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UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

We investigated the pyrolysis of propyne and propene using aerosol mass spectrometry coupled with tunable synchrotron vacuum ultraviolet photoionization. The results show that propyne forms particles at pyrolysis temperatures approximately 100 K below the lowest temperature at which propene produces particles. The aerosol mass spectra show that the carbon-to-hydrogen (C/H) ratios of the pyrolysis products from both reactants increase with temperature between the particle onset temperature and 1275 K. In this temperature range, the mass peaks corresponding to species with 18 or more carbon atoms are more saturated (i.e., have lower C/H ratios) than species predicted by the stabilomer grid. The observation of relatively high saturation (low C/H ratios) at temperatures near particle onset is consistent with the presence of aliphatically linked hydrocarbons during the preliminary stages of soot formation. The masses of the species presumed to be aliphatically linked suggest that these linked species are adducts of species smaller than chrysene (C18H12). We performed a comparative analysis of the initial PAH-growth pathways consistent with aerosol mass spectra and associated mass-specific photoionization-efficiency curves. The results from the comparative analysis indicate that the development of PAHs up to the size of acenaphthylene (C12H8) follow similar formation pathways for propyne and propene, but the isomeric composition of species larger than acenaphthylene diverges for the two reactants.

Abstract Background Nonsuicidal self-injury (NSSI) is highly prevalent in adolescents and young adults worldwide. It is linked to a broad variety of mental disorders and an increased suicide risk. Despite its high prevalence, research on the underlying mechanisms and on potential risk and resilience factors for maintaining or quitting NSSI remains scarce. This manuscript presents an overview of the “Self-injury: Treatment-Assessment-Recovery” (STAR) collaboration, which aimed to address these gaps. Methods We investigated the natural course of NSSI as well as its social, psychological, and neurobiological predictors (observational study; OS). OS data collection occurred at four timepoints (baseline [T0], 4 [post, T1], 12 [follow-up (FU), T2], and 18 [FU, T3] months after baseline) for the NSSI group, which was compared to a healthy control (HC) group at T0 only. Online self-report was used at all timepoints, while semi-structured interviews (face-to-face (f2f)) were conducted at T0 and T3. At T0 only, we conducted ecological momentary assessment and neurobiological investigations. Here, we present the general methodology and sample characteristics of the completed OS including the f2f subprojects, while other subprojects are not within the scope of this paper. Sample description The OS sample consists of 343 participants at T0 (180 NSSI, 163 HC). Mean age in the NSSI group (T0) was 18.1 years (SD = 2.09, range: 15–25), gender-related data is available for 166: 156 = female, 7 = male, 3 = transgender, 10 = not disclosed). In the HC group, mean age (T0) was 19.1 years (SD = 2.35, range: 15–25) (142 = female, 21 = male). At T1, 128 (71.11%) of the NSSI participants completed the questionnaires, at T2 125 (69.44%) and at T3 104 (57.78%). In the fMRI subproject, 126 adolescents participated (NSSI = 66, HC = 60, 100% female; mean age (T0): NSSI = 18.10 years, SD = 2.21; HC = 19.08, SD = 2.36). Conclusion Understanding predictors is of utmost importance for adequate diagnosis and intervention for NSSI. Our OS applied a multimodal investigation of social, psychological, and neurobiological parameters and is the largest sample of adolescents with NSSI to date including follow-up assessments. As health care providers require specific knowledge to develop new treatments, we believe that our in-depth assessments can potentially enhance care for youths engaging in NSSI.

Abstract We aimed to explore novel biomarker candidates and biomarker signatures of late-onset preeclampsia (LOPE) by profiling samples collected in a longitudinal discovery cohort with a high-throughput proteomics platform. Using the Somalogic 5000-plex platform, we analyzed proteins in plasma samples collected at three visits (gestational weeks (GW) 12–19, 20–26 and 28–34 in 35 women with LOPE (birth ≥ 34 GW) and 70 healthy pregnant women). To identify biomarker signatures, we combined Elastic Net with Stability Selection for stable variable selection and validated their predictive performance in a validation cohort. The biomarker signature with the highest predictive performance (AUC 0.88 (95% CI 0.85–0.97)) was identified in the last trimester of pregnancy (GW 28–34) and included the Fatty acid amid hydrolase 2 (FAAH2), HtrA serine peptidase 1 (HTRA1) and Interleukin-17 receptor C (IL17RC) together with sFLT1 and maternal age, BMI and nulliparity. Our biomarker signature showed increased or similar predictive performance to the sFLT1/PGF-ratio within our data set, and we were able to validate the biomarker signature in a validation cohort (AUC ≥ 0.90). Further validation of these candidates should be performed using another protein quantification platform in an independent cohort where the negative and positive predictive values can be validly calculated.

