搜索结果：Journal of precision medicine (Amsterdam, Netherlands)

Endoscopy is essential for measuring luminal disease activity in Crohn's disease. Existing indices for evaluating endoscopic Crohn's disease activity are only modestly correlated with clinical disease activity, contain items with ambiguous definitions and poor interobserver reliability, and do not have validated thresholds for defining clinically relevant changes. To address these issues, we conducted a multiphase study to develop and validate a novel endoscopic index for Crohn's disease. Paired baseline and post-induction ileocolonoscopy videos from a phase 3b adalimumab trial (NCT00348283) and phase 2 risankizumab trial (NCT02031276) were assessed by multiple central readers using candidate endoscopic items with face validity derived using modified RAND/UCLA appropriateness methods. The four readers were masked to all clinical information, including treatment assignment and patient symptom scores. A total of 112 and 99 paired ileocolonoscopy videos with treatment assignment were available from the adalimumab trial and risankizumab trial, respectively; after the four readers assessed the 112 videos, two readers then reassessed 44 post-treatment videos to assess inter-rater reliability in index development. Items with acceptable inter-rater reliability (with an intraclass correlation coefficient [ICC] of &#x2265;0&#xb7;41) and responsiveness (win probability [WinP], the probability that a patient receiving active treatment has a better endoscopy score than a patient receiving placebo, of &#x2265;0&#xb7;56) were included as covariables in regression for model building with internal validation with bootstrapping. External validation was conducted using the paired videos from the risankizumab trial. Ten endoscopic items met ICC and WinP thresholds and were considered for novel index development. They included items from the SES-CD (presence and size of ulcers, extent of ulcerated surface, and extent of affected surface) and CDEIS (percentage of surface involved by Crohn's disease, percentage of ulcerated surface, deep ulceration, and superficial ulceration) and exploratory items (presence of Crohn's disease-related lesions, Crohn's disease-related lesion severity, and Crohn's disease-related lesion involvement). The final model, Endoscopic ulcer Activity Score for Evaluating CD (EASE-CD), included the presence and size of ulcerations measured on an ordinal scale of 0 (none), 1 (ulcers <5 mm), 2 (ulcers between 5 mm and 20 mm), and 3 (ulcers >20 mm); the presence or absence of deep ulcerations measured dichotomously, with 0 for absent and 1 for present; and the proportion of ulcerated surface area, expressed as a continuous proportion from 0-1, with each item evaluated and averaged across visualised bowel segments. The total score ranges from 0-100 with higher scores indicating greater endoscopic activity. The r2 and optimism adjusted r2 of EASE-CD in internal validation were 0&#xb7;608 and 0&#xb7;554, and the index was well calibrated with a slope of 0&#xb7;983. In external validation, the adjusted r2 was 0&#xb7;565 and the calibration slope was 0&#xb7;997. EASE-CD also demonstrated substantial inter-rater reliability (ICC 0&#xb7;798 [95% CI 0&#xb7;711-0&#xb7;836]) and a large degree of responsiveness (WinP 0&#xb7;769 [95% CI 0&#xb7;658-0&#xb7;851], p<0&#xb7;001) in external validation. A 10-point reduction in EASE-CD had 82&#xb7;4% specificity (95% CI 78&#xb7;6-86&#xb7;0) and 69&#xb7;9% sensitivity (63&#xb7;3-76&#xb7;4) for endoscopic response, defined by at least 50% reduction in SES-CD or CDEIS. Ulcer-free endoscopic remission results in EASE-CD score of 0. EASE-CD is a novel, internally and externally validated continuous measure of endoscopic ulcer activity in Crohn's disease that is reliable and responsive to treatment. None.

Gait recognition is critical for daily-life fall risk assessment and rehabilitation monitoring, but existing models face many challenges that limit their use in daily life for older adults. We aimed to develop an open-source gait recognition for older adults using sensor data and explore the effect of data augmentation on model training. A convolutional neural network was trained using lower-back inertial sensor data from 20 participants (mean age 76.4) and externally validated on 47 participants (mean age 72.3). The model was trained using 6-channel data (accelerations and angular velocities) and 3-channel data (accelerations only), with and without data augmentation. On the testing dataset, the best 6-channel model achieved accuracy of 91.4%, precision of 59.7%, sensitivity of 99.5%, F1-score of 74.7%, and specificity of 90.3%, and the best 3-channel model achieved accuracy of 96.5%, precision of 78.7%, sensitivity of 98.9%, F1-score of 87.6%, and specificity of 96.1%. On the external validation dataset, the best models with both channels show near-perfect scores. This study demonstrates that the convolutional neural network algorithm based on lower-back inertial sensor data can accurately recognize daily-life gait of older adults, and data augmentation was especially beneficial for models using acceleration data only.

