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Abstract Background Understanding psychological responses to acute exercise, defined as a single bout of physical exercise, in clinical populations is essential for developing tailored interventions that account for the psychological benefits and challenges of exercise. Given its effectiveness in reducing symptoms in various psychological disorders, exercise should be further explored in Exhaustion Disorder ICD-10-SE: F43.8A (ED), characterized by persistent exhaustion following long-term psychosocial stress. Currently, no studies address the psychological responses to acute exercise in ED patients. Aims This study aims to (1) compare the psychological responses to acute exercise between ED patients and healthy controls and (2) assess response differences between low and moderate exercise intensities. Methods We conducted a two-armed cross-over trial comparing ED patients (n = 30) and healthy controls (n = 30). Participants completed a 22-min exercise at low or moderate intensity on a cycle ergometer, on separate occasions, in randomized order. The primary outcome was perceived fatigue (POMS); secondary outcomes included feelings of energy, anxiety, stress, exertion, and psychological discomfort, measured before, during, and up to 24 h post-exercise. Exercise effects were assessed using repeated measures analysis of variance. Results ED patients reported higher levels of exertion, psychological discomfort, fatigue, anxiety, and stress but lower energy throughout the trial compared to controls. Unlike controls, the ED group showed significant fatigue and stress reductions post-exercise (p

Background and objective: Our objective was to evaluate whether a very large prostate volume significantly affects the incidence of perioperative complications and compromises outcomes among patients undergoing holmium laser enucleation of the prostate (HoLEP). Methods: We retrospectively analyzed data for 1815 adult patients who underwent HoLEP at Evangelisches Krankenhaus Königin Elisabeth Herzberge, Berlin, between January 2019 and May 2024. Patients were divided into two groups according to their prostate volume: ≤149 ml (group A) and ≥150 ml (group B). Propensity score matching on age, body mass index, American Society of Anesthesiologists physical status, and the presence of an indwelling catheter was used to balance baseline differences. A Mann-Whitney U test was used for comparison of continuous variables between the groups, and a χ2 test for comparison of categorical variables, with p

Background: Vesicoureteral reflux (VUR) is common in children and adolescents undergoing kidney transplantation (KTx) and may adversely affect allograft kidney function. Methods: To explore the current management of symptomatic native and allograft VUR in pediatric KTx recipients, an online survey was distributed to European surgical transplant professionals. Results: Surgeons from 40 pediatric KTx centers in 18 countries participated in this survey. Symptomatic native kidney VUR was treated before or during KTx by 68% of the centers (all/selected patients: 33%/67%; before/during KTx: 89%/11%), with a preference for endoscopic treatment (59%). At KTx, 90% favored an anti‐reflux ureteral reimplantation procedure (extravesical/transvesical approach: 92%/8%; preferred extravesical technique: Lich‐Gregoir [85%]). Management strategies for symptomatic allograft VUR included surgical repair (90%), continuous antibiotic prophylaxis (51%), bladder training (49%), or noninterventional surveillance (21%). Redo ureteral implantation and endoscopic intervention for allograft VUR were equally reported (51%/49%). Conclusions: This survey shows uniformity in some surgical aspects of the pediatric KTx procedure. However, with regard to VUR, there is a significant variation in practice patterns that need to be addressed by future well‐designed and prospective studies. In this way, more robust data could be translated into consensus guidelines for a more standardized and evidence‐based management of this common condition in pediatric KTx. [ABSTRACT FROM AUTHOR]

Abstract Background Quantification of Amyloid beta (Aβ) oligomers in plasma enables early diagnosis of Alzheimer’s Disease (AD) and improves our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology because of very low Aβ oligomer concentrations and possible interference from matrix components. Methods In this report, we developed and validated a surface-based fluorescence distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. Results The blood-based sFIDA assay delivers a sensitivity of 1.8 fM, an inter- and intra-assay variation below 20% for oligomer calibration standards and no interference with matrix components. Quantification of Aβ oligomers in 359 plasma samples from the DELCODE cohort reveals lower oligomer concentrations in subjective cognitive decline and AD patients than healthy Control participants. Conclusions Correlation analysis between CSF and plasma oligomer concentrations indicates an impaired clearance of Aβ oligomers that is dependent on the ApoE ε4 status.

Abstract Background Insomnia is more frequently reported in stroke survivors but its independent role in mortality in stroke survivors is unknown. The purpose of this study was to investigate the association of insomnia symptoms with all-cause mortality among stroke survivors. Methods The Health and Retirement Study, a survey of Americans older than 50 years and their spouses of any age from 2002 to 2018 was used. Only participants with a history of stroke were included. The exposure variable of interest was insomnia symptoms including difficulty initiating sleep, difficulty maintaining sleep, waking up too early, and nonrestorative sleep. The outcome was all-cause mortality. Cox proportional hazards regression models were employed to investigate the association between insomnia symptoms and all-cause mortality. Results A total of 3,501 stroke survivors were included of which 55% were females. Over a mean follow-up of 6 years, 1,782 deaths occurred. Difficulty initiating sleep (HR = 1.87, 95% CI: 1.07, 3.25) and difficulty maintaining sleep (1.89, 95% CI: 1.09, 3.29) were associated with all-cause mortality only among male stroke survivors younger than 65 years old while nonrestorative sleep (HR = 1.31, 95% CI: 1.05, 1.62) was associated with all-cause mortality only among male stroke survivors aged 65 years and older. Furthermore, male stroke survivors younger than 65 years of age and older than 65 with insomnia symptom scores ranging from 5 to 8 (mean = 6.2) had a higher but statistically nonsignificant risk of all-cause mortality (HR = 1.56, 95% CI: 0.81, 3.01 and HR = 1.08 95% CI: 0.85, 1.38, respectively) compared to their counterparts without insomnia symptoms. There was no association between insomnia symptoms and all-cause mortality among female stroke survivors. Conclusion Insomnia symptoms were associated with an increased risk of death especially in male stroke survivors younger than 65 years of age. Future studies should explore the benefit of insomnia symptom management in stroke survivors.

Abstract Background Phosphorylated tau (p-tau) and amyloid beta (Aβ) in human plasma may provide an affordable and minimally invasive method to evaluate Alzheimer’s disease (AD) pathophysiology. The medial temporal lobe (MTL) is susceptible to changes in structural integrity that are indicative of the disease progression. Among healthy adults, higher dynamic network flexibility within the MTL was shown to mediate better generalization of prior learning, a measure which has been demonstrated to predict cognitive decline and neural changes in preclinical AD longitudinally. Recent developments in cognitive, neural, and blood-based biomarkers of AD risk that may correspond with MTL changes. However, there is no comprehensive study on how these generalization biomarkers, long-term memory, MTL dynamic network flexibility, and plasma biomarkers are interrelated. This study investigated (1) the relationship between long-term memory, generalization performance, and MTL dynamic network flexibility and (2) how plasma p-tau231, p-tau181, and Aβ42/Aβ40 influence generalization, long-term memory, and MTL dynamics in cognitively unimpaired older African Americans. Methods 148 participants (Mean age : 70.88,SD age : 6.05) were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. Cognition was evaluated with the Rutgers Acquired Equivalence Task (generalization task) and Rey Auditory Learning Test (RAVLT) delayed recall. MTL dynamic network connectivity was measured from functional Magnetic Resonance Imaging data. Plasma p-tau231, p-tau181, and Aβ42/Aβ40 were measured from blood samples. Results There was a significant positive correlation between generalization performance and MTL Dynamic Network Flexibility (t = 3.372, β = 0.280, p

Abstract The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.

Abstract Advances in theoretical understanding are frequently unlocked by access to large, diverse experimental datasets. Our understanding of olfactory neuroscience and psychophysics remain years behind the other senses, in part because rich datasets linking olfactory stimuli with their corresponding percepts, behaviors, and neural pathways remain scarce. Here we present a concerted effort to unlock and unify dozens of stimulus-linked olfactory datasets across species and modalities under a unified framework called Pyrfume. We present examples of how researchers might use Pyrfume to conduct novel analyses uncovering new principles, introduce trainees to the field, or construct benchmarks for machine olfaction.

Abstract Specificity of a T cell receptor (TCR) is determined by the combination of its interactions to the peptide and human leukocyte antigen (HLA). TCR-based therapeutic molecules have to date targeted a single peptide in the context of a single HLA allele. Some peptides are presented on multiple HLA alleles, and by engineering TCRs for specific recognition of more than one allele, there is potential to expand the targetable patient population. Here, as a proof of concept, we studied two TCRs, S2 and S8, binding to the PRAME peptide antigen (ELFSYLIEK) presented by HLA alleles HLA-A*03:01 and HLA-A*11:01. By structure-guided affinity maturation targeting a specific residue on the HLA surface, we show that the affinity of the TCR can be modulated for different alleles. Using a combination of affinity maturation and functional T cell assay, we demonstrate that an engineered TCR can target the same peptide on two different HLA alleles with similar affinity and potency. This work highlights the importance of engineering alloselectivity for designing TCR based therapeutics suitable for differing global populations.

Abstract Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition that usually affects younger adults but has a second incidence peak in the older population. Although diagnosis of IBD is driven by symptoms, some patients are asymptomatic and incidentally discovered while participating in colon screening program (CSP). We aimed to identify the incidence and outcome of IBD in fecal immunochemical test (FIT) positive patients in the British Columbia CSP. We conducted a retrospective chart review of patients who had colonoscopies for positive FIT and were found to have colitis based on endoscopic and histological assessment. Of 93,994 patients who underwent screening colonoscopy for positive FIT between 2009 and 2017, 608 (0.6%) were found to have colitis. From 11 CSP sites, 191 patients met the inclusion criteria. 58 patients (30.4%) were diagnosed with ulcerative colitis, 109 (57.1%) with Crohn’s disease (CD), and 24 (12.6%) with IBD unclassified. 124 patients (64.9%) received treatment, of which 34 (17.8%) received biologics and 4 (2.1%) required surgery. Our study demonstrated a clinically significant incidence of IBD, with novel finding of CD predominance, within a Canadian provincial CSP. Further research is needed to guide management of older patients with varying rates of IBD progression after incidental diagnosis.

Abstract Sleep is a complex and conserved biological process that affects several body functions and behaviors. Evidence suggests that there is a reciprocal interaction between sleep and immunity. For instance, fragmented sleep can increase the probability of parasitic infections and reduce the ability to fight infections. Moreover, viral and bacterial infections alter the sleep patterns of infected individuals. However, the effects of macro-parasitic infections on sleep remain largely unknown, and measuring sleep in non-model organisms remains challenging. In this study, we investigated whether macro-parasite infections could alter sleep-like behavior of their hosts. We experimentally infected three-spined sticklebacks (Gasterosteus aculeatus), a freshwater fish, with the tapeworm Schistocephalus solidus and used a hidden Markov model to characterize sleep-like behavior in sticklebacks. One to four days after parasite exposure, infected fish showed no difference in sleep-like behavior compared with non-exposed fish, and fish that were exposed-but-not-infected only showed a slight reduction in sleep-like behavior during daytime. Twenty-nine to 32 days after exposure, infected fish showed more sleep-like behavior than control fish, while exposed-but-not-infected fish showed overall less sleep-like behavior. Using brain transcriptomics, we identified immune- and sleep-associated genes that potentially underlie the observed behavioral changes. These results provide insights into the complex association between macro-parasite infection, immunity, and sleep in fish and may thus contribute to a better understanding of reciprocal interactions between sleep and immunity.

Abstract BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

Abstract Background For over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce. Methods We applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk. Results Our findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P

Abstract Background Perivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. Methods We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre “DZNE Longitudinal Cognitive Impairment and Dementia Study” (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). Results PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p A-T-, p FDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, p FDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, p FDR = 0.021). Conclusion Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. Trial registration German Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .

Background and objective: Kidney transplant recipients (KTRs) have an increased risk of developing genitourinary cancers, including prostate cancer (PCa), which is expected to become more prevalent due to an aging KTR population. Thus, knowledge of surgical outcomes, including treatment of PCa, within this unique cohort is required. Methods: Data of 62 KTRs undergoing radical prostatectomy (RP) between 2006 and 2023 at nine urologic transplant centers were analyzed. Complications were assessed using the Clavien-Dindo classification. Perioperative outcomes were evaluated, and a follow-up was conducted. Overall survival (OS), biochemical recurrence–free survival (BRFS), and death-censored graft survival were determined via the Kaplan-Meier method and log-rank testing. Key findings and limitations: Overall, 50 open radical retropubic RPs and 12 robot-assisted RPs (RARPs) were included. The intraoperative blood loss was lower after RARP, but operative time was longer. Of the patients, 50% experienced no postoperative complication, and grade ≥3 complications were observed in 14.5%. There was no graft loss related to RP. A histopathologic analysis revealed pN1 in 8.1% and positive surgical margins in 25.8% of the cases. At a median follow-up of 48.5 mo, the median OS was 128 (95% confidence interval [CI] 71.2–184.8) mo, BRFS was 106 (95% CI 55.8; 156.2) mo, and graft survival was 127 (95% CI 66.7–187.3) mo. Limitations include the retrospective design, and variations between groups and centers. Conclusions and clinical implications: Our findings support RP as a feasible and safe treatment option for localized PCa in KTRs with acceptable oncologic outcome. Special care is required in screening and awareness for the risk of understaging. Patient summary: This study analyzed the safety and effectiveness of two prostate cancer surgery methods—open and robot-assisted surgery—in the special group of kidney transplant recipients. Both surgical methods were performed safely with acceptable oncologic outcomes; however, sample size was too small to draw definite conclusions between the two operative methods.

Abstract Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.

Background: In light of growing evidence highlighting interactions between cardiac and brain health, we investigated associations of biomarkers of neurodegenerative diseases with adverse outcomes (all-cause and cardiovascular mortality, major cardiovascular events, and stroke) in persons with chronic coronary syndrome (CCS). Methods: We used data from a cohort of persons with CCS for whom major adverse events were recorded over a follow-up of 20 years. We measured biomarkers of neurodegenerative diseases in baseline blood samples, using the Single-Molecule Array Technology on a HD-1 Analyzer. These include biomarkers of neuronal (neurofilament light chain (NfL) (n = 379)) and glial neurodegeneration (glial fibrillary acidic protein (GFAP) (n = 379)), and Alzheimer's disease pathology (phosphorylated tau181 (n = 379), total tau (n = 377), and amyloid β (Aβ40, Aβ42, Aβ42/Aβ40) (n = 377)). We applied Cox-proportional hazards models to evaluate associations of these biomarkers with adverse outcomes, adjusting for covariates and exploring interactions with apolipoprotein E (ApoE) ε4 genotype. Results: Participants with higher NfL levels had increased rates of all-cause and cardiovascular mortality (Hazard ratio per increase by one standard deviation (95 % confidence interval): all-cause mortality: 1.36 (1.10–1.68); cardiovascular mortality: 1.42 (1.05–1.93)). The Aβ40/Aβ42-ratio was linked to incident stroke (0.72 (0.52–1.00)). Associations of GFAP with all-cause mortality and incident stroke were depending on ApoE ε4 genotype. The other biomarkers were not significantly associated with the studied outcomes. Conclusions: In persons with CSS, NfL and the Aβ40/Aβ42-ratio were related to mortality and incident stroke, respectively, whereas associations of GFAP with adverse outcomes varied by ApoE genotype. These biomarkers might play a role in linking aging, cardiovascular and neurodegenerative diseases.

Aim: Standardized evaluation of [18F]PI-2620 tau-PET scans in 4R-tauopathies represents an unmet need in clinical practice. This study aims to investigate the effectiveness of visual evaluation of [18F]PI-2620 images for diagnosing 4R-tauopathies and to develop a straight-forward reading algorithm to improve objectivity and data reproducibility. Methods: A total of 83 individuals with [18F]PI-2620 PET scans were included. Participants were classified as probable 4R-tauopathies (n = 29), Alzheimer's disease (AD) (n = 20), α-synucleinopathies (n = 15), and healthy controls (n = 19) based on clinical criteria. Visual assessment of tau-PET scans (choice: 4R-tauopathy, AD-tauopathy, no-tauopathy) was conducted using either 20–40-minute or 40–60-minute intervals, with raw (common) and cerebellar grey matter scaled standardized reading settings (intensity-scaled). Two readers evaluated scans independently and blinded, with a third reader providing consensus in case of discrepant primary evaluation. A regional analysis was performed using the cortex, basal ganglia, midbrain, and dentate nucleus. Sensitivity, specificity, and interrater agreement were calculated for all settings and compared against the visual reads of parametric images (0–60-minutes, distribution volume ratios, DVR). Results: Patients with 4R-tauopathies in contrast to non-4R-tauopathies were detected at higher sensitivity in the 20–40-minute frame (common: 79%, scaled: 76%) compared to the 40–60-minute frame (common: 55%, scaled: 62%), albeit with reduced specificity in the common setting (20–40-min: 78%, 40–60-min: 95%), which was ameliorated in the intensity-scaled setting (20–40-min: 91%, 40–60-min: 96%). Combined assessment of multiple brain regions did not significantly improve diagnostic sensitivity, compared to assessing the basal ganglia alone (76% each). Evaluation of intensity-scaled parametric images resulted in higher sensitivity compared to intensity-scaled static scans (86% vs. 76%) at similar specificity (89% vs. 91%). Conclusion: Visual reading of [18F]PI-2620 tau-PET scans demonstrated reliable detection of 4R-tauopathies, particularly when standardized processing methods and early imaging windows were employed. Parametric images should be preferred for visual assessment of 4R-tauopathies.

Myelodysplastic syndromes (MDS) patients with DEAD-box helicase 41 (DDX41) mutations have been reported to be treated effectively with lenalidomide; however, there are no randomized studies to prove it. Venetoclax and azacitidine are safe and effective in high-risk MDS/AML. In this study, we evaluated the efficacy of venetoclax and azacitidine combination therapy in eight consecutive MDS patients with DDX41 mutations at our centre from March 2021 to November 2023. We retrospectively analyzed the genetic features and clinical characteristics of these patients. Our findings suggest that MDS patients with DDX41 mutation may benefit from the therapy, for six subjects received this regimen as initial therapy and five of the six subjects achieved complete remission.

Objective: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy.Methods: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events.Results: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%−94.8%) and 97.1% (95%CI, 80.1%−99.6%), respectively. Most adverse events were hematological and easily managed.Conclusions: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508).Trial registration: ClinicalTrials.gov identifier: NCT02705508.

Summary: Background: Due to its late stage of diagnosis lung cancer is the commonest cause of death from cancer in the UK. Existing epidemiological risk models in clinical usage, which have Positive Predictive Values (PPV) of less than 10%, do not consider the temporal relations expressed in sequential electronic health record (EHR) data. We aimed to build a model for lung cancer early detection in primary care using machine learning with deep ‘transformer’ models on EHR data to learn from these complex sequential ‘care pathways’. Methods: We split the Whole Systems Integrated Care (WSIC) dataset into 70% training and 30% validation. Within the training set we created a case–control study with lung cancer cases and control cases of ‘other’ cancers or respiratory conditions or ‘other’ non cancer conditions. Based on 3,303,992 patients from January 1981 to December 2020 there were 11,847 lung cancer cases. 5789 cases and 7240 controls were used for training and 50,000 randomly selected patients out of the whole validation population of 368,906 for validation. GP EHR data going back three years from the date of diagnosis less the most recent one months were semantically pre-processed by mapping from more than 30,000 terms to 450. Model building was performed using ALBERT with a Logistic Regression Classifier (LRC) head. Clustering was explored using k-means. An additional regression model alone was built on the pre-processed data as a comparator. Findings: Our model achieved an AUROC of 0.924 (95% CI 0.921–0.927) with a PPV of 3.6% (95% CI 3.5–3.7) and Sensitivity of 86.6% (95% CI 85.3–87.8) based on the three year's data prior to diagnosis less the immediate month before index diagnosis. The comparator regression model achieved a PPV of 3.1% (95% CI 3.0–3.1) and AUROC of 0.887 (95% CI 0.884–0.889). We interpreted our model using cluster analysis and have identified six groups of patients exhibiting similar lung cancer progression patterns and clinical investigation patterns. Interpretation: Capturing temporal sequencing between cancer and non-cancer pathways to diagnosis enables much more accurate models. Future work will focus on external dataset validation and integration into GP clinical systems for evaluation. Funding: Cancer Research UK.

Minimising pain with effective local anaesthesia is an essential step towards improving the level of dentally anxious patients’ comfort during dental treatment. It can be provided by many different techniques. One of them is using the Computer-Controlled Local Anaesthesia Delivery systems (CCLADs). This study was conducted to compare the efficacy of computerised anaesthesia with the conventional technique in terms of perceived pain. A database literature search was performed on PubMed, Cochrane Library and Google Scholar, covering up the period between 2015 and 2023. Only the studies comparing computerised anaesthesia technique with the use of conventional carpule were included. An overview of 20 relevant studies (n = 1347 subjects) was provided including pediatric patients, as well as the adults. The evaluated parameters were: pain, child’s behaviour, heart rate, blood pressure, level of satisfaction, anxiety, further anaesthesia method preference, need for additional anaesthetic, as well as the duration of anaesthesia, measured by different scales, devices and questionnaires. The present literature review led the authors to the conclusion, that the use of CCLADs is significantly less painful than the traditional anaesthesia and it is a promising technique for helping patients deal with pain perception. However, it is advisable to conduct further research on the use of CCLAD.

Abstract Deep brain stimulation (DBS) has emerged as a revolutionary technique for accessing and modulating brain circuits. DBS is used to treat dysfunctional neuronal circuits in neurological and psychiatric disorders. Despite over two decades of clinical application, the fundamental mechanisms underlying DBS are still not well understood. One reason is the complexity of in vivo electrical manipulation of the central nervous system, particularly in rodent models. DBS-devices for freely moving rodents are typically custom-designed and not commercially available, thus making it difficult to perform experimental DBS according to common standards. Addressing these challenges, we have developed a novel wireless microstimulation system for deep brain stimulation (wDBS) tailored for rodents. We demonstrate the efficacy of this device for the restoration of behavioral impairments in hemiparkinsonian mice through unilateral wDBS of the subthalamic nucleus. Moreover, we introduce a standardized and innovative pipeline, integrating machine learning techniques to analyze Parkinson’s disease-like and DBS-induced gait changes.

Abstract Background IgA nephropathy (IgAN) is a common primary glomerulonephritis leading to end-stage renal disease. Living donor kidney transplantation (LDKT) is considered a favorable treatment option, but IgAN recurrence rates and the impact on outcome is unclear. In the present study, we retrospectively analyzed the rate of IgAN recurrence, risk factors and clinical outcomes in LDKT recipients. Methods We analyzed 193 adult patients who received a LDKT between 2011 and 2017 of which 32 (16.7%) had IgAN as underlying disease. Demographic data and clinical outcomes, especially regarding IgAN recurrence, were evaluated. Mean follow-up period was 102.13 months in the IgAN group vs. 97.27 months in the control group. Results Among the IgAN cohort, five (15.63%) experienced IgAN recurrence. Patients with IgAN underwent LDKT at a significantly younger age (p

Background: Xylopic acid (XA), a kaurene diterpene from the dried fruits of Xylopia aethiopica, has anxiolytic- and antidepressant-like activity in mice and zebrafish. We aimed to assess the potential synergistic antidepressant-like effects of XA when combined with selected antidepressants in the mouse forced-swim test. Materials and methods: The antidepressant-like effect of xylopic acid (XA) (10, 30, 100 mgkg−1), fluoxetine (Flx) (3, 10, 30 mgkg−1), sertraline (Sert) (3, 10, 30 mgkg−1), imipramine (Imi) (10, 30, 100 mgkg-1) and ketamine (Ket) (0.1, 0.3, 1.0 mgkg−1), was evaluated in forced swim test. The dose (ED50) that achieved a 50% reduction in immobility time was determined from the respective log-dose response curves. XA and the selected antidepressants were co-administered in fixed-dose ratio combinations (1/2:1/2, 1/4:1/4, 1/8:1/8) of the ED50 to identify the experimental ED50 (ED50mix). The theoretical ED50(ED50add), of all combinations was determined using isobolograms and compared with the ED50mix to identify the nature of the interaction. The effect of dose combinations on general locomotor activity was assessed in the open-field test. Results: The interaction index (γ) for the following XA combinations, XA/Flx, XA/Sert, XA/Imi and XA/Ket were 0.42, 0.41, 0.31 and 0.34. An independent sample t-test revealed that the experimental ED50 (ED50mix) was significantly lower than the theoretical ED50 (ED50add) in all combinations of XA, indicative of a synergistic antidepressant-like effect. However, combinations of XA with ketamine significantly reduced general locomotor activity at all dose combinations. Conclusion: The co-administration of xylopic acid and fluoxetine, imipramine, sertraline and ketamine produces a synergistic antidepressant-like effect in mice.

Abstract Tremor is one of the most common neurological symptoms. Its clinical and neurobiological complexity necessitates novel approaches for granular phenotyping. Instrumented neurophysiological analyses have proven useful, but are highly resource-intensive and lack broad accessibility. In contrast, bedside scores are simple to administer, but lack the granularity to capture subtle but relevant tremor features. We utilise the open-source computer vision pose tracking algorithm Mediapipe to track hands in clinical video recordings and use the resulting time series to compute canonical tremor features. This approach is compared to marker-based 3D motion capture, wrist-worn accelerometry, clinical scoring and a second, specifically trained tremor-specific algorithm in two independent clinical cohorts. These cohorts consisted of 66 patients diagnosed with essential tremor, assessed in different task conditions and states of deep brain stimulation therapy. We find that Mediapipe-derived tremor metrics exhibit high convergent clinical validity to scores (Spearman’s ρ = 0.55–0.86, p≤ .01) as well as an accuracy of up to 2.60 mm (95% CI [−3.13, 8.23]) and ≤0.21 Hz (95% CI [−0.05, 0.46]) for tremor amplitude and frequency measurements, matching gold-standard equipment. Mediapipe, but not the disease-specific algorithm, was capable of analysing videos involving complex configurational changes of the hands. Moreover, it enabled the extraction of tremor features with diagnostic and prognostic relevance, a dimension which conventional tremor scores were unable to provide. Collectively, this demonstrates that current computer vision algorithms can be transformed into an accurate and highly accessible tool for video-based tremor analysis, yielding comparable results to gold standard tremor recordings.

Abstract Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clinical management and limiting understanding of the underlying neurobiology. To address this, we developed a visual perceptive deep learning framework that utilizes standard clinical videos to comprehensively evaluate and quantify disease states and the impact of therapeutic interventions, specifically deep brain stimulation. This framework overcomes the limitations of traditional rating scales and offers an efficient and accurate method that is rater-independent for evaluating and monitoring dystonia patients. To evaluate the framework, we leveraged semi-standardized clinical video data collected in three retrospective, longitudinal cohort studies across seven academic centres. We extracted static head angle excursions for clinical validation and derived kinematic variables reflecting naturalistic head dynamics to predict dystonia severity, subtype, and neuromodulation effects. The framework was also applied to a fully independent cohort of generalised dystonia patients for comparison between dystonia sub-types. Computer vision-derived measurements of head angle excursions showed a strong correlation with clinically assigned scores. Across comparisons, we identified consistent kinematic features from full video assessments encoding information critical to disease severity, subtype, and effects of neural circuit interventions, independent of static head angle deviations used in scoring. Our visual perceptive machine learning framework reveals kinematic pathosignatures of dystonia, potentially augmenting clinical management, facilitating scientific translation, and informing personalized precision neurology approaches.

Abstract Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Objectives Ramadan fasting is an Islamic religious practice involving abstinence from food and drink from dawn to sunset. Its consequences on kidney-relevant outcomes in patients with chronic kidney disease (CKD) and kidney transplant recipients remain unclear.Design Systematic review and meta-analysis.Data sources MEDLINE, Embase, Global Health, CINAHL (EBSCOhost), Scopus, Web of Science and Google Scholar were searched up to 18 September 2023.Eligibility criteria We included observational studies among non-dialysis CKD and kidney transplant recipients who fasted during Ramadan and examined changes in kidney function.Data extraction and synthesis Standardised methods were used by two independent reviewers to screen, select and extract data. Outcomes included changes in serum creatinine (SCr), estimated glomerular filtration rate (eGFR), proteinuria, blood pressure, electrolytes and adverse events—all pre- and post-Ramadan. Results were pooled using random effects modelling.Results We included 32 observational studies with a total of 2592 participants. 21 studies reported on participants with CKD and 11 studies reported on kidney transplant recipients (studies variably including non-fasting control arms). Meta-analysis of 25 studies revealed that Ramadan fasting was not associated with changes to SCr for the following groups according to study design: CKD with a non-fasting arm (mean difference (MD)=0.82 µmol/L; 95% CI −7.22, 8.86; I2=38%); transplant with a non-fasting arm (MD=−0.17 µmol/L; 95% CI −2.50, 2.15; I2=0%) and CKD without a non-fasting arm (post–pre MD=13.84 µmol/L; 95% CI −3.78, 31.47; I2=88%). For transplant studies without a non-fasting arm, lower SCr was associated with the post-Ramadan period (post–pre MD=−5.40 µmol/L; 95% CI –10.78, –0.02; I2=0%). In the 18 studies that reported on eGFR, fasting during Ramadan was not associated with an effect on eGFR for any of the groups.Conclusion We report inconsistent effects of Ramadan fasting on kidney function in CKD or kidney transplantation. Results should be interpreted with caution due to the significant limitations of the underlying studies.

Objectives: The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly Drosophila melanogaster to investigate the endogenous functions of L2hgdh. Methods: L2hgdh mutant adult male flies were analyzed under normoxic and hypoxic conditions using a combination of semi-targeted metabolomics and RNA-seq. These multi-omic analyses were complemented by tissue-specific genetic studies that examined the effects of L2hgdh mutations on the Drosophila renal system (Malpighian tubules; MTs). Results: Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions, L2hgdh mutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system is a key site of L2hgdh activity, as L2hgdh mutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions, L2hgdh mutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation. Conclusions: These findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.

Abstract Introduction This study evaluates the clinical value of a deep learning–based artificial intelligence (AI) system that performs rapid brain volumetry with automatic lobe segmentation and age‐ and sex‐adjusted percentile comparisons. Methods Fifty‐five patients—17 with Alzheimer's disease (AD), 18 with frontotemporal dementia (FTD), and 20 healthy controls—underwent cranial magnetic resonance imaging scans. Two board‐certified neuroradiologists (BCNR), two board‐certified radiologists (BCR), and three radiology residents (RR) assessed the scans twice: first without AI support and then with AI assistance. Results AI significantly improved diagnostic accuracy for AD (area under the curve −AI: 0.800, +AI: 0.926, p

Abstract INTRODUCTION With the advent of disease‐modifying therapies, accurate assessment of biomarkers indicating the presence of disease‐associated amyloid beta (Aβ) pathology becomes crucial in patients with clinically suspected Alzheimer's disease (AD). We evaluated Aβ levels in cerebrospinal fluid (Aβ CSF) and Aβ levels in positron emission tomography (Aβ PET) biomarkers in a real‐world memory‐clinic setting to develop an efficient algorithm for clinical use. METHODS Patients were evaluated for AD‐related Aβ pathology from two independent cohorts (Ludwig Maximilian University [LMU], n = 402, and Medical University of Vienna [MUV], n = 144). Optimal thresholds of CSF biomarkers were deduced from receiver operating characteristic curves and validated against Aβ PET positivity. RESULTS In both cohorts, a CSF Aβ42/40 ratio ≥ 7.1% was associated with a low risk of a positive Aβ PET scan (negative predictive value: 94.3%). Implementing two cutoffs revealed 14% to 16% of patients with intermediate results (CSF Aβ42/40 ratio: 5.5%–7.1%), which had a strong benefit from Aβ PET imaging (44%–52% Aβ PET positivity). DISCUSSION A two‐cutoff approach for CSF Aβ42/40 including Aβ PET imaging at intermediate results provides an effective assessment of Aβ pathology in real‐world settings. Highlights We evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid beta (Aβ) biomarkers for Alzheimer's disease in real‐world cohorts. A CSF Aβ 42/40 ratio between 5.5% and 7.1% defines patients at borderline levels. Patients at borderline levels strongly benefit from additional Aβ PET imaging. Two‐cutoff CSF Aβ 42/40 and PET will allow effective treatment stratification.

Situated within the context of increasing “adult regulatory practices” in skateboarding, this article draws attention to and interrogates the ways normative ideas of “youth,” “adolescence,” and “youth/adolescent development” often interplay with such efforts. In doing so, this article offers a critique, from a Critical Youth Studies perspective, of dominant, developmentalist notions of youth that typically cast young people as deficits in need of specific forms of intervention and surveillance. The article concludes with areas of inquiry emergent from critiques of dominant renderings of youth to be considered when engaging in processes of forming regulatory programs, policies, and practices related to skateboarding.

[Background] Internet-based Cognitive Behavior Therapy (ICBT) and mindfulness interventions are commonly used to treat elevated levels of stress. There are however few high-quality studies that examine ICBT with integrated mindfulness components for symptoms of stress and exhaustion, and the role of mindfulness exercises in digital treatment. [Method] The aim of the present study was to evaluate if a mindfulness-focused ICBT-program could reduce symptoms of stress and exhaustion, and increase quality of life, in a randomized controlled trial including 97 self-referred participants between 18 and 65 years who experienced elevated levels of stress. [Results] The intervention group had significantly reduced symptoms of stress and exhaustion, and increased quality of life, compared to the control group. Compared with the controls, participants in the intervention group showed a significant improvement with moderate to large effects on the primary outcome measure perceived stress (d = 0.79), and the secondary outcomes, exhaustion (d = 0.65), and quality of life (d = 0.40). Participants in the ICBT group also increased their level of mindfulness (d = 0.66) during the program. The amount of mindfulness training was significantly associated with an increased level of mindfulness, which in turn was significantly associated with reduced stress symptoms. [Conclusions] Mindfulness-focused ICBT can be an effective method to reduce stress-related mental health problems and the amount of mindfulness training seems to be of importance to increase the level of experienced mindfulness after treatment.

Abstract ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low‐risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low‐risk ETV6::RUNX1‐positive B‐cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome‐wide transcriptome and single‐nucleotide variants. We found high TIMD4 expression (> 85th‐percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low‐risk ETV6::RUNX1‐positive B‐cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low‐risk ETV6::RUNX1‐negative B‐cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low‐risk B‐cell ALL in children might be associated with high risk for early relapse.

Abstract Background Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether–lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy. Methods Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR–RFLP. Results A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0–2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors. Conclusions The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Abstract Acute genital ulcers can affect females of all ages. In children, they often appear as an emergency and remain a diagnostic challenge for pediatricians, gynecologists and dermatologists. Prompt diagnosis and identification of disease- related factors help to implement appropriate treatment. Firstly, it is crucial to properly compile the past medical history of the patient. Past infectious, autoimmune, malignant or traumatic conditions, as well as vaccinations may contribute to the occurrence of acute genital ulcers. Moreover, new infectious agents, such as severe acute respiratory syndrome coronavirus 2 and vaccinations against Coronavirus disease of 2019, may play a significant role in the development of atypical clinical symptoms. Here we present a case of a 12-year-old girl with acute genital ulcers. Additional symptoms accompanying the ulcer included: abdominal pain, nausea, vomiting, dysuria, vulvar pain and fever. Blood test showed leukocytosis, especially neutrophilia and monocytosis and increased levels of c-reactive protein and procalcitonin. Serological tests for the most common infections were negative. Moreover, the patient had a history of autoimmune diseases. She had periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome, and IgA vasculitis, also known as Henoch-Schönlein purpura in her past medical history. Additionally, she was vaccinated against SARS-CoV-2 shortly before the lesions appeared.

There are many possible quality tools available for RCA and this research seeks to identify which quality tools are used by quality professionals specifically when performing an RCA. An anonymous survey was emailed to an organization’s quality leaders at locations around the world. The survey asked the respondents to list the quality tools that they use when performing an RCA as well as the quality tools that they think everybody should know for RCA. The results were then statistically analyzed. The Ishikawa diagram is both the most commonly used quality tool and the most recommended quality tool for RCA. Five whys and is/is-not were also commonly used quality tools. This research identifies which quality tools are actually used by quality professionals in industry when performing an RCA. This information can be useful for organizations when selecting a limited tool set for RCA.

Abstract Remote monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer’s disease, this is particularly relevant for patients who seek medical advice due to memory problems. Here, we develop a remote digital memory composite (RDMC) score from an unsupervised remote cognitive assessment battery focused on episodic memory and long-term recall and assess its construct validity, retest reliability, and diagnostic accuracy when predicting MCI-grade impairment in a memory clinic sample and healthy controls. A total of 199 participants were recruited from three cohorts and included as healthy controls (n = 97), individuals with subjective cognitive decline (n = 59), or patients with mild cognitive impairment (n = 43). Participants performed cognitive assessments in a fully remote and unsupervised setting via a smartphone app. The derived RDMC score is significantly correlated with the PACC5 score across participants and demonstrates good retest reliability. Diagnostic accuracy for discriminating memory impairment from no impairment is high (cross-validated AUC = 0.83, 95% CI [0.66, 0.99]) with a sensitivity of 0.82 and a specificity of 0.72. Thus, unsupervised remote cognitive assessments implemented in the neotiv digital platform show good discrimination between cognitively impaired and unimpaired individuals, further demonstrating that it is feasible to complement the neuropsychological assessment of episodic memory with unsupervised and remote assessments on mobile devices. This contributes to recent efforts to implement remote assessment of episodic memory for case-finding and monitoring in large research studies and clinical care.

Background: Acute myeloid leukemia (AML) is an aggressive cancer with variable treatment responses. While clinical factors such as age and genetic mutations contribute to prognosis, recent studies suggest that CT attenuation scores may also predict treatment outcomes. This study aims to develop a nomogram combining clinical and CT-based factors to predict treatment response and guide personalized therapy for AML patients. Methods: This retrospective study included 74 newly diagnosed AML patients who underwent unenhanced abdominal CT scans within one week before receiving their first induction chemotherapy. Clinical biomarkers of tumor burden were also collected. Patients were classified into two groups based on treatment response: complete remission (CR; n = 24) and non-complete remission (NCR; n = 50). Multivariable logistic regression was used to identify independent predictors of treatment response. Predictive performance was evaluated using receiver operating characteristic (ROC) curves, and model consistency was assessed through calibration and decision curve analysis (DCA). Results: Significant differences in hemoglobin (Hb), platelets (Plt), and CT attenuation scores were observed between the CR and NCR groups (all p < 0.05). Multivariable logistic regression identified Hb, Plt, and CT attenuation scores as independent predictors of treatment response. A nomogram incorporating these factors demonstrated excellent predictive performance, with an area under the curve (AUC) of 0.912 (95% CI: 0.842–0.983), accuracy of 0.865 (95% CI: 0.765–0.933), sensitivity of 0.880 (95% CI: 0.790–0.970), and specificity of 0.833 (95% CI: 0.684–0.982). The CR nomogram displayed significant clinical value and excellent goodness of fit. Conclusions: The nomogram, which incorporates Hb, Plt, and CT attenuation scores, provides valuable insights into predicting treatment response in AML patients. This model offers strong discriminatory ability and could enhance personalized treatment planning and prognosis prediction for AML.

Background/Objectives: Salter–Harris II (SH-II) distal tibia fractures are the most common physeal ankle fractures in children; however, indications for surgical management remain controversial, and patient-reported outcomes for different management strategies are unknown. The purpose of the current study is to compare differences in clinical and patient-reported outcomes following operative and non-operative management of this injury. Methods: We performed a retrospective cohort study of pediatric patients who were treated at a single institution for SH-II distal tibia fractures between 2013 and 2020. Variables included age, gender, operative versus non-operative treatment, and premature physeal closure (PPC). Patients were also contacted for patient-reported outcome scores (PROs), which included the visual analog scale foot and ankle (VAS-FA) and the PROMIS pediatric mobility instrument obtained at a minimum of 2 years post-injury. Results: Demographic and clinical information was obtained for 46 patients. Our cohort was 52% male with mean age of 11.9 years at injury. At 6 months, the rate of PPC in our cohort was 25%, with no differences between operative and non-operative patients (29% vs. 24%, p = 0.80). A total of 15 of the 46 patients provided PROs, with an average follow-up time of 5.1 years (range: 2.9–9.1). VAS-FA and PROMIS pediatric mobility scores were similar between operative and non-operative patients. Conclusions: This pilot study suggests no differences in PROs following operative and non-operative management for SH-II distal tibia fractures; however, future studies with larger cohort sizes and longer follow-up times are needed to further examine these outcomes.