Abstract Aims Decision‐makers still predominantly focus on the perspective of non‐patient stakeholders, which may deviate from the unique perspective of heart failure (HF) patients. To enhance patient‐centred decision‐making, there is a need for more patient‐based evidence derived directly from the patients themselves. Hence, this study aimed to understand (i) HF patients' unmet medical needs and preferred treatment outcomes; (ii) patients' risk tolerance; and (iii) their information needs, uncertainties and satisfaction towards HF treatment. Methods This qualitative patient preference study consisted of a literature review with a systematic search strategy and semi‐structured interviews with HF patients, analysed using the framework method. During the interviews, patients were asked to rank a predefined list of disease and treatment‐related characteristics informed by the literature review and were able to spontaneously raise additional characteristics. Results The study included 14 Belgian HF patients (age range: 58–79, mean age: 72). (i) Regarding their unmet medical needs, HF patients reported that the most important unmet medical needs were shortness of breath and fatigue, as they negatively impact their quality of life (QoL) and independence. In the ranking exercise, patients prioritized improvements in QoL over improvements in life expectancy, whereby the following characteristics received the highest cumulative score: (1) independence, (2) shortness of breath, (3) impaired renal function, (4) survival, (5) fatigue, (6) risk of hospitalization and (7) communication with and between physicians. Patients most often spontaneously raise characteristics related to the general care process. Mechanism of action, route of administration, dose frequency and weight fluctuations scored among the least important characteristics. (ii) Regarding patients' risk tolerance towards HF treatment, some of the patients expressed zero tolerance for side effects, as they had not yet experienced any discomfort caused by the treatment or disease. (iii) Regarding their information needs, patients voiced their desire to receive practical and comprehensible advice orally from their physician because they highly value individualized treatment decision‐making. Patients also expressed uncertainties regarding whether the experienced effects were due to their treatment, disease, ageing or other comorbidities. Conclusions This study shows that, besides increasing life expectancy, HF patients prioritize improvements in symptoms and side effects reducing their QoL and independence, such as shortness of breath and fatigue. The patient‐relevant characteristics identified in this study, from the perspective of HF patients themselves, may be useful to inform clinical trial endpoint selection and guide downstream drug development, evaluation and clinical decision‐making towards addressing the unmet medical needs and treatment outcomes of importance to HF patients.

Abstract Background Eating disorders (EDs) constitute a considerable burden for individuals and society, but adequate and timely professional treatment is rare. Evidence-based Digital Mental Health Interventions (DMHIs) have the potential both to reduce this treatment gap and to increase treatment effectiveness. However, their integration into routine care is lacking. Understanding practitioners’ attitudes towards DMHIs for EDs is crucial for their effective use. Aims To investigate the consensus among German ED treatment experts on the relevance of different influencing factors for DMHI use in EDs. Methods This Delphi study consisted of two rounds and was conducted online with an initial sample of N = 24 ED experts (M age=41.96, SD age=9.92, n = 22 female). Prior to the Delphi rounds, semi-structured qualitative telephone interviews were performed to explore participants’ attitudes, experiences, and expectations towards DMHIs. In order to construct the Delphi survey, content analysis was applied to a subset of ten interviews. A total of 63 influencing factors were identified and grouped into three main categories: contextual conditions, design, and content of DMHIs. In both Delphi rounds, the interview participants were subsequently invited to rate each of the factors with regard to their importance on 10-point scales. Group percentages and individual ratings of the first round (n = 23) were presented in the second round (n = 21). Consensus was calculated for each item (defined as IQR ≤ 2). Results Importance ratings were high across items (M = 7.88, SD = 2.07, Mdn = 8). In the first round, 48% of the items reached consensus, with its most important (Mdn = 10) factors referring to data security, evidence base, technical requirements, usability, and specific DMHI content (psychoeducation, crisis intervention). In the second Delphi round, a consensus was reached on 73% of the items. No consensus was reached on 17 items. Conclusions The findings on practitioners’ attitudes and priorities have relevant implications for subsequent DMHI development, dissemination, and implementation strategies, indicating that the highest-rated factors should be highlighted in the process.

