measured using invasive pressure-volume (PV) loops in the RV., Methods: SPARCL1 and NT-proBNP were measured in the plasma of patients with idiopathic pulmonary artery hypertension (IPAH, n = 73). Participants without LV or RV abnormalities served as controls (n = 28). All patients underwent echocardiography and right heart catheterization with invasive PV loop measurements., Results: Our cohort had more females with IPAH than the control group (64% vs. 35%; P = 0.01) and was older [69 (interquartile range, IQR 57-76) vs. 51 (IQR 35-62) years; P < 0.001]. SPARCL1 and NT-proBNP levels were significantly higher in patients with IPAH as compared with controls (P < 0.0001). Patients with IPAH and maladaptive RV remodelling had higher SPARCL1 and NT-proBNP concentrations than those with adaptive RV remodelling (P < 0.01). Both SPARCL1 and NT-proBNP were good predictors of maladaptive RV remodelling in receiver operating characteristic analysis [area under the curve (AUC) (AUC SPARCL1  = 0.75, AUC NT-proBNP  = 0.72, P = 0.36 for AUC SPARCL1 vs. AUC NT-proBNP ]. The combined predictive value of SPARCL1 and NT-proBNP (AUC 0.78, P < 0.001) for maladaptive RV was numerically higher than that of either SPARCL1 or NT-proBNP alone (P = 0.16 for AUC SPARCL1 + NT-proBNP vs. AUC NT-proBNP and P = 0.18 for AUC SPARCL1 + NT-proBNP vs. AUC SPARC1 ). SPARCL1 showed numerically a tendency for a better predictive power than NT-proBNP for parameters of early maladaptive RV remodelling such as RV ejection fraction < 50% (AUC SPARCL1  = 0.77, AUC NT-proBNP  = 0.67, P = 0.06 for AUC SPARCL1 vs. AUC NT-proBNP ), RV end-diastolic diameter > 42 mm (AUC SPARCL1  = 0.72, AUC NT-proBNP  = 0.65, P = 0.19 for AUC SPARCL1 vs. AUC NT-proBNP ) and RV end-systolic volume index RVESVI > 31 mL/m 2 (AUC SPARCL1  = 0.78, AUC NT-proBNP  = 0.71, PP = 0.10 for AUC SPARCL1 vs. AUC NT-proBNP )., Conclusions: SPARCL1 and NT-proBNP are good predictors of maladaptive RV remodelling and RV-PA uncoupling in IPAH patients. SPARCL1 may be a better predictor of early maladaptive RV remodelling than NT-proBNP., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2-hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X-ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug-resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur-containing derivatives. X-ray crystallographic analysis of a tubulin-bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We evaluated current experiences and future needs for the long-term engagement of patients in a hypertension hybrid care pathway (Maasstad Hospital, NL). Patients >18 y/o with ≥3 months care pathway participation were recruited by telephone and divided into three age/focus groups with distinct digital skills and attitudes toward lifestyle interventions (group 1:18-40 y/o, group 2:40-65 y/o, group 3:>65 y/o). We used deductive thematic content analysis to cluster the results to the different digital elements (remote monitoring, communication, digital lifestyle intervention) of the care pathway. Fifteen patients were interviewed in March 2023 (Group 1;2;3, 3;6;6 participants). The care pathway improved disease insight, engagement, and shared decision capabilities in all groups. For further improved adherence and engagement, all patients indicated the need to incorporate a more personalized approach and interaction with their healthcare provider. In addition, the oldest group preferred simplification of the telemonitoring application, while the other groups preferred enrichment with more complex information. To ensure optimal engagement, digital elements in hybrid care pathways should be personalized and tailored to individual as well as to age-specific needs., Competing Interests: Job van Steenkiste, MD: nothing to declare. Iris Verberk-Jonkers, MD, PhD: nothing to declare. Stephanie de Koning, CNS: nothing to declare. Joyce Voss-de Haan, CNS: nothing to declare. Bianca Verhagen, Msc: nothing to declare. Daan Dohmen, Prof, PhD: Prof. D. Dohmen is the CEO of Luscii, the involved HBPT platform used in the Maasstad hospital which was evaluated in this study. There was no financial support provided by Luscii to facilitate this study., (© The Author(s) 2024.)

Background: In response to climate change-induced increases in heat periods, the WHO recommends the implementation of heat health action plans (HHAPs). In Germany, HHAPs are implemented neither comprehensively nor nationwide. Several recommendations have identified the public health service (PHS) at municipal and federal state levels as a key actor regarding to heat and health. Therefore, this study aimed at assessing the role of the PHS in implementing HHAPs at municipal and federal state levels in Germany., Methods: We conducted a policy document analysis to assess the legal basis for the work of the PHS in the 16 federal states in Germany. Furthermore, we conducted semi-structured interviews with 16 experts from within and outside the PHS to explore their perceptions of the PHS in the implementation of HHAPs. The interviews were analysed using reflective thematic analysis., Results: The policy document analysis revealed that heat is not mentioned in any of the federal states' regulatory frameworks for the PHS, while tasks related to environment and health are addressed, but tend to remain vague. The interviews confirmed that there is currently no clearly defined role for the PHS in implementing HHAPs in Germany and that the actual role primarily depends on the local setting. Main barriers and facilitators could be assigned to three levels (individual, organizational and political), and two overarching contextual factors (awareness of the need for adaptation and existence of other public health emergencies) influenced the implementation of HHAPs across all levels. At the individual level, motivation, knowledge and competencies, and previous experience were possible barriers or enablers. At the organizational level, administrative structures, financial and human resources, leadership and networks were barriers or facilitators, while at the political level they included legislation and political decisions., Conclusions: The PHS could and should be a relevant actor for implementing measures addressing health and climate change locally, in particular because of its focus on vulnerable populations. However, our findings suggest that the legal basis in the federal states of Germany is insufficient. Tailored approaches are needed to overcome barriers such as rigid, non-agile administrative structures and competing priorities, while taking advantage of facilitators such as awareness of relevant actors., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in compliance with the ethical principles for medical research involving human subjects set out in the Declaration of Helsinki [32]. It received ethical approval from the ethical committees of the LSHTM (reference number: 26796) and the LMU Munich (project number: 22–0184). All individuals interviewed gave written informed consent to participate in the study and that the results may be used anonymously for publication. Consent for publication: Not applicable. Competing interests: K.G. is a deputy member of the scientific advisory board for the pact for the public health service., (© 2024. The Author(s).)