Sepsis is a dysregulated host response to infection resulting in life-threatening organ failure. Although immune dysregulation is central to the sepsis definition, immunomodulation trials enrol participants based on clinical severity, not the extent of dysregulation, which could contribute to treatment heterogeneity. A pragmatic way to quantify immune dysregulation could improve prognostication, help to evaluate treatment responses, and identify individuals most likely to benefit from immunomodulation. We aimed to construct a parsimonious machine-learning tool that defines and quantifies immune dysregulation, thereby supporting biologically informed immunomodulation. In this multicohort analysis and reanalysis of a randomised controlled trial, the primary objective was to derive and validate a categorical and continuous immune dysregulation score that is independent of clinical presentation or outcome. We measured 35 plasma biomarkers reflecting key host response domains in individuals with community-acquired pneumonia (CAP) across different care settings (emergency department, general ward, and intensive care unit) and disease severities using data from three independent cohorts. We applied unsupervised trajectory inference analysis to identify an immune dysregulation gradient captured as discrete immune dysregulation stages (Dysregulated Immune Profile [DIP]) and a continuous score (cDIP; 0-1). We developed two parsimonious machine-learning models to predict the DIP stages and cDIP scores based on 35 biomarkers, and validated their ability to capture immune dysregulation and predict clinical outcomes in five independent cohorts. On the basis of our hypothesis that only individuals with severe immune dysregulation benefit from immunomodulation, we carried out a post-hoc analysis of a randomised trial evaluating hydrocortisone in severe CAP (CAPE COD trial, NCT02517489), assessing treatment effects across DIP stages and the cDIP continuum, and how hydrocortisone influenced dysregulation trajectories over time. We organised 398 participants with CAP along a continuum of immune dysregulation from mild to severe on the basis of 35 plasma biomarkers, yielding three dysregulation stages (DIP1-3) and a continuous score (cDIP). Clinical severity proved to be an inadequate proxy for immune dysregulation. A three-biomarker machine-learning framework (procalcitonin, soluble TREM-1, and IL-6) accurately predicted the degree of dysregulation derived from 35 biomarkers (DIP stage accuracy 91&#xb7;2%; cDIP root mean square error 0&#xb7;056). Although the framework was not designed for outcome prediction, increased immune dysregulation-reflected in DIP and cDIP-was associated with a gradual rise in mortality (cDIP odds ratio [OR] 1&#xb7;26 [95% CI 1&#xb7;13-1&#xb7;40] per 10% increase, p<0&#xb7;0001) and secondary infections (OR 1&#xb7;50 [1&#xb7;22-1&#xb7;93] per 10% increase, p=0&#xb7;0005), independent of clinical severity. The three-biomarker tool was validated in five external cohorts of varying infections, severities, and care settings (n=1191). Reanalysis of the CAPE COD trial showed that hydrocortisone conferred a survival benefit only in participants classified as severely dysregulated by our model (30-day mortality: DIP3 OR 0&#xb7;25 [0&#xb7;05-0&#xb7;85], p=0&#xb7;042; cDIP &#x2265;0&#xb7;63 OR 0&#xb7;21 [0&#xb7;10-0&#xb7;72], p=0&#xb7;011), accompanied by faster immune recovery (time&#x2009;&#xd7;&#x2009;treatment interaction, p<0&#xb7;0001). No such effect modification was observed when stratifying participants by clinical severity. We have provided a publicly available three-biomarker framework to determine the extent of host response dysregulation with potential value for precision-guided immunomodulatory therapy. EU Horizon 2020.