Abstract Background Despite the detrimental impact of abnormal glucose metabolism on cardiovascular prognosis after myocardial infarction (MI), diabetes is both underdiagnosed and undertreated. We investigated associations between structured diabetes care routines in cardiac rehabilitation (CR) and detection and treatment of diabetes at one-year post-MI. Methods Center-level data was derived from the Perfect-CR survey, which evaluated work routines applied at Swedish CR centers (n = 76). Work routines involving diabetes care included: (1) routine assessment of fasting glucose and/or HbA1c, (2) routine use of oral glucose tolerance test (OGTT), (3) having regular case rounds with diabetologists, and (4) whether glucose-lowering medication was adjusted by CR physicians. Patient-level data was obtained from the national MI registry SWEDEHEART (n = 7601, 76% male, mean age 62.6 years) and included all post-MI patients irrespective of diabetes diagnosis. Using mixed-effects regression we estimated differences between patients exposed versus. not exposed to the four above-mentioned diabetes care routines. Outcomes were newly detected diabetes and the proportion of patients receiving oral glucose-lowering medication at one-year post-MI. Results Routine assessment of fasting glucose/HbA1c was performed at 63.2% (n = 48) of the centers, while 38.2% (n = 29) reported using OGTT for detecting glucose abnormalities. Glucose-lowering medication adjusted by CR physicians (n = 13, 17.1%) or regular case rounds with diabetologists (n = 7, 9.2%) were less frequently reported. In total, 4.0% of all patients (n = 304) were diagnosed with diabetes during follow-up and 17.9% (n = 1361) were on oral glucose-lowering treatment one-year post-MI. Routine use of OGTT was associated with a higher rate of newly detected diabetes at one-year (risk ratio [95% confidence interval]: 1.62 [1.26, 1.98], p = 0.0007). At one-year a higher proportion of patients were receiving oral glucose-lowering medication at centers using OGTT (1.22 [1.07, 1.37], p = 0.0046) and where such medication was adjusted by CR physicians (1.31 [1.06, 1.56], p = 0.0155). Compared to having none of the structured diabetes care routines, the more routines implemented the higher the rate of newly detected diabetes (from 0 routines: 2.7% to 4 routines: 6.3%; p for trend = 0.0014). Conclusions Having structured routines for diabetes care implemented within CR can improve detection and treatment of diabetes post-MI. A cluster-randomized trial is warranted to ascertain causality.

Abstract Background To combat coronavirus disease 2019 (COVID-19), booster vaccination strategies are important. However, the optimal administration of booster vaccine platforms remains unclear. Herein, we aimed to assess the benefits and harms of three or four heterologous versus homologous booster regimens. Methods From November 3 2022 to December 21, 2023, we searched five databases for randomised clinical trials (RCT). Reviewers screened, extracted data, and assessed bias risks independently with the Cochrane risk-of-bias 2 tool. We conducted meta-analyses and trial sequential analyses (TSA) on our primary (all-cause mortality; laboratory confirmed symptomatic and severe COVID-19; serious adverse events [SAE]) and secondary outcomes (quality of life [QoL]; adverse events [AE] considered non-serious). We assessed the evidence with the GRADE approach. Subgroup analyses were stratified for trials before and after 2023, three or four boosters, immunocompromised status, follow-up, risk of bias, heterologous booster vaccine platforms, and valency of booster. Results We included 29 RCTs with 43 comparisons (12,538 participants). Heterologous booster regimens may not reduce the relative risk (RR) of all-cause mortality (11 trials; RR 0.86; 95% CI 0.33 to 2.26; I 2 0%; very low certainty evidence); laboratory-confirmed symptomatic COVID-19 (14 trials; RR 0.95; 95% CI 0.72 to 1.25; I 2 0%; very low certainty); or severe COVID-19 (10 trials; RR 0.51; 95% CI 0.20 to 1.33; I 2 0%; very low certainty). For safety outcomes, heterologous booster regimens may have no effect on SAE (27 trials; RR 1.15; 95% CI 0.68 to 1.95; I 2 0%; very low certainty) but may raise AE considered non-serious (20 trials; RR 1.19; 95% CI 1.08 to 1.32; I 2 64.4%; very low certainty). No data on QoL was available. Our TSAs showed that the cumulative Z curves did not reach futility for any outcome. Conclusions With our current sample sizes, we were not able to infer differences of effects for any outcomes, but heterologous booster regimens seem to cause more non-serious AE. Furthermore, more robust data are instrumental to update this review.