Analytes, from sample preparation, until entering an analytical instrument, are prone to adsorb to surfaces, driven by the chemical properties of the surface and the liquids they are dissolved in. This problem can be addressed with internal standards when a single or few known analytes are quantified that are usually not available in omics. However, minimal to no loss of analytes is the aim. Here, we present a novel assay for qualifying and quantifying interactions responsible for adsorption of molecules to surfaces (APS) by using LC-MS/MS-based differential quantitative analysis. To reflect a broad range of chemical interactions with surfaces, a reference mixture of thousands of tryptic peptides, with known compositions was selected, representing a variety of different chemical characteristics. The assay was tested by investigating the adsorption properties of several different vials with different surface chemistries. A significant number of hydrophobic peptides adsorbed to conventional polypropylene vials. In contrast, only few peptides adsorbed to polypropylene vials, assigned as low-protein-binding. The highest number of peptides adsorbed to glass vials driven by electrostatic interactions. In summary, the new assay is suitable to characterize adsorption properties of different surfaces and to approximate the loss of analytes during sample preparation., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: Opioid use disorder is one of the most severe forms of substance use disorder and is associated with high morbidity and mortality. Opiate overdose deaths in the US are increasing every year, claiming over 100,000 lives in 2022. Psychological trauma exposure and post-traumatic stress disorder are major health problems in the United States and may contribute to the development of an opiate use disorder. The purpose of this study was to examine the association of psychological trauma exposure and post-traumatic stress disorder with opiate use disorder., Methods: This study used a retrospective design with a convenience sample size of n = 150 participants diagnosed with opiate use disorder or substance use disorder from a drug treatment center in urban Pennsylvania. Retrospective data was collected on demographic characteristics, trauma exposures, diagnoses of post-traumatic stress disorder, opiate use disorder, and substance use disorder. Demographic data was gathered using a demographic survey, psychological trauma exposure was documented using the self-reported Life Events Checklist, and a diagnosis of post-traumatic stress disorder, opiate use disorder, and substance use disorder was confirmed as documented in the medical record by mental health providers., Results: Persons with psychological trauma exposure >5 are more likely to develop opiate use disorder, Chi-Square (χ 2  = 5.17, df = 1, p = 0.023)., Conclusion: Our study showed that psychological trauma exposure may lead to opiate use disorder, emphasizing the importance of identification of psychological trauma exposure and post-traumatic stress disorder diagnosis as part of trauma-informed strategies during the treatment of persons with opiate use disorder to help prevent disability and death., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest related to this manuscript. Roxanne Jeffries-Baxter, DNP, PMHNP-BC, FNP-BC, GNP-BC, has received research grants from SAMHSA, Grant Number 5H79SM080386-04. Roxanne Jeffries-Baxter, DNP, PMHNP-BC, FNP-BC, GNP-BC, has received research grants from Alpha Mu Research Grant. The author confirms that the funding sources had no role in the design, execution, analysis, or interpretation of the study results., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Older patients (aged ≥65 years) with glioblastoma have a worse prognosis than younger patients and a median overall survival of 6-9 months. 3,4-Dihydroxy-6-[ 18 F]fluoro-L-phenylalanine ( 18 F-DOPA) PET sensitively and specifically identifies metabolically active glioblastoma for preferential targeting. Proton beam therapy potentially improves quality of life (QOL) by sparing more healthy brain tissue than photon radiotherapy. With improved targeting and the dosimetric advantages of proton beam therapy, we aimed to test whether hypofractionated proton beam therapy could improve survival and QOL in older patients with glioblastoma., Methods: In this single-arm phase 2 trial, we enrolled patients aged 65 years and older with an Eastern Cooperative Oncology Group performance status score of 0-2 and newly diagnosed WHO grade 4, malignant glioblastoma from two Mayo Clinic campuses (Phoenix, AZ, and Rochester, MN, USA). Radiotherapy target volumes were defined by 18 F-DOPA PET and MRI regions of contrast enhancement. Patients were given dose-escalated hypofractionated proton beam therapy (35-40 Gy equivalents in five or ten treatments) plus oral concurrent temozolomide (75 mg/m 2 daily on days 1-7 for the five-treatment regimen or on days 1-14 for the ten-treatment regimen), and 1 month after completing radiotherapy patients were given adjuvant temozolomide (150-200 mg/m 2 on days 1-5 for six 28-day cycles). The primary endpoint was overall survival at 12 months after enrolment. The primary endpoint and safety were assessed in the intention-to-treat population (defined as all eligible patients who started radiotherapy). This study is registered with ClinicalTrials.gov, NCT03778294, and is now complete., Findings: Between May 22, 2019, and May 25, 2021, 43 patients were enrolled, of whom four did not receive treatment because of progression (n=2), death (n=1), or insurance denial (n=1), such that 39 patients received treatment (median age 70·2 years [IQR 67·4-74·3]; 11 [28%] of 39 patients were female, 28 [72%] were male, 37 [95%] were White, one [3%] was Black or African American, and one chose not to disclose their race). As of data cutoff (Jan 30, 2024), median follow-up was 25·4 months (IQR 22·1-29·7). 22 (56% [95% CI 39-72]) of 39 patients were alive at 12 months. Median overall survival was 13·1 months (95% CI 11·1-19·1). Grade 3 baseline-adjusted, treatment-associated adverse events were CNS necrosis (four [10%] of 39) and thrombocytopenia (one [3%]). No baseline-adjusted, treatment-associated grade 4 adverse events or deaths occurred., Interpretation: We observed improved overall survival compared with historical controls and a promising adverse event profile by using 18 F-DOPA PET-guided, dose-escalated, hypofractionated proton beam therapy. These findings have resulted in the opening of a phase 2 study (NCT05781321) investigating this regimen versus standard-of-care treatment in adults of any age with newly diagnosed glioblastoma., Funding: Mayo Clinic Marley Endowment Funds and the Lawrence W and Marilyn W Matteson Fund in Cancer Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is limited evidence depicting ways that behavioral theory and techniques have been incorporated into cancer rehabilitation interventions. Examining their use within cancer rehabilitation interventions may provide insight into the active ingredients that can maximize patient engagement and intervention effectiveness., Aim: This secondary analysis aimed to describe the use of behavior change theory and behavior change techniques (BCTs) in two previously conducted systematic reviews of cancer rehabilitation interventions., Design: Secondary analysis of randomized controlled trials (RCTs) drawn from two systematic reviews examining the effect of cancer rehabilitation interventions on function and disability., Setting: In-person and remotely delivered rehabilitation interventions., Population: Adult cancer survivors., Methods: Data extraction included: behavior change theory use, functional outcome data, and BCTs using the Behavior Change Technique Taxonomy (BCTTv1). Based on their effects on function, interventions were categorized as "very", "quite" or "non-promising". To assess the relative effectiveness of coded BCTs, a BCT promise ratio was calculated (the ratio of promising to non-promising interventions that included the BCT)., Results: Of 180 eligible RCTs, 25 (14%) reported using a behavior change theory. Fifty-four (58%) of the 93 BCTs were used in least one intervention (range 0-29). Interventions reporting theory use utilized more BCTs (median=7) compared to those with no theory (median=3.5; U=2827.00, P=0.001). The number of BCTs did not differ between the very, quite, and non-promising intervention groups (H(2)=0.24, P=0.85). 20 BCTs were considered promising (promise ratio >2) with goal setting, graded tasks, and social support (unspecified) having the highest promise ratios., Conclusions: While there was a wide range of BCTs utilized, they were rarely based on theoretically-proposed pathways and the number of BCTs reported was not related to intervention effectiveness., Clinical Rehabilitation Impact: Clinicians should consider basing new interventions upon a relevant behavior change theory. Intentionally incorporating the BCTs of goal setting, graded tasks, and social support may improve intervention efficacy.

The evolution of adjustable stomatal pores, enabling CO 2 acquisition, was one of the most significant events in the development of life on land. Here, we investigate how the guard cell signalling pathways that regulate stomatal movements evolved. We compare fern and angiosperm guard cell transcriptomes and physiological responses, and examine the functionality of ion channels from diverse plant species. We find that, despite conserved expression in guard cells, fern anion channels from the SLAC/SLAH family are not activated by the same abscisic acid (ABA) pathways that provoke stomatal closure in angiosperms. Accordingly, we find an insensitivity of fern stomata to ABA. Moreover, our analysis points to a complex evolutionary history, featuring multiple gains and/or losses of SLAC activation mechanisms, as these channels were recruited to a role in stomatal closure. Our results show that the guard cells of flowering and nonflowering plants share similar core features, with lineage-specific and ecological niche-related adaptations, likely underlying differences in behaviour., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Background: Effective, scalable interventions are needed to prevent poor mental health in young people. Although mental health apps can provide scalable prevention, few have been rigorously tested in high-powered trials built on models of healthy emotional functioning or tailored to individual profiles. We aimed to test a personalised emotional competence app versus a cognitive behavioural therapy (CBT) self-help app versus a self-monitoring app to prevent an increase in depression symptoms in young people., Methods: This multicentre, parallel, open-label, randomised controlled trial, within a cohort multiple randomised trial (including a parallel trial of wellbeing promotion) was done at four university trial sites in the UK, Germany, Spain, and Belgium. Participants were recruited from schools, universities, and social media from the four respective countries. Eligible participants were aged 16-22 years with increased vulnerability indexed by baseline emotional competence profile, without current or past diagnosis of major depression. Participants were randomly assigned (1:1:1) to usual practice plus either the personalised emotional competence self-help app, the generic CBT self-help app, or the self-monitoring app by an independent computerised system, minimised by country, age, and self-reported gender, and followed up for 12 months post-randomisation. Outcome assessors were masked to group allocation. The primary outcome was depression symptoms (according to Patient Health Questionnaire-9 [PHQ-9]) at 3-month follow-up, analysed in participants who completed the 3-month follow-up assessment. The study is registered with ClinicalTrials.gov, NCT04148508, and is closed., Findings: Between Oct 15, 2020, and Aug 3, 2021, 1262 participants were enrolled, including 417 to the emotional competence app, 423 to the CBT app, and 422 to the self-monitoring app. Mean age was 18·8 years (SD 2·0). Of 1262 participants self-reporting gender, 984 (78·0%) were female, 253 (20·0%) were male, 15 (1·2%) were neither, and ten (0·8%) were both. 178 participants in the emotional competence app group, 191 in the CBT app group, and 199 in the self-monitoring app group completed the follow-up assessment at 3 months. At 3 months, depression symptoms were lower with the CBT app than the self-monitoring app (mean difference in PHQ-9 -1·18 [95% CI -2·01 to -0·34]; p=0·006), but depression symptoms did not differ between the emotional competence app and the CBT app (0·63 [-0·22 to 1·49]; p=0·15) or the self-monitoring app and emotional competence app (-0·54 [-1·39 to 0·31]; p=0·21). 31 of the 541 participants who completed any of the follow-up assessments received treatment in hospital or were admitted to hospital for mental health-related reasons considered unrelated to interventions (eight in the emotional competence app group, 15 in the CBT app group, and eight in the self-monitoring app group). No deaths occurred., Interpretation: The CBT app delayed increases in depression symptoms in at-risk young people relative to the self-monitoring app, although this benefit faded by 12 months. Against hypotheses, the emotional competence app was not more effective at reducing depression symptoms than the self-monitoring app. CBT self-help apps might be valuable public mental health interventions for young people given their scalability, non-consumable nature, and affordability., Funding: European Commission., Competing Interests: Declaration of interests ERW reports royalties from Guilford Press for a CBT treatment manual he authored and is an expert member of the NICE Guidelines for treatment of adult depression. MFr is a founder and shareholder of Monsenso. BWS is a founder and shareholder of audEERING. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Based on evidence that mental health is more than an absence of mental disorders, there have been calls to find ways to promote flourishing at a population level, especially in young people, which requires effective and scalable interventions. Despite their potential for scalability, few mental wellbeing apps have been rigorously tested in high-powered trials, derived from models of healthy emotional functioning, or tailored to individual profiles. We aimed to test a personalised emotional competence self-help app versus a cognitive behavioural therapy (CBT) self-help app versus a self-monitoring app to promote mental wellbeing in healthy young people., Methods: This international, multicentre, parallel, open-label, randomised controlled trial within a cohort multiple randomised trial (including a parallel trial of depression prevention) was done at four university trial sites in four countries (the UK, Germany, Spain, and Belgium). Participants were recruited from schools and universities and via social media from the four respective countries. Eligible participants were aged 16-22 years with well adjusted emotional competence profiles and no current or past diagnosis of major depression. Participants were randomised (1:1:1) to usual practice plus either the emotional competence app, the CBT app or the self-monitoring app, by an independent computerised system, minimised by country, age, and self-reported gender, and followed up for 12 months post-randomisation. The primary outcome was mental wellbeing (indexed by the Warwick-Edinburgh Mental Well Being Scale [WEMWBS]) at 3-month follow-up, analysed in participants who completed the 3-month follow-up assessment. Outcome assessors were masked to group allocation. The study is registered with ClinicalTrials.gov, NCT04148508, and is closed., Findings: Between Oct 15, 2020, and Aug 3, 2021, 2532 participants were enrolled, and 847 were randomly assigned to the emotional competence app, 841 to the CBT app, and 844 to the self-monitoring app. Mean age was 19·2 years (SD 1·8). Of 2532 participants self-reporting gender, 1896 (74·9%) were female, 613 (24·2%) were male, 16 (0·6%) were neither, and seven (0·3%) were both. 425 participants in the emotional competence app group, 443 in the CT app group, and 447 in the self-monitoring app group completed the follow-up assessment at 3 months. There was no difference in mental wellbeing between the groups at 3 months (global p=0·47). The emotional competence app did not differ from the CBT app (mean difference in WEMWBS -0·21 [95% CI -1·08 to 0·66]) or the self-monitoring app (0·32 [-0·54 to 1·19]) and the CBT app did not differ from the self-monitoring app (0·53 [-0·33 to 1·39]). 14 of 1315 participants were admitted to or treated in hospital (or both) for mental health-related reasons, which were considered unrelated to the interventions (five participants in the emotional competence app group, eight in the CBT app group, and one in the self-monitoring app group). No deaths occurred., Interpretation: The emotional competence app and the CBT app provided limited benefit in promoting mental wellbeing in healthy young people. This finding might reflect the low intensity of these interventions and the difficulty improving mental wellbeing via universal digital interventions implemented in low-risk populations., Funding: European Commission., Competing Interests: Declaration of interests ERW receives royalties from Guilford Press for a CBT treatment manual he authored and was an expert member of the NICE Guidelines for treatment of adult depression. MFr is a founder and shareholder of Monsenso. BWS is a founder and shareholder of audEERING. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx., Methods: Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx., Results: Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs., Conclusions: These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Darwinian evolution has given rise to all the enzymes that enable life on Earth. Mimicking natural selection, scientists have learned to tailor these biocatalysts through recursive cycles of mutation, selection and amplification, often relying on screening large protein libraries to productively modulate the complex interplay between protein structure, dynamics and function. Here we show that by removing destabilizing mutations at the library design stage and taking advantage of recent advances in gene synthesis, we can accelerate the evolution of a computationally designed enzyme. In only five rounds of evolution, we generated a Kemp eliminase-an enzymatic model system for proton transfer from carbon-that accelerates the proton abstraction step >10 8 -fold over the uncatalyzed reaction. Recombining the resulting variant with a previously evolved Kemp eliminase HG3.17, which exhibits similar activity but differs by 29 substitutions, allowed us to chart the topography of the designer enzyme's fitness landscape, highlighting that a given protein scaffold can accommodate several, equally viable solutions to a specific catalytic problem., Competing Interests: Competing interests: All authors declare no competing interests., (© 2024. The Author(s).)