Lung cancer is the leading global cause of cancer mortality with substantial evidence of inequity, disparity in process and outcomes, and unwarranted clinical variation. Over the last decades, there has been major evolution and discovery in best evidence-based practice (EBP), enhancing diagnostics, management, and the delivery of precision medicine. However, questions remain about the completeness of translation of best EBP into delivered care. Learning health systems (LHSs) have been defined as improvement environments where knowledge generation processes are embedded into daily clinical practice to continually improve the quality, safety, and outcomes of health care delivery. Lung cancer clinical quality registries (CQRs) provide a rigorous infrastructure supporting LHS function through the collection, analysis, and reporting of care process and outcome information delivered by health service organizations. CQRs measure the appropriateness and effectiveness of delivered care and report on the degree of best EBP delivery by stakeholder providers. The provision of risk-adjusted, benchmark reporting to stakeholders describes equity, disparity, and unwarranted clinical variation and is a fundamental driver of improvement in the safety and quality of care provided to consumers. There is mounting international evidence of the positive impacts of CQR reporting on management processes, health care infrastructure, survival, quality improvement, and education within lung cancer communities. The use of implementation science approaches including the Knowledge to Action framework targets bridging the gaps between evidence-based knowledge and practice. Registry evolution is exampled by the Danish Lung Cancer Registry, National Lung Cancer Audit (United Kingdom), Dutch Lung Cancer Audit, and Victorian Lung Cancer Registry (Australia), which identify innovation opportunities to close the evidence-practice gap, overcome service deficits, and lead to better decision making for health care improvement.

The integration of artificial intelligence into pathology is transforming the assessment of histological and immunohistochemical (IHC) slides, offering opportunities to reduce variability and streamline diagnostics. In practical terms, most available tools and research models emulate the diagnostic capabilities of pathologists by detecting, grading, and classifying tumours and other diseases. More recent applications have moved beyond mimicry, aiming to predict established biomarkers, such as microsatellite instability or IHC-based markers, and to tackle even more ambitious tasks, such as directly predicting patient prognosis from H&E whole slide images. Remarkably, novel computational tools are now being designed as companion diagnostic assays, linking the automated evaluation of specific IHC biomarkers to the prediction of response to specific drugs, potentially marking a new chapter in the evolution of digital and computational pathology. The TROPION-PanTumor01 trial recently demonstrated the superiority of a supervised machine learning model (termed the quantitative continuous score [QCS] by the vendor) in assessing TROP2 IHC compared with human scoring, promising better stratification of patients with non-small cell lung cancer for treatment with datopotamab deruxtecan. The same approach has shown promise in refining HER2 (human epidermal growth factor receptor 2) and PD-L1 (programmed death-ligand 1) evaluations, revealing patient subgroups that may benefit from targeted therapies. Moreover, other similar approaches are progressively reaching the market, posing significant opportunities and challenges for clinicians involved in the care of patients with cancer. This Perspective is promoted by the European Society of Digital and Integrative Pathology (ESDIP, founded in 2016, and having long-standing experience in computational pathology, esdipath.org) and the European Interdisciplinary Society of Artificial Intelligence for Cancer Research (ESAC, a recently established initiative, founded in 2024, esac-network.eu), both bringing together clinicians, engineers and other professionals dedicated to the development and clinical translation of computational approaches aimed at improving patient care. It aims to provide an informed overview of novel computational pathology companion diagnostic tools, with a particular focus on the background that practicing pathologists and oncologists need to have with these tools, when transitioning from research to clinical practice, irrespective of their prior familiarity with computational approaches. &#xa9; 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Genetic risk could be informative for identifying individuals at risk of depression with severe outcomes. With the novel approach of combined health care registries and self-report measures related to depression, the authors aimed to identify the impact of polygenic risk scores (PRS) for major depression on self report measures and a diagnosis of depression across diagnostic thresholds. The study sample comprised participants from the Norwegian Mother, Father and Child Cohort Study with linked information of depression diagnoses during 2006-2022 from health registries. Linear and logistic models were used to estimate the associations between PRS for major depression and self-reported measures related to depression (Symptom Checklist- 5, Satisfaction With Life Scale, Rosenberg Self-Esteem Scale), and a diagnosis of depression. Analyses were performed in groups stratified by level of depression severity defined by registrations in primary and specialist health care. Among the 105 623 individuals included in the study, mean (SD) age was 33.9 (5.3) and 58.5% were female. The associations between PRS for major depression and Rosenberg Self-Esteem Scale were more prominent in individuals with a history of inpatient status compared to outpatient status (&#x3b2;&#x2009;=&#x2009;0.095, cluster robust 95% CI 0.029-0.162; P&#x2009;=&#x2009;0.005) and status of primary care (&#x3b2;&#x2009;=&#x2009;0.098, cluster robust 95% CI 0.035-0.160; P&#x2009;=&#x2009;0.002). PRS for major depression were associated with a diagnosis of depression in all groups of depression severity, with highest effect sizes for more severe types (history of inpatient status: OR&#x2009;=&#x2009;1.85, cluster robust 95% CI 1.75-1.94; P&#x2009;<&#x2009;0.01). The results provide new knowledge of how PRS for major depression vary with depression severity.

To assess the effects of and related evidence certainty of interventions for attention deficit/hyperactivity disorder (ADHD) across an individual's lifespan, and to develop a continuously updated web platform for people with lived experience of ADHD as a method to disseminate living evidence synthesis for shared decision making. Umbrella review and platform for shared decision making. Six databases from inception to 19 January 2025. Study authors were contacted for additional information when necessary. Systematic reviews that used meta-analyses of randomised controlled trials were eligible if they compared a drug or non-drug intervention with a passive control in individuals with a diagnosis of ADHD. Primary outcomes were severity of ADHD symptoms, analysed by rater type (clinician-rated, parent-rated, teacher-rated, or self-rated) and time point (short term (12 weeks, or study endpoint), medium term (26 weeks), and long term (52 weeks)),acceptability (participants dropping out for any reason), and tolerability (participants dropping out owing to any side effects). Secondary outcomes included daily functioning, quality of life, comorbid symptoms, and key side effects (decreased sleep and appetite). Eligible meta-analyses were re-estimated with a standardised statistical approach. Methodological quality was assessed using AMSTAR-2. Evidence certainty was evaluated using an algorithmic version of the GRADE framework, adapted for drug and non-drug interventions. 115 of 414 full text articles were deemed eligible and 299 were excluded; the eligible articles comprised 221 unique combinations of participants, interventions, comparators, and outcomes. For each combination, the most recent and methodologically robust meta-analysis was selected for re-estimation, which gave 221 re-estimated meta-analyses in total, derived from 47 meta-analytic reports. In the short term, alpha-2 agonists, amphetamines, atomoxetine, methylphenidate, and viloxazine showed medium to large effect sizes in reducing the severity of ADHD symptoms in children and adolescents, with moderate to high certainty evidence. Methylphenidate showed consistent benefits across raters (standardised mean difference >0.75, 95% confidence interval (CI) 0.56 to 1.03; moderate or high certainty evidence). These interventions showed lower tolerability than the placebo, but this effect was not significant for methylphenidate and atomoxetine. In adults, atomoxetine, cognitive behavioural therapy, methylphenidate (and, when restricting analyses to high quality trials, amphetamines) showed at least moderate certainty evidence of efficacy on ADHD symptoms, with medium effect sizes. Methylphenidate, amphetamines, and atomoxetine had worse tolerability than placebo (methylphenidate, risk ratio 0.50, 95% CI 0.36 to 0.69; amphetamines, 0.40, 0.22 to 0.72; atomoxetine, 0.45, 0.35 to 0.58). Some non-drug interventions (acupuncture and cognitive behavioural therapy in children and adolescents, and mindfulness in adults) showed large effect sizes for ADHD symptoms, but with low certainty evidence. No high certainty, long term evidence was found for any intervention. An online platform showing effects and evidence certainty of each intervention across age groups, time points, and outcomes (https://ebiadhd-database.org/) was developed. This review provides updated evidence to inform patients, practitioners, and guideline developers how best to manage ADHD symptoms. The online platform should facilitate the implementation of shared decision making in daily practice. Open Science Framework https://osf.io/ugqy6/.

DSCAM occupies a 1-Mb locus in the original Down syndrome critical region on chromosome 21q22 and encodes a neuronal cell adhesion molecule of importance for brain and eye development. Singleton individuals, both born to first-cousin parents, with intellectual disability and homozygous DSCAM loss-of-function variants were reported in 2017 and in 2021, the latter also presenting with nystagmus and visual impairment. We present a cohort of five individuals, four new, including two sibling pairs with homozygosity or compound heterozygosity for predicted loss-of-function DSCAM variants. We identify a common clinical pattern of moderate to severe neurodevelopmental delay with poor language development, risk of focal seizures with onset in infancy, and nystagmus with poor vision. Electroretinography in two of the affected revealed cone-pathway dysfunction with a b-wave pattern indicating main dysfunction at the level of the cone-associated bipolar cells of the central retina. Our electroclinical findings are in line with previous DSCAM knockout chicken and mice studies that evidenced disturbed horizontal and vertical patterning of the retina. Taken together, we delineate a rare syndromic form of recessive intellectual disability with a distinctive type of visual impairment.

Well-organised electronic health records (EHR) are essential for high quality patient care, but EHR user interfaces can be cumbersome for entry of structured information, resulting in the majority of information being in free text rather than a structured form. This makes it difficult to retrieve information for clinical purposes and limits the research potential of the data. Natural language processing (NLP) at the point of care has been suggested as a way of improving data quality and completeness, but there is little evidence as to its effectiveness. We sought to generate such evidence by developing an open source, modular, configurable NLP system called MiADE, which is designed to integrate with an EHR. This paper describes the design of MiADE and the deployment at University College London Hospitals (UCLH), and is intended to benefit those who may wish to develop or implement a similar system elsewhere. The MiADE system includes components to extract diagnoses, medications and allergies from a clinical note, and communicate with an EHR system in real time using Health Level 7 Clinical Document Architecture (HL7 CDA) messaging. This enables NLP results to be displayed to a clinician for verification before saving them to the patient's record. MiADE utilises the MedCAT library (part of the Cogstack family of NLP tools) for named entity recognition (NER) and linking to SNOMED CT, as well as context detection. MedCAT models underwent unsupervised and supervised training on patient notes from UCLH, achieving precision of 83.2% (95% CI 77.0, 88.1), and recall of 85.2% (95% CI 79.1, 89.8) for detection of diagnosis concepts. In simulation testing we found that MiADE reduced the time taken for clinicians to enter structured problem lists by 89%. We have commenced a trial implementation of MiADE at UCLH in live clinical use, integrated with the Epic EHR at UCLH. We have developed an open source point of care NLP system and successfully integrated it with the EHR in live clinical use at a major hospital. Simulation testing has shown that our system significantly reduces the time taken for clinicians to enter structured diagnosis codes.

Using a hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust the HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. This observational study included patients (N&#xa0;=&#xa0;2,010) across the Systemic Lupus International Collaborating Clinics, Wisconsin, international, and French studies who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified an HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for the Systemic Lupus Erythematosus Disease Activity Index 2000 [score &#x2265;6]). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. Among 1,842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ-related toxicity. Odds of toxicity were 2.1-fold higher with blood levels &#x2265;1,150 ng/mL and 1.7-fold higher with the cumulative HCQ dose per 1,000-g increase. Blood levels &#x2265;1,150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage &#x2265;3 had 2.3-fold higher odds of having supratherapeutic levels (&#x2265;1,150 ng/mL). The therapeutic reference range for HCQ blood level monitoring is 750 to <1,150 ng/mL. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage &#x2265;3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.

Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) can be used to characterize the steady-state in&#xa0;vivo myocardial energy status via the phosphocreatine (PCr) over adenosine triphosphate (ATP) tissue concentration ratio. Although used in many studies, this modality suffers from low sensitivity and poor measurement precision. This work reports on the acquisition of 31P-MR spectra of the in&#xa0;vivo human heart using a 7&#x2009;T MR system equipped with an integrated whole-body RF transmit coil for 31P spin excitation. Eight volunteers (male/female, n&#x2009;=&#x2009;4/4) underwent 31P-MRS at 7&#x2009;T twice, using a low-flip angle, short-repetition time 3D 31P-MR spectroscopic imaging sequence with a 20-mm isotropic resolution and a 21-min acquisition time. A 16-channel 31P receive array was used for signal reception. Myocardial voxels were identified on transversal cine proton MR images. Signals of PCr, phosphodiesters (PDE), and inorganic phosphate (Pi) were quantified relative to ATP and corrected for partial saturation and blood signal contamination. Bland-Altman analyses were used to establish intersession measurement repeatability. A comparison of supine and prone positioning was made for two subjects, yielding similar results but superior comfort for lying supine. Mid-septal myocardial PCr/ATP was 1.85&#x2009;&#xb1;&#x2009;0.37, with a repeatability coefficient of 17.7%. The repeatability coefficients for Pi/ATP and PDE/ATP were 142.7% and 51.6%, respectively. Using the spatially homogeneous 31P spin excitation with the integrated whole-body RF transmit coil, we made quantitative estimates of the myocardial energy status at a higher precision than previously achieved at lower main magnetic field strengths. The noninvasive nature and high precision of the presented 31P-MR spectroscopic imaging approach will allow for therapeutic efficacy monitoring with repeated measurements in longitudinal study designs and investigations of normal physiology in healthy volunteers.