The Metropolitan Water District (MWD) serves local member agencies which in turn supply water to nearly half of California’s population. The MWD’s Local Resources Program (LRP) helps fund projects designed and proposed by its member agencies to produce more locally-sourced water in Southern California, to bolster the region’s self-resiliency and reduce reliance on imported water sources. As of 2022, MWD states that its LRP supports close to half of the recycled water and groundwater recovery production in the district’s service area (MWD CAP, 2022). Southern California has been in a state of water crisis since patterns of record-breaking drought began in the early 1990s.Southern California’s reliance upon imported water supplied from the State Water Project (SWP) and the Colorado River has come under threat. Faced with expanding cuts in water supplies delivered via the SWP, the region has needed to draw more and more water from the Colorado River to meet residential needs, putting water sources at risk of drying up or being unable to produce hydroelectric power. Hence, programs like the LRP which stand to help reduce water demand from member agencies have only grown in importance. Before our study, an independent, public analysis of LRP funding distribution and an in-depth survey concerning the perspectives of receiving member agencies had not yet been conducted. Accordingly, in this study, in cooperation with MWD and many of its member agencies, our research team assessed existing documents, conducted interviews, and performed statistical analyses on funding trends from the program’s inception in 1984 to today. In our evaluation of the LRP, the overarching question we are aiming to address is: “What has been the effectiveness of MWD’s Local Resources Program in terms of water resilience and equity, and can it be improved?” This research seeks to inform how the LRP fits into a comprehensive vision for Southern California of a long-term transition to local water resources.

Dealing with students' conceptions is one of the central elements of student-oriented teaching. To be able to organize learning processes efficiently, it is necessary to look at the learners in a differentiated way and to approach their conceptions individually. The first necessary step is the individual diagnosis of each student's conceptions. This article presents a qualitative study (n = 8) that focused on the development of drawing assignments for the diagnosis of conceptions on the topic of plant nutrition. Based on the conceptual metaphor theory (CMT), features were identified that are beneficial for the diagnosis of the conceptions. To achieve this goal, it was crucial to reliably diagnose existing conceptions with valid assignments, which can also be carried out in schools. Research about task design and the proceeding diagnosis of conceptions in the light of the CMT has received little attention so far. This article, therefore, deals predominantly with the question about the design of assignments in the context of conceptual change. Based on this, guidelines were derived for the design of assignments for practical use in science education. This study represents the basis for developing a Moodle-based digital learning environment for working with students' conceptions on the topic of plant nutrition in schools.

Objectives To re-evaluate cut-offs for disease activity states according to the Axial Spondyloarthritis Disease Activity Score (ASDAS), and study the impact of sex, age, calendar time, disease and symptom duration on ASDAS and ASDAS cut-offs in a large contemporary cohort.Methods Data from 2939 patients with axial spondyloarthritis (axSpA) starting their first tumour necrosis factor inhibitor in nine European registries were pooled and analysed. Receiver operating characteristic analyses were performed to identify cut-offs against external criteria. Six-month data including patient and physician global assessments, both ≤1 (0–10 integer scale), and Assessment of SpondyloArthritis International Society partial remission were used for separation of inactive disease (ID) from low disease activity (LDA), while patient and physician global ≤3 were applied as external criteria to separate LDA from high disease activity (HDA). Patient and physician global ≥6 were applied to separate HDA from very high disease activity in baseline data.Results The three ASDAS cut-offs identified to separate the four disease activity states in the overall patient population were 3.5. Cut-offs for ID and LDA in women were higher (

IntroductionThe maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn’s disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses.Results and discussionHowever, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2) or dendritic cells (Atg16l1ΔCd11c) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7.ConclusionIn conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.

Abstract Background Providing secondary prevention through structured and comprehensive cardiac rehabilitation programmes to patients after a myocardial infarction (MI) reduces mortality and morbidity and improves health-related quality of life. Cardiac rehabilitation has the highest recommendation in current guidelines. While treatment target attainment rates at Swedish cardiac rehabilitation centres is among the highest in Europe, there are considerable differences in service delivery and variations in patient-level outcomes between centres. In this trial, we aim to study whether centre-level guideline adherence and patient-level outcomes across Swedish cardiac rehabilitation centres can be improved through a) regular audit and feedback of cardiac rehabilitation structure and processes through a national quality registry and b) supporting cardiac rehabilitation centres in implementing guidelines on secondary prevention. Furthermore, we aim to evaluate the implementation process and costs. Methods The study is an open-label cluster-randomized effectiveness-implementation hybrid trial including all 78 cardiac rehabilitation centres (attending to approximately 10 000 MI patients/year) that report to the SWEDEHEART registry. The centres will be randomized 1:1:1 to three clusters: 1) reporting cardiac rehabilitation structure and process variables to SWEDEHEART every six months (audit intervention) and being offered implementation support to implement guidelines on secondary prevention (implementation support intervention); 2) audit intervention only; or 3) no intervention offered. Baseline cardiac rehabilitation structure and process variables will be collected. The primary outcome is an adherence score measuring centre-level adherence to secondary prevention guidelines. Secondary outcomes include patient-level secondary prevention risk factor goal attainment at one-year after MI and major adverse coronary outcomes for up to five-years post-MI. Implementation outcomes include barriers and facilitators to guideline adherence evaluated using semi-structured focus-group interviews and relevant questionnaires, as well as costs and cost-effectiveness assessed by a comparative health economic evaluation. Discussion Optimizing cardiac rehabilitation centres’ delivery of services to meet standards set in guidelines may lead to improvement in cardiovascular risk factors, including lifestyle factors, and ultimately a decrease in morbidity and mortality after MI. Trial registration ClinicalTrials.gov. Identifier: NCT05889416 . Registered 2023-03-23.

Abstract Dominant microorganisms of the Sargasso Sea are key drivers of the global carbon cycle. However, associated viruses that shape microbial community structure and function are not well characterised. Here, we combined short and long read sequencing to survey Sargasso Sea phage communities in virus- and cellular fractions at viral maximum (80 m) and mesopelagic (200 m) depths. We identified 2,301 Sargasso Sea phage populations from 186 genera. Over half of the phage populations identified here lacked representation in global ocean viral metagenomes, whilst 177 of the 186 identified genera lacked representation in genomic databases of phage isolates. Viral fraction and cell-associated viral communities were decoupled, indicating viral turnover occurred across periods longer than the sampling period of three days. Inclusion of long-read data was critical for capturing the breadth of viral diversity. Phage isolates that infect the dominant bacterial taxa Prochlorococcus and Pelagibacter, usually regarded as cosmopolitan and abundant, were poorly represented.

Abstract Background The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. Method Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase‐associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). Results At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. Conclusion Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Introduction: The COVID-19 pandemic has had a significant social and health impact. Given the high risk of contagion and the potential collapse of the healthcare system, strategies such as social isolation, the use of personal protective equipment, and an increased reliance on telemedicine were adopted. These measures altered the dynamics of end-of-life patient care. Methodology: This observational cross-sectional study explored the experiences of home care staff providing end-of-life care and the impact of the pandemic on the care process, as well as on their quality of life and emotional well-being. A survey incorporating the adapted Care Of the Dying Evaluation (iCODE) questionnaire was conducted, alongside an assessment of quality of life using question 30 of the EORTC QLQ, and emotional wellbeing using the PANAS scale. Results: The experiences of 131 deceased patients were characterized. Professionals reported adequate therapeutic efforts in managing pain, dyspnea, and delirium. Additionally, they noted that the pandemic impeded treatment in 24% of the patients. The average quality of life score for professionals was 6 points, with a predominantly positive affect reported. Conclusions: Healthcare professionals in home-based care programs observed that the pandemic affected the treatment of nearly a quarter of end-of-life patients. Nonetheless, they highlighted that satisfactory symptomatic care and control were maintained. Additionally, they reported an adequate quality of life.

