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Remote sensing was used to map the invasion of yellow-flowered legumes on the Central Plateau of New Zealand to inform weed management strategy. The distributions of Cytisus scoparius (broom), Ulex europaeus (gorse) and Lupinus arboreus (tree lupin) were captured with high-resolution RGB photographs of the plants while flowering. The outcomes of herbicide operations to control C. scoparius and U. europaeus over time were also assessed through repeat photography and change mapping. A grid-square sampling tool previously developed by Manaaki Whenua—Landcare Research was used to help transfer data rapidly from photography to maps using manual classification. Artificial intelligence was trialled and ruled out because the number of false positives could not be tolerated. Future actions to protect the natural values and vistas of the Central Plateau from legume invasion were identified. While previous control operations have mostly targeted large, highly visible legume patches, the importance of removing outlying plants to prevent the establishment of new seed banks and slow spread has been underestimated. Outliers not only establish new, large, long-lived seed banks in previously seed-free areas, but they also contribute more to range expansion than larger patches. Our C. scoparius and U. europaeus change mapping confirms and helps to visualise the establishment and expansion of uncontrolled outliers. The power of visualizing weed control strategies through remote sensing has supported recommendations to improve outlier control to achieve long-term, sustainable landscape-scale suppression of invasive legumes.

Cancer-associated venous thromboembolism (CAT) guidelines recommend direct oral anticoagulants as alternatives to low-molecular-weight heparin (LMWH) in most patients. This study compared the effectiveness and safety of rivaroxaban versus LMWH for a broad CAT cohort. The cohort study used electronic health data from January 2012 to December 2020 to evaluate patients with active cancer experiencing acute venous thromboembolism (VTE) and treated with rivaroxaban or LMWH. Propensity score-overlap weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE, bleeding-related hospitalization, and all-cause mortality were calculated. In total, 4935 patients were identified (27.9% on rivaroxaban and 72.1% on LMWH). The cancer types included gastrointestinal (29.4%), genitourinary (26.2%), lung (24.0%), breast (19.7%), and hematologic (14.4%). Rivaroxaban was associated with a reduction in recurrent VTE versus LMWH among all patients with cancer (HR = 0.78; 95%CI = 0.61-0.99) at 3 months. No differences in bleeding-related hospitalization or all-cause mortality were observed. Directionally similar results to those at 3 months were observed at 6 months for all outcomes. In conclusion, we observed fewer recurrent VTE cases and no increase in bleeding-related hospitalizations with rivaroxaban versus LMWH at 3 months in this patient cohort with various cancer types.

Abstract Objective To characterize the burden of illness associated with oral factor Xa (FXa) inhibitor‐related bleeding in the US Medicare population. Methods This retrospective cohort study used the full 20% Medicare random sample claims database to identify patients who experienced their first hospitalization for an FXa inhibitor‐related major bleed between October 2013 and September 2017. Bleeding types were classified as intracranial hemorrhage (ICH), gastrointestinal (GI), and other. Associations between risk factors and outcomes (in‐hospital and 30‐day mortality, 30‐day readmission, and discharge to a location other than home) adjusted for patient demographic characteristics, baseline clinical conditions, index event characteristics, treatment with hemostatic/factor replacement agents or transfusion (ie, usual care prereversal agent availability), multicompartment ICH and neurosurgical procedures (ICH cohort), and endoscopy (GI cohort) were assessed using multivariable regression and reported as crude incidences and adjusted odds ratios (ORs) stratified by bleed type. Results Of the 11,593 patients identified, 2737 (23.6%) had ICH, 8169 (70.5%) had GI bleeds, and 687 (5.9%) had other bleeds. The incidences of in‐hospital mortality, 30‐day mortality, need for postdischarge out‐of‐home care, and 30‐day readmission were 15.7%, 29.1%, 78.3%, and 20.3% in the single‐compartment ICH cohort, respectively; and 1.7%, 6.8%, 41.3%, and 18.8% in the GI bleeds cohort, respectively. Increased odds of both in‐hospital mortality and 30‐day mortality were significantly associated with: multicompartment ICH (reference, single compartment ICH; OR = 3.35 [95% confidence interval (CI): 2.41–4.66]; 2.18 [95% CI: 1.63–2.91]), loss of consciousness during index hospitalization (yes vs no; OR = 2.03 [95% CI: 1.38–2.97]; 1.49 [95% CI: 1.11–2.02]), receiving usual care (yes vs no; OR = 1.55 [95% CI: 1.22–1.98]; 1.33 [95% CI: 1.09–1.63]) during index hospitalization, and increasing number of Elixhauser comorbidities at baseline (OR = 1.07 [95% CI: 1.03–1.10]; 1.09 [95% CI: 1.06–1.12]) in the ICH cohort; intensive care unit admission (yes vs no; OR = 1.88 [95% CI: 1.32–2.67]; 1.51 [95% CI: 1.26–1.81]), increasing number of Elixhauser comorbidities at baseline (OR = 1.12 [95% CI: 1.07–1.18]; 1.15 [1.12–1.18]), and increasing age on index date (OR = 1.04 [95% CI: 1.02–1.07]; 1.05 [95% CI: 1.04–1.07]) in the GI bleeds cohort. Conclusions In this large sample of Medicare patients, FXa inhibitor‐related major bleeding was associated with substantial burden in terms of adverse clinical outcomes and health care resource use. Incidence of ICH was lower than GI bleeds; however, burden of illness was notably higher with ICH.