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Alpha-cyclodextrin (α-CD) is a non-absorbable and soluble fiber that causes weight loss. We studied whether this is due to an effect on GLP-1 secretion. In GLUTag cells, α-CD increased GLP-1 secretion up to 170% via adenylyl cyclase, phospholipase C, and L-type calcium channels dependent processes. In rat isolated colon perfusions, luminal α-CD increased GLP-1 secretion with 20%. In lean mice, once daily α-CD versus saline caused weight loss and lowered the peak in glucose after an oral glucose tolerance test (OGTT). In obese mice, α-CD added to high-fat diet caused weight loss similar to the control group (receiving cellulose). However, compared to cellulose, the α-CD group ate less. During an OGTT, no differences were observed in glucose, insulin and GLP-1. Thus, α-CD increases GLP-1 secretion in a dose-dependent manner and could be a safe and easy addition to food products to help reduce body weight., Competing Interests: Declaration of competing interest MMS, LV, AKD, EEB and AOB have nothing to disclose. MMR and JJH are cofounders and minority shareholders in Antag Therapeutics. JJH: Advisory boards: Novo Nordisk; Lecture fees: Novo Nordisk; Merck. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark Smits reports financial support was provided by Lundbeck Foundation. Jens Juul Holst reports a relationship with Novo Nordisk that includes: consulting or advisory and speaking and lecture fees. Jens Juul Holst reports a relationship with Merck & Co Inc. that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: We aimed to determine if ultrahypofractionated proton therapy delivered via stereotactic body proton therapy (SBPT) is noninferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer., Methods and Materials: This study was a multicenter, randomized, controlled, noninferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score grouping 1, Prostate-specific antigen <10 ng/mL, and clinical stage T1-T2a N0 M0 according to 7th edition of the American Joint Committee on Cancer tumor-node-metastasis cancer staging system. Eligible participants were randomly assigned initially at a 1:1 ratio and later at a 2:1 ratio to SBPT (38 Gy in 5 fractions) or CFPT (79.2 Gy in 44 fractions). The primary endpoint was freedom from failure (FFF) at 2 years from the date of randomization. Noninferiority for FFF was determined based on 1-sided confidence intervals. Toxicities were compared at different time points using Fisher's exact test. Health-related quality-of-life (HRQoL) was analyzed at different time points using a mixed-effects linear model. This trial is registered with ClinicalTrials.gov, NCT01230866, and is closed to accrual., Results: Between December 10, 2010, and September 29, 2020, 144 patients were enrolled and 135 were randomly assigned (90 to the SBPT group and 45 to the CFPT group). The median follow-up was 5 years (IQR, 3.9-5.2). The 2-year FFF was 100% for both groups, with the 1-sided 5-year risk difference in FFF between groups reported as 2.63% (90% CI, -1.70% to 6.96%), favoring the SBRT arm, thus fulfilling the prespecified criteria for noninferiority of SBPT compared with CFPT. Rates of gastrointestinal and genitourinary G2 and G3 toxicities did not differ significantly between groups. Further, HRQoL metrics did not differ significantly between groups over the study's median follow-up., Conclusions: SBPT is noninferior to CFPT regarding FFF, with similar long-term genitourinary and gastrointestinal toxicity rates and minimal impact in patient-reported HRQoL over time., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Vulvar lichen sclerosus (LS) is a chronic inflammatory dermatosis which can progress to precursor lesion differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar squamous cell carcinoma (VSCC). The risk of developing recurrent vulvar cancer following LS-associated VSCC is high. Evidence suggests that treatment of LS with topical corticosteroids (TCS) can prevent progression to dVIN, VSCC and recurrences. However, current guidelines do not give any recommendation on the management of LS following surgery for VSCC. The aim of this study was to conduct a survey among all registered gynaecologic oncologists (GOs) in the Netherlands to evaluate the current management of LS patients without a history of VSCC (LS noVSCC ) and patients with LS following surgery for VSCC (LS VSCC )., Methods: An online survey was distributed to all registered GOs in the Netherlands. Primary outcome measures were the frequency, type and duration of TCS treatment prescribed for LS noVSCC and LS VSCC patients, separately. As a secondary outcome measure, reasons for treating or not treating patients with LS noVSCC and LS VSCC with TCS were analysed., Results: Forty-four GOs completed the survey, resulting in a response rate of 75%. TCS were prescribed more often to patients with LS noVSCC as compared to patients with LS VSCC (86% versus 52%, respectively, p  < 0.001). If treatment was initiated, ultra-potent (class IV) TCS were most commonly prescribed for an indefinite period of time for both patient groups. The most reported reason for treating patients in both groups with TCS was symptoms, followed by clinical aspects of the lesion and prevention of progression to dVIN and VSCC., Conclusion: The majority of GOs who participated in our study endorse the utilisation of long-term ultra-potent TCS therapy in both patients with LS noVSCC and LS VSCC . Nevertheless, Dutch GOs are currently prescribing TCS more frequently to patients with LS noVSCC than to patients with LS VSCC .

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combination with S. pneumoniae infection further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma concentrations of proinflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage, and pulmonary inflammation in mice infected with S. pneumoniae . Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier during S. pneumoniae infection. Notably, enzymatic pretreatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococci-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, and epithelial barrier function and integrity.