This work aimed to demonstrate the feasibility of quantifying heart function during bicycling exercise with dynamic real-time cine MRI at 3 Tesla, and to assess its measurement precision. Twelve volunteers performed steady-state bicycling exercise, while real-time cine MR images were collected using a 72-channel receiver coil array and a parallel imaging acceleration factor of 5. Biventricular end-diastolic and end-systolic (ESV) volumes and function during exercise were compared with resting-state real-time cine MRI and conventional cardiac-gated cine MRI under breath holding, and validated against 2D phase-contrast MRI-based estimates of aortic blood flow. Precision was evaluated as the inter-session measurement repeatability. Left (LV) and right ventricular (RV) stroke volumes (SV) increased progressively with exercise intensity, which was mediated by a decrease in ESV. Likewise, LV SV estimated with 2D phase-contrast MRI increased from 90&#x2009;&#xb1;&#x2009;17&#xa0;mL at rest to 114&#x2009;&#xb1;&#x2009;29&#xa0;mL during vigorous-intensity exercise. Repeatability coefficients were 52% and 41% for LV SV at moderate- and vigorous-intensity exercise, while RV SV repeatability coefficients were 58% and 42%, respectively. We established an exercise MRI stress testing protocol for quantifying biventricular volumes and function during moderate- and vigorous-intensity steady-state bicycling exercise.

GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in GRIN2B, leading to impaired N-methyl d-aspartate receptor (NMDAR) function. l-serine, a precursor to d-serine that modulates NMDAR activity, has shown therapeutic potential for GRIN2B loss-of-function (LoF) variants. The efficacy of oral l-serine supplementation in 4 children with GRIN2B LoF variants were evaluated in the first double-blind, randomized, placebo-controlled, one-year n-of-1 trials. The trial consisted of 2&#xa0;cycles of 6&#xa0;months. The Perceive, Recall, Plan, and Perform Assessment (PRPP-A) showed a significant improvement in Performance Mastery at 1.5&#xa0;months (p&#xa0;=&#xa0;0.0373), while 11 of 14 other PRPP-A measures showed mean differences that were numerically in the same direction toward a positive l-serine effect (not significant). Secondary outcomes varied across patients, for those with statistical group analysis, no significant difference were observed. Individual improvements were noted in information processing/adaptive function (n&#xa0;=&#xa0;3/4), quality of life (n&#xa0;=&#xa0;3/4), sleep (n&#xa0;=&#xa0;1/2), irritability (n&#xa0;=&#xa0;2/4), and language (n&#xa0;=&#xa0;1/3), based on objective assessments and anecdotal parent reports. These pioneering n-of-1 trials provide insights into l-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified. Future trials should focus on refining patient selection, the use of multiple baseline designs, establishing a core outcome set and pooling treatment data to better understand patient-specific responses.

The aim of this study is to develop a European Organisation of Research and Treatment of Cancer (EORTC) patient-reported outcome measure (PROM) to assess quality of life (QOL) in individuals diagnosed with a hereditary cancer predisposition syndrome (HCPS) with or without a previous cancer diagnosis. We report on content generation, questionnaire construction, and questionnaire evaluation of acceptability, comprehensiveness, and linguistic validity. Following phase 1-3a of the EORTC Quality of Life Group module development guidelines, QOL issues were identified through a literature review and interviews with health-care professionals and individuals undergoing HCPS genetic counseling or testing. Based upon the results, a preliminary questionnaire was developed and pre-tested internationally for relevance, clarity, and linguistic appropriateness. Revisions were guided by qualitative feedback and predefined criteria. 63 issues were identified from the literature and expanded to a 73-item questionnaire through interviews. Pre-testing of the questionnaire in 119 individuals (79.8&#x202f;% female) across twelve centers in nine countries, including carriers of BRCA, Lynch syndrome, and Li-Fraumeni, showed limited applicability for those with negative or pending results. The target population was therefore refined to mutation carriers. Following item reduction, the final instrument comprised thirty validated and linguistically appropriate items. The EORTC QLQ-HCR30 is relevant and applicable for assessing QOL in individuals diagnosed with a HCPS and is now ready for preliminary psychometric evaluation (phase 3b and 4).