Abstract Background Andexanet alfa is approved (FDA “accelerated approval”; EMA “conditional approval”) as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). Methods This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. Results The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16–6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13–0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. Conclusions In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

ObjectiveTo develop a composite score for predicting functional outcome post–intracerebral hemorrhage (ICeH) using proxy measures that can be assessed retrospectively.MethodsData from the observational ERICH study were used to derive a composite score (SAVED2) to predict an unfavorable 90-day modified Rankin scale (mRS) score. Independent predictors of unfavorable mRS were identified via multivariable logistic regression and assigned score weights based on effect size. Area under the curve (AUC) was used to measure the score's discriminative ability. External validation was performed in the randomized ATACH-2 trial.ResultsThere were 2,449 patients from ERICH with valid mRS data who survived to hospital discharge. Predictors associated with unfavorable 90-day mRS score and their corresponding point values were: age ≥70 years (odds ratio [OR], 3.8; 1-point); prior stroke (OR, 2.8; 1-point); need for ventilation (OR, 2.7; 1-point); extended hospital stay (OR, 2.7; 1-point); and non-home discharge location (OR, 5.3; 2-points). Incidence of unfavorable 90-day mRS increased with higher SAVED2 scores (P < 0.001); AUC in ERICH was 0.82 (95% CI, 0.80–0.84). External validation in ATACH-2 (n = 904) found an AUC of 0.74 (95% CI, 0.70–0.77).ConclusionsUsing data collected at hospital discharge, the SAVED2 score predicted unfavorable mRS in patients with ICeH.

Background Obstructive sleep apnea (OSA) is associated with an increased incidence of atrial fibrillation (AF), hypertension, diabetes, heart failure, coronary heart disease, stroke, and death. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular AF (NVAF) patients with concomitant OSA. Methods This was an analysis of electronic health record (EHR) data from November 2010 to December 2021. We included adults with NVAF and OSA at baseline, newly initiated on rivaroxaban or warfarin, and with ≥12 months of prior EHR activity. Patients with valvular disease, alternative indications for oral anticoagulation, or who were pregnant were excluded. The incidence rates of developing stroke or systemic embolism (SSE) and bleeding-related hospitalization were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using propensity score-overlap weighted proportional hazards regression. Multiple sensitivity and subgroup analyses were performed. Results We included 21,940 rivaroxaban (20.1% at the 15 mg dose) and 38,213 warfarin (time-in-therapeutic range = 47.3 ± 28.3%) patients. Rivaroxaban was found to have similar hazard of SSE compared to warfarin (HR = 0.92, 95% CI = 0.82–1.03). Rivaroxaban was associated with a reduced rate of bleeding-related hospitalizations (HR = 0.85, 95% CI = 0.78–0.92) versus warfarin, as well as reductions in intracranial (HR = 0.76, 95% CI = 0.62–0.94) and extracranial (HR = 0.89, 95%CI = 0.81–0.97) bleeding. Upon sensitivity analysis restricting the population to men with a CHA2DS2VASc score ≥2 or women with a score ≥3, rivaroxaban was associated with a significant 33% risk reduction in SSE and 43% reduction in the risk of bleeding-related hospitalization. No significant interaction for the SSE or bleeding-related hospitalization outcomes was observed upon subgroup analyses. Conclusion Among patients with NVAF and OSA, rivaroxaban had similar SSE risk versus warfarin but was associated with reductions in any intracranial and extracranial bleeding-related hospitalizations. Rivaroxaban was associated with significant reductions in SSE and bleeding-related hospitalizations when the study population was restricted to patients with a moderate-to-high risk of SSE. These data should provide prescribers with additional confidence in selecting rivaroxaban in NVAF patients who have OSA at the time of anticoagulation initiation.

