Distinct biological property of tau in tau-first cognitive proteinopathy: Evidence by longitudinal clinical neuroimaging profiles and compared with late-onset Alzheimer disease.

BACKGROUND: Tau-first cognitive proteinopathy (TCP) denotes a clinical phenotype of Alzheimer disease (AD) showing Florzolotau(18F) positron emission tomography (PET) positivity but a negative amyloid status. AIM: We explored the biological property of tau using longitudinal cognitive and neuroimaging data in TCP and compared with late-onset AD (LOAD). METHOD: We enrolled 56 patients with LOAD, 34 patients with TCP, and 26 cognitive unimpaired controls. All of the participants had historical data of 2 to 4 three-dimensional T1 images and 2 to 6 annual cognitive evaluations over a follow-up period of 7 years. Tau topography was measured using Florzolotau(18F) PET. In the LOAD and TCP groups, we constructed tau or gray matter clusters covarying with the cognitive measurements. We used mediator analysis to explore the regional tau load as predictor, gray matter partitions as mediators, and significant cognitive test scores as outcomes. Longitudinal cognitive decline and cortical thickness degeneration pattern were analyzed using a linear mixed-effects model. RESULTS: The TCP group had longitudinal declines in nonexecutive domains. The deterministic factor predicting the short-term memory score in TCP was the hippocampal volume and not directly via the medial and lateral temporal tau load. These features formed the conceptual differences with LOAD. DISCUSSION: The biological properties of tau and the longitudinal cognitive-imaging trajectory support the conceptual distinction between TCP and LOAD. TCP represents one specific entity featuring salient short-term memory impairment, declines in nonexecutive domains, a slower gray matter degenerative pattern, and a restricted impact of tau.

Characteristics of acute ischemic stroke in patients with Nephrotic syndrome.

The incidence of ischemic stroke (IS) is higher in nephrotic syndrome (NS) patients compared to general population. However, there is limited information on the specific characteristics to stroke patients with NS. In this study, we aimed to examine the clinical manifestations of acute IS in a large group of NS patients, comparing to those without NS. We conducted a retrospective cohort study to compare the clinical presentations of acute IS in patients with and without NS. This study was a multi-institutional study and used data from Chang Gung Research Database of Taiwan from 1 January 2001, to 31 December 2017. A total of 233 IS patients with NS and 1358 IS patients without NS were enrolled. The median age of participants was 68 (range: 59-79) years. The risk of dependent functional status (modified Rankin Scale score≧3) after IS was higher in NS patients compared to those without NS (Odd ratio (OR) 4.02, 95% confidence interval (CI) 2.39 to 6.76, p < 0.001), particularly in stroke subtypes as small-artery occlusion (OR 8.02, 95% CI 3.94 to 16.32, p < 0.001), and stroke of undetermined etiology (OR 2.47, CI 1.06 to 5.76, p = 037). The risks of mortality or stroke recurrence within 30 days were similar between the two groups for all stroke subtypes. In conclusion, NS was associated with a higher risk of functional dependence following IS. Intensive treatment and rehabilitation should be considered for IS patients with NS.

Upregulation of APAF1 and CSF1R in Peripheral Blood Mononuclear Cells of Parkinson's Disease.

Increased oxidative stress and neuroinflammation play a crucial role in the pathogenesis of Parkinson's disease (PD). In this study, the expression levels of 52 genes related to oxidative stress and inflammation were measured in peripheral blood mononuclear cells of the discovery cohort including 48 PD patients and 25 healthy controls. Four genes, including ALDH1A, APAF1, CR1, and CSF1R, were found to be upregulated in PD patients. The expression patterns of these genes were validated in a second cohort of 101 PD patients and 61 healthy controls. The results confirmed the upregulation of APAF1 (PD: 0.34 ± 0.18, control: 0.26 ± 0.11, p < 0.001) and CSF1R (PD: 0.38 ± 0.12, control: 0.33 ± 0.10, p = 0.005) in PD patients. The expression level of APAF1 was correlated with the scores of the Unified Parkinson's Disease Rating Scale (UPDRS, r = 0.235, p = 0.018) and 39-item PD questionnaire (PDQ-39, r = 0.250, p = 0.012). The expression level of CSF1R was negatively correlated with the scores of the mini-mental status examination (MMSE, r = -0.200, p = 0.047) and Montréal Cognitive Assessment (MoCA, r = -0.226, p = 0.023). These results highly suggest that oxidative stress biomarkers in peripheral blood may be useful in monitoring the progression of motor disabilities and cognitive decline in PD patients.

Relationship between nurses' mood at work and work engagement: Work morale as a mediator.

AIM: To determine the effect of nurses' mood at work (positive and negative) on work engagement and whether work morale mediates this relationship. BACKGROUND: Nurses' work engagement is a key research area, yet limited data regarding the relationship between nurses' mood at work and work engagement are available. Therefore, how nurses' positive or negative mood at work affects their work engagement remains unclear. METHODS: This study analyzed nurses from a medical center in Taipei City. A total of 279 completed questionnaires were returned. The data were analyzed using two-stage structural equation modeling to test the hypothesized relationships. FINDINGS: Nurses' positive mood had a significantly positive effect on work morale, whereas their negative mood had a significantly negative effect on work morale. Additionally, work morale played a mediating role in the relationship between mood at work and work engagement. CONCLUSION: The results revealed that nurses' moods affected their work engagement and that this relationship was affected by work morale. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Healthcare institutions and hospitals could develop a positive work environment to help nurses maintain their good mood and reduce negative affectivity. They should also provide nurses with counseling services, offer morale-boosting activities, and adopt an inspirational leadership style to maintain their work morale.

Hypothyroidism and risks of cerebrovascular complications among patients with head and neck cancer after radiotherapy.

BACKGROUND: Hypothyroidism (HT) and carotid artery stenosis (CAS) are complications of radiotherapy (RT) in patients with head and neck cancer (HNC). The impact of post-RT HT on CAS progression remains unclear. METHODS: Between 2013 and 2014, HNC patients who had ever received RT and were under regular follow-up in our hospital were initially screened. Patients were categorized into euthyroid (EU) and HT groups. Details of RT and HNC were recorded. Total plaque scores and degrees of CAS were measured during annual extracranial duplex follow-up. Patients were monitored for CAS progression to > 50 % stenosis or ischemic stroke (IS). Cumulative time to CAS progression and IS between the 2 groups were compared. Data were further analyzed based on the use or nonuse of thyroxine of the HT group. RESULTS: 333 HNC patients with RT history were screened. Finally, 216 patients were recruited (94 and 122 patients in the EU and HT groups). Patients of the HT group received higher mean RT doses (HT vs. EU; 7021.55 ± 401.67 vs. 6869.69 ± 425.32 centi-grays, p = 0.02). Multivariate Cox models showed comparable CAS progression (p = 0.24) and IS occurrence (p = 0.51) between the 2 groups. Moreover, no significant difference was observed in time to CAS progression (p = 0.49) or IS (p = 0.31) among patients with EU and HT using and not using thyroxine supplement. CONCLUSIONS: Our results did not demonstrate significant effects of HT and thyroxine supplementation on CAS progression and IS incidence in patients with HNC after RT.

Characteristics of ischemic stroke and intracranial hemorrhage in patients with nephrotic syndrome.

BACKGROUND: The incidence of cerebral stroke, including ischemic infarction and intracranial hemorrhage (ICH), increases in patients with nephrotic syndrome (NS). However, the clinical characteristics of patients with NS and stroke remain elusive. We aimed to investigate the clinical presentation and prognosis among patients with NS and ischemic stroke (IS) or ICH. METHODS: We conducted a population-based retrospective cohort study of patients with NS and acute stroke using the Chang Gung Research Database of Taiwan from January 1, 2001, to December 31, 2017. The participants were recruited from the 7 branches of Chang Gung Memorial Hospital. RESULTS: A total of 233 patients with IS and 57 patients with ICH were enrolled. The median age was 60 (52-70) years. The prevalence rates of hyperlipidemia, hyperuricemia, and smoking were higher in IS than in ICH. IS demonstrated lower white blood cell count (7.80 vs. 8.92 × 109/L) and high-sensitivity C-reactive protein level (33.42 vs. 144.10 nmol/L) and higher cholesterol (5.74 vs. 4.84 mmol/L), triglyceride (1.60 vs. 1.28 mmol/L), and albumin (24 vs. 18 g/L) levels compared with ICH. The dependent functional status and 30-day mortality were higher in ICH than in IS. The risk factors for 30-day mortality for patients with NS and stroke were coronary artery disease (CAD), ICH, and total anterior circulation syndrome. The multivariate Cox regression analysis revealed that CAD was positively associated with 30-day mortality in patients with IS (hazard ratio 24.58, 95 % CI 1.48 to 408.90). In patients with ICH, CAD and subarachnoid hemorrhage were positively associated with 30-day mortality (hazard ratio 5.49, 95 % CI 1.54 to 19.56; hazard ratio 6.32, 95 % CI 1.57 to 25.53, respectively). CONCLUSIONS: ICH demonstrated a higher risk of dependence and 30-day mortality compared with IS in patients with NS. Intensive monitoring and treatment should be applied particularly in patients with NS and ICH.

Computed Tomography Angiography in Acute Stroke Patients Receiving Recombinant Tissue Plasminogen Activator: Outcome and Safety Evaluations in an Asian Population.

INTRODUCTION: The multiphase computed tomography angiography (mCTA) is superior to the noncontrast computed tomography (NCCT) in selecting patients that would benefit from mechanical thrombectomy following an acute ischemic stroke (AIS). It remains unclear whether the longer examination time of mCTA worsens outcomes of intravenous recombinant tissue plasminogen activator (IV r-tPA) or increases the risk of hemorrhagic transformation (HT) compared to NCCT in Asian stroke patients. METHODS: Between January 2011 and December 2017, 199 AIS patients receiving IV r-tPA with initial National Institute of Health Stroke Scale (NIHSS) scores between 6 and 25 were enrolled in a single medical center. Onset-to-needle time (ONT), door-to-needle time (DNT), and creatinine levels before and after thrombolysis were recorded. We evaluated NIHSS scores 2, 24 h after treatment, and at discharge, the modified Rankin Scale (mRS) at discharge, and mortality rate. The presence of HT was reviewed within 7 days after thrombolysis. RESULTS: DNT, perithrombolysis creatinine levels, NIHSS, and mRS scores at the emergency room were similar between the NCCT and mCTA groups. ONT was shorter in the mCTA group. AIS patients got more significant neurologic improvement (NIHSS decrease ≥4) after thrombolysis and physically independent (mRS ≤2) at discharge in the mCTA group. Mortality rates, symptomatic, and total HT rates were similar between the NCCT and mCTA groups. CONCLUSION: Comparing to NCCT, mCTA-based IV r-tPA would not delay DNT nor worsen the outcome. Furthermore, mCTA provides more information for early identification of candidates for mechanical thrombectomy in Asian AIS patients.

Lysine 27 ubiquitination of the mitochondrial transport protein Miro is dependent on serine 65 of the Parkin ubiquitin ligase.

Mitochondrial transport plays an important role in matching mitochondrial distribution to localized energy production and calcium buffering requirements. Here, we demonstrate that Miro1, an outer mitochondrial membrane (OMM) protein crucial for the regulation of mitochondrial trafficking and distribution, is a substrate of the PINK1/Parkin mitochondrial quality control system in human dopaminergic neuroblastoma cells. Moreover, Miro1 turnover on damaged mitochondria is altered in Parkinson disease (PD) patient-derived fibroblasts containing a pathogenic mutation in the PARK2 gene (encoding Parkin). By analyzing the kinetics of Miro1 ubiquitination, we further demonstrate that mitochondrial damage triggers rapid (within minutes) and persistent Lys-27-type ubiquitination of Miro1 on the OMM, dependent on PINK1 and Parkin. Proteasomal degradation of Miro1 is then seen on a slower time scale, within 2-3 h of the onset of ubiquitination. We find Miro ubiquitination in dopaminergic neuroblastoma cells is independent of Miro1 phosphorylation at Ser-156 but is dependent on the recently identified Ser-65 residue within Parkin that is phosphorylated by PINK1. Interestingly, we find that Miro1 can stabilize phospho-mutant versions of Parkin on the OMM, suggesting that Miro is also part of a Parkin receptor complex. Moreover, we demonstrate that Ser-65 in Parkin is critical for regulating Miro levels upon mitochondrial damage in rodent cortical neurons. Our results provide new insights into the ubiquitination-dependent regulation of the Miro-mediated mitochondrial transport machinery by PINK1/Parkin and also suggest that disruption of this regulation may be implicated in Parkinson disease pathogenesis.

Presence of Gyriform Air Predicts Unfavorable Outcome in Venous Catheter-Related Cerebral Air Embolism.

BACKGROUND: This study aimed to investigate the clinical predictors of unfavorable prognosis in patients with venous catheter-related cerebral air embolism. METHODS: An extensive review of English literature was performed to obtain reports on cerebral air embolism published between January 1982 and July 2014 through PubMed, Journal at Ovid, and Web of Science using the Mesh terms and keywords "cerebral air embolism" and "cerebral gas embolism." Reports not fulfilling the diagnosis of cerebral air embolism and iterant articles were excluded. Demographics, clinical manifestations, and imaging findings were recorded. The air distribution on initial brain computed tomography (CT) was recorded as gyriform air (GF), cavernous sinus bubble, venous sinus bubble, and parenchymal and subarachnoid bubble. The enrolled subjects were further divided into favorable and unfavorable outcome groups for analyses. RESULTS: Of the 33 cases enrolled, 31 had documented follow-up outcomes, including 14 with favorable and 17 with unfavorable prognoses. Patients with unfavorable outcome had older onset age (67.5 ± 15.8 versus 46.7 ± 17.0 years, P < .001), higher frequency of GF on brain CT (58.8% versus 0%, P < .01), initial consciousness disturbance (100% versus 42.9%, P < .001), and hemiparesis (100% versus 42.9%, P < .001), but lower frequency of cardiopulmonary symptoms (5.9% versus 64.3%, P < .01). In patients with central venous catheter-related cerebral air embolism, the retrograde mechanism had a tendency for worse outcomes (43.8% versus 0%, P = .023). CONCLUSIONS: In patients with venous catheter-related cerebral air embolism, the presence of GF on brain CT imaging, old age, initial conscious disturbance, and hemiparesis may predict unfavorable outcomes.

Evaluation of Dietary Intake in Individuals with Mild Cognitive Impairment.

The phase of mild cognitive impairment (MCI) holds significant importance for postponing the onset of dementia. Therefore, MCI has become a central focus in research related to dementia prevention. The purpose of this study was to investigate the dietary intake and dietary patterns of MCI patients in Taiwan. In total, 40 subjects were enrolled in this cross-sectional study that was conducted from July 2019 to September 2021 at the Linkou Chang Gung Memorial Hospital. The results of the clinical dementia rating (CDR) and mini-mental state examination (MMSE) were obtained from medical records. Participants were divided into two groups: a healthy group (MMSE ≥ 26 points, CDR = 0) and an MCI group (MMSE ≥ 26 points, CDR = 0.5). Results indicated that the MCI group had significantly higher copper and lower low-fat meat intake compared to the healthy group. Furthermore, the high MIND (Mediterranean dietary approaches to stop hypertension intervention for neurodegenerative delay) diet score represented a lower risk of MCI. After adjusting for age, gender, diabetes mellitus, hypertension, and calorie intake in the multivariate regression analysis, calcium and fruit intake levels were positively associated with the MMSE, whereas low-fat meat intake was negatively associated with the CDR. In conclusion, the prevalence of MCI demonstrated a close correlation with nutrient intake, including copper and calcium. Furthermore, a MIND diet, particularly one high in n-3 polyunsaturated fatty acids, might be useful for preventing MCI. However, more extensive research with larger populations is needed to confirm this potential.

Risk of intracranial hemorrhage with protease-activated receptor-1 antagonists.

BACKGROUND AND PURPOSE: Recent clinical trial data suggest that protease-activated receptor-1 (PAR-1) antagonists may increase the risk of intracranial hemorrhage. Our objective was to investigate the qualitative and quantitative risks of intracranial hemorrhage in patients receiving PAR-1 antagonist therapy. METHODS: Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from 1966 to May 2012, were searched to identify relevant studies. We included randomized controlled trials that included a comparison of PAR-1 antagonist with placebo and in which the total number of patients and intracranial hemorrhage events were reported separately for active treatment and control groups. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using random-effects models. Between-study heterogeneity was assessed using the I2 statistic. RESULTS: In 9 PAR-1 antagonist trials with 42000 patients with a history of thrombotic vascular disease or acute coronary syndrome, PAR-1 antagonist treatment was associated with increased risk of intracranial hemorrhage (0.59% vs 0.30%; relative risk, 1.98; 95% CI, 1.46-2.68; P<0.00001; number needed to harm, 345). There was no heterogeneity across trials (P=0.84; I2=0%), PAR-1 antagonist agent (P=0.52), treatment duration (P=0.38), or trial-qualifying event (P=0.59). Risk of death from any cause or a cardiovascular cause did not differ between active treatment and control groups. CONCLUSIONS: In a pooled analysis of data from 9 trials, PAR-1 antagonist therapy was associated with an increased risk for intracranial hemorrhage.

Alterations of Sphingolipid and Phospholipid Pathways and Ornithine Level in the Plasma as Biomarkers of Parkinson's Disease.

The biomarkers of Parkinson's disease (PD) remain to be investigated. This work aimed to identify blood biomarkers for PD using targeted metabolomics analysis. We quantified the plasma levels of 255 metabolites in 92 PD patients and 60 healthy controls (HC). PD patients were sub-grouped into early (Hoehn-Yahr stage ≤ 2, n = 72) and advanced (Hoehn-Yahr stage > 2, n = 20) stages. Fifty-nine phospholipids, 3 fatty acids, 3 amino acids, and 7 biogenic amines, demonstrated significant alterations in PD patients. Six of them, dihydro sphingomyelin (SM) 24:0, 22:0, 20:0, phosphatidylethanolamine-plasmalogen (PEp) 38:6, and phosphatidylcholine 38:5 and 36:6, demonstrated lowest levels in PD patients in the advanced stage, followed by those in the early stage and HC. By contrast, the level of ornithine was highest in PD patients at the advanced stage, followed by those at the early stage and HC. These biomarker candidates demonstrated significant correlations with scores of motor disability, cognitive dysfunction, depression, and quality of daily life. The support vector machine algorithm using α-synuclein, dihydro SM 24:0, and PEp 38:6 demonstrated good ability to separate PD from HC (AUC: 0.820). This metabolomic analysis demonstrates new plasma biomarker candidates for PD and supports their role in participating PD pathogenesis and monitoring disease progression.

Clinical Characteristics and Prognostic Factors of Non-Infectious Cerebral Venous Sinus Thrombosis.

Non-infectious cerebral venous thrombosis (CVT) is an uncommon type of cerebrovascular disease that usually affects young patients. It occurs frequently in female patients, probably due to the association of sex-specific risk factors for coagulopathies. Currently, the prognostic factors of CVT remain unclear. We retrospectively reviewed the clinical characteristics among 260 CVT patients, including 147 females and 113 males. A favorable clinical outcome was defined by the scores of the modified Rankin Scale (mRS) ≤ 2 at hospital discharge, while a poor clinical outcome was defined by an mRS score of 3 to 6. A headache (28.5%) was the most frequent presentation. The most commonly affected sinus was the transverse-sigmoid sinus (59.6%). Most of the cases (78.5%) were treated with anticoagulants. One hundred and fifty-seven patients (60.4%) were discharged with favorable clinical outcomes. Consciousness disturbance (odds ratio: 5.01, p < 0.001) was associated with a poor clinical outcome. Patients with poor clinical outcomes demonstrated higher D-dimer levels on admission (4137.76 ± 3317.07 vs. 2476.74 ± 2330.87 ng/mL FEU, p = 0.029) and longer hospitalization days (31.81 ± 26.29 vs. 13.96 ± 8.82 days, p < 0.001) compared with favorable clinical outcomes. These findings provide important information of clinical characteristics and prognosis for CVT. Aggressive monitoring and treatment should be considered in CVT patients with poor prognostic factors.

Polarity-Differentiated Dielectric Materials in Monolayer Graphene Charge-Regulated Field-Effect Transistors for an Artificial Reflex Arc and Pain-Modulation System of the Spinal Cord.

The nervous system is a vital part of organisms to survive and it endows them with remarkable abilities, such as perception, recognition, regulation, learning, and decision-making, by intertwining myriad neurons. To realize such outstanding efficacies and functions, many artificial devices and systems have been investigated to emulate the operating principles of the nervous system. Here, an artificial reflex arc (ARA) and artificial pain modulation system (APMS) are proposed to imitate the unconscious behaviors of the spinal cord. Gdx Oy - and Alx Oy -based charge-regulated field-effect transistors (CRFETs) with a monolayer graphene channel are fabricated and adopted as inhibitory and excitatory synapses, respectively, under the same pulse signals to mimic the biological reflex arc through a connection with a poly(vinylidene fluoride-co-trifluoroethylene)-based actuator. Additionally, a memristor is integrated with a CRFET as the interneuron to regulate the Dirac point by controlling the voltage drop on the graphene channel, analogous to the descending pain-inhibition system in the spinal cord, to prevent excessive pain perception. The proposed ARA and APMS provide a significant step forward to realizing the functions of the nervous system, giving promising potential for developing future intelligent alarm systems, neuroprosthetics, and neurorobotics.

Mediating roles of leukoaraiosis and infarcts in the effects of unilateral carotid artery stenosis on cognition.

Background and objectives: Leukoaraiosis and infarcts are common in patients with carotid artery stenosis (CAS), and CAS severity, leukoaraiosis and infarcts all have been implicated in cognitive impairments. CAS severity was not only hypothesized to directly impede specific cognitive domains, but also transmit its effects indirectly to cognitive function through ipsilateral infarcts as well as periventricular leukoaraiosis (PVL) and deep white matter leukoaraiosis (DWML). We aimed to delineate the contributions of leukoaraiosis, infarcts and CAS to different specific cognitive domains. Materials and methods: One hundred and sixty one participants with unilateral CAS (>50%) on the left (n = 85) or right (n = 76) side and 65 volunteers without significant CAS (<50%) were recruited. The PVL, DWML, and infarct severity were visually rated on MRI. A comprehensive cognitive battery was administered and standardized based on age norms. Correlation and mediation analyses were adopted to examine the direct and indirect influence of CAS, leukoaraiosis, and infarct on specific cognitive domains with adjustment for education, hypertension, diabetes mellitus, and hyperlipidemia. Results: Carotid artery stenosis severity was associated with ipsilateral leukoaraiosis and infarct. Left CAS had direct effects on most cognitive domains, except for visual memory and constructional ability, and transmitted its indirect effects on all cognitive domains through ipsilateral PVL, and on constructional ability and psychomotor through infarcts. Right CAS only had negative direct effects on visual memory, psychomotor, design fluency and color processing speed, and transmitted its indirect effects on visual memory, word and color processing speed through ipsilateral infarcts. The trends of direct and indirect cognitive effects remained similar after covariate adjustment. Conclusion: Left and right CAS would predominantly lead to verbal and non-verbal cognitive impairment respectively, and such effects could be mediated through CAS-related leukoaraiosis and infarct. Given that cognition is subject to heterogeneous pathologies, the exact relationships between markers of large and small vessel diseases and their composite prognostic effects on cognition requires further investigation.

Evaluating the Different Stages of Parkinson's Disease Using Electroencephalography With Holo-Hilbert Spectral Analysis.

Electroencephalography (EEG) can reveal the abnormalities of dopaminergic subcortico-cortical circuits in patients with Parkinson's disease (PD). However, conventional time-frequency analysis of EEG signals cannot fully reveal the non-linear processes of neural activities and interactions. A novel Holo-Hilbert Spectral Analysis (HHSA) was applied to reveal non-linear features of resting state EEG in 99 PD patients and 59 healthy controls (HCs). PD patients demonstrated a reduction of ß bands in frontal and central regions, and reduction of γ bands in central, parietal, and temporal regions. Compared with early-stage PD patients, late-stage PD patients demonstrated reduction of ß bands in the posterior central region, and increased θ and δ2 bands in the left parietal region. θ and ß bands in all brain regions were positively correlated with Hamilton depression rating scale scores. Machine learning algorithms using three prioritized HHSA features demonstrated "Bag" with the best accuracy of 0.90, followed by "LogitBoost" with an accuracy of 0.89. Our findings strengthen the application of HHSA to reveal high-dimensional frequency features in EEG signals of PD patients. The EEG characteristics extracted by HHSA are important markers for the identification of depression severity and diagnosis of PD.

Major Bleeding Risk in Atrial Fibrillation Patients Co-Medicated With Non-Vitamin K Oral Anticoagulants and Antipsychotics.

Major bleeding risks associated with non-vitamin K oral anticoagulants (NOACs) used with and without concurrent antipsychotics in patients with non-valvular atrial fibrillation (AF) were assessed. A total of 98,863 patients with non-valvular AF receiving at least one NOAC prescription from Taiwan's National Health Insurance database were enrolled. Major bleeding was defined as a primary diagnosis of intracranial or gastrointestinal hemorrhage or bleeding at other sites. The adjusted incidence rate difference (AIRD) per 1,000 person-years and adjusted rate ratio of major bleeding were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. A total of 8,037 major bleeding events occurred during 705,521 person-quarters with NOAC prescriptions. Antipsychotics were used in 26.35% of NOAC-exposed patients. Compared to using NOAC alone, co-medication of either typical (AIRD: 79.18, 95% confidence interval [CI]: 70.63-87.72) or atypical (AIRD: 40.5, 95% CI: 33.64-47.35) antipsychotic with NOAC had a significant increase in the adjusted incidence rate per 1,000 person-years of major bleeding. The concomitant use of a NOAC with chlorpromazine (AIRD: 103.87, 95% CI: 51.22-156.52), haloperidol (AIRD: 149.52, 95% CI: 125.03-174.00), prochlorperazine (AIRD: 90.43, 95% CI: 78.55-102.32), quetiapine (AIRD: 44.6, 95% CI: 37.11-52.09), or risperidone (AIRD: 41.55, 95% CI: 22.86-60.24) (All p < 0.01) showed a higher adjusted incidence rate of major bleeding than using NOACs alone. The concomitant use of typical (chlorpromazine, haloperidol, or prochlorperazine) or atypical (quetiapine or risperidone) antipsychotic with NOACs was associated with a significantly increased risk of major bleeding.

Major Bleeding Risk in Patients With Non-valvular Atrial Fibrillation Concurrently Taking Direct Oral Anticoagulants and Antidepressants.

Direct oral anticoagulants (DOACs) are commonly prescribed with antidepressants that may increase bleeding risk. Here we assessed the association between DOACs with and without concurrent antidepressants and major bleeding risk in patients with atrial fibrillation (AF) by a retrospective cohort study included patients with AF who received prescriptions of DOACs in Taiwan's National Health Insurance database between 2012 and 2017. Adjusted rate ratio (ARR) of major bleeding was calculated by comparing incidence rate adjusted with Poisson regression and inverse probability of treatment weighting using the propensity score between patient-times with and without antidepressants. Among 98863 patients with AF, concurrent use of bupropion with DOACs increased the risks of all major bleeding (ARR: 1.49, 95% CI: 1.02-2.16) and gastrointestinal hemorrhage (ARR: 1.57, 95% CI: 1.04-2.33). An increased risk of intracerebral hemorrhage (ICH) was associated with the combinations of DOACs with selective serotonin reuptake inhibitors (SSRIs, ARR: 1.38, 95% CI: 1.08-1.76), particularly in paroxetine (ARR: 2.11, 95% CI: 1.17-3.81), and tetracyclic antidepressants (TeCAs, ARR: 1.34, 95% CI: 1.01-1.78). In subgroup analyses stratified by individual NOACs, SSRIs increased the risk of ICH in the dabigatran-treated patients (ARR: 1.55, 95% CI: 1.04-2.33). The combinations of apixaban and serotonin-norepinephrine reuptake inhibitors (SNRIs) were associated with a higher risk of all major bleeding (ARR: 1.63, 95% CI: 1.04-2.55). These results clearly indicate the drug-drug interactions between DOACs and antidepressants, which should be carefully considered when prescribing DOACs in adult patients. Careful monitoring for bleeding should be performed while concurrently prescribing DOACs with bupropion, SSRI, SNRI, and TeCA. Concomitant use of DOACs and TCAs may be a relatively safe strategy for patients with AF.

Head and Neck Cancer Types and Risks of Cervical-Cranial Vascular Complications within 5 Years after Radiation Therapy.

Background and purpose: to investigate the frequency of cervical−cranial vascular complications soon after radiation therapy (RT) and identify differences among patients with various types of head and neck cancer (HNC). Methods: We enrolled 496 patients with HNC who had received their final RT dose in our hospital. These patients underwent carotid duplex ultrasound (CDU) for monitoring significant carotid artery stenosis (CAS). Brain imaging were reviewed to detect vertebral, intracranial artery stenosis, or preexisted CAS before RT. Primary outcome was significant CAS at the internal or common carotid artery within first 5 years after RT. We categorized the patients into nasopharyngeal carcinoma (NPC) and non-NPC groups and compared the cumulative occurrence of significant CAS between the groups using Kaplan−Meier and Cox-regression analyses. Results: Compared to the NPC group, the non-NPC group had a higher frequency of significant CAS (12.7% vs. 2.0%) and were more commonly associated with significant CAS after adjusting the covariates (Adjusted hazard ratio: 0.17, 95% confident interval: 0.05−0.57) during the follow-up period. All the non-NPC subtypes (oral cancer/oropharyngeal, hypopharyngeal, and laryngeal cancers) were associated with higher risks of significant CAS than the NPC group (p < 0.001 respectively). Conclusion: Significant CAS was more frequently noted within 5 years of RT among the patients with non-NPC HNC than among the patients with NPC. Scheduled carotid artery surveillance and vascular risk monitoring should be commenced earlier for patients with non-NPC HNC. By contrast, vascular surveillance could be deferred to 5 years after RT completion in NPC patients.

Alterations of Plasma Galectin-3 and C3 Levels in Patients with Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive neurodegeneration of dopaminergic neurons in the ventral midbrain. The complement-phagosome pathway is involved in the pathogenesis of PD. Here we measured levels of complement-phagocytosis molecules, including galectin-3, C3, C4, and cathepsin D, in the plasma of 56 patients with PD, and 46 normal controls (NCs). Plasma levels of galectin-3 (9.93 ± 3.94 ng/mL) were significantly higher in PD patients compared with NCs (8.39 ± 1.95 ng/mL, p = 0.012), and demonstrated a positive correlation with Hoehn and Yahr stages in PD patients (R2 = 0.218, p < 0.001). On the other hand, plasma C3 levels were significantly lower in PD patients (305.27 ± 205.16 µg/mL) compared with NCs (444.34 ± 245.54 µg/mL, p = 0.002). However, the levels did not correlate with Hoehn and Yahr stages (R2 = 0.010, p = 0.469). Plasma levels of C4 and cathepsin D in PD patients were similar to those in NCs. Our results show possible altered complement-phagocytosis signals in the peripheral blood of PD patients, highlighting the potential of galectin-3 as a biomarker of PD.