Serum creatinine (SCr), the most used biomarker to evaluate glomerular filtration rate (GFR), might be inaccurate in children with sickle cell anemia (SCA). In this context, cystatin C (SCys) could be of interest. This study evaluated the performance of commonly used SCr- and SCys-based estimated GFR (eGFR) equations in African children with SCA. This cross-sectional study included 109 steady-state children with SCA aged 3-18&#xa0;years, from the Democratic Republic of Congo. Measured GFR (mGFR) was obtained using iohexol plasma clearance. eGFR was calculated using commonly used SCr- and SCys-based equations in children. The performance of these equations was evaluated by calculating the bias, precision, and accuracy within 30% (P30) of mGFR. The mean age of participants was 9.9&#x2009;&#xb1;&#x2009;4.2&#xa0;years, and 48.6% were female. The median mGFR was 142 (IQR 119-169) mL/min/1.73 m2. Of the equations studied, the FAS-Age SCr had the lowest bias (0.9&#xa0;mL/min/1.73 m2). However, the 95% limit of agreement was very wide (-80.3 to&#x2009;+&#x2009;81.6). SCr failed to rise in an age-dependent manner, reflecting a progressive loss of muscle mass or increased tubular secretion. All SCys-based equations underestimated GFR and failed to detect hyperfiltration, but there was no age-related change in bias. These data show that all common eGFR equations using SCr or SCys poorly predict mGFR in African children with SCA. SCr-based equations potentially miss a decline in kidney function, which suggests that SCys could be the preferred marker in this population.

Variants of unknown significance (VUS) pose a barrier to cascade genetic screening in families affected by inherited cardiomyopathies. Here, we investigate scalable computational methods for assessing pathogenicity of TPM1 VUS in the context of cardiomyopathy and test them against in vitro data. Twenty TPM1 VUS (all missense) from clinical databases were computationally evaluated by inserting each into atomistic representations of tropomyosin. Molecular dynamic simulations were used to assess changes in tropomyosin flexibility, and a structural model of tropomyosin on actin allowed calculation of altered electrostatic interaction energies. Four variants representing diverse changes in these properties were carried forward for functional studies that included in vitro motility, contractility of engineered heart tissues (EHTs), and morphology of iPSC-derived cardiomyocytes. The TPM1 variants A102D, D258E, K233N, and A239T all showed at least one significantly altered facet of contractile function. A102D was associated with increased thin filament Ca2+ sensitivity, increased twitch contraction force, and slowed relaxation. D258E was shown to cause a slowing of twitch relaxation and reduced ability to block myosin activity at low Ca2+. K233N and A239T both reduced in vitro thin filament motility, drastically decreased twitch contraction force, and triggered pronounced increases in cardiomyocyte aspect ratio. By showing that large molecular aberrations predicted by thin filament structural models translate into meaningful functional changes (as benchmarked against clinically pathogenic mutations), this study supports the feasibility of TPM1 variant classification by means of a scalable computational pipeline.

Multinational clinical trials are increasingly common in the European Economic Area, yet no guideline exists on which EQ-5D value set(s) should be used for health economic evaluations alongside multinational trials. Either a single value set or country-specific value sets can be applied, and previous studies have shown that the choice of value set can impact the estimated utility scores. For the EQ-5D-5L, the impact on European pooled cost-utility analyses has not been established. This study evaluates the impact of EQ-5D-5L value sets on cost-utility outcomes in two multinational trials. Data from two multinational randomized controlled trials were used: (i) supervised exercise compared to usual care for patients with metastatic breast cancer (PREFERABLE-EFFECT), (ii) hemodiafiltration compared to hemodialysis for patients with kidney failure (CONVINCE). EQ-5D-5L was assessed at baseline and during follow-up. Utility scores and quality-adjusted life years (QALYs) were calculated with the country-specific value set for each participant, and with the value set of each included country. The probability of cost-effectiveness was estimated using bootstrapping. Mean assigned utility scores per year alive ranged between 0.762 and 0.889 for PREFERABLE-EFFECT, and 0.673 and 0.806 for CONVINCE. The difference in utility scores is largest when participants report low quality of life. Estimated QALY gains ranged between 0.013 and 0.020 for PREFERABLE-EFFECT and 0.045 and 0.058 for CONVINCE. The maximum difference in probability of cost-effectiveness between the value sets was &#x394;8.3% at &#x20ac;80,000/QALY in PREFERABLE-EFFECT, and &#x394;11.1% at &#x20ac;40,000/QALY for CONVINCE. Choice of value set led to substantial variation in absolute utility scores and QALYs, which may influence cost-utility outcomes. This impact could be greater when an intervention prevents or aids recovery of health conditions associated with low quality of life, or results in large mortality differences. Scenario analyses using multiple value sets should be conducted for multinational trials.