How IL-21 functions during development of high affinity antibody in germinal centres (GC) is not fully known. Here using a cell cycle reporter mouse, the authors show that IL-21 promotes cell cycle progression within the GC light zone and enables release from the G1 cell cycle stage.

Objectives: To perform a systematic review of studies evaluating prognostic factors (proxy measures) to predict patients’ post-stroke functional outcome status recommended by clinical guidelines. Materials and methods: MEDLINE and Embase databases were searched from January 1, 2000, through January 8, 2021. Studies that evaluated stroke survivors and assessed a proxy measure's ability to predict functional outcome status as measured by the modified Rankin Scale (mRS), Barthel Index (BI), Glasgow Outcomes Scale, and/or Functional Independence Measure between 30 and 365 days post-stroke were included. Results: Nine studies met inclusion criteria (median N per study = 1699; range: 530–6809). Seven studies evaluated ischemic stroke ± transient ischemic attack (TIA), 1 evaluated subarachnoid hemorrhage, and 1 evaluated both ischemic and hemorrhagic stroke and TIA (each reported separately). All studies utilized mRS score to assess post-stroke functional outcome, while 3 utilized the BI. Home-time was the most frequently evaluated proxy (7/9, 77.8%) and had moderate-to-strong correlation/discriminative ability with 3- to 12-month post-stroke functional outcome measurement. Home-time was less able to discriminate between neighboring mRS score values >3 and was only weakly-to-moderately correlated with mRS in TIA patients. Discharge to a location other than home or a relative's home was assessed in 2 of 9 studies (22.2%) and was found to be a moderate-to-strong correlate/predictor of unfavorable mRS score. In a single study, index hospital length of stay weakly correlated with post-stroke function status. Conclusions: This systematic review provides evidence supporting the use of home-time and discharge destination as proxy measures for predicting post-stroke functional outcome.

Background Advanced age and type 2 diabetes (T2D) are common in patients with nonvalvular atrial fibrillation (NVAF). We evaluated the impact of age on the effectiveness and safety of rivaroxaban versus warfarin in this population. Methods We analyzed electronic health record data from November 2010, to December 2019 including adults with NVAF and T2D, newly started on rivaroxaban or warfarin. Propensity score-overlap weighted hazard ratios (HRs) for stroke/systemic embolism (SSE), hospitalization for major or clinically relevant nonmajor bleeding (CRNMB), vascular death, major adverse limb events (MALE), major bleeding, and intracranial hemorrhage (ICH) were calculated for older (≥80 years) and younger (

Abstract Background Diabetes increases a patient’s risk of developing atrial fibrillation by 49%. Patients with nonvalvular atrial fibrillation are at a fivefold increased risk of stroke and die more frequently from vascular causes. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular atrial fibrillation patients with type 2 diabetes. Methods This was an analysis of Optum® De-Identified electronic health record data from 11/2010 to 12/2019. We included adults with nonvalvular atrial fibrillation and type 2 diabetes, newly started on rivaroxaban or warfarin and with ≥ 12-months of prior electronic health record activity. Patients who were pregnant, had alternative indications for oral anticoagulation or valvular heart disease were excluded. We evaluated the incidence rate (%/year) of developing the composite outcome of stroke/systemic embolism or vascular death and major or clinically relevant nonmajor bleeding as well as each endpoint individually. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted proportional hazards regression. Results We included 32,078 rivaroxaban (31% initiated on 15 mg dose) and 83,971warfarin users (time-in-therapeutic range = 47 ± 28%). Rivaroxaban was associated with a reduced risk of stroke/systemic embolism or vascular death (3.79 vs. 4.19; hazard ratio = 0.91, 95% confdience interval = 0.88–0.95), driven mostly by reductions in vascular death (2.81 vs 3.18, hazard ratio = 0.90, 95% confidence interval = 0.86–0.95) and systemic embolism (0.13 vs. 0.16; hazard ratio = 0.82, 95% confidence interval = 0.66–1.02). Major/clinically relevant nonmajor bleeding was less frequent with rivaroxaban versus warfarin (2.17 vs. 2.31; hazard ratio = 0.94, 95% confidence interval = 0.89–0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs. 0.54; hazard ratio = 0.63, 95% confidence interval = 0.55–0.72). Conclusions In nonvalvular atrial fibrillation patients with type 2 diabetes, rivaroxaban was associated with an ~ 10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations versus warfarin.

Abstract Background African Americans are under-represented in trials evaluating oral anticoagulants for the treatment of acute venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban versus warfarin for the treatment of VTE in African Americans. Methods We utilized Optum® De-Identified Electronic Health Record data from 11/1/2012–9/30/2018. We included African Americans experiencing an acute VTE during a hospital or emergency department visit, who received rivaroxaban or warfarin as their first oral anticoagulant within 7-days of the acute VTE event and had ≥1 provider visit in the prior 12-months. Differences in baseline characteristics between cohorts were adjusted using inverse probability-of-treatment weighting based on propensity scores (standard differences

In insects, many critical olfactory behaviours are mediated by the large odorant receptor (Or) gene family, which determines the response properties of different classes of olfactory receptor neurons (ORNs). While ORN responses are generally conserved within and between Drosophila species, variant alleles of the D. melanogaster Or22 locus have previously been shown to alter the response profile of an ORN class called ab3A. These alleles show potential clinal variation, suggesting that selection is acting at this locus. Here, we investigated if the changes seen in ab3A responses lead to changes in olfactory-related behaviours. We show that variation at the Or22 locus and in the ab3A neurons are not fully compensated for by other ORNs and lead to overall changes in antennal odorant detection. We further show that this correlates with differences in odorant preference behaviour and with differences in oviposition site preference, with flies that have the chimaeric short allele strongly preferring to oviposit on banana. These findings indicate that variation at the Or22 locus leads to changes in olfactory-driven behaviours, and add support to the idea that the ab3A neurons are of especial importance to the ecology of Drosophila flies.

Studying flower color evolution can be challenging as it may require several different areas of expertise, ranging from botany and ecology through to understanding color sensing of insects and thus how they perceive flower signals. Whilst studies often view plant-pollinator interactions from the plant's perspective, there is growing evidence from psychophysics studies that pollinators have their own complex decision making processes depending on their perception of color, viewing conditions and individual experience. Mimicry of rewarding flowers by orchids is a fascinating system for studying the pollinator decision making process, as rewarding model flowering plants and mimics can be clearly characterized. Here, we focus on a system where the rewardless orchid Eulophia zeyheriana mimics the floral color of Wahlenbergia cuspidata (Campanulaceae) to attract its pollinator species, a halictid bee. Using recently developed psychophysics principles, we explore whether the color perception of an insect observer encountering variable model and mimic flower color signals can help explain why species with non-rewarding flowers can exist in nature. Our approach involves the use of color discrimination functions rather than relying on discrimination thresholds, and the use of statistical distributions to model intraspecific color variations. Results show that whilst an experienced insect observer can frequently make accurate discriminations between mimic and rewarding flowers, intraspecific signal variability leads to overlap in the perceived color, which will frequently confuse an inexperienced pollinator. This new perspective provides an improved way to incorporate pollinator decision making into the complex field of plant-pollinator interactions.

African Americans (AAs) and obese individuals have increased thrombotic risk. This study evaluated the effectiveness and safety of rivaroxaban versus warfarin in obese, AAