Explore the vast range of titles available.

IntroductionEnd-stage kidney disease (ESKD) is a major public health problem affecting more than 2 million people worldwide. It is one of the most severe chronic non-communicable diseases. Haemodialysis (HD) is the most common therapeutic option but is also associated with a risk of cardiovascular events, hospitalisation and suboptimal quality of life. Over the past decades, haemodiafiltration (HDF) has become available. Although high-dose HDF has shown some promising survival advantage compared to conventional HD, the evidence remains controversial. A Cochrane systematic review found, in low-quality trials, with various convective forms of dialysis, a reduction in cardiovascular, but not all-cause mortality and the effects on non-fatal cardiovascular events and hospitalisation were uncertain. In contrast, an individual patient data analysis suggested that high-dose HDF reduced both all-cause and cardiovascular mortality compared to HD. In view of these discrepant results, a definitive trial is required to determine whether high-dose HDF is preferable to high-flux HD. The comparison of high-dose HDF with high-flux HD (CONVINCE) study will assess the benefits and harms of high-dose HDF versus a conventional high-flux HD in adults with ESKD.Methods and analysisThis international, prospective, open label, randomised controlled trial aims to recruit 1800 ESKD adults treated with HD in nine European countries. Patients will be randomised 1:1 to high-dose HDF versus continuation of conventional high-flux HD. The primary outcome will be all-cause mortality at 3 years’ follow-up. Secondary outcomes will include cause-specific mortality, cardiovascular events, all-cause and infection-related hospitalisations, patient-reported outcomes (eg, health-related quality of life) and cost-effectiveness.Ethics and disseminationThe CONVINCE study will address the question of benefits and harms of high-dose HDF compared to high-flux HD for kidney replacement therapy in patients with ESKD with a focus on survival, patient perspectives and cost-effectiveness.Trial registration numberNetherlands National Trial Register (NTR 7138).

Background Technical innovation to assess patient-reported outcomes (PROs) facilitates their implementation in clinical practice. In particular, mobile applications (apps) allow PROs to be assessed outside of the clinical setting. A patient’s health status can be remotely monitored and evaluated after discharge, and their recovery process tracked. This is of particular interest for patients after knee arthroplasty, as the recovery phase after surgery usually takes place in an outpatient setting and requires a high level of patient engagement. Providing results of PRO assessments to patients in the form of a feedback report could increase patient engagement and may improve communication between health care professionals and patients. The aim of the study is to develop a PRO feedback report for mobile devices that is comprehensible and provides valuable information for patients after knee arthroplasty. Results In an iterative development process, our expert group developed two preliminary feedback reports (a text-based version and a graphical display) based on previous research results and practical experience. In a second step, we discussed these reports with orthopedic patients ( n  = 8) in terms of comprehensibility and value using semi-structured interviews and cognitive debriefing methods. Participants assessed the reports as informative, but had some difficulties in fully comprehending all of the information provided. Based on the feedback from patients, we modified both versions and reduced complexity to increase comprehensibility. Conclusions A PRO feedback report for patients for mobile app use has to take account of the heterogeneous user group, particularly demographics such as age and experience with mobile devices. Information should be presented in a simple way to be comprehensible and of value to patients. Technological advancements allow a simple default report to be set, something which enables patients interested in additional information to make customizations.

To investigate whether a multi-item performance outcome measure, the physical performance test (PPT), can be calibrated to a common scale with patient-reported outcome measures, using the Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) metric. We analyzed baseline data (N = 1,113) from the CONVINCE study, an international trial in end-stage kidney disease patients comparing high-dose hemodiafiltration with high-flux hemodialysis. Assumptions of item response theory (IRT) modelling were investigated for the combined set of the nine-item PPT and a four-item PROMIS PF short form (PROMIS-PF4a). We applied unidimensional IRT linking for calibrating the PPT to the PROMIS PF metric. Although some evidence for multidimensionality was found, classical test statistics (Cronbach's Alpha = 0.93), Mokken (Loevinger's H = 0.50), and bifactor analysis (explained common variance = 0.65) indicated that PPT and PROMIS-PF4a items can be used to assess a common PF construct. On the group level, the agreement between PROMIS-PF4a and linked PPT scores was stable across several subsamples. On the individual level, scores differed considerably. We found preliminary evidence that the PPT can be linked to the PROMIS PF metric in hemodialysis patients, enabling group comparisons across patient-reported outcome and performance outcome measures. Alternative linking methods should be applied in future studies using a more comprehensive PROMIS PF item set. •PRO and PerfO items formed a psychometrically sound physical function scale.•We found high potential for using a composite score of different assessment types.•PerfO items were found to be suitable for calibration to the PROMIS PF metric.•This study provides preliminary algorithms for linking PerfO items to PROMIS PF.

