Off-label reduced-dose apixaban does not reduce hemorrhagic risk in Taiwanese patients with nonvalvular atrial fibrillation: A retrospective,observational study

East Asians are reportedly at high risk of anticoagulant-related bleeding; therefore, some physicians prefer to prescribe low-dose direct oral anticoagulants (DOACs). Little is known about the therapeutic effectiveness and safety of off-label reduced-dose apixaban in East Asians with nonvalvular atrial fibrillation (AF). We aimed to investigate the effectiveness and safety of off-label reduced-dose apixaban in Taiwanese patients with nonvalvular AF.This retrospective cohort study enrolled 1073 patients with nonvalvular AF who took apixaban between July 2014 and October 2018 from 4 medical centers in southern Taiwan. The primary outcomes included thromboembolic events (stroke/transient ischemic attack or systemic embolism), major bleeding, and all-cause mortality.Among all patients, 826 (77%) patients were classified as the “per-label adequate-dose” treatment group (i.e., consistent with the Food and Drug Administration label recommendations) while 247 (23%) patients were the “off-label reduced-dose” treatment group. The mean follow-up period was 17.5 ± 13 months. The “off-label reduced-dose” group did not have a lower major bleeding rate than the “per-label adequate-dose” group (4.8% vs 3.8%, adjusted hazard ratio [HR] 1.20, 95% confidence interval [CI] 0.69–2.09), but had a nonsignificantly higher incidence of thromboembolic events (4.23% vs 3.05%, adjusted HR: 1.29, 95% CI: 0.71–2.34).An off-label reduced-dose apixaban treatment strategy may not provide incremental benefits or safety for Taiwanese patients with nonvalvular AF.     

Improved health outcomes in integrative medicine visits may reflect differences in physician and patient behaviors compared to standard medical visits

ObjectiveTo identify differences in patient-physician interactions associated with improvements in GERD symptoms in a randomized controlled trial comparing integrative medicine and primary care/standard visits.MethodsWe analyzed video recordings of 2-minute excerpts (thin slices) from the beginning, middle, and end of 21 study visits (11 standard, 10 integrative medicine).ResultsAccording to blind coders’ analysis of the excerpts, prospective improvement in GERD symptoms was most highly correlated with patients appearing pleased (r = 0.71, p < 0.01) and friendly (r = 0.67, p < 0.01) at the end of the visit, controlling for visit type. The combination of patient and physician smiling at the end of the visit was associated with improvement in GERD symptoms (r² = 0.45, p = 0.004). The physician in the integrative visits was more engaged (p = 0.009), friendly (p = 0.005), relaxed (p = 0.002), smiled longer (p = 0.006), gazed longer (p = 0.02), and gestured more (p = 0.007), compared to standard visits. Patients in integrative visits also smiled longer (p = 0.004).ConclusionThe expanded history-taking questions asked by integrative clinicians may enhance relationship building, modifying patients’ responses and improving patient-centered behaviors from clinicians,ultimately facilitating symptom improvement.Practice ImplicationsAnalysis of nonverbal behaviors may facilitate a better understanding of patient-clinician interactions in integrative medicine visits and yield insights to improve clinical interactions in conventional medicine.     

Evolving potassium channels by means of yeast selection reveals structural elements important for selectivity

Potassium channels are widely distributed. To serve their physiological functions, such as neuronal signaling, control of insulin release, and regulation of heart rate and blood flow, it is essential that K+ channels allow K+ but not the smaller and more abundant Na+ ions to go through. The narrowest part of the channel pore, the selectivity filter formed by backbone carbonyls of the GYG-containing K+ channel signature sequence, approximates the hydration shell of K+ ions. However, the K+ channel signature sequence is not sufficient for K+ selectivity. To identify structural elements important for K+ selectivity, we randomly mutagenized the G protein-coupled inwardly rectifying potassium channel 3.2 (GIRK2) bearing the S177W mutation on the second transmembrane segment. This mutation confers constitutive channel activity but abolishes K+ selectivity and hence the channel's ability to complement the K+ transport deficiency of Deltatrk1Deltatrk2 mutant yeast. S177W-containing GIRK2 mutants that support yeast growth in low-K+ medium contain multiple suppressors, each partially restoring K+ selectivity to S177W-containing double mutants. These suppressors include mutations in the first transmembrane segment and the pore helix, likely exerting long-range actions to restore K+ selectivity, as well as a mutation of a second transmembrane segment residue facing the cytoplasmic half of the pore, below the selectivity filter. Some of these suppressors also affected channel gating (channel open time and opening frequency determined in single-channel analyses), revealing intriguing interplay between ion permeation and channel gating.     

Disposition and metabolic profiles of [14C]viramidine and [14C]ribavirin in rat and monkey red blood cells and liver

The disposition and metabolic profiles of [14C]viramidine and [14C]ribavirin were compared in rat and monkey red blood cells and liver. Our data reveal that the total ribavirin-related components (ribavirin plus its mono-, di-, and triphosphate metabolites) may account for most of the drug in monkey liver following prolonged oral administration of viramidine.     

Interleukin 3 enhances cytotoxic T lymphocyte development and class I major histocompatibility complex "re-presentation" of exogenous antigen by tumor-infiltrating antigen-presenting cells.

We show that interleukin 3 (IL-3) enhances the generation of tumor-specific cytotoxic T lymphocytes (CTLs) through the stimulation of host antigen-presenting cells (APCs). The BALB/c (H-2d) spontaneous lung carcinoma line 1 was modified by gene transfection to express ovalbumin as a nominal "tumor antigen" and to secrete IL-3, a cytokine enhancing myeloid development. IL-3-transfected tumor cells are less tumorigenic than the parental cell line, and tumor-infiltrating lymphocytes isolated from these tumors contain increased numbers of tumor-specific CTLs. By using B3Z86/90.14 (B3Z), a unique T-cell hybridoma system restricted to ovalbumin/H-2b and implanting the tumors in (BALB/c x C57BL/6)F1 (H-2d/b) mice, we demonstrate that the IL-3-transfected tumors contain an increased number of a rare population of host cells that can process and "re-present" tumor antigen to CTLs. Electron microscopy allowed direct visualization of these host APCs, and these studies, along with surface marker phenotyping, indicate that these APCs are macrophage-like. The identification of these cells and their enhancement by IL-3 offers a new opportunity for tumor immunotherapy.     

Increased Risk of Parkinson's Disease in Patients With Obstructive Sleep Apnea: A Population-Based,Propensity Score-Matched,Longitudinal Follow-Up Study

Obstructive sleep apnea (OSA), characterized by repetitive episodes of apnea/hypopnea and hypoxia, is associated with systemic inflammation and induces metabolic, endocrine, and cardiovascular diseases. Inflammation might have an impact on neurodegenerative diseases. This study investigates the possible association between OSA and Parkinson''s disease (PD). Random samples out of 1 million individuals were collected from Taiwan''s National Health Insurance database. A total of 16,730 patients with newly diagnosed OSA from 2002 to 2008 were recruited and compared with a cohort of 16,730 patients without OSA matched for age, gender, and comorbidities using propensity scoring. All patients were tracked until a diagnosis of PD, death, or the end of 2011.During the mean 5.6-year follow-up period, the incidence rates of PD were 2.30 per 1000 person-years in the OSA cohort and 1.71per 1000 person-years in the comparison group. The incidence rate ratio (IRR) for PD was greater in older patients (≧ 65 years) and male patients with OSA than the controls, respective IRRs being 1.34 and 1.47. After adjustment for the comorbidities, patients with OSA were 1.37 times more likely to have PD than patients without (95% CI = 1.12–1.68, P < 0.05). Subgroup analysis showed that older patients and patients with coronary artery disease, stroke, or chronic kidney disease had a higher risk for PD than their counter parts. Log-rank analysis revealed that patients with OSA had significantly higher cumulative incidence rates of PD than the comparison group (P = 0.0048). Patients with OSA are at an increased risk for subsequent PD, especially elderly male patients.     

In vivo comparison of tantalum,tungsten, and bismuth enteric contrast agents to complement intravenous iodine for double‐contrast dual‐energy CT of the bowel

To assess the ability of dual‐energy CT (DECT) to separate intravenous contrast of bowel wall from intraluminal contrast, we scanned 16 rabbits on a clinical DECT scanner: n = 3 using only iodinated intravenous contrast, and n = 13 double‐contrast enhanced scans using iodinated intravenous contrast and experimental enteric non‐iodinated contrast agents in the bowel lumen (five bismuth, four tungsten, and four tantalum based). Representative image pairs from conventional CT images and DECT iodine density maps of small bowel (116 pairs from 232 images) were viewed by four abdominal imaging attending radiologists to independently score each comparison pair on a visual analog scale (?100 to +100%) for (1) preference in small bowel wall visualization and (2) preference in completeness of intraluminal enteric contrast subtraction. Median small bowel wall visualization was scored 39 and 42 percentage points (95% CI 30–44% and 36–45%, both p < 0.001) higher for double‐contrast DECT than for conventional CT with enteric tungsten and tantalum contrast, respectively. Median small bowel wall visualization for double‐contrast DECT was scored 29 and 35 percentage points (95% CI 20–35% and 33–39%, both p < 0.001) higher with enteric tungsten and tantalum, respectively, than with bismuth contrast. Median completeness of intraluminal enteric contrast subtraction in double‐contrast DECT iodine density maps was scored 28 and 29 percentage points (95% CI 15–31% and 28–33%, both p < 0.001) higher with enteric tungsten and tantalum, respectively, than with bismuth contrast. Results suggest that in vivo double‐contrast DECT with iodinated intravenous and either tantalum‐ or tungsten‐based enteric contrast provides better visualization of small bowel than conventional CT. Copyright © 2016 John Wiley & Sons, Ltd.     

Serum levels of interferon-α and-γ in acute and chronic hepatitis B virus infection

To evaluate the potential implication ofin vivo interferon production in the pathogenesis of different forms of acute and chronic hepatitis B virus infection, serum levels of interferon- and- were measured using immunoassay techniques in 20 patients with acute hepatitis B who subsequently cleared the virus (group Ia), 8 patients with acute hepatitis B who became HBsAg carriers (group Ib), 55 patients with chronic hepatitis B (group II), and 15 healthy controls. None of the controls had interferon- or- detectable in serum, while 15% and 100% of group Ia patients, 25% and 100% of group Ib patients, and 22% and 15% of group II patients, had raised serum levels of interferon- and-, respectively. Serum interferon- was detected significantly more frequently in group Ia and Ib patients than in controls and in group II patients. Among patients with acute hepatitis B, serum levels of interferon- and- showed no significant difference between group Ia and group Ib patients. Among patients with chronic hepatitis B, interferon- was detected significantly more frequently in patients with serum HBV-DNA (31.4% or 11/35) than in those without (5% or 1/20), whereas interferon- was detected significantly more frequently in patients with chronic active hepatitis (28% or 7/25) than in those with chronic persistent hepatitis (3.3% or 1/30). In conclusion, in acute hepatitis B, serum levels of interferon- and- did not show a significant difference between patients who subsequently cleared the virus and those who became HBsAg carriers. In chronic hepatitis B, the raised serum levels of interferon- correlated with the presence of viral replication, while the raised serum levels of interferon- correlated with the presence of histological evidence of active hepatitis.