There is limited real-world evidence on the use and positioning of inhaled long-acting muscarinic antagonists (LAMAs) for treating severe asthma. We aimed to assess the differences in clinicians' perspectives on prescribing LAMA for severe asthma across Europe. Within the Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) network, we conducted a multi-country survey of 470 respiratory clinicians in 2023-24. Most participants were pneumonologists (83%). 68% reported using specific criteria for prescribing LAMA for severe asthma, primarily fixed bronchial obstruction (68%), frequent asthma exacerbations (65%), and a history of smoking (53%). Improved quality of life, lung function improvement, and reduction of asthma exacerbations were the three expected outcomes of LAMA treatment that showed the largest agreement across clinicians (85-95%). As compared to non-severe asthma specialists (about 50% of the sample), severe asthma specialists were more likely to report always prescribing LAMA before biologics (54 vs. 41%) and before oral corticosteroids (OCS) (51 vs. 40%). Approximately 90% of participants prioritised tapering or discontinuing OCS before stopping LAMA. Overall, participants in Northern (n&#x2009;=&#x2009;73) and Western Europe (n&#x2009;=&#x2009;71) appeared less prone to prescribe LAMA and less confident in their benefits compared to those from Eastern (n&#x2009;=&#x2009;88) and Southern Europe (n&#x2009;=&#x2009;238). In particular, most participants from Latvia (91%) and Lithuania (67%) reported that LAMAs are not reimbursed for severe asthma in their countries. Most participants who expressed their opinion favoured triple therapy (n&#x2009;=&#x2009;236) over single inhaler therapy (n&#x2009;=&#x2009;91). Our findings show that barriers and heterogeneous approaches still limit LAMA prescription for severe asthma in Europe, potentially leading to the underuse of this treatment option. Establishing a clear role for LAMA within a precision medicine framework is crucial; this aspect is not yet firmly supported by current international recommendations.

We conducted a systematic review and meta-analysis to estimate the efficacy of pharmacogenetic (PGx)-guided antidepressant treatment compared to treatment as usual (TAU) on functional outcomes and quality of life (QoL) in people with anxiety and affective disorders. A PRISMA-compliant systematic search was performed up to 26/06/2025 to identify relevant prospective, randomised controlled trials (RCTs) in seven databases. The revised tool for Risk of Bias (RoB2) was used to assess the methodological qualities of the included studies (PROSPERO CRD42024518683). Of 2774 records, six studies were included comprising 2285 adult patients (PGx group: n = 1395, Mean age = 48.14 years; 55.68 % females; TAU group: n = 890, Mean age = 47.83 years, 58.22 % females). Three studies were included in random-effect meta-analyses. In these, PGx-guided antidepressant treatment significantly decreased functional disability, measured by the Sheehan Disability Scale/Inventory (SDS/I), compared to TAU (k = 3, Mean Difference = -2.85, SE = 1.32 [95 % CI: -5.44, -0.26], p = .031). The Hartung-Knapp adjustment of p-values yielded non-significant effects. Individually, one of these three studies reported a significant effect of PGx-guided treatment on overall SDS score, one on SDI Perceived Social Support partial score, and one no effect. Risk for bias was rated high for one study, with some concerns for the other five. Due to the small number of included trials, our ability to conduct analyses of heterogeneity, moderators and publication bias was limited. Nonetheless, our results suggest that PGx-guided antidepressant treatment may improve functioning in people with anxiety and affective disorders.