PurposeWe applied a previously established common T-score metric for patient-reported and performance-based physical function (PF), offering the unique opportunity to directly compare measurement type-specific patterns of associations with potential laboratory-based, psychosocial, sociodemographic, and health-related determinants in hemodialysis patients.MethodsWe analyzed baseline data from the CONVINCE trial (N = 1,360), a multinational randomized controlled trial comparing high-flux hemodialysis with high-dose hemodiafiltration. To explore the associations of potential determinants with performance-based versus patient-reported PF, we conducted multiple linear regression (backward elimination with cross-validation and Lasso regression). We used standardized T-scores as estimated from the PROMIS PF short-form 4a (patient-reported PF) and the Physical Performance Test (performance-based PF) as dependent variables.ResultsPerformance-based and patient-reported PF were both significantly associated with a laboratory marker-based indicator of muscle mass (simplified creatinine index), although the effects were relatively small (partial f2 = 0.04). Age was negatively associated with PF; the effect size was larger for performance-based (partial f2 = 0.12) than for patient-reported PF (partial f2 = 0.08). Compared to performance-based PF, patient-reported PF showed a stronger association with self-reported health domains, particularly pain interference and fatigue. When using the individual difference between patient-reported and performance-based T-scores as outcome, we found that younger age and more fatigue were associated with lower patient-reported PF compared to performance-based PF (small effect size).ConclusionPatient-reported and performance-based assessments were similarly associated with an objective marker of physical impairment in hemodialysis patients. Age and fatigue may result in discrepancies when comparing performance-based and patient-reported scores on the common PF scale.Trial Registration CONVINCE is registered in the Dutch Trial Register (Register ID: NL64750.041.18). The registration can be accessed at: https://onderzoekmetmensen.nl/en/trial/52958.

An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein 1 . Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18–55 years of age. Two doses of 1–50 μg of BNT162b1 elicited robust CD4 + and CD8 + T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-μg dose) to 3.5 - fold (50-μg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (T H 1)-skewed T cell immune responses with RBD-specific CD8 + and CD4 + T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8 + and CD4 + T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms. In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

Type 2 diabetes mellitus (T2D) represents a major public health challenge with significant effects on morbidity and mortality. Clinical guidelines provide treatment recommendations, but there is limited understanding of patients' preferences. This study aimed to elicit preferences for second-line drug treatments for T2D. A Discrete Choice Experiment with a partial-profile design was conducted from August to November 2023, involving German patients with experience in either monotherapy or second-line drug treatment. Participants completed 12 choice tasks, each presenting three alternatives described by attributes: risk of myocardial infarction, risk of stroke, risk of nerve damage, risk of nausea, risk of severe hypoglycemia, weight change, type and frequency of intake, and schedule of intake. Statistical analyses employed the Conditional Logit and Random Parameter Logit models to assess main effects and heterogeneity. The study encompassed 583 adult individuals with T2D, evenly divided between the two populations. Key factors influencing choice decisions included risk of nausea, risk of nerve damage, and weight change, with weekly type and frequency of intake risk of myocardial infarction followed. Less impactful but still relevant were risks of stroke, and severe hypoglycemia, while the intake schedule was least significant. Analysis of BMI categories revealed distinct preferences, particularly in weight change, with significant heterogeneity observed among respondents. This study highlights the importance of incorporating patient preferences into clinical decision-making. By quantifying preferences for second-line drug treatments, the study underscores the need for low-risk options that also consider weight change and intake conditions, aligning with the German National Health Care Guideline for T2D objectives for shared decision-making and treatment adherence. Recognizing individual sensitivities to risks and benefits is crucial for tailoring effective T2D treatment strategies. The study bridges clinical findings with patient perspectives, offering valuable insights into clinical practice, consideration for HTA processes, and design of clinical studies.

Three neonicotinoids, imidacloprid, clothianidin and thiacloprid, agonists of the nicotinic acetylcholine receptor in the central brain of insects, were applied at non-lethal doses in order to test their effects on honeybee navigation. A catch-and-release experimental design was applied in which feeder trained bees were caught when arriving at the feeder, treated with one of the neonicotinoids, and released 1.5 hours later at a remote site. The flight paths of individual bees were tracked with harmonic radar. The initial flight phase controlled by the recently acquired navigation memory (vector memory) was less compromised than the second phase that leads the animal back to the hive (homing flight). The rate of successful return was significantly lower in treated bees, the probability of a correct turn at a salient landscape structure was reduced, and less directed flights during homing flights were performed. Since the homing phase in catch-and-release experiments documents the ability of a foraging honeybee to activate a remote memory acquired during its exploratory orientation flights, we conclude that non-lethal doses of the three neonicotinoids tested either block the retrieval of exploratory navigation memory or alter this form of navigation memory. These findings are discussed in the context of the application of neonicotinoids in plant protection.

Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network. Endothelial cells play a critical role in the adaptation of tissues to injury and show a remarkable plasticity. Here the authors show, using single cell sequencing, that endothelial cells acquire a transient mesenchymal state associated with metabolic adaptation after myocardial infarction.

In this work, different variants of a branch-and-bound procedure for yard crane scheduling at seaport container terminals and their effect on the terminal’s performance are studied. In particular, this work investigates the level of detail needed to take the exact crane characteristics, e.g., movements and crane interference, into account in the scheduling algorithm. This is examined for four different automated yard crane systems with one or more cranes that operate on rectangular yard blocks with transfer positions at both ends of the block and with the yard blocks arranged orthogonally to the quay. Using a simulation model with realistic scenario data and an automated guided vehicles system for horizontal transport, the results are compared with respect to different key performance indicators, e.g., yard crane productivity and average lateness of jobs. It turns out that especially the consideration of crane interference leads to significant improvements in yard crane productivity. As a result of the long computation times for some crane systems that render the practical application of the algorithm difficult, an approximation procedure is also developed that generates good results in reasonable time and hence allows for real-time application at a container terminal.

Tissue-intrinsic defense mechanisms eliminate aberrant cells from epithelia and thereby maintain the health of developing tissues or adult organisms. ‘Interface surveillance’ comprises one such distinct mechanism that specifically guards against aberrant cells which undergo inappropriate cell fate and differentiation programs. The cellular mechanisms which facilitate detection and elimination of these aberrant cells are currently unknown. We find that in Drosophila imaginal discs, clones of cells with inappropriate activation of cell fate programs induce bilateral JNK activation at clonal interfaces, where wild type and aberrant cells make contact. JNK activation is required to drive apoptotic elimination of interface cells. Importantly, JNK activity and apoptosis are highest in interface cells within small aberrant clones, which likely supports the successful elimination of aberrant cells when they arise. Our findings are consistent with a model where clone size affects the topology of interface contacts and thereby the strength of JNK activation in wild type and aberrant interface cells. Bilateral JNK activation is unique to ‘interface surveillance’ and is not observed in other tissue-intrinsic defense mechanisms, such as classical ‘cell-cell competition’. Thus, bilateral JNK interface signaling provides an independent tissue-level mechanism to eliminate cells with inappropriate developmental fate but normal cellular fitness. Finally, oncogenic Ras-expressing clones activate ‘interface surveillance’ but evade elimination by bilateral JNK activation. Combined, our work establishes bilateral JNK interface signaling and interface apoptosis as a new hallmark of interface surveillance and highlights how oncogenic mutations evade tumor suppressor function encoded by this tissue-intrinsic surveillance system.