Are we really Bayesian? Probabilistic inference shows sub-optimal knowledge transfer.

Numerous studies have found that the Bayesian framework, which formulates the optimal integration of the knowledge of the world (i.e. prior) and current sensory evidence (i.e. likelihood), captures human behaviours sufficiently well. However, there are debates regarding whether humans use precise but cognitively demanding Bayesian computations for behaviours. Across two studies, we trained participants to estimate hidden locations of a target drawn from priors with different levels of uncertainty. In each trial, scattered dots provided noisy likelihood information about the target location. Participants showed that they learned the priors and combined prior and likelihood information to infer target locations in a Bayes fashion. We then introduced a transfer condition presenting a trained prior and a likelihood that has never been put together during training. How well participants integrate this novel likelihood with their learned prior is an indicator of whether participants perform Bayesian computations. In one study, participants experienced the newly introduced likelihood, which was paired with a different prior, during training. Participants changed likelihood weighting following expected directions although the degrees of change were significantly lower than Bayes-optimal predictions. In another group, the novel likelihoods were never used during training. We found people integrated a new likelihood within (interpolation) better than the one outside (extrapolation) the range of their previous learning experience and they were quantitatively Bayes-suboptimal in both. We replicated the findings of both studies in a validation dataset. Our results showed that Bayesian behaviours may not always be achieved by a full Bayesian computation. Future studies can apply our approach to different tasks to enhance the understanding of decision-making mechanisms.

Osteoporotic Precise Screening Using Chest Radiography and Artificial Neural Network: The OPSCAN Randomized Controlled Trial.

Background Diagnosing osteoporosis is challenging due to its often asymptomatic presentation, which highlights the importance of providing screening for high-risk populations. Purpose To evaluate the effectiveness of dual-energy x-ray absorptiometry (DXA) screening in high-risk patients with osteoporosis identified by an artificial intelligence (AI) model using chest radiographs. Materials and Methods This randomized controlled trial conducted at an academic medical center included participants 40 years of age or older who had undergone chest radiography between January and December 2022 without a history of DXA examination. High-risk participants identified with the AI-enabled chest radiographs were randomly allocated to either a screening group, which was offered fully reimbursed DXA examinations between January and June 2023, or a control group, which received usual care, defined as DXA examination by a physician or patient on their own initiative without AI intervention. A logistic regression was used to test the difference in the primary outcome, new-onset osteoporosis, between the screening and control groups. Results Of the 40 658 enrolled participants, 4912 (12.1%) were identified by the AI model as high risk, with 2456 assigned to the screening group (mean age, 71.8 years ± 11.5 [SD]; 1909 female) and 2456 assigned to the control group (mean age, 72.1 years ± 11.8; 1872 female). A total of 315 of 2456 (12.8%) participants in the screening group underwent fully reimbursed DXA, and 237 of 315 (75.2%) were identified with new-onset osteoporosis. After including DXA results by means of usual care in both screening and control groups, the screening group exhibited higher rates of osteoporosis detection (272 of 2456 [11.1%] vs 27 of 2456 [1.1%]; odds ratio [OR], 11.2 [95% CI: 7.5, 16.7]; P < .001) compared with the control group. The ORs of osteoporosis diagnosis were increased in screening group participants who did not meet formalized criteria for DXA compared with those who did (OR, 23.2 [95% CI: 10.2, 53.1] vs OR, 8.0 [95% CI: 5.0, 12.6]; interactive P = .03). Conclusion Providing DXA screening to a high-risk group identified with AI-enabled chest radiographs can effectively diagnose more patients with osteoporosis. Clinical trial registration no. NCT05721157 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Smith and Rothenberg in this issue.

Augmenting Neutrophil Extracellular Traps with Carbonized Polymer Dots: A Potential Treatment for Bacterial Sepsis.

Sepsis is a life-threatening condition that can progress to septic shock as the body's extreme response to pathogenesis damages its own vital organs. Staphylococcus aureus (S. aureus) accounts for 50% of nosocomial infections, which are clinically treated with antibiotics. However, methicillin-resistant strains (MRSA) have emerged and can withstand harsh antibiotic treatment. To address this problem, curcumin (CCM) is employed to prepare carbonized polymer dots (CPDs) through mild pyrolysis. Contrary to curcumin, the as-formed CCM-CPDs are highly biocompatible and soluble in aqueous solution. Most importantly, the CCM-CPDs induce the release of neutrophil extracellular traps (NETs) from the neutrophils, which entrap and eliminate microbes. In an MRSA-induced septic mouse model, it is observed that CCM-CPDs efficiently suppress bacterial colonization. Moreover, the intrinsic antioxidative, anti-inflammatory, and anticoagulation activities resulting from the preserved functional groups of the precursor molecule on the CCM-CPDs prevent progression to severe sepsis. As a result, infected mice treated with CCM-CPDs show a significant decrease in mortality even through oral administration. Histological staining indicates negligible organ damage in the MRSA-infected mice treated with CCM-CPDs. It is believed that the in vivo studies presented herein demonstrate that multifunctional therapeutic CPDs hold great potential against life-threatening infectious diseases.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Feasibility of Auto-Quantified Epicardial Adipose Tissue in Predicting Atrial Fibrillation Recurrence After Catheter Ablation.

BACKGROUND: The aim of this study was to build an auto-segmented artificial intelligence model of the atria and epicardial adipose tissue (EAT) on computed tomography (CT) images, and examine the prognostic significance of auto-quantified left atrium (LA) and EAT volumes for AF. METHODS AND RESULTS: This retrospective study included 334 patients with AF who were referred for catheter ablation (CA) between 2015 and 2017. Atria and EAT volumes were auto-quantified using a pre-trained 3-dimensional (3D) U-Net model from pre-ablation CT images. After adjusting for factors associated with AF, Cox regression analysis was used to examine predictors of AF recurrence. The mean (±SD) age of patients was 56±11 years; 251 (75%) were men, and 79 (24%) had non-paroxysmal AF. Over 2 years of follow-up, 139 (42%) patients experienced recurrence. Diabetes, non-paroxysmal AF, non-pulmonary vein triggers, mitral line ablation, and larger LA, right atrium, and EAT volume indices were linked to increased hazards of AF recurrence. After multivariate adjustment, non-paroxysmal AF (hazard ratio [HR] 0.6; 95% confidence interval [CI] 0.4-0.8; P=0.003) and larger LA-EAT volume index (HR 1.1; 95% CI 1.0-1.2; P=0.009) remained independent predictors of AF recurrence. CONCLUSIONS: LA-EAT volume measured using the auto-quantified 3D U-Net model is feasible for predicting AF recurrence after CA, regardless of AF type.

Maintenance therapy for chronic lymphocytic leukaemia.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain. OBJECTIVES: To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL. SEARCH METHODS: We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs). MAIN RESULTS: We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found. The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low. Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone. Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group. One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference -1.70, 95% CI -8.59 to 5.19; 480 participants; 1 study; low-certainty evidence). Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. No studies assessed HRQoL. Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs. AUTHORS' CONCLUSIONS: There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.

Impaired gut barrier integrity and reduced colonic expression of free fatty acid receptors in patients with Parkinson's disease.

BACKGROUND: Altered gut metabolites, especially short-chain fatty acids (SCFAs), in feces and plasma are observed in patients with Parkinson's disease (PD). OBJECTIVE: We aimed to investigate the colonic expression of two SCFA receptors, free fatty acid receptor (FFAR)2 and FFAR3, and gut barrier integrity in patients with PD and correlations with clinical severity. METHODS: In this retrospective study, colonic biopsy specimens were collected from 37 PD patients and 34 unaffected controls. Of this cohort, 31 participants (14 PD, 17 controls) underwent a series of colon biopsies. Colonic expression of FFAR2, FFAR3, and the tight junction marker ZO-1 were assayed by immunofluorescence staining. The You Only Look Once (version 8, YOLOv8) algorithm was used for automated detection and segmentation of immunostaining signal. PD motor function was assessed with the Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (UPDRS), and constipation was assessed using Rome-IV criteria. RESULTS: Compared with controls, PD patients had significantly lower colonic expression of ZO-1 (p < 0.01) and FFAR2 (p = 0.01). On serial biopsy, colonic expression of FFAR2 and FFAR3 was reduced in the pre-motor stage before PD diagnosis (both p < 0.01). MDS-UPDRS motor scores did not correlate with colonic marker levels. Constipation severity negatively correlated with colonic ZO-1 levels (r = -0.49, p = 0.02). CONCLUSIONS: Colonic expression of ZO-1 and FFAR2 is lower in PD patients compared with unaffected controls, and FFAR2 and FFAR3 levels decline in the pre-motor stage of PD. Our findings implicate a leaky gut phenomenon in PD and reinforce that gut metabolites may contribute to the process of PD.

Pitavastatin attenuates hypercholesterolemia-induced decline in serotonin transporter availability.

INTRODUCTION: Hypercholesterolemia is associated with increased inflammation and impaired serotonin neurotransmission, potentially contributing to depressive symptoms. However, the role of statins, particularly pitavastatin, in modulating serotonin transporter (SERT) function within this context remains underexplored. This study aimed to investigate whether pitavastatin counteracts the neurobiological effects of hypercholesterolemia. METHODS: Low-density lipoprotein receptor knockout (LDLR-/-) mice on a C57BL/6 background were assigned to three groups: a control group fed a standard chow diet, a group fed a high-fat diet (HFD), and a third group fed a high-fat diet supplemented with pitavastatin (HFD + Pita). We evaluated the effects of HFD with or without pitavastatin on lipid profiles, inflammatory markers, and SERT availability using small-animal positron emission tomography (PET) scans with the radioligand 4-[18F]-ADAM over a 20-week period. RESULTS: Pitavastatin treatment in HFD-fed mice significantly reduced both total cholesterol and LDL cholesterol levels in HFD-fed mice compared to those on HFD alone. Elevated inflammatory markers such as IL-1α, MCP-1/CCL2, and TNF-α in HFD mice were notably decreased in the HFD + Pita group. PET scans showed reduced SERT availability in the brains of HFD mice; however, pitavastatin improved this in brain regions associated with mood regulation, suggesting enhanced serotonin neurotransmission. Additionally, the sucrose preference test showed a trend towards increased preference in the HFD + Pita group compared to the HFD group, indicating a potential reduction in depressive-like behavior. CONCLUSION: Our findings demonstrate that pitavastatin not only lowers cholesterol and reduces inflammation but also enhances SERT availability, suggesting a potential role in alleviating depressive symptoms associated with hypercholesterolemia. These results highlight the multifaceted benefits of pitavastatin, extending beyond its lipid-lowering effects to potentially improving mood regulation and neurotransmitter function.

Methods and participant characteristics in the Cancer Risk in Vegetarians Consortium: a cross-sectional analysis across 11 prospective studies.

BACKGROUND: The associations of vegetarian diets with risks for site-specific cancers have not been estimated reliably due to the low number of vegetarians in previous studies. Therefore, the Cancer Risk in Vegetarians Consortium was established. The aim is to describe and compare the baseline characteristics between non-vegetarian and vegetarian diet groups and between the collaborating studies. METHODS: We harmonised individual-level data from 11 prospective cohort studies from Western Europe, North America, South Asia and East Asia. Comparisons of food intakes, sociodemographic and lifestyle factors were made between diet groups and between cohorts using descriptive statistics. RESULTS: 2.3 million participants were included; 66% women and 34% men, with mean ages at recruitment of 57 (SD: 7.8) and 57 (8.6) years, respectively. There were 2.1 million meat eaters, 60,903 poultry eaters, 44,780 pescatarians, 81,165 vegetarians, and 14,167 vegans. Food intake differences between the diet groups varied across the cohorts; for example, fruit and vegetable intakes were generally higher in vegetarians than in meat eaters in all the cohorts except in China. BMI was generally lower in vegetarians, particularly vegans, except for the cohorts in India and China. In general, but with some exceptions, vegetarians were also more likely to be highly educated and physically active and less likely to smoke. In the available resurveys, stability of diet groups was high in all the cohorts except in China. CONCLUSIONS: Food intakes and lifestyle factors of both non-vegetarians and vegetarians varied markedly across the individual cohorts, which may be due to differences in both culture and socioeconomic status, as well as differences in questionnaire design. Therefore, care is needed in the interpretation of the impacts of vegetarian diets on cancer risk.

Adapting the serious illness conversation guide for unhoused older adults: a rapid qualitative study.

BACKGROUND: Older adults experiencing homelessness (OAEH) age quickly and die earlier than their housed counterparts. Illness-related decisions are best guided by patients' values, but healthcare and homelessness service providers need support in facilitating these discussions. The Serious Illness Conversation Guide (SICG) is a communication tool to guide discussions but has not yet been adapted for OAEH. METHODS: We aimed to adapt the SICG for use with OAEH by nurses, social workers, and other homelessness service providers. We conducted semi-structured interviews with homelessness service providers and cognitive interviews with OAEH using the SICG. Service providers included nurses, social workers, or others working in homeless settings. OAEH were at least 50 years old and diagnosed with a serious illness. Interviews were conducted and audio recorded in shelters, transitional housing, a hospital, public spaces, and over Zoom. The research team reviewed transcripts, identifying common themes across transcripts and applying analytic notetaking. We summarized transcripts from each participant group, applying rapid qualitative analysis. For OAEH, data that referenced proposed adaptations or feedback about the SICG tool were grouped into two domains: "SICG interpretation" and "SICG feedback". For providers, we used domains from the Toolkit of Adaptation Approaches: "collaborative working", "team", "endorsement", "materials", "messages", and "delivery". Summaries were grouped into matrices to help visualize themes to inform adaptations. The adapted guide was then reviewed by expert palliative care clinicians for further refinement. RESULTS: The final sample included 11 OAEH (45% Black, 61 ± 7 years old) and 10 providers (80% White, 8.9 ± years practice). Adaptation themes included changing words and phrases to (1) increase transparency about the purpose of the conversation, (2) promote OAEH autonomy and empowerment, (3) align with nurses' and social workers' scope of practice regarding facilitating diagnostic and prognostic awareness, and (4) be sensitive to the realities of fragmented healthcare. Responses also revealed training and implementation considerations. CONCLUSIONS: The adapted SICG is a promising clinical tool to aid in the delivery of serious illness conversations with OAEH. Future research should use this updated guide for implementation planning. Additional adaptations may be dependent on specific settings where the SICG will be delivered.

Depressive Symptoms and Sleep Quality Mediate the Relationship Between Race and Quality of Life Among Patients With Heart Failure: A Serial Multiple Mediator Model.

BACKGROUND: Black patients with heart failure (HF) report worse quality of life (QoL) than White patients. Few investigators have examined mediators of the association between race and QoL, but depressive symptoms and sleep quality are associated with QoL. OBJECTIVE: The aim of this study was to determine whether depressive symptoms and sleep quality are mediators of the relationship between race and QoL among patients with HF. METHODS: This was a cross-sectional study. We included 271 outpatients with HF. Self-reported race (White/Black), depressive symptoms (Patient Health Questionnaire), sleep quality (Pittsburgh Sleep Quality Index), and QoL (Kansas City Cardiomyopathy Questionnaire) were collected at baseline. A serial multiple mediator analysis was conducted using the PROCESS macro for SPSS. RESULTS: Ninety-six patients (35.4%) were Black. Black participants reported higher levels of depressive symptoms and poorer sleep quality than White participants. Race was not directly associated with QoL but indirectly associated with QoL through depressive symptoms and poorer sleep quality. Because of higher levels of depressive symptoms and poorer sleep quality, Black participants reported poorer QoL than White participants. CONCLUSIONS: Depressive symptoms and sleep quality together mediated the relationship between race and QoL. These findings suggest that screening for depressive symptoms and sleep quality could identify patients at risk for poor QoL, especially in Black patients.

Mediators of the Association Between Cognitive Function and Self-care Behaviors in Patients Hospitalized With an Exacerbation of Heart Failure.

BACKGROUND: Patients with heart failure (HF) must engage in self-care, yet their self-care is often poor. Cognitive function commonly is impaired in HF and is associated with poor self-care. Heart failure knowledge and self-care confidence also are needed to preform self-care. Few investigators have examined mediators of the association of cognitive function with self-care. OBJECTIVES: The aim of this study was to determine whether HF knowledge and self-care confidence mediated the association of cognitive function with self-care maintenance and management among patients with HF. METHODS: This was a cross-sectional observational study of 164 patients with HF. Cognitive function was assessed using the Montreal Cognitive Assessment. Self-care maintenance and self-care management behaviors and self-care confidence were measured using the Self-care of Heart Failure Index. Heart failure knowledge was measured using the Dutch Heart Failure Knowledge Scale. We conducted 2 parallel mediation analyses using the PROCESS macro in SPSS, one for self-care maintenance and one for self-care management. RESULTS: Cognitive function was indirectly associated with self-care maintenance through HF knowledge (indirect effect, 0.54; 95% confidence interval, 0.10-1.02) and self-care confidence (indirect effect, 0.26; 95% confidence interval, 0.04-0.54). Those with better cognitive function had more HF knowledge and self-care confidence. Better cognitive function was not directly associated with self-care management but indirectly associated with better self-care management through higher self-care confidence (indirect effect, 0.50; 95% confidence interval, 0.04-1.05). CONCLUSIONS: Both HF knowledge and self-care confidence mediated the association of cognitive function with self-care maintenance, and only self-care confidence mediated the association between cognitive function and self-care management. Interventions targeting HF knowledge and self-care confidence may improve self-care even for those with lower cognitive function and need to be developed and tested.

Perceived Control, Functional Status, Depressive Symptoms, and Anxiety: Mediating and Moderating Influences on Health-Related Quality of Life in Patients With Heart Failure.

BACKGROUND: Health-related quality of life (HRQoL) is poor in patients with heart failure. Psychological (ie, depressive symptoms [DS], anxiety, and perceived control) and physical (ie, functional status) factors are associated with HRQoL. The dynamic relationships among these variables and their impact on HRQoL remain unclear, limiting the ability to design effective interventions. PURPOSE: Our aim was to evaluate a moderated mediation model, in which the association between perceived control and HRQoL was hypothesized to be mediated by DS and anxiety in the presence of a moderator, functional status. METHODS: Patients (N = 426) with heart failure completed the Control Attitudes Scale-Revised to measure perceived control, Duke Activity Status Index for functional status, Patient Health Questionnaire-9 for DS, Brief Symptom Inventory for anxiety, and Minnesota Living with Heart Failure Questionnaire for HRQoL. We performed a moderated parallel mediation analysis. RESULTS: Higher levels of perceived control were associated with better HRQoL through lower levels of anxiety and DS in the presence of functional status (index of moderated mediation for DS, b = 0.029; 95% confidence interval, 0.016-0.045; for anxiety: b = 0.009, 95% confidence interval, 0.002-0.018). The effect of perceived control on psychological symptoms was stronger at low and moderate functional statuses; however, this effect diminished with increasing functional status. CONCLUSION: Functional status moderated the indirect effects of perceived control on HRQoL through DS and anxiety in patients with heart failure. Efforts to improve HRQoL by targeting perceived control may be more effective when considering DS and anxiety in patients with low to moderate levels of functional status.

The HSP40 family chaperone isoform DNAJB6b prevents neuronal cells from tau aggregation.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear. RESULTS: We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology. CONCLUSIONS: In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.

Optimizing the selection of the endoscopically assisted supracerebellar transtentorial approach to the medial temporo-occipital region: Clinical application of one novel grid coordinate system.

The endoscopically assisted supracerebellar transtentorial (eSCTT) approach is advocated for managing pathologies of the medial temporo-occipital region, but quantitative analysis is currently lacking. The aims of this study were to establish a grid coordinate system on the tentorium to model the anatomical relationship between medial temporo-occipital region pathology and the slope of the tentorium, and then to compare the paramedian eSCTT and extreme-lateral eSCTT approaches quantitatively. Bilateral paramedian and extreme-lateral eSCTT approaches were used to dissect three adult cadaveric heads anatomically. A grid coordinate system was established on the tentorium, and the angles of attack and depth of the surgical corridor of each coordinate point were obtained so that the two eSCTT approaches could be compared statistically. The measurements were then analyzed to determine the condition for selecting each eSCTT approach, and its clinical feasibility was assessed in three patients with large tumors in the medial temporo-occipital region. For coordinate points where the X-coordinate on the grid coordinate system was 1 cm outside the apex of the tentorium, the paramedian eSCTT approach had a significantly wider angle of attack and shorter depth of surgical corridor than the extreme-lateral eSCTT approach. In contrast, the extreme-lateral eSCTT approach was better for coordinate points where the Y-coordinate on the grid coordinate system was 1 cm in front of the apex of the tentorium. The long axis of each patient's tumor was projected on to the tentorium and its corresponding coordinate points were used to match the more appropriate eSCTT approach. Preliminary results for three patients treated with the eSCTT approach for large tumors in the medial temporo-occipital region were encouraging. When the eSCTT approach is applied to manage a large tumor of the medial temporo-occipital region, assessment of the long axis of the tumor and knowledge of the selective condition for each eSCTT approach can help in clinical decision-making.

Persistent Mesodermal Differentiation Capability of Bone Marrow MSCs Isolated from Aging Patients with Low-Energy Traumatic Hip Fracture and Osteoporosis: A Clinical Evidence.

A low-energy hit, such as a slight fall from a bed, results in a bone fracture, especially in the hip, which is a life-threatening risk for the older adult and a heavy burden for the social economy. Patients with low-energy traumatic bone fractures usually suffer a higher level of bony catabolism accompanied by osteoporosis. Bone marrow-derived stem cells (BMSCs) are critical in osteogenesis, leading to metabolic homeostasis in the healthy bony microenvironment. However, whether the BMSCs derived from the patients who suffered osteoporosis and low-energy traumatic hip fractures preserve a sustained mesodermal differentiation capability, especially in osteogenesis, is yet to be explored in a clinical setting. Therefore, we aimed to collect BMSCs from clinical hip fracture patients with osteoporosis, followed by osteogenic differentiation comparison with BMSCs from healthy young donors. The CD markers identification, cytokines examination, and adipogenic differentiation were also evaluated. The data reveal that BMSCs collected from elderly osteoporotic patients secreted approximately 122.8 pg/mL interleukin 6 (IL-6) and 180.6 pg/mL vascular endothelial growth factor (VEGF), but no PDGF-BB, IL-1b, TGF-b1, IGF-1, or TNF-α secretion. The CD markers and osteogenic and adipogenic differentiation capability in BMSCs from these elderly osteoporotic patients and healthy young donors are equivalent and compliant with the standards defined by the International Society of Cell Therapy (ISCT). Collectively, our data suggest that the elderly osteoporotic patients-derived BMSCs hold equivalent differentiation and proliferation capability and intact surface markers identical to BMSCs collected from healthy youth and are available for clinical cell therapy.

Artificial Intelligence-enabled Chest X-ray Classifies Osteoporosis and Identifies Mortality Risk.

A deep learning model was developed to identify osteoporosis from chest X-ray (CXR) features with high accuracy in internal and external validation. It has significant prognostic implications, identifying individuals at higher risk of all-cause mortality. This Artificial Intelligence (AI)-enabled CXR strategy may function as an early detection screening tool for osteoporosis. The aim of this study was to develop a deep learning model (DLM) to identify osteoporosis via CXR features and investigate the performance and clinical implications. This study collected 48,353 CXRs with the corresponding T score according to Dual energy X-ray Absorptiometry (DXA) from the academic medical center. Among these, 35,633 CXRs were used to identify CXR- Osteoporosis (CXR-OP). Another 12,720 CXRs were used to validate the performance, which was evaluated by the area under the receiver operating characteristic curve (AUC). Furthermore, CXR-OP was tested to assess the long-term risks of mortality, which were evaluated by Kaplan‒Meier survival analysis and the Cox proportional hazards model. The DLM utilizing CXR achieved AUCs of 0.930 and 0.892 during internal and external validation, respectively. The group that underwent DXA with CXR-OP had a higher risk of all-cause mortality (hazard ratio [HR] 2.59, 95% CI: 1.83-3.67), and those classified as CXR-OP in the group without DXA also had higher all-cause mortality (HR: 1.67, 95% CI: 1.61-1.72) in the internal validation set. The external validation set produced similar results. Our DLM uses CXRs for early detection of osteoporosis, aiding physicians to identify those at risk. It has significant prognostic implications, improving life quality and reducing mortality. AI-enabled CXR strategy may serve as a screening tool.

Artificial Intelligence-Enabled Electrocardiography Predicts Future Pacemaker Implantation and Adverse Cardiovascular Events.

Medical advances prolonging life have led to more permanent pacemaker implants. When pacemaker implantation (PMI) is commonly caused by sick sinus syndrome or conduction disorders, predicting PMI is challenging, as patients often experience related symptoms. This study was designed to create a deep learning model (DLM) for predicting future PMI from ECG data and assess its ability to predict future cardiovascular events. In this study, a DLM was trained on a dataset of 158,471 ECGs from 42,903 academic medical center patients, with additional validation involving 25,640 medical center patients and 26,538 community hospital patients. Primary analysis focused on predicting PMI within 90 days, while all-cause mortality, cardiovascular disease (CVD) mortality, and the development of various cardiovascular conditions were addressed with secondary analysis. The study's raw ECG DLM achieved area under the curve (AUC) values of 0.870, 0.878, and 0.883 for PMI prediction within 30, 60, and 90 days, respectively, along with sensitivities exceeding 82.0% and specificities over 81.9% in the internal validation. Significant ECG features included the PR interval, corrected QT interval, heart rate, QRS duration, P-wave axis, T-wave axis, and QRS complex axis. The AI-predicted PMI group had higher risks of PMI after 90 days (hazard ratio [HR]: 7.49, 95% CI: 5.40-10.39), all-cause mortality (HR: 1.91, 95% CI: 1.74-2.10), CVD mortality (HR: 3.53, 95% CI: 2.73-4.57), and new-onset adverse cardiovascular events. External validation confirmed the model's accuracy. Through ECG analyses, our AI DLM can alert clinicians and patients to the possibility of future PMI and related mortality and cardiovascular risks, aiding in timely patient intervention.

Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122.

Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.

Catheter Ablation in Arrhythmic Cardiac Diseases: Endocardial and Epicardial Ablation.

Arrhythmogenic cardiomyopathy (ACM) is a group of arrhythmogenic disorders of the myocardium that are not caused by ischemic, hypertensive, or valvular heart disease. The clinical manifestations of ACMs may overlap those of dilated cardiomyopathy, complicating the differential diagnosis. In several ACMs, ventricular tachycardia (VT) has been observed at an early stage, regardless of the severity of the disease. Therefore, preventing recurrences of VT can be a clinical challenge. There is a wide range of efficacy and side effects associated with the use of antiarrhythmic drugs (AADs) in the treatment of VT. In addition to AADs, patients with ACM and ventricular tachyarrhythmias may benefit from catheter ablation, especially if they are drug-refractory. The differences in pathogenesis between the various types of ACMs can lead to heterogeneous distributions of arrhythmogenic substrates, non-uniform ablation strategies, and distinct ablation outcomes. Ablation has been documented to be effective in eliminating ventricular tachyarrhythmias in arrhythmogenic right ventricular dysplasia (ARVC), sarcoidosis, Chagas cardiomyopathy, and Brugada syndrome (BrS). As an entity that is rare in nature, ablation for ventricular tachycardia in certain forms of ACM may only be reported through case reports, such as amyloidosis and left ventricular noncompaction. Several types of ACMs, including ARVC, sarcoidosis, Chagas cardiomyopathy, BrS, and left ventricular noncompaction, may exhibit diseased substrates within or adjacent to the epicardium that may be accountable for ventricular arrhythmogenesis. As a result, combining endocardial and epicardial ablation is of clinical importance for successful ablation. The purpose of this article is to provide a comprehensive overview of the substrate characteristics, ablation strategies, and ablation outcomes of various types of ACMs using endocardial and epicardial approaches.