The complexity of chronic pain requires interdisciplinary collaboration. Although this is recognisable in the framework for pain centres, few studies have investigated how interdisciplinary collaboration in pain centres is experienced by healthcare professionals, including the facilitators and barriers to interdisciplinary collaboration. The aim of the current study was therefore to investigate experiences of interdisciplinary collaboration in the treatment of patients with chronic pain among healthcare professionals in tertiary care pain centres.

Abstract Plant biomass is a fundamental ecosystem attribute that is sensitive to rapid climatic changes occurring in the Arctic. Nevertheless, measuring plant biomass in the Arctic is logistically challenging and resource intensive. Lack of accessible field data hinders efforts to understand the amount, composition, distribution, and changes in plant biomass in these northern ecosystems. Here, we present The Arctic plant aboveground biomass synthesis dataset, which includes field measurements of lichen, bryophyte, herb, shrub, and/or tree aboveground biomass (g m−2) on 2,327 sample plots from 636 field sites in seven countries. We created the synthesis dataset by assembling and harmonizing 32 individual datasets. Aboveground biomass was primarily quantified by harvesting sample plots during mid- to late-summer, though tree and often tall shrub biomass were quantified using surveys and allometric models. Each biomass measurement is associated with metadata including sample date, location, method, data source, and other information. This unique dataset can be leveraged to monitor, map, and model plant biomass across the rapidly warming Arctic.

In this study we aim to explore healthcare and social work students’ experiences with VR simulation as a means of preparing for professional practice, and how these experiences contribute to their readiness for future professional roles. We collected data through focus group interviews with 28 students from bachelor’s programs in nursing, social education, social work, and occupational therapy, which we subsequently transcribed and analyzed using thematic analysis. Our findings highlight VR simulation’s potential as a valuable tool for professional practice training. VR simulation can be especially helpful for students who benefit less from ordinary clinical placements due to their need for more time and experience to become more confident in their professional role. By incorporating relevant aspects of the workplace and providing opportunities for repeated training, VR simulation can contribute to preparing students for the demands of professional practice.

Abstract Normal pressure hydrocephalus (NPH) leads to cognitive impairment (CI) as part of its triad of symptoms. Assessment of CI before and after a tap test can be used to inform diagnosis, differentiate NPH symptoms from alternative or concomitant causes of CI, and suggest the potential benefits of valve placement. The aims of this study are: to describe cognitive performance in patients with NPH diagnosis before and after a tap test, and to compare CI between patients with NPH meeting criteria for a dementia diagnosis (D +) and those without criteria for dementia (D−) at both baseline and after the tap-test. We performed a Before-and-after study evaluating clinical features and performance on cognitive tests (CERAD, ADAS-COG, SVF, PVF, ROCF and IFS). We included 76 NPH patients, with a median age of 81 years. 65 patients (87.8%) improved cognitive performance after tap test. ROCF (p = 0.018) and IFS (p