Background: Internalized weight bias is the belief in negative, weight-based stereotypes and the application of these stereotypes to oneself. These negative stereotypes have harmful impacts on people with overweight/obesity, and weight-based discrimination is well-documented across a variety of settings. Given poor outcomes associated with internalized weight bias, particularly among individuals with obesity, it is necessary to validate measures assessing internalized weight bias among diverse samples. The present study sets out to investigate measurement invariance properties across weight status (women with vs. without overweight/obesity) and race (White vs. Asian; White vs. bi- or multi-racial) of the Modified Weight Bias Internalization Scale (WBIS-M), an 11 item self-report measure., Methods: Participants were 746 racially/ethnically diverse women across the weight spectrum (24.9% with overweight/obesity). Confirmatory factor analyses of the WBIS-M were initially performed among the full sample, and all sub-samples. Each model showed good to excellent descriptive model fit. Subsequent analyses examined factor loadings and item thresholds of the WBIS-M to assess metric, threshold, and scalar invariance. Invariance was determined by assessing changes in Comparative Fit Index (ΔCFI ≤ -0.010), Root Mean Square Error of Approximation (ΔRMSEA ≤ 0.015), and Standardized Root Mean Square Residuals (ΔSRMR ≤ 0.030)., Results: Based on these previously established statistical cutoffs, the WBIS-M showed invariance across weight status and racial groups in the present sample. The current results lend support for use of the WBIS-M to measure internalized weight bias in women who do and do not have overweight/obesity, and among White, Asian, and bi- or multi-racial women., Conclusion: This may inform future studies that wish to utilize the WBIS-M, such as investigations of mean level differences in internalized weight bias. These findings may have clinical applications in the treatment and prevention of obesity, given the heightened levels of internalized weight bias and weight-based discrimination faced by individuals with higher body weights., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The present research was conducted on human subjects and in accordance with the Declaration of Helsinki. This study was approved by the University Review Board (#2020-00059). All participants gave informed consent electronically prior to participation. Participants who enrolled in the study were asked to complete an anonymous online survey including survey measures and demographic information., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Site-specific incorporation of noncanonical amino acids (ncAAs) into proteins in eukaryotes has predominantly relied on the pyrrolysyl-tRNA synthetase/tRNA pair. However, access to additional easily engineered pairs is crucial for expanding the structural diversity of the ncAA toolbox in eukaryotes. The Escherichia coli -derived leucyl-tRNA synthetase (EcLeuRS)/tRNA pair presents a particularly promising alternative. This pair has been engineered to charge a small yet structurally diverse group of ncAAs in eukaryotic cells. However, expanding the substrate scope of EcLeuRS has been difficult due to the suboptimal yeast-based directed evolution platform used for its engineering. In this study, we address this limitation by optimizing the yeast-based directed evolution platform for efficient selection of ncAA-selective EcLeuRS mutants. Using the optimized selection system, we demonstrate rapid isolation of many novel EcLeuRS mutants capable of incorporating various ncAAs in mammalian cells, including ornithine and N ε -acetyl-methyllysine, a recently discovered post-translational modification in mammalian cells.

Background: Global longitudinal strain (GLS) has been used to identify patients at risk for cancer-therapy related cardiac dysfunction (CTRCD). However, there is limited data on the effectiveness of initiating cardioprotective therapy based on a strain-guided strategy in early stage HER2+ breast cancer patients. This randomized clinical trial assessed if treatment with carvedilol based on a strain-guided strategy can prevent development of CTRCD in HER2+ breast cancer patients on non-anthracycline based regimens., Methods: Study participants were prospectively assigned to one of four arms. Patients with normal LVEF and GLS remained in Arm A. Patients whose GLS decreased by > 15% from baseline or to < -15% during follow up were randomized 1:1 to prophylactic carvedilol (Arm B) or no therapy (Arm C). Patients who developed CTRCD were assigned to Arm D. The primary endpoint was GLS stability. The secondary endpoints were development of CTRCD and rate of anti-HER2 treatment interruption., Results: Among 110 patients who completed follow up, 84 were assigned to Arm A, 10 each were randomized to Arms B or C, and 6 were assigned to Arm D. At the end of the study period, there were no significant differences in GLS stability, development of CTRCD, or number of cancer therapy cycles completed between patients who did and did not receive cardioprotective therapy., Conclusions: In this prospective randomized GLS-guided study of prophylactic carvedilol in early stage HER2+ breast cancer patients on non-anthracycline regimens, there were no significant difference between groups in GLS stability, CTRCD or trastuzumab cycles held. These findings may identify a low-risk group of patients who may be considered for less intensive cardiac surveillance., Trial Registration: https://clinicaltrials.gov/study/NCT02993198 . Start date: 4/2015. This trial included patients who were retrospectively registered., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Northwestern University Institutional Review Board. Consent for publication: Not applicable. Competing interests: SR is a consultant for Abbott Laboratories. GM is a full-time employee and shareholder of Abbott Laboratories. NA received research funding from Abbott Laboratories. The other authors declare no conflict of interest., (© 2024. The Author(s).)

Introduction: The main obstacle to achieving an HIV-1 cure is the proviral reservoir. To promote equity in HIV cure strategies, it is crucial to study the viral reservoir of the predominant HIV-1 subtype C in both women and men. Therefore, we investigated the dynamics of the (intact) viral reservoir in relation to plasma viral load (VL), CD4 + T cell count, and immune activation before and during 96 weeks of successful antiretroviral therapy (ART)., Methods: Eighty-two participants (62% female) newly initiating ART in a rural clinic in South Africa were included in the study. Blood samples were collected at baseline, week 48, and week 96, and CD4 count was determined. Plasma was used for VL and immune marker analyses, while isolated peripheral blood mononuclear cells (PBMCs) were used for the quantification of cellular multiple spliced HIV-1 RNA (msRNA) and the intact proviral DNA assay. For the longitudinal analyses on ART, we selected only those participants who durably suppressed their VL to <200 copies/mL during 48 (n=65) and/or 96 (n=60) weeks of treatment., Results: At ART initiation, the median CD4 count was 234 cells/mm3 and VL was 68,897 copies/mL. Interestingly, at baseline the number of defective proviruses was significantly correlated with VL (p<0.0001), msRNA (p<0.0001), CD4 count (p=0.0008), CXCL10 (p=0.0003) and TNF-α (p=0.0394). During successful ART, a significant decrease of both the intact and defective proviral reservoir was observed (p<0.0001). The decrease of the intact proviral reservoir was more profound compared to the defective fraction after 96 weeks of therapy. In addition, a significant decrease in cellular msRNA and IL-6, IL-7, TNF-α, sCD14, sCD163, CCL2, CXCL10, and CRP was detected., Discussion: This study underscores the significant relationship observed prior to therapy initiation between the number of defective proviruses, viral transcription/production and their association with immune response indicators such as CD4 count, CXCL10, and TNF-α. Furthermore, the observation of a less pronounced decrease of the defective proviral DNA highlights the importance of addressing both intact and defective proviruses in therapeutic strategies to enhance clinical outcomes for people with HIV-1. Together, these findings suggest a significant role of the defective proviruses in HIV-related disease progression., 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 Buchholtz, Hermans, Umunnakwe, Nühn, Voss, Need, Kootstra, Maurer, de Jong, Symons, Tempelman, Wensing and Nijhuis.)

Background: The Norwegian trauma plan was established in 2007 and renewed in 2017 defining national trauma team activation (TTA) criteria. Norwegian studies validating the performance of previous TTA protocols have found overtriage and undertriage to be out of line with the quality indicators set in the national trauma plan, but studies have not yet been published validating the new TTA protocol., Material and Method: This was a registry study of a prospectively maintained database in the period from 01/01/2018 to 12/31/2020. Data were collected from the Trauma Registry including prehospital documents. A total of 1519 patients were eligible, of which 95 were excluded, yielding a study population of 1424 patients. All patients were evaluated for a total of 29 criteria in four criteria groups: 1 Physiology, 2 Anatomical injury, 3 Mechanism of injury, and 4 Special considerations. Overtriage, undertriage, sensitivity and positive predictive value (PPV) were estimated for the current and alternative TTA protocols, criteria groups, and single criteria., Results: The current Norwegian TTA protocol involving criteria groups 1-3 had a total sensitivity of 84.8 %, hence an undertriage of 15.2 % (95 % confidence interval, 11.1-20.3 %), and PPV of 19.2 % hence an overtriage of 80.8 % (78.3-83.1 %). Patients 60 years and older had an undertriage of 21.6 %, whilst patients under 60 years of age had an undertriage of 11.2 %. A TTA protocol including criteria group 4 as well yielded a lower undertriage (5.6 %) without significantly increasing overtriage (81.7 %), and a TTA protocol with criteria group 4 replacing group 3 yielded an undertriage of 7.4 % and an overtriage of 81.0 %. Criteria group 3 Mechanism of injury was the criteria group with the most overtriage, at 95 %. Patients that did not meet any criteria had a similar overtriage of 94 %., Conclusion: Both overtriage and undertriage are out of line with the goals set in the Norwegian trauma plan. Undertriage is often caused by older patients that do not fulfill the trauma criteria in the current TTA protocol. Mechanism of injury increases overtriage but does not reduce undertriage. The TTA protocol could be improved by changing the composition of criteria groups, removal of single criteria with low PPV, and by better compliance to the existing criteria., Competing Interests: Declaration of competing interest none., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Mechanisms of repair failure after mitral valve repair (MVr) using chordal replacement and annuloplasty for degenerative mitral regurgitation were analyzed., Methods: All mitral valve reoperations after isolated MVr using solely chordal replacement and annuloplasty for degenerative mitral regurgitation at the German Heart Center Munich were reviewed. This retrospective observational study aims to analyze mechanisms of repair failure leading to reoperations., Results: Between 2003 and 2010, a total of 344 patients received MVr with chordal replacement and annuloplasty. During a mean follow-up of 9.7 years (0.00 - 15.9 years) in 38 (11.0%) cases reoperation on the mitral valve was necessary. Reoperations were performed after a mean of 6.8 years (0.00 - 14.1 years). The mechanisms of MVr failure were disease progression (39.5%), technical failure (36.8%) and endocarditis (18.4%). Re-repair was performed in 28.9% and was accomplished using redo annuloplasty (90.9%), chordal replacement (90.9%), resection techniques (27.3%) and leaflet patch reconstruction (9.1%). One patient (2.6%) received transcatheter edge-to-edge repair for reoperation. Mitral valve replacement (MVR) was necessary in 63.2%. Redo MVr was mainly performed in cases of technical failure and MVR was more frequently performed in cases with mitral valve sclerosis. Re-reoperation was necessary in 3/24 cases of MVR and in 2/11 cases of redo MVr after a median of 3.8 (0.01 - 10.04) years., Conclusions: MVr using chordal replacement allows a variety of methods for re-repair including transcatheter solutions. Redo MVr is more often feasible in cases of technical failure, while MVR for reoperation is more frequently necessary in mitral valve sclerosis., (Copyright © 2024. Published by Elsevier Inc.)

Normal pressure hydrocephalus (NPH) is marked by enlarged cerebral ventricles with normal intracranial pressure, plus three stereotypical symptoms: gait impairment, cognitive dysfunction, and urinary frequency with urge incontinence. The neural circuit dysfunction responsible for each of these symptoms remains unknown, and an adult mouse model would expand opportunities to explore these mechanisms in preclinical experiments. Here, we describe the first mouse model of chronic, communicating hydrocephalus with normal intracranial pressure. Hydrocephalic male and female mice had unsteady gait and reduced maximum velocity. Despite performing well on a variety of behavioral tests, they exhibited subtle learning impairments. Hydrocephalic mice also developed urinary frequency, and many became incontinent. This mouse model, with symptoms resembling human NPH, can be combined with molecular-genetic tools in any mouse strain to explore the neural circuit mechanisms of these symptoms. Preclinical work using this hydrocephalus model will lead to the development of new treatments for NPH symptoms., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Tish et al.)

Glycosylation, which plays an important role in modifying lipids and sorting of proteins, is regulated by asymmetric intra-Golgi distribution and SPPL3-mediated cleavage of Golgi enzymes. We found that cells lacking LYSET/TMEM251, a retention factor for Golgi N-acetylglucosamine-1-phosphotransferase (GNPT), display SPPL3-dependent hypersecretion of the Golgi membrane protein B4GALT5. We demonstrate that in wild-type cells B4GALT5 is tagged with mannose 6-phosphate (M6P), a sorting tag typical of soluble lysosomal hydrolases. Hence, M6P-tagging of B4GALT5 may represent a novel degradative lysosomal pathway. We also observed B4GALT5 hypersecretion and prominent destabilization of LYSET-GNPT complexes, impaired M6P-tagging, and disturbed maturation and trafficking of lysosomal enzymes in multiple human cell lines lacking the COPI adaptors GOLPH3 and GOLPH3L. Mechanistically, we identified LYSET as a novel, atypical client of GOLPH3/GOLPH3L. Thus, by ensuring the cis-Golgi localization of the LYSET-GNPT complex and maintaining its Golgi polarity, GOLPH3/GOLPH3L is essential for the integrity of the M6P-tagging machinery and homeostasis of lysosomes., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests. YN and HC have a financial interest in GlycoDisplay Aps. HC has a financial interest in GO Therapeutics Inc. YN and HC’s interests are reviewed and managed by the University of Copenhagen in accordance with their conflict of interest policies., (© 2024. The Author(s).)

The biarylitide crosslinking enzyme P450 Blt can perform crosslinking between m -F-Tyr-3 and His-5 residues within peptide substrates with concomitant and specific loss of fluorine. Our investigations suggest that a small intrinsic preference for coupling ipso to fluorine is magnified by the binding of the peptide in a specific orientation that enforces the loss of fluorine during peptide crosslinking, likely via a two-step reaction mechanism involving the non-enzyme catalysed reductive elimination of fluoride.

The malaria parasite Plasmodium falciparum employs antigenic variation of the virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copy var gene family. var genes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singular var gene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator of var gene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 in var gene regulation. We demonstrate that PfSET10 is not required for mutually exclusive var gene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulating var gene expression and is not required for blood-stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.IMPORTANCEThe malaria parasite Plasmodium falciparum infects hundreds of millions of people every year. To survive and proliferate in the human bloodstream, the parasites need to escape recognition by the host's immune system. To achieve this, P. falciparum can change the expression of surface antigens via a process called antigenic variation. This fascinating survival strategy is based on infrequent switches in the expression of single members of the var multigene family. Previous research reported conflicting results on the role of the epigenetic regulator PfSET10 in controlling mutually exclusive var gene expression and switching. Here, we unequivocally demonstrate that PfSET10 is neither required for antigenic variation nor the expression of any other proteins during blood-stage infection. This information is critical in directing our attention toward exploring alternative molecular mechanisms underlying the control of antigenic variation and investigating the function of PfSET10 in other life cycle stages., Competing Interests: The authors declare no conflict of interest.

Competing Interests: Conflicts of interest None disclosed.

The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer's disease (AD). The lack of specified conformational states in these species complicates efforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insufficient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new candidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small molecules that both remodel the AβO structure and localize a potent antioxidant that mimics the activity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold with nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and remolding along with assessments of bioactivity allow for the extraction of useful SAR information from screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate's bioactivity and its ability to reduce the fraction of antiparallel β-strand.

Chimeric antigen receptor T-cell (CAR-T) therapy is emerging as a novel treatment for systemic autoimmune rheumatic diseases. To date, CAR-T therapy in rheumatology has been reported only in case studies and conference abstracts, but clinical trial results are forthcoming. Current evidence indicates a rapid and highly effective therapeutic response with a favourable side effect profile, suggesting that CD19 CAR-T therapy could be beneficially established for these conditions. Initially, CAR-T therapy appears relevant for a select group of severe, treatment-resistant rheumatic diseases., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Biased signaling and ligand bias, often termed functional selectivity or selective nuclear receptor modulation, have been reported for nuclear receptor partial agonists over the past 20 years. Whether signaling differences produced by partial agonists result from less intense modulation, off-target effects, or biased signaling remains unclear. A commonly postulated mechanism for biased signaling is coactivator favoritism, where agonists induce different coactivator recruitment profiles. We find that both GW1929 (full agonist) and MRL24 (partial agonist) favor recruitment of 100 to 300 residue regions from S-motif coactivators compared with a reference full agonist (rosiglitazone), yielding 95% bias value confidence intervals of 0.05-0.17 and 0.29-0.38, respectively. Calculations based on these data indicate that GW1929 and MRL24 would induce 30% to 60% higher S-motif coactivator occupancy at the receptor compared with rosiglitazone. We compare the transcriptional effects of these same three ligands on human adipocytes using RNA sequencing and exploratory Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Only 50% (rosiglitazone) and 77% (GW1929) of all gene expression changes are shared between these full agonists after 3 hours of exposure. After 24 hours of exposure, 13/98 KEGG pathways appear more intensely modulated by rosiglitazone than GW1929 (e.g., 95% confidence interval of bias in the regulation of lipolysis in adipocytes pathway is 0.03-0.09), despite similar signaling for the remaining 85 affected pathways. Similarly, rosiglitazone has an unusually large effect on several lipid metabolism-related pathways compared with the partial agonist MRL24. These data indicate that nuclear receptor full and partial agonists can induce biased signaling, likely through differences in coactivator recruitment. SIGNIFICANCE STATEMENT: Many nuclear receptor partial agonists cause fewer adverse effects and similar efficacy compared with full agonists, potentially by inducing biased agonism. Our data support the idea that partial agonists, and a full agonist, of the nuclear receptor Peroxisome proliferator-activated receptor gamma (PPARγ) are biased agonists, causing different signaling by inducing PPARγ to favor different coactivators. These data indicate that biased agonism can occur in nuclear receptors and should be considered in efforts to develop improved nuclear receptor-targeted drugs., (Copyright © 2024 by The Author(s).)

Background: One third of adults with cancer suffer from common mental disorders in addition to their malignant disease. However, it is unknown whether this proportion is the same in patients who have brain tumors and which factors modulate the risk for psychiatric comorbidity., Methods: In a multicenter study, patients with high-grade glioma at 13 neurooncology clinics were enrolled consecutively and interviewed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID) to diagnose common mental disorders. Predictors of psychiatric comorbidity were investigated using binary logistic regression., Results: Six hundred ninety-one patients were interviewed. The proportion of patients who had mental disorders was 31% (95% confidence interval [CI], 28%-35%). There was evidence for an association of psychiatric comorbidity with the following factors: younger age (odds ratio [OR], 1.9; 95% CI, 1.1-3.4; p = .04), stable disease versus complete remission (OR, 1.7; 95% CI, 1.1-2.8; p = .04), lower income (OR, 1.7; 95% CI, 1.0-2.8; p = .04), living alone (OR, 1.6; 95% CI, 1.0-2.6; p = .05), fatigue (OR, 1.6; 95% CI, 1.1-2.4; p = .03), and impaired cognitive functioning (OR, 2.3; 95% CI, 1.5-3.6; p < .01). There was no evidence for independent effects of gender, histology, affected lobe, time since diagnosis, or employment status., Conclusions: Approximately one third of adult patients with high-grade glioma may suffer from a clinically relevant common mental disorder, without notable disparity between the genders. In particular, clinicians should pay attention to possible comorbidities for cases in which patients exhibit compromised subjective cognitive function, are younger than 50 years, maintain a state of stable disease, or live alone., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objectives: The purpose of the study was to assess the impact of a pretherapeutic Multidisciplinary Tumor Board (MTB) presentation on the prognosis and treatment outcomes in patients with primary oral cavity carcinoma., Materials and Methods: This single-center study included 630 patients diagnosed with oral cavity carcinoma treated between 2010 and 2020. The study cohort was divided in a group with and without pretherapeutic MTB presentation. Data on patient demographics, tumor characteristics, treatment and the time to treatment initiation (TTI) were collected retrospectively., Results: Primary findings revealed no significant difference in 3-year survival rate (3-YSR) and 3-year disease-free survival rate (3-YDFSR) for the non-MTB and MTB group. The 3-YSR was 73.1% in the non-MTB group and 67.1% in the MTB group ( p   =  0.112). The 3-YDFSR was 73.8% in the non-MTB group and 76.5% in the MTB group ( p  = 0.447). Estimated mean 5-year survival (5-YS) and 5-year disease-free survival in (5-YDFS) did not differ significantly between both groups, across the UICC stages I-IV, as well as for the entire cohort. The TTI was significantly longer in the MTB group (33.5 days, CI: 31.3;35.7) compared to the non-MTB group (20.1 days, CI: 17.9;22.4, p  < 0.001). The MTB group adhered more frequently to the national guidelines (68% vs. 79.6%, p  < 0.01)., Conclusion: The results demonstrate both positive and negative side effects of the MTB presentation in patients with oral cavity cancer. Further multicenter studies will be required to assess the impact of TTI and adherence to guidelines on the survival of oral cavity cancer patients., 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., (© 2024 Burkhardt, El-Shabrawi, Riemann, Voss and Becker.)

Per- and polyfluoroalkyl substances (PFAS), known colloquially as "forever chemicals," have been associated with adverse human health effects and have contaminated drinking water supplies across the United States owing to their long-term and widespread use. People in the United States may unknowingly be drinking water that contains PFAS because of a lack of systematic analysis, particularly in domestic water supplies. We present an extreme gradient-boosting model for predicting the occurrence of PFAS in groundwater at the depths of drinking water supply for the conterminous United States. Our model results indicate that 71 million to 95 million people in the conterminous United States potentially rely on groundwater with detectable concentrations of PFAS for their drinking water supplies before any treatment.

Whole-body MRI (WBMRI) is an integral part of screening infants, children, and adolescents for presymptomatic neoplasms in certain cancer predisposition syndromes, which include Li-Fraumeni and constitutional mismatch repair deficiency syndromes, among others. The list of syndromes in which WBMRI adds value, as part of a comprehensive surveillance protocol, continues to evolve in response to new evidence, growing experience, and more widespread adoption. In July 2023, the AACR reconvened an international, multidisciplinary panel to revise and update recommendations stemming from the 2016 AACR Special Workshop on Childhood Cancer Predisposition. That initial meeting resulted in a series of publications in Clinical Cancer Research in 2017, including "Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI." This 2024 review of WBMRI in cancer predisposition syndrome updates the 2017 WBMRI publication, the revised recommendations derived from the 2023 AACR Childhood Cancer Predisposition Workshop based on available data, societal guidelines, and expert opinion. Different aspects of acquiring and interpreting WBMRI, including diagnostic accuracy, are discussed. The application of WBMRI in resource-poor environments, as well as integration of whole-body imaging techniques with emerging technologies, such as cell-free DNA ("liquid biopsies") and artificial intelligence/machine learning, is also considered., (©2024 American Association for Cancer Research.)

