Co-axial dual-core resonant leaky fibre for optical amplifiers

We present a co-axial dual-core resonant leaky optical fibre design, in which the outer core is made highly leaky. A suitable choice of parameters can enable us to resonantly couple power from the inner core to the outer core. In a large-core fibre, such a resonant coupling can considerably increase the differential leakage loss between the fundamental and the higher order modes and can result in effective single-mode operation. In a small-core single-mode fibre, such a coupling can lead to sharp increase in the wavelength dependent leakage loss near the resonant wavelength and can be utilized for the suppression of amplified spontaneous emission and thereby gain equalization of an optical amplifier. We study the propagation characteristics of the fibre using the transfer matrix method and present an example of each, the large-mode-area design for high power amplifiers and the wavelength tunable leakage loss design for inherent gain equalization of optical amplifiers.Comment: 6 page

Outcomes Associated With Oral Anticoagulants Plus Antiplatelets in Patients With Newly Diagnosed Atrial Fibrillation.

Importance: Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy. Objective: To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone. Design, Setting, and Participants: Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019. Exposure: Participants received either OAC plus AP or OAC alone. Main Outcomes and Measures: Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications. Results: A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months). Conclusions and Relevance: This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation

Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.

This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty.In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding.A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1\%) in the rivaroxaban group and in 58 of 1558 patients (3.7\%) in the enoxaparin group (absolute risk reduction, 2.6\%; 95\% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2\%) in the rivaroxaban group and in 33 of 1678 patients (2.0\%) in the enoxaparin group (absolute risk reduction, 1.7\%; 95\% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3\%) in the rivaroxaban group and in 2 of 2224 patients (0.1\%) in the enoxaparin group (P=0.18).A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.

Mycobacterium vaccae immunization in rats ameliorates features of age-associated microglia activation in the amygdala and hippocampus

Aging and reduced exposure to environmental microbes can both potentiate neuroinflammatory responses. Prior studies indicate that immunization with the immunoregulatory and anti-inflammatory bacterium, Mycobacterium vaccae (M. vaccae), in aged rats limits neuroimmune activation and cognitive impairments. However, the mechanisms by which M. vaccae immunization ameliorates age-associated neuroinflammatory &ldquo;priming&rdquo; and whether microglia are a primary target remain unclear. Here, we investigated whether M. vaccae immunization protects against microglia morphological changes in response to aging. Adult (3 mos) and aged (24 mos) Fisher 344&thinsp;&times;&thinsp;Brown Norway rats were immunized with either M. vaccae or vehicle once every week for 3&nbsp;weeks. Aging led to elevated Iba1 immunoreactivity, microglial density, and deramification of microglia processes in the hippocampus and amygdala but not other brain regions. Additionally, aged rats exhibited larger microglial somas in the dorsal hippocampus, suggestive of a more activated phenotype. Notably, M. vaccae treatment ameliorated indicators of microglia activation in both the amygdala and hippocampus. While changes in morphology appeared to be region-specific, gene markers indicative of microglia activation were upregulated by age and lowered in response to M. vaccae in all brain regions evaluated. Taken together, these data suggest that peripheral immunization with M. vaccae quells markers of age-associated microglia activation. &nbsp;</p

Natural Terpenes Prevent Mitochondrial Dysfunction, Oxidative Stress and Release of Apoptotic Proteins during Nimesulide-Hepatotoxicity in Rats

Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1∶1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity

Assessment of Outcomes Among Patients With Venous Thromboembolism With and Without Chronic Kidney Disease

Importance: Patients with venous thromboembolism (VTE) and concomitant chronic kidney disease (CKD) have been reported to have a higher risk of thrombosis and major bleeding complications compared with patients without concomitant CKD. The use of anticoagulation therapy is challenging, as many anticoagulant medications are excreted by the kidney. Large-scale data are needed to clarify the impact of CKD for anticoagulant treatment strategies and clinical outcomes of patients with VTE. Objective: To compare clinical characteristics, treatment patterns, and 12-month outcomes among patients with VTE and concomitant moderate to severe CKD (stages 3-5) vs patients with VTE and mild to no CKD (stages 1-2) in a contemporary international registry. Design, Setting, and Participants: The Global Anticoagulant Registry in the Field-Venous Thromboembolism (GARFIELD-VTE) study is a prospective noninterventional investigation of real-world treatment practices. A total of 10 684 patients from 415 sites in 28 countries were enrolled in the GARFIELD-VTE between May 2014 and January 2017. This cohort study included 8979 patients (6924 patients with mild to no CKD and 2055 patients with moderate to severe CKD) who had objectively confirmed VTE within 30 days before entry in the registry. Chronic kidney disease stages were defined by estimated glomerular filtration rates. Data were extracted from the study database on December 8, 2018, and analyzed between May 1, 2019, and July 30, 2020. Exposure: Moderate to severe CKD vs mild to no CKD. Main Outcomes and Measures: The primary outcomes were all-cause mortality, recurrent VTE, and major bleeding. Event rates and 95% CIs were calculated and expressed per 100 person-years. Hazard ratios (HRs) were estimated with Cox proportional hazards regression models and adjusted for relevant confounding variables. All-cause mortality was considered a competing risk for other clinical outcomes in the estimation of cumulative incidences. Results: Of the 10 684 patients with objectively confirmed VTE, serum creatinine data were available for 8979 patients (84.0%). Of those, 4432 patients (49.4%) were female and 5912 patients (65.8%) were White; 6924 patients (77.1%; median age, 57 years; interquartile range [IQR], 44-69 years) were classified as having mild to no CKD, and 2055 patients (22.9%; median age, 70 years; IQR, 59-78 years) were classified as having moderate to severe CKD. Calculations using the equation from the Modification of Diet in Renal Disease study indicated that, among the 6924 patients with mild to no CKD, 2991 patients had stage 1 CKD, and 3933 patients had stage 2 CKD; among the 2055 patients with moderate to severe CKD, 1650 patients had stage 3 CKD, 190 patients had stage 4 CKD, and 215 patients had stage 5 CKD. The distribution of VTE presentation was comparable between groups. In total, 1171 patients (57.0%) with moderate to severe CKD and 4079 patients (58.9%) with mild to no CKD presented with deep vein thrombosis alone, 547 patients (26.6%) with moderate to severe CKD and 1723 patients (24.9%) with mild to no CKD presented with pulmonary embolism alone, and 337 patients (16.4%) with moderate to severe CKD and 1122 patients (16.2%) with mild to no CKD presented with both pulmonary embolism and deep vein thrombosis. Compared with patients with mild to no CKD, patients with moderate to severe CKD were more likely to be female (3259 women [47.1%] vs 1173 women [57.1%]) and older than 65 years (2313 patients [33.4%] vs 1278 patients [62.2%]). At baseline, the receipt of parenteral therapy alone was comparable between the 2 groups (355 patients [17.3%] with moderate to severe CKD vs 1253 patients [18.1%] with mild to no CKD). Patients with moderate to severe CKD compared with those with mild to no CKD were less likely to be receiving direct oral anticoagulant therapy, either alone (557 patients [27.1%] vs 2139 patients [30.9%]) or in combination with parenteral therapy (319 patients [15.5%] vs 1239 patients [17.9%]). Patients with moderate to severe CKD had a higher risk of all-cause mortality (adjusted hazard ratio [aHR], 1.44; 95% CI, 1.21-1.73), major bleeding (aHR, 1.40; 95% CI, 1.03-1.90), and recurrent VTE (aHR, 1.40; 95% CI, 1.10-1.77) than patients with mild to no CKD. Conclusions and Relevance: In this study of patients with VTE, the presence of moderate to severe CKD was associated with increases in the risk of death, VTE recurrence, and major bleeding compared with the presence of mild to no CKD

Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score

Aims Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation. Methods and results Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48–0.71 (recurrence) and 0.61–0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% –19% for bleeding. Conclusion The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making

International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. We aimed to provide comprehensive data on international patterns of AF stroke prevention treatment. METHODS: Demographics, comorbidities, and stroke risk of the patients in the GARFIELD-AF (n=51,270), ORBIT-AF I (n=10,132), and ORBIT-AF II (n=11,602) registries were compared (overall N=73,004 from 35 countries). Stroke prevention therapies were assessed among patients with new-onset AF (≤6 weeks). RESULTS: Patients from GARFIELD-AF were less likely to be white (63% vs 89% for ORBIT-AF I and 86% for ORBIT-AF II) or have coronary artery disease (19% vs 36% and 27%), but had similar stroke risk (85% CHA2DS2-VASc ≥2 vs 91% and 85%) and lower bleeding risk (11% with HAS-BLED ≥3 vs 24% and 15%). Oral anticoagulant use was 46% and 57% for patients with a CHA2DS2-VASc=0 and 69% and 87% for CHA2DS2-VASc ≥2 in GARFIELD-AF and ORBIT-AF II, respectively, but with substantial geographic heterogeneity in use of oral anticoagulant (range: 31%-93% [GARFIELD-AF] and 66%-100% [ORBIT-AF II]). Among patients with new-onset AF, non-vitamin K antagonist oral anticoagulant use increased over time to 43% in 2016 for GARFIELD-AF and 71% for ORBIT-AF II, whereas use of antiplatelet monotherapy decreased from 36% to 17% (GARFIELD-AF) and 18% to 8% (ORBIT-AF I and II). CONCLUSIONS: Among new-onset AF patients, non-vitamin K antagonist oral anticoagulant use has increased and antiplatelet monotherapy has decreased. However, anticoagulation is used frequently in low-risk patients and inconsistently in those at high risk of stroke. Significant geographic variability in anticoagulation persists and represents an opportunity for improvement

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease