Efficacy, safety, and response predictors of Astragalus in patients with mild to moderate Alzheimer's disease: A study protocol of an assessor-blind, statistician-blind open-label randomized controlled trial.

Background: This pragmatic clinical trial aims to determine the efficacy and safety of add-on Astragalus membranaceus (AM) for cognition and non-cognition in patients with of mild to moderate Alzheimer's disease complicated with orthostatic hypotension in orthostatic hypotension, elucidate the underlying mechanisms, identify related response predictors, and explore effective drug components. Methods: This is an add-on, assessor-blinded, parallel, pragmatic, randomized controlled trial. At least 66 adults with mild to moderate Alzheimer's disease (AD) and OH aged 50-85 years will be recruited. Participants will be randomized in a 1:1:1 ratio to receive 24 weeks of routine care or add-on low dose AM or add-on high dose AM group. The primary efficacy outcome will be measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Chinese version. Secondary efficacy outcome assessment will include neuropsychological tests, blood pressure, plasma biomarkers, multimodal electroencephalograms, and neuroimaging. Safety outcome measures will include physical examinations, vital signs, electrocardiography, laboratory tests (such as hematologic and blood chemical tests), and adverse event records. Ethics and dissemination: This trial was approved and supervised by Fujian Medical University Union Hospital (2021KJCX040). Independent results, findings will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number: NCT05647473; ClinicalTrials.gov Identifier.

Abnormal brain-heart electrophysiology in mild and severe orthostatic hypotension.

INTRODUCTION: This study investigated the changes in cardiocerebral electrophysiology in patients with mild orthostatic hypotension (MOH) and severe orthostatic hypotension (SOH) and their relationship with the severity of orthostatic hypotension, psychiatric symptoms, and cognitive dysfunction. METHODS: This study included 72 nonorthostatic hypotension (NOH), 17 with MOH, and 11 with SOH. Seated resting-state heart rate variability (HRV) and quantitative electroencephalogram parameters were synchronized and recorded. HRV measures in the time and frequency domains were analyzed, along with the peak frequency and power of the brain waves. RESULTS: Abnormal neuronal activity was found in FP1 in patients with MOH, whereas it was more widespread in FP1, FP2, and O2 in patients with SOH (P < 0.05). Cardiac and cerebral electrophysiological abnormalities were significantly associated with orthostatic hypotension severity, psychiatric symptoms, and cognitive dysfunction. CONCLUSION: Abnormal EEG activity in patients are mainly manifested in the prefrontal and occipital lobes, especially in patients with SOH. These results may help patients to better understand the mechanisms underlying orthostatic hypotension severity and psychiatric and cognitive impairment in orthostatic hypotension.

Racial and Ethnic Underserved Populations Prescription Analgesic Use Before and After Lower Extremity Amputation in US Medicare.

BACKGROUND: Racial disparities exist in access to health care and management of multiple health conditions including chronic pain; however, racial disparities in pre- and postoperative pain management in lower extremity amputation are not well-studied. Our objective was to examine the association between different racial and ethnic groups and prescription opioid and other analgesics use before and after lower extremity amputation. We hypothesize prescription opioid and other analgesic use among Black, Hispanic, and Native American US Medicare beneficiaries undergoing lower extremity amputations will be lower compared to White US Medicare beneficiaries. METHODS: This retrospective cohort study included a 5% national sample of all Medicare beneficiaries from 2011 to 2015 and 15% national sample of fee-for-service Medicare beneficiaries from 2016 to 2018 undergoing nontraumatic, lower extremity amputations. The exposure of interest was racial and ethnic group membership (ie, Black, Hispanic, Native American, White, and others-with others being the combination of the categories Asian and other) as provided in Medicare claims data. Using multivariable generalized estimating equations with a logistic link to account for repeated measurements over time, we estimated the odds of prescription opioid use within 6 months before and after lower extremity amputation across different racial and ethnic groups separately, adjusting for sociodemographic and health status factors (eg, Elixhauser index). Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) were reported. RESULTS: Among 16,068 eligible beneficiaries who underwent major and minor amputations (mean age = 65.1 ± 12.7 years; female = 36.1%), 10,107 (62.9%) were White, 3462 (21.5%) were Black, 1959 (12.2%) were Hispanic, 247 (1.5%) were Native American, and 151 (2.9%) were beneficiaries of other races. During the 6 months before lower extremity amputation, Hispanic beneficiaries (aOR, 0.71, 95% CI, 0.65-0.78) and beneficiaries of other races (aOR, 0.60, 95% CI, 0.47-0.76) had significantly lower odds of using prescription opioids compared to White beneficiaries. Similarly, Hispanic beneficiaries (aOR, 0.78, 95% CI, 0.71-0.84) and beneficiaries of other races (aOR, 0.63, 95% CI, 0.51-0.78) were associated with lower odds of opioid use in the 6 months after amputation compared to White beneficiaries. CONCLUSIONS: Among fee-for-service Medicare beneficiaries, Hispanic and other (eg, Asian) fee-for-service Medicare beneficiaries had lower odds of prescription opioid use than their White counterparts before and after nontraumatic, lower extremity amputations. Efforts to determine the underlying reasons are needed to ensure equitable health care access.

Hypotension with neurovascular changes and cognitive dysfunction: An epidemiological, pathobiological, and treatment review.

ABSTRACT: Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer's disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

Brain white matter changes and their associations with non-motor dysfunction in orthostatic hypotension in α-synucleinopathy: A NODDI study.

BACKGROUND: The specific non-motor symptoms associated with α-synucleinopathies, including orthostatic hypotension (OH), cognitive impairment, and emotional abnormalities, have been a subject of ongoing controversy over the mechanisms underlying the development of a vicious cycle among them. The distinct structural alterations in white matter (WM) in patients with α-synucleinopathies experiencing OH, alongside their association with other non-motor symptoms, remain unexplored. This study employs axial diffusivity and density imaging (NODDI) to investigate WM damage specific to α-synucleinopathies with concurrent OH, delivering fresh evidence to supplement our understanding of the pathogenic mechanisms and pathological rationales behind the occurrence of a spectrum of non-motor functional impairments in α-synucleinopathies. METHODS: This study recruited 49 individuals diagnosed with α-synucleinopathies, stratified into an α-OH group (n = 24) and an α-NOH group (without OH, n = 25). Additionally, 17 healthy controls were included for supine and standing blood pressure data collection, as well as neuropsychological assessments. Magnetic resonance imaging (MRI) was utilized for the calculation of NODDI parameters, and tract-based spatial statistics (TBSS) were employed to explore differential clusters. The fibers covered by these clusters were defined as regions of interest (ROI) for the extraction of NODDI parameter values and the analysis of their correlation with neuropsychological scores. RESULTS: The TBSS analysis unveiled specific cerebral regions exhibiting disparities within the α-OH group as compared to both the α-NOH group and the healthy controls. These differences were evident in clusters that indicated a decrease in the acquisition of the neurite density index (NDI), a reduction in the orientation dispersion index (ODI), and an increase in the isotropic volume fraction (FISO) (p < 0.05). The extracted values from these ROIs demonstrated significant correlations with clinically assessed differences in supine and standing blood pressure, overall cognitive scores, and anxiety-depression ratings (p < 0.05). CONCLUSION: Patients with α-synucleinopathies experiencing OH exhibit distinctive patterns of microstructural damage in the WM as revealed by the NODDI model, and there is a correlation with the onset and progression of non-motor functional impairments.

Mitochondrial energy metabolism-related gene signature as a prognostic indicator for pancreatic adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor and is associated with an unfavorable prognosis worldwide. Considering the effect of mitochondrial metabolism on the prognosis of pancreatic cancer has rarely been investigated, we aimed to establish prognostic gene markers associated with mitochondrial energy metabolism for the prediction of survival probability in patients with PAAD. Methods: Gene expression data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, and the mitochondrial energy metabolism-related genes were obtained from the GeneCards database. Based on mitochondrial energy metabolism score (MMs), differentially expressed MMRGs were established for MMs-high and MMs-low groups using ssGSEA. After the univariate Cox and least absolute and selection operator (LASSO) analyses, a prognostic MMRG signature was used in the multivariate Cox proportional regression model. Survival and immune cell infiltration analyses were performed. In addition, a nomogram based on the risk model was used to predict the survival probability of patients with PAAD. Finally, the expression of key genes was verified using quantitative polymerase chain reaction and immunohistochemical staining. Intro cell experiments were performed to evaluated the proliferation and invasion of pancreatic cancer cells. Results: A prognostic signature was constructed consisting of two mitochondrial energy metabolism-related genes (MMP11, COL10A1). Calibration and receiver operating characteristic (ROC) curves verified the good predictability performance of the risk model for the survival rate of patients with PAAD. Finally, immune-related analysis explained the differences in immune status between the two subgroups based on the risk model. The high-risk score group showed higher estimate, immune, and stromal scores, expression of eight checkpoint genes, and infiltration of M0 macrophages, which might indicate a beneficial response to immunotherapy. The qPCR results confirmed high expression of MMP11 in pancreatic cancer cell lines, and IHC also verified high expression of MMP11 in clinical pancreatic ductal adenocarcinoma tissues. In vitro cell experiments also demonstrated the role of MMP11 in cell proliferation and invasion. Conclusion: Our study provides a novel two-prognostic gene signature-based on MMRGs-that accurately predicted the survival of patients with PAAD and could be used for mitochondrial energy metabolism-related therapies in the future.

Aberrant microstructural integrity of white matter in mild and severe orthostatic hypotension: A NODDI study.

OBJECTIVE: Scarce evidence is available to elucidate the association between the abnormal microstructure of white matter (WM) and cognitive performance in patients with orthostatic hypotension (OH). This study investigated the microstructural integrity of WM in patients with mild OH (MOH) and severe OH (SOH) and evaluated the association of abnormal WM microstructure with the broad cognitive domains and cognition-related plasma biomarkers. METHODS: Our study included 72 non-OH (NOH), 17 MOH, and 11 SOH participants. Across the groups, the WM integrity was analyzed by neurite orientation dispersion and density imaging (NODDI), and differences in WM microstructure were evaluated by nonparametric tests and post hoc models. The correlations between WM microstructure and broad cognitive domains and cognition-related plasma biomarkers were assessed by Spearman's correlation analysis. RESULTS: The abnormal WM microstructure was localized to the WM fiber bundles in MOH patients but distributed widely in SOH cohorts (p < 0.05). Further analysis showed that the neurite density index of the left cingulate gyrus was negatively associated with amyloid ß-40, glial fibrillary acidic protein, neurofilament light chain, phospho-tau181 (p < 0.05) but positively with global cognitive function (MOCA, MMSE, AER-III), memory, attention, language, language fluency, visuospatial function and amyloid ß-40 / amyloid ß-42 (p < 0.05). Additionally, other abnormal WM microstructures of OH were associated with broad cognitive domains and cognition-related plasma biomarkers to varying degrees. CONCLUSION: The findings evidence that abnormal WM microstructures may present themselves as early as in the MOH phase and that these structural abnormalities are associated with cognitive functions and cognition-related plasma biomarkers.

Synchronous monitoring of brain-heart electrophysiology using heart rate variability coupled with rapid quantitative electroencephalography in orthostatic hypotension patients with α-synucleinopathies: Rapid prediction of orthostatic hypotension and preliminary exploration of brain stimulation therapy.

BACKGROUND: In α-synucleinopathies, the dysfunction of the autonomic nervous system which typically manifests as orthostatic hypotension (OH) often leads to severe consequences and poses therapeutic challenges. This study aims to discover the brain-cardiac electrophysiological changes in OH patients with α-synucleinopathies using the rapid quantitative electroencephalography (qEEG) coupled with heart rate variability (HRV) technique to identify rapid, noninvasive biomarkers for early warning and diagnosis, as well as shed new light on complementary treatment approaches such as brain stimulation targets. METHODS: In this study, 26 subjects of α-synucleinopathies with OH (α-OH group), 21 subjects of α-synucleinopathies without OH (α-NOH group), and 34 healthy controls (control group) were included from September 2021 to August 2023 (NCT05527067). The heart rate-blood pressure variations in supine and standing positions were monitored, and synchronization parameters of seated resting-state HRV coupled with qEEG were collected. Time-domain and frequency-domain of HRV measures as well as peak frequency and power of the brainwaves were extracted. Differences between these three groups were compared, and correlations between brain-heart parameters were analyzed. RESULTS: The research results showed that the time-domain parameters such as MxDMn, pNN50, RMSSD, and SDSD of seated resting-state HRV exhibited a significant decrease only in the α-OH group compared to the healthy control group (p < 0.05), while there was no significant difference between the α-NOH group and the healthy control group. Several time-domain and frequency-domain parameters of seated resting-state HRV were found to be correlated with the blood pressure changes within the first 5 min of transitioning from supine to standing position (p < 0.05). Differences were observed in the power of beta1 waves (F4 and Fp2) and beta2 waves (Fp2 and F4) in the seated resting-state qEEG between the α-OH and α-NOH groups (p < 0.05). The peak frequency of theta waves in the Cz region also showed a difference (p < 0.05). The power of beta2 waves in the Fp2 and F4 brain regions correlated with frequency-domain parameters of HRV (p < 0.05). Additionally, abnormal electrical activity in the alpha, theta, and beta1 waves was associated with changes in heart rate and blood pressure within the first 5 min of transitioning from supine to standing position (p < 0.05). CONCLUSION: Rapid resting-state HRV with certain time-domain parameters below normal levels may serve as a predictive indicator for the occurrence of orthostatic hypotension (OH) in patients with α-synucleinopathies. Additionally, the deterioration of HRV parameters correlates with synchronous abnormal qEEG patterns, which can provide insights into the brain stimulation target areas for OH in α-synucleinopathy patients.

Efficacy analysis of three brain stimulation techniques for Alzheimer's disease: a meta-analysis of repeated transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation.

INTRODUCTION: This systematic review and meta-analysis study investigates the efficacy of repeated transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS) using neuropsychological assessments as a potential treatment option for Alzheimer's disease (AD). METHODS: PubMed, Embase, and the Cochrane Library were searched for studies on rTMS, tDCS, and DBS for the treatment of patients with AD between April 1970 and October 2022. The mini-Mental State Examination (MMSE) and AD Assessment Scale - Cognitive Subscale (ADAS-Cog) were adopted as the efficacy index. RESULTS: The analysis yielded 17 eligible studies. rTMS greatly improved the cognition of patients with AD (immediate post-treatment WMD of MMSE score: 2.06, p < 0.00001; short-term follow-up WMD of MMSE score: 2.12, p = 0.006; WMD of ADAS-Cog score in single-arm studies: -4.97, p = 0.001). DBS did not reverse the progression of cognitive decline (WMD of ADAS-Cog score in single-arm studies: 7.40, p < 0.00001). Furthermore, tDCS demonstrated no significant efficacy in improving cognition in random clinical trials or single-arm studies. CONCLUSION: rTMS is a promising non-medicinal alternative for cognitive improvement inpatients with AD.

Trajectories of adherence to extended treatment with direct oral anticoagulants and risks of recurrent venous thromboembolism and major bleeding.

BACKGROUND: Little is known about medication adherence patterns and their association with effectiveness and safety among patients with venous thromboembolism (VTE) receiving direct oral anticoagulant (DOAC) therapy beyond 3-6 months of initial treatment. OBJECTIVE: To examine the associations between adherence trajectories of extended treatment with DOAC and the risks of recurrent VTE and major bleeding among patients with VTE. METHODS: We conducted a retrospective cohort study of patients with incident VTE who completed 6 months of initial anticoagulant treatment and received either DOAC extended therapy or no extended therapy using MarketScan Commercial and Medicare Supplemental databases (2013-2019). We used group-based trajectory models to identify distinct adherence patterns during extended treatment. Using inverse probability treatment weighted Cox proportional hazards models, we examined the association between the adherence trajectories and the risks of recurrent VTE and major bleeding. RESULTS: Among 10,960 patients with extended treatment with DOACs (rivaroxaban, apixaban, dabigatran, edoxaban) and 5,133 patients with no extended treatment, we identified 4 distinct trajectories (consistently high, gradually declining, rapidly declining, and no extended treatment). Compared with the no extended treatment group, the groups with consistently high adherence (hazard ratio = 0.09, 95% CI = 0.05-0.17) and with gradually declining adherence (0.13, 0.03-0.53) showed decreased recurrent VTE risk without increased major bleeding risk (consistently high adherence 1.19, 0.71-1.99; gradually declining adherence 1.96, 0.81-4.70). There was no difference in the risk of recurrent VTE (0.34, 0.10-1.16) for the group with rapidly declining adherence, but this group was associated with increased major bleeding risk (2.65, 1.01-6.92). CONCLUSIONS: Our findings underscore the clinical importance of continuing and remaining adherent to extended DOAC treatment without increased major bleeding risk for patients with VTE. DISCLOSURES: This research was supported by the BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program. The funding source had no role in the design, collection, analysis, or interpretation of the data or the decision to submit the article for publication. Dr Lo-Ciganic reported receiving research funding from Merck Sharp & Dohme Corp. Dr Dietrich reported receiving honorarium for training and education from BMS/Pfizer. Dr DeRemer is a stockholder of Portola Pharmaceuticals and reported receiving personal fees for advisory board meeting from BMS. No other disclosures were reported.

How does 2D and 3D of urban morphology affect the seasonal land surface temperature in Island City? A block-scale perspective.

The global climate warming caused by urbanization has significantly affected the urban environment. Whilst land surface temperature (LST) is an important factor reflecting urban temperature, previous research on LST mostly focused on two-dimensional (2D) factors and rarely mentioned about the role of three-dimensional (3D) factors, particularly the LST variation characteristics of island cities. Therefore, this study examined the seasonal variation characteristics of urban LST by analyzing the impact of 2D and 3D urban morphology factors of different urban block types on LST in Xiamen Island. The main results are as follows. First, compact low layer (CL), a block type with a higher density of low-rise buildings, has a higher LST in any season. Under the same block density (BD), the higher the block average height (BH), the lower the LST. Second, among the 2D urban morphology factors, normalized difference vegetation index (NDVI) was the main factor for cities to reduce urban LST, especially in summer, while normalized difference built-up index (NDBI) was the opposite. Different from land cities, we found a positive correlation between modified normalized difference water body index (MNDWI) and LST in autumn and winter. Third, in the 3D urban morphology factors, sky view factor (SVF) was significantly positively correlated with LST, while building fluctuation (BF) was negatively correlated. The higher the SVF, the worse the radiation shielding effect between buildings. On the contrary, the higher the BF, the higher the building undulation, and the better the building radiation shielding. These findings should provide some quantitative insights for the future construction and planning of island cities, which can be used to improve the thermal environment of island cities and support the sustainable development of cities.

Dynamic orbital hybridization triggered spin-disorder renormalization via super-exchange interaction for oxygen evolution reaction.

The oxygen evolution reaction (OER) underpins many aspects of energy storage and conversion in modern industry and technology, but which still be suffering from the dilemma of sluggish reaction kinetics and poor electrochemical performance. Different from the viewpoint of nanostructuring, this work focuses on an intriguing dynamic orbital hybridization approach to renormalize the disordering spin configuration in porous noble-metal-free metal-organic frameworks (MOFs) to accelerate the spin-dependent reaction kinetics in OER. Herein, we propose an extraordinary super-exchange interaction to reconfigure the domain direction of spin nets at porous MOFs through temporarily bonding with dynamic magnetic ions in electrolytes under alternating electromagnetic field stimulation, in which the spin renormalization from disordering low-spin state to high-spin state facilitates rapid water dissociation and optimal carrier migration, leading to a spin-dependent reaction pathway. Therefore, the spin-renormalized MOFs demonstrate a mass activity of 2,095.1 A gmetal-1 at an overpotential of 0.33 V, which is about 5.9 time of pristine ones. Our findings provide a insight into reconfiguring spin-related catalysts with ordering domain directions to accelerate the oxygen reaction kinetics.

Trajectories of adherence to extended treatment with warfarin and risks of recurrent venous thromboembolism and major bleeding.

Background: Little is published about warfarin therapy adherence patterns beyond 6 months of initial anticoagulant treatment and their association with effectiveness and safety for patients with venous thromboembolism (VTE). Objectives: To compare the risks of recurrent VTE and major bleeding during extended treatment between adherence patterns using MarketScan Commercial and Medicare Supplemental databases (2013-2019). Methods: In a retrospective cohort study, we included patients with incident VTE who completed an initial 6-month anticoagulant treatment and received either warfarin or no extended therapy. Group-based trajectory models were used to identify distinct extended treatment trajectories. Associations between the trajectories and risk of hospitalization due to recurrent VTE and major bleeding were assessed using inverse probability treatment-weighted Cox proportional hazards models. Results: Compared with no extended treatment, consistently high warfarin adherence was associated with a significantly decreased risk of hospitalization due to recurrent VTE (hazard ratio [HR] = 0.23; 95% CI, 0.12-0.45), but gradually (HR = 0.29; 95CI, 0.08-1.06) or rapidly declining (HR = 0.14; 95% CI, 0.02-1.24) adherence showed no association with the risk of hospitalization due to recurrent VTE. Compared with no extended treatment, warfarin extended therapy was associated with an increased risk of hospitalization due to major bleeding regardless of adherence patterns (consistently high: HR = 2.08; 95% CI, 1.18-3.64, gradually declining: HR = 2.10; 95% CI, 0.74-5.95, and rapidly declining: HR = 9.19; 95% CI, 4.38-19.29). However, compared with rapidly declining adherence, consistently high (HR = 0.23; 95% CI, 0.11-0.47) and gradually declining (HR = 0.23; 95% CI, 0.08-0.64) adherence were associated with decreased risk of hospitalization due to major bleeding. Conclusion: The findings indicated that consistently high adherence to extended warfarin treatment was associated with a decreased risk of hospitalization due to recurrent VTE but an increased risk of hospitalization due to major bleeding compared with no extended treatment.

Trajectories of Oral Anticoagulation Adherence and Associated Clinical Outcomes During Long-Term Anticoagulation Among Medicare Beneficiaries With Venous Thromboembolism.

BACKGROUND: Little is known about anticoagulation medication nonadherence patterns impacting effectiveness and safety outcomes in clinical practice. OBJECTIVE: We identified adherence trajectories of extended therapy with direct-acting oral anticoagulants (DOACs) and warfarin after 6 months initial anticoagulant therapy among Medicare beneficiaries with venous thromboembolism (VTE). We further assessed the associated recurrent VTE and major bleeding risks. METHODS: Using group-based trajectory models, this retrospective cohort study identified distinct beneficiary subgroups with similar adherence patterns of extended-phase anticoagulant treatment (DOACs or warfarin) for patients with VTE who completed 6 months of initial anticoagulant treatment. We examined associations between adherence trajectories and risks of recurrent VTE and major bleeding using inverse probability treatment weighted Cox proportional hazards models. RESULTS: Compared with no extended treatment, consistently high DOAC adherence was associated with decreased recurrent VTE risk (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21-0.51) without increased major bleeding risk, and consistently high warfarin adherence was associated with decreased recurrent VTE risk (HR = 0.62, 95% CI = 0.40-0.95) and increased major bleeding risk (HR = 1.64, 95% CI = 1.12-2.41). Gradually declining adherence to DOACs (HR = 1.80, 95% CI = 1.07-3.03) or warfarin (HR = 2.34, 95% CI = 1.57-3.47) was associated with increased bleeding risk with no change in recurrent VTE risk. CONCLUSION AND RELEVANCE: This real-world evidence suggests persistently adhering to extended DOAC therapy is associated with lower recurrent VTE risk without increasing major bleeding among Medicare beneficiaries with VTE. Persistently adhering to extended warfarin therapy was associated with lower recurrent VTE risk but higher major bleeding risk.

Deprescribing Strategies for Opioids and Benzodiazepines with Emphasis on Concurrent Use: A Scoping Review.

While the Food and Drug Administration's black-box warnings caution against concurrent opioid and benzodiazepine (OPI-BZD) use, there is little guidance on how to deprescribe these medications. This scoping review analyzes the available opioid and/or benzodiazepine deprescribing strategies from the PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases (01/1995-08/2020) and the gray literature. We identified 39 original research studies (opioids: n = 5, benzodiazepines: n = 31, concurrent use: n = 3) and 26 guidelines (opioids: n = 16, benzodiazepines: n = 11, concurrent use: n = 0). Among the three studies deprescribing concurrent use (success rates of 21-100%), two evaluated a 3-week rehabilitation program, and one assessed a 24-week primary care intervention for veterans. Initial opioid dose deprescribing rates ranged from (1) 10-20%/weekday followed by 2.5-10%/weekday over three weeks to (2) 10-25%/1-4 weeks. Initial benzodiazepine dose deprescribing rates ranged from (1) patient-specific reductions over three weeks to (2) 50% dose reduction for 2-4 weeks, followed by 2-8 weeks of dose maintenance and then a 25% reduction biweekly. Among the 26 guidelines identified, 22 highlighted the risks of co-prescribing OPI-BZD, and 4 provided conflicting recommendations on the OPI-BZD deprescribing sequence. Thirty-five states' websites provided resources for opioid deprescription and three states' websites had benzodiazepine deprescribing recommendations. Further studies are needed to better guide OPI-BZD deprescription.

Comparative effectiveness and safety of direct oral anticoagulants versus warfarin among patients with recurrent venous thromboembolism.

The comparative effectiveness and safety of oral anticoagulant therapies to prevent a second recurrent venous thromboembolism (VTE) remains undetermined. We aimed to compare the benefits and harms of direct oral anticoagulant (DOAC) and warfarin therapies in preventing second recurrent VTE and major bleeding events among patients with a recurrent VTE episode following anticoagulation therapy for incident VTE. A retrospective cohort analysis of two large national insurance claims databases was conducted for patients with two episodes of VTE. Cox proportional hazards models were used after inverse probability treatment weighting to compare risks of second recurrent VTE and major bleeding events. Compared with warfarin, DOAC therapy was associated with significantly decreased risk of second recurrent VTE with no significant difference in risk of major bleeding events. Our findings suggest that, compared with warfarin, DOACs may reduce risk of second VTE recurrence among patients who have experienced one recurrence.

Clinician barriers, perceptions, and practices in treating patients with hepatitis C virus and substance use disorder in the United States.

The likelihood of clinicians prescribing direct-acting antiviral (DAA) therapy for patients with chronic hepatitis C virus (HCV) and substance use disorder (SUD) was assessed via a survey emailed throughout the United States to clinicians (physicians and advanced practice providers) in gastroenterology, hepatology, and infectious disease specialties. Clinicians' perceived barriers and preparedness and actions associated with current and future DAA prescribing practices of HCV-infected patients with SUD were assessed. Of 846 clinicians presumably receiving the survey, 96 completed and returned it. Exploratory factor analyses of perceived barriers indicated a highly reliable (Cronbach alpha = 0.89) model with five factors: HCV stigma and knowledge, prior authorization requirements, and patient- clinician-, and system-related barriers. In multivariable analyses, after controlling for covariates, patient-related barriers (P < 0.01) and prior authorization requirements (P < 0.01) were negatively associated with the likelihood of prescribing DAAs. Exploratory factor analyses of clinician preparedness and actions indicated a highly reliable (Cronbach alpha = 0.75) model with three factors: beliefs and comfort level; action; and perceived limitations. Clinician beliefs and comfort levels were negatively associated with the likelihood of prescribing DAAs (P = 0.01). Composite scores of barriers (P < 0.01) and clinician preparedness and actions (P < 0.05) were also negatively associated with the intent to prescribe DAAs. Conclusion: These findings underscore the importance of addressing patient-related barriers and prior authorization requirements-significant problematic barriers-and improving clinicians' beliefs (e.g., medication-assisted therapy should be prescribed before DAAs) and comfort levels for treating patients with HCV and SUD to enhance treatment access for patients with both HCV and SUD.

Light-driven Orderly Assembly of Ir-atomic Chains to Integrate a Dynamic Reaction Pathway for Acidic Oxygen Evolution.

This work suggests an intriguing light-driven atomic assembly proposal to orderly configure the distribution of reactive sites to optimize the spin-entropy-related orbital interaction and charge transfer from electrocatalysts to intermediates. Herein, the introduced fluorine (F) atoms acting as photo-corrosion centres in MnO1.9 F0.1 effectively soften the bonding interaction of Mn-O bonds in the IrCl3 solution. Therefore, partial Mn atoms can be successively replaced to form orderly atomic-hybridized catalysts with a spin-related low entropy due to the coexistence of Ir-atomic chains and clusters. The time-related elemental analysis demonstrates that the dynamic dissolution/redeposition of Ir clusters in acidic oxygen evolution leads to a reintegration of the reaction pathway to seek the switchable rate-limiting step with a lower activation energy.

Photo-induced heterogeneous regeneration of Fe(â ¡) in Fenton reaction for efficient polycyclic antibiotics removal and in-depth charge transfer mechanism.

Fenton reaction is regarded as a potential treatment for antibiotics removal, but challenges remain due to the sluggish reaction kinetics of Fe(III) reduction and incomplete degradation from insufficient active substance. Distinguished from traditional Fe(Ⅱ) regeneration techniques, this work focuses on utilizing the aliovalent redox pairs and built-in electric field to induce photo-excited electrons to cross the material interface and achieve Fe(III) reduction (heterogeneous regeneration). Herein, oxygen-deficient CeO2 particles are anchored on metal-organic frameworks (MIL-88A) and thus constitute the heterojunction with enhanced photoelectric properties, accelerating the directional charge transfer. Consequently, the synthesized MIL-88A/CeO2(OV) composite can degrade 95.76% of oxytetracycline within 60 min in photo-Fenton reaction and maintain a high mineralization rate (75.33%) after 4 cyclic tests. Furthermore, the charge transfer mechanisms of Fe cycle and antibiotics mineralization are both unveiled via experiment results and theorical calculation. This work proposes a new paradigm for constructing self-sufficient photo-Fenton catalytic system for efficient and sustainable removal of polycyclic antibiotics.

Artificial intelligence assisted cytological detection for early esophageal squamous epithelial lesions by using low-grade squamous intraepithelial lesion as diagnostic threshold.

BACKGROUND: Manual cytological diagnosis for early esophageal squamous cell carcinoma (early ESCC) and high-grade intraepithelial neoplasia (HGIN) is unsatisfactory. Herein, we have introduced an artificial intelligence (AI)-assisted cytological diagnosis for such lesions. METHODS: Low-grade squamous intraepithelial lesion or worse was set as the diagnostic threshold for AI-assisted diagnosis. The performance of AI-assisted diagnosis was evaluated and compared to that of manual diagnosis. Feasibility in large-scale screening was also assessed. RESULTS: AI-assisted diagnosis for abnormal cells was superior to manual reading by presenting a higher efficiency for each slide (50.9 ± 0.8 s vs 236.8 ± 3.9 s, p = 1.52 × 10-76 ) and a better interobserver agreement (93.27% [95% CI, 92.76%-93.74%] vs 65.29% [95% CI, 64.35%-66.22%], p = 1.03 × 10-84 ). AI-assisted detection showed a higher diagnostic accuracy (96.89% [92.38%-98.57%] vs 72.54% [65.85%-78.35%], p = 1.42 × 10-14 ), sensitivity (99.35% [95.92%-99.97%] vs 68.39% [60.36%-75.48%], p = 7.11 × 10-15 ), and negative predictive value (NPV) (97.06% [82.95%-99.85%] vs 40.96% [30.46%-52.31%], p = 1.42 × 10-14 ). Specificity and positive predictive value (PPV) were not significantly differed. AI-assisted diagnosis demonstrated a smaller proportion of participants of interest (3.73%, [79/2117] vs.12.84% [272/2117], p = 1.59 × 10-58 ), a higher consistence between cytology and endoscopy (40.51% [32/79] vs. 12.13% [33/272], p = 1.54 × 10- 8), specificity (97.74% [96.98%-98.32%] vs 88.52% [87.05%-89.84%], p = 3.19 × 10-58 ), and PPV (40.51% [29.79%-52.15%] vs 12.13% [8.61%-16.75%], p = 1.54 × 10-8 ) in community-based screening. Sensitivity and NPV were not significantly differed. AI-assisted diagnosis as primary screening significantly reduced average cost for detecting positive cases. CONCLUSION: Our study provides a novel cytological method for detecting and screening early ESCC and HGIN.