Background: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have NPM1 mutations. There is controversy regarding their prognosis and best therapy. Methods: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried out based on risk factors, and we assessed the effects of two post-remission strategies with and without transplant across risk cohorts. Results: In multi-variable analyses, a positive MRD test after the second consolidation cycle (HR = 6.00; 95% CI [3.31, 10.85]; p < 0.001), DNMT3A mutations (HR = 3.01 [1.57, 5.78]; p < 0.001), FLT3-ITD mutation with high variant allele frequency (HR = 4.40 [1.89, 10.24]; p < 0.001) and DDX11 mutations (HR = 4.38 [2.38, 8.04]; p < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) (HR = 5.49 [3.01, 10.04]; p < 0.001; HR = 2.99 [1.60, 5.62]; p < 0.001; HR = 4.20 [1.87, 9.40]; p < 0.001; and HR = 4.22, 95% CI [1.99, 8.95], p < 0.001). Subjects with ≥1 high-risk co-variate who received a transplant had a lower CIR and better LFS, whereas others did not. Conclusions: We identified co-variates associated with CIR and LFS in subjects of NPM1-mutated CN-AML.

Alkaline lakes are thought to have facilitated prebiotic synthesis reactions on the early Earth because their modern analogs accumulate vital chemical feedstocks such as phosphate through the evaporation of dilute groundwaters. Yet, the conditions required for some building block synthesis reactions are distinct from others, and these conditions are generally incompatible with those permissible for nascent cellular function. However, because current scenarios for prebiotic synthesis have not taken account of the physical processes that drive the chemical evolution of alkaline lakes, the potential for the co-occurrence of both prebiotic synthesis and the origins and early evolution of life in prebiotic alkaline lake environments remains poorly constrained. Here, we investigate the dynamics of active, prebiotically relevant alkaline lakes using near-surface geophysics, aqueous geochemistry, and hydrogeologic modeling. Due to their small size, representative range of chemistry, and contrasting evaporation behavior, the investigated, neighboring Last Chance and Goodenough Lakes in British Columbia, Canada offer a uniquely tractable environment for investigating the dynamics of alkaline lake behavior. The results show that the required, extreme phosphate enrichments in alkaline lake waters demand geomorphologically-driven vulnerability to evaporation, while the resultant contrast between evaporated brines and inflowing groundwaters yields Rayleigh–Taylor instabilities and vigorous surface–subsurface cycling and mixing of lake and groundwaters. These results provide a quantitative basis to reconcile conflicting prebiotic requirements of UV light, salinity, metal concentration, and pH in alkaline lake environments. The complex physical and chemical processing inherent to prebiotic alkaline lake environments thus may have not only facilitated prebiotic reaction networks, but also provided habitable environments for the earliest evolution of life.

Pancreaticoduodenal artery aneurysms (PDAAs) are an extremely rare visceral artery aneurysm subtype, usually managed by endovascular techniques. We report the case of a 57-year-old man with an intrapancreatic, inferior PDAA abutting the superior mesenteric artery (SMA). This location, in relation to the SMA, risks SMA thrombosis using an endovascular-only approach. Our approach consisted of open exploration and ligation of the inferior PDAA junction at the SMA, followed by endovascular coil embolization of the aneurysm. This case serves as a reminder that although many vascular diseases can be treated with less invasive endovascular strategies, open surgery can sometimes be the safer alternative.

Objective To perform a detailed characterisation of diabetes burden and pre-diabetes risk in a rural county with previously documented poor health outcomes in order to understand the local within-county distribution of diabetes in rural areas of America.Design, setting, and participants In 2021, we prospectively mailed health surveys to all households in Sullivan County, a rural county with the second-worst health outcomes of all counties in New York State. Our survey included questions on demographics, medical history and the American Diabetes Association’s Pre-diabetes Risk Test.Primary outcome and methods Our primary outcome was an assessment of diabetes burden within this rural county. To help mitigate non-response bias in our survey, raking adjustments were performed across strata of age, sex, race/ethnicity and health insurance. We analysed diabetes prevalence by demographic characteristics and used geospatial analysis to assess for clustering of diagnosed diabetes cases.Results After applying raking procedures for the 4725 survey responses, our adjusted diagnosed diabetes prevalence for Sullivan County was 12.9% compared with the 2019 Behavioural Risk Factor Surveillance System (BRFSS) estimate of 8.6%. In this rural area, diagnosed diabetes prevalence was notably higher among non-Hispanic Black (21%) and Hispanic (15%) residents compared with non-Hispanic White (12%) residents. 53% of respondents without a known history of pre-diabetes or diabetes scored as high risk for pre-diabetes. Nearest neighbour analyses revealed that hotspots of diagnosed diabetes were primarily located in the more densely populated areas of this rural county.Conclusions Our mailed health survey to all residents in Sullivan County demonstrated higher diabetes prevalence compared with modelled BRFSS estimates that were based on small telephone samples. Our results suggest the need for better diabetes surveillance in rural communities, which may benefit from interventions specifically tailored for improving glycaemic control among rural residents.

Through interviews with key stakeholders within skateboard organizations that explicitly attend to issues of diversity, access, and equity, this article explores pedagogical practices that undergird these organizations' programming for justice. More specifically, this article focuses on the interplay between the implementation of practices of exclusion to promote, ultimately, inclusion. In theorizing this pedagogical approach, this article discusses how notions of “brave spaces” work in tandem with ideas and practices of cultivating “safe spaces” to work toward social transformation within and beyond skateboarding.

A two-level hierarchical framework for early-stage sustainability assessment (FESSA) amongst a set of alternatives applicable from the earliest stages of process or product development is introduced, and its use in combination with an improved method weighted-sum method multi-criteria decision analysis (WSM-MCDA) in the presence of uncertainty is presented through application to a case study based upon a real-world decision scenario from speciality polymer manufacture. The approach taken addresses the challenge faced by those responsible for innovation management in the manufacturing process industries to make simultaneously timely and rational decisions early in the innovation cycle when knowledge gaps and uncertainty about the options tend to be at their highest. The Computed Uncertainty Range Evaluations (CURE) WSM-MCDA method provides better discrimination than the existing Multiple Attribute Range Evaluations (MARE) method without the computational burden of generating heuristic outcome distributions via Monte-Carlo simulation.