Abstract Background In the context of rising costs of raw materials and environmental degradation caused by livestock farming, the agri-food sector faces significant challenges in sourcing sustainable proteins. Grain legumes have emerged as cost-effective protein sources, with lower water footprint and GHG emissions compared to animal sources. However, their cultivation is threatened by strong yield fluctuations. Leveraging intra-specific diversity through cultivar mixtures in cropping systems can effectively buffer biotic and abiotic stresses, hence increasing yield stability. In this study, we investigate the effect of intra-specific diversity on lentil nitrogen uptake under pot (2020) and field conditions (2021). We hypothesize that cultivars with higher affinity for nitrogen fixation influence the other components of the mixture, and that nitrogen uptake dynamics are a possible driver in modulating cultivar mixture behaviour. We designed two-, three-, and four-cultivar mixtures with a trait-blind approach and compared them to sole cultivars. Results and conclusions Our results show inconsistencies across the two experimental years, indicating that lentils may shift their nitrogen source from the atmosphere to the soil when grown in pots. Mixtures 15N enrichment was not always consistent with pure stand performance, suggesting that cultivar mixtures may have an unpredictable cumulative effect on nitrogen uptake. Regarding correlations with agronomic parameters, we observed a significant correlation between nodules number and nitrogen concentration, regardless of experimental conditions. Finally, we found that 15N excess emerged as a significant predictor for pure stands’ yield, but the differences were diluted with the increase in diversity levels. The findings on 15N enrichment responses, cultivar impacts, and complex mixture effects on soil microbiota underscore the need for further research.

Background & aimsTumor necrosis factor (TNF) superfamily member tumor necrosis factor-like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor-like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration.MethodsClinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), Tl1a-/- and Dr3-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential.ResultsDr3-/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3-/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were altered, leading to increased homeostatic intestinal permeability. Dr3ΔIEC mice recapitulated the phenotype observed in Dr3-/- mice with increased intestinal permeability and IEC proliferation under homeostatic conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3ΔIEC enteroids.ConclusionsOur findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells.

Popular modern diets are often seen as a panacea for improving health and promoting weight reduction. While there is a large body of literature reporting the health benefits of popular diets, few studies have described their planetary benefits. Our investigation aims to evaluate the simultaneous impacts of six popular diets within the United States on both human and planetary health. Using carbon footprint databases and representative meal plans, the environmental and health-related impacts of the Standard American, Mediterranean, vegan, paleo, keto, and climatarian diets are compared using the currently available literature. Results indicate that diets that exhibit lower carbon footprints also have positive effects on human health. The diets found to have the lowest environmental impacts were the vegan, climatarian, and Mediterranean diets. These low-carbon-footprint diets can likely be attributed to a reduced reliance on ruminant meat (cattle and sheep) and processed food consumption, while diets with high carbon footprints are more dependent on ruminant meat and saturated fat. Moderate consumption of meats such as chicken, pork, and fish in conjunction with an emphasis on locally grown fruits and vegetables can be maintained without adversely affecting the planetary carbon footprint and with the added benefit of promoting good health. Thus, making simple substitutions within each individual's diet can be advertised as an effective approach to collectively lower the environmental impact in tandem with improving health and longevity.

Melissa Macauley. Distant Shores: Colonial Encounters on China's Maritime Frontier (Princeton University Press, 2021). viii, 362 pages. Paperback, $14.98. This book conducts an in-depth examination of the activities pertaining to [...]

Objectives Insufficient training and the absence of guidelines increase the risk of retraumatisation in torture survivors during surgical procedures. This study aims to develop guidelines to mitigate this risk and gather healthcare professionals’ experiences treating torture survivors and insights on the guideline’s feasibility and acceptability.Design The study was conducted in two phases. Phase ‘a’ involved developing guidelines based on reviews of torture survivors’ encounters in somatic care and potential retraumatisation triggers, as well as a qualitative study on survivors’ experiences during surgical interventions. The development process adhered to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles and the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument for methodological rigour. Phase ‘b’ involved focus groups and individual interviews with healthcare professionals to explore challenges in caring for torture survivors and to evaluate the guidelines.Setting The study, conducted from May to August 2023, involved participants from surgical departments in three hospitals in southern and southeastern Norway.Participants Twenty-one healthcare professionals, including surgeons, anaesthesiologists, nurses and a dentist, participated in the study. Both focus group interviews and individual interviews were conducted.Results Phase ‘a’: guidelines comprising six sections were developed: an introduction, general guidelines and four sections covering the preoperative, perioperative and postoperative surgical stages. Phase ‘b’: healthcare professionals struggled to understand torture’s complexities and identify survivors’ unique needs. They faced challenges using interpreters and assisting patients with strong reactions. While the guidelines were viewed as practical and useful for raising awareness, their length was questioned.Conclusions We provide recommendations for preventing retraumatisation in torture survivors undergoing surgical treatment. The guidelines may serve as a starting point for offering safe and individualised care to torture survivors. Teaching institutions and hospitals may incorporate the guidelines into healthcare professionals’ education.

