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INTRODUCTION The importance of biomarkers as a primary outcome or as supportive evidence of clinical effect is rising as the field shifts toward disease‐modifying treatments and earlier intervention, because they have lower variability and can indicate disease progression earlier than clinical outcomes. This study assessed the performance of plasma pTau 181 and 217 as a predictive biomarker and potential primary endpoint in early‐phase Alzheimer's disease (AD) trials. METHODS Summary data from recent monoclonal antibody (mAb) trials including plasma pTau 181 and 217 were analyzed to evaluate associations between plasma pTau 181/217 and clinical outcomes. The suitability of plasma pTau 181/217 as a surrogate endpoint for internal decision making was assessed using Prentice criteria. Simulations were conducted to explore the statistical power of using plasma pTau 181/217 as a primary outcome in dose‐escalation, proof‐of‐concept (POC) trial designs. Additional criteria for biomarker validation were applied to simulated data. RESULTS A strong group‐level correlation (r = 0.781) was observed between treatment effects on plasma pTau 181/217 and Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Mean change in plasma pTau 181/217 significantly predicted mean change in CDR‐SB (p = 0.013). The treatment effect on pTau 181/217 was ∼2.6 times greater than on CDR‐SB. Prentice Criteria 1, 2, and 4 were met or reasonably met; Criterion 3 is not applicable in the POC setting. CONCLUSION Plasma pTau 181/217 at 6 months shows future promise to reasonably likely predict clinical benefit for drugs that reduce pTau 181/217 levels, supporting its use as a primary endpoint in early‐phase trials. With effect sizes similar to those seen with donanemab, adequately powered trials may require as few as 100 participants. Such trials should include prespecified analyses to evaluate individual‐level Prentice criteria, and pTau 181/217 results can be used to predict potential Phase 3 clinical outcomes. Highlights The group‐level correlation between a biomarker treatment effect and clinical endpoint treatment effect is a measurement of the biomarker's ability to predict clinical outcome. The correlation of group level plasma pT217 or pT181 effect size at 6 months with clinical outcome Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB) effect size at 12 months was approximately 0.781 with p values of 0.013. Cohen's d effect size of plasma pTau as an outcome was 2.6 times greater than the Cohen's d of CDR‐SB, leading to higher power or lower sample sizes. As a primary endpoint, plasma pTau meets or reasonably meets Prentice Criteria 1, 2, and 4, while Criterion 3 was deemed not applicable in the proof‐of‐concept study setting.

Introduction Low physical activity and poor dietary quality can negatively influence Covid‐19 recovery and increase the risk and duration of post‐Covid‐19 condition (PCC). This proof‐of‐concept nested intervention study aimed to evaluate the feasibility of a digital personalised combined lifestyle intervention (CLI) in patients with PCC using a mixed‐methods design, assessing compliance, experiences and perceived effectiveness. Methods A nested intervention study, incorporating motivational interviewing aiming to enhance physical activity and dietary quality, was conducted within a multicentre prospective cohort study including 95 post‐Covid‐19 patients (aged 40–60) between May 2021 and September 2022. Patients in the intervention and control groups were followed at ±3–6 and ±12–15 months post Covid‐19. The intervention consisted of nine monthly individual counselling sessions (30 min), two interactive‐group sessions (60 min), and three educative webinars (45 min). Additionally, a nutritional supplement (NS; Remune, Smartfish, Oslo, Norway) high in omega‐3 fatty acids, vitamin D and protein was provided to facilitate recovery. After the intervention, a process evaluation was conducted, comprising an evaluation questionnaire and semi‐structured in‐depth interviews. Results The intervention‐to‐treat group consisted of 47 patients (age 54.7 ± 6.0 years; 40% males; BMI 30.6 ± 5.8 kg/m2) of whom 74% had ≥ 8 individual sessions via telephone (66%) or video call (34%). Over half of the group (55%) attended the educative webinars, while attendance was lower in the interactive‐group sessions, with 32% attending one session and 15% two sessions. The process evaluation indicated that patients were satisfied with the digital coaching and the frequency, duration and content of the sessions. Half of the patients reported perceived improvements in physical activity levels and dietary quality throughout the intervention, with the majority also reporting sustainment of these lifestyle changes post‐intervention. Conclusion A digital personalised CLI was well‐received among patients with PCC regarding compliance, experiences and perceived effectiveness. These findings will guide the development and implementation of tailored interventions to enhance overall well‐being among patients with PCC. Patient or Public Contribution Patients' experiences regarding the design and implementation of the study were retrieved. Although participants were not directly involved in the initial design of the study, their experiences were actively incorporated into the refinement and implementation of the study procedures, thereby ensuring meaningful patient involvement.

Medication safety is the most patient-centered aspect of nursing, and the medication process needs patients’ active participation to effectively prevent medication errors. The aim of this study was to develop the concept of a patient–nurse partnership for medication safety activities. The study design used the three-phase hybrid model for concept analysis: the theoretical phase, fieldwork phase, and final phase for integration. The results of a study define the concept of patient–nurse partnership for medication safety as “a fair cooperative relationship of mutual responsibility in which patients and nurses share information and communicate with each other through mutual trust.” Seven attributes were derived: mutual trust, mutual respect, mutual sharing, mutual communication, mutual responsibility, fair relationship, and mutual cooperation. The conclusion of the study of patient–nurse partnerships for medication safety was that it is necessary to ensure a balance in power between patient and nurse. This balance can be established through patient-centered nursing by implementing the active transfer of authority from nurses as professionals to patients.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP) 1 . Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated 2 . Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die 3 . Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan. During senescence, minority mitochondrial outer membrane permeabilization leads to the release of mtDNA into the cytosol through BAX and BAK macropores, in turn activating the cGAS–STING pathway, a major regulator of the senescence-associated secretory phenotype.

BackgroundHelium in oxygen (HELIOX) can relieve airway obstruction and lower the work of breathing because it increases the threshold at which turbulent gas flow is induced. Less turbulent and more laminar flow lowers the work of breathing. According to guidelines, the fraction of Helium in HELIOX should be maximized (e.g. to 79%). Here, we investigate whether HELIOX with less than 60% of Helium is able to relieve the sensation of dyspnea in healthy volunteers.Methods44 volunteers underwent resistive loading breathing different gases (medical air and HELIOX with a fraction of 25%, 50% or 75% helium in oxygen) in a double-blinded crossover design. Subjects rated their degree of dyspnea (primary outcome parameter) and the variability of noninvasively measured systolic blood pressure was assessed.ResultsDyspnea was significantly reduced by HELIOX-containing mixtures with a fraction of helium of 25% or more. Similarly, blood pressure variability was reduced significantly even with helium 25% during respiratory loading with the higher load, whereas with the smaller load an effect could only be obtained with the highest helium fraction of 75%.ConclusionIn this clinical trial, HELIOX with less than 60% of helium in oxygen decreased the sensation of dyspnea and blood pressure variability, a surrogate parameter for airway obstruction. Therefore, higher oxygen fractions might be applied without losing the helium-related benefits for the treatment of upper airway obstruction.Trial registrationRegistration with clinical trials (NCT00788788) and EMA (EudraCT number: 2006-005289-37).

Artificial intelligence (AI)-based methods have emerged as powerful tools to transform medical care. Although machine learning classifiers (MLCs) have already demonstrated strong performance in image-based diagnoses, analysis of diverse and massive electronic health record (EHR) data remains challenging. Here, we show that MLCs can query EHRs in a manner similar to the hypothetico-deductive reasoning used by physicians and unearth associations that previous statistical methods have not found. Our model applies an automated natural language processing system using deep learning techniques to extract clinically relevant information from EHRs. In total, 101.6 million data points from 1,362,559 pediatric patient visits presenting to a major referral center were analyzed to train and validate the framework. Our model demonstrates high diagnostic accuracy across multiple organ systems and is comparable to experienced pediatricians in diagnosing common childhood diseases. Our study provides a proof of concept for implementing an AI-based system as a means to aid physicians in tackling large amounts of data, augmenting diagnostic evaluations, and to provide clinical decision support in cases of diagnostic uncertainty or complexity. Although this impact may be most evident in areas where healthcare providers are in relative shortage, the benefits of such an AI system are likely to be universal.A natural language processing system can support physicians in diagnostic assessments by extracting clinical information from electronic medical records to accurately predict diagnosis in pediatric patients.

Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy. The generation of biomimetic nanoparticles that retain the integrity of proteins has been a challenge. Here, the authors generate biomimetic nanoparticles that are exocytosed from tumour cells and show their therapeutic potential in targeting tumours and cancer stem cells in multiple mouse models.

Spatial light modulators are essential optical elements in applications that require the ability to regulate the amplitude, phase and polarization of light, such as digital holography, optical communications and biomedical imaging. With the push towards miniaturization of optical components, static metasurfaces are used as competent alternatives. These evolved to active metasurfaces in which light-wavefront manipulation can be done in a time-dependent fashion. The active metasurfaces reported so far, however, still show incomplete phase modulation (below 360°). Here we present an all-solid-state, electrically tunable and reflective metasurface array that can generate a specific phase or a continuous sweep between 0 and 360° at an estimated rate of 5.4 MHz while independently adjusting the amplitude. The metasurface features 550 individually addressable nanoresonators in a 250 × 250 μm 2 area with no micromechanical elements or liquid crystals. A key feature of our design is the presence of two independent control parameters (top and bottom gate voltages) in each nanoresonator, which are used to adjust the real and imaginary parts of the reflection coefficient independently. To demonstrate this array’s use in light detection and ranging, we performed a three-dimensional depth scan of an emulated street scene that consisted of a model car and a human figure up to a distance of 4.7 m. By controlling two voltage gates separately from one another, a spatial light modulator has been made that can continuously vary the phase of 360 degrees while independently adjusting the amplitude.

Two patients with amyotrophic lateral sclerosis caused by SOD1 mutations received an intrathecal infusion of adeno-associated virus containing microRNA targeting SOD1 . SOD1 protein levels did not change in the patients’ cerebrospinal fluid, but one patient had reduced spinal cord SOD1 expression.