TGFβ-signaling regulates cancer progression by controlling cell division, migration, and death. These outcomes are mediated by gene expression changes, but the mechanisms of decision-making toward specific fates remain unclear. Here, we combine SMAD transcription factor imaging, genome-wide RNA sequencing, and morphological assays to quantitatively link signaling, gene expression, and fate decisions in mammary epithelial cells. Fitting genome-wide kinetic models to our time-resolved data, we find that most of the TGFβ target genes can be explained as direct targets of SMAD transcription factors, whereas the remainder show signs of complex regulation, involving delayed regulation and strong amplification at high TGFβ doses. Knockdown experiments followed by global RNA sequencing revealed transcription factors interacting with SMADs in feedforward loops to control delayed and dose-discriminating target genes, thereby reinforcing the specific epithelial-to-mesenchymal transition at high TGFβ doses. We identified early repressors, preventing premature activation, and a late activator, boosting gene expression responses for a sufficiently strong TGFβ stimulus. Taken together, we present a global view of TGFβ-dependent gene regulation and describe specificity mechanisms reinforcing cellular decision-making., (© 2024 Hartmann et al.)

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds' potencies were evaluated in calcium mobilization and radioligand binding assays, and structure-activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3'-methoxy-[1,1'-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid ( 52 , PSB-22269, K i 8.91 nM) and its 3'-trifluoromethyl analog ( 54 , PSB-24040, K i 83.2 nM). Receptor-ligand docking studies revealed that the compounds' binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.

Purpose: Clinical trials enable renal cell carcinoma (RCC) patients to receive promising investigational agents, yet access may be limited. Telemedicine (TM) is an increasingly utilized platform that can expand access, but perspectives on its use in clinical trial care are unknown., Patients and Methods: A prospective study was conducted between Jan 2023 - Oct 2023 at Memorial Sloan Kettering Cancer Center. RCC patients enrolled on therapeutic clinical trials who had prior TM visits were eligible. Surveys in English were distributed to patients, treating clinical trial nurses (CTNs), and oncology providers engaged in clinical trials., Results: 39 patients, 7 CTNs, and 15 oncology providers were included in our analysis. Regarding clinical trial care, 26 patients (67%) preferred in-person, 4 (11%) preferred TM, and 9 (22%) had no preference. However, 25 patients (64%) reported TM provided an equal quality of care, and 38 (97%) reported a positive or neutral experience. Conversely, 7 CTNs (100%) and 11 providers (73%) preferred in-person care while 4 (27%) indicated no preference. Most, including 6 CTNs (86%) and 13 providers (87%), reported that TM quality of care was inferior. However, most, including 7 CTNs (100%) and 14 providers (93%), reported a positive experience with TM., Conclusions: In this study, one third of RCC participants preferred TM or had no preference, and a majority felt TM delivered equal quality of care. Providers, however, preferred in-person visits and reported inferior quality of care with TM. These findings warrant further evaluation of safety and feasibility to optimize TM integration for clinical trial care delivery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pangenomes are collections of annotated genome sequences of multiple individuals of a species 1 . The structural variants uncovered by these datasets are a major asset to genetic analysis in crop plants 2 . Here we report a pangenome of barley comprising long-read sequence assemblies of 76 wild and domesticated genomes and short-read sequence data of 1,315 genotypes. An expanded catalogue of sequence variation in the crop includes structurally complex loci that are rich in gene copy number variation. To demonstrate the utility of the pangenome, we focus on four loci involved in disease resistance, plant architecture, nutrient release and trichome development. Novel allelic variation at a powdery mildew resistance locus and population-specific copy number gains in a regulator of vegetative branching were found. Expansion of a family of starch-cleaving enzymes in elite malting barleys was linked to shifts in enzymatic activity in micro-malting trials. Deletion of an enhancer motif is likely to change the developmental trajectory of the hairy appendages on barley grains. Our findings indicate that allelic diversity at structurally complex loci may have helped crop plants to adapt to new selective regimes in agricultural ecosystems., Competing Interests: Competing interests: K.B., C.D., M.E.J., S.M.K., Q.L., E.M., P.R.P., B.S., H.C.T., M.T.S.N., C.V. and M.W.R. are current or previous Carlsberg A/S employees. P.A.P. and D.V. are SECOBRA Recherches employees. The other authors declare no competing interests., (© 2024. The Author(s).)

Heterozygous mutations in the histone lysine acetyltransferase gene KAT6B ( MYST4/MORF/QKF ) underlie neurodevelopmental disorders, but the mechanistic roles of KAT6B remain poorly understood. Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth. Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particular Sox2 , which is a key driver of neural progenitor proliferation, multipotency and brain development. In the fetal cortex, KAT6B occupied the Sox2 locus. Loss of KAT6B caused a reduction in Sox2 promoter activity in NSPCs. Sox2 overexpression partially rescued the proliferative defect of Kat6b -/- NSPCs. Collectively, these results elucidate molecular requirements for KAT6B in brain development and identify key KAT6B targets in neural precursor cells and the developing brain., (© 2024 Bergamasco et al.)

Objectives: Antibiotic resistance poses a major global public health threat. However, research on this issue is limited, especially among nursing students. This study aims to examine knowledge of antibiotics and antibiotic resistance, antibiotic use, and eHealth literacy in Thailand., Design: A cross-sectional study was conducted using an online self-administered questionnaire. The WHO Antibiotic Resistance: Multi-Country Public Awareness Survey and the eHealth Literacy Scale were used. Descriptive and multiple regression analyses were performed., Setting: Thailand's North, South, Central and Northeast between January and February 2024., Participants: A total of 1180 nursing students aged 18 or older, from first to fourth year and fluent in Thai, were invited to participate., Results: The participants were mostly female (89.8%), with an average age of 20.64±1.81 years. Over half of the respondents (67.7%) have used antibiotics, mistakenly believing that antibiotics could treat colds and influenza (70.3%), malaria (66.8%), measles (63.6%) and sore throats (60.9%). About 71.5% recognised the impact of antibiotic resistance on themselves and their families, but 93.1% incorrectly believed antibiotic resistance means the body resists antibiotics. Participants scored 35.92±4.21 out of 40 on eHealth literacy. In a multiple regression analysis, three factors predict knowledge of antibiotic resistance: knowledge of antibiotics (B=0.199, p<0.001, 95% CI 0.165 to 0.234), eHealth literacy (B=0.078, p<0.001, 95% CI 0.056 to 0.100) and academic year (B=0.271, p<0.001, 95% CI 0.184 to 0.358), with knowledge of antibiotics being the most impact (β=0.318). These three variables explained 23.7% of the variance in antibiotic resistance knowledge scores., Conclusions: Despite high eHealth literacy, nursing students hold misconceptions about antibiotic treatable conditions and insufficient knowledge of antibiotic resistance. This highlights the need to integrate antibiotic contents into nursing curricular and enhance eHealth literacy for better access and navigate health information., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)