Objectives To compare the treatment effectiveness of secukinumab in radiographic (r) versus non-radiographic (nr) axial spondyloarthritis (axSpA) patients treated in routine care across Europe.Methods Prospectively collected data on secukinumab-treated axSpA patients with known radiographic status were pooled from nine countries.Remission rates based on patient-reported outcomes (PROs; Numeric Rating Scale (0–10), for example, pain ≤2/Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≤2 and Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (ID)

There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.

We measured aerosol mass spectra and mobility size distributions of particles formed during the pyrolysis of ethylene, indene, and a mixture of ethylene with a small amount of indene. Measurements were recorded with a scanning mobility particle sizer and an aerosol mass spectrometer employing vacuum ultraviolet photoionization using tunable radiation from the Advanced Light Source at Lawrence Berkeley National Laboratory. The results demonstrate that particle formation occurs at a temperature of ∼1123±50 K for ethylene alone, at ∼923±50 K for indene alone, and at a comparable temperature to that of indene for ethylene seeded with a small amount of indene. Our results demonstrate that indene and indenyl, a resonance-stabilized radical (RSR) formed from indene pyrolysis, promote particle formation at lower temperatures and in the absence of acetylene, supporting the hypothesis that RSRs promote soot-particle inception. Even a small amount of indene added to ethylene promotes particle formation while circumventing the traditional pathways for mass growth by acetylene-addition reactions. Further support is provided by the appearance in the aerosol mass spectra of prominent peaks for masses corresponding to other RSRs from particles formed at lower pyrolysis temperatures. In addition, odd-numbered carbon species, associated with RSRs, appear in higher concentrations at low temperatures and are closely tied to particle inception. In indene pyrolysis, mass signals indicative of covalently bound indenyl dimers and trimers are prominent at pyrolysis temperatures near soot onset. Photoionization efficiency (PIE) curves demonstrate that, while the isomeric composition for some of these peaks may differ between ethylene and indene, the addition of indene to ethylene does not notably alter the isomers formed at these peaks between ethylene and the ethylene-indene mixture. PIE curves also show that m/z 202, which is commonly assumed to be pyrene, is composed principally of fluoranthene under these conditions.

Abstract Introduction Digital mental health interventions (DMHIs) are getting increasingly important for mental health care. In the case of eating disorders (EDs), DMHIs are still in early stages. Few studies so far investigated the views of mental health professionals for EDs on the integration of DMHIs in routine care. Objective To gain insights into the experiences, perspectives, and expectations of mental health professionals for EDs regarding DMHIs and to identify requirements for the future integration of DMHIs into routine care. Methods Semi-structured qualitative telephone interviews with 24 German mental health professionals treating patients with EDs were conducted. A content analysis following a deductive-inductive approach asked for experiences, advantages and chances, disadvantages and boundaries, desired functions and properties, target groups, and general conditions and requirements for DMHIs for patients with EDs. Results Only few professionals reported experiences with DMHIs besides video-based psychotherapy during the pandemic. From the therapists’ point of view, DMHIs have the potential to deliver low-threshold access for patients with EDs. Useful functionalities were seen in digital meal records, skills training, and psychoeducation. However, a stable therapeutic alliance was reported as an important prerequisite for the successful integration into care. Therapists expressed concerns in case of severe anorexia nervosa or suicidality. The participants felt to be informed inadequately on recent developments and on the evidence base of DMHIs. Conclusions Mental health professionals for EDs show positive attitudes towards DMHIs, however many barriers to the integration in routine care were observed. The highest potential was seen for the use of DMHIs in addition to outpatient care and in aftercare. Specific requirements for DMHIs are related to different areas of the healthcare spectrum and for the different symptom profiles in anorexia nervosa, bulimia nervosa and binge eating disorder. Targeted DMHIs are needed and appropriate especially for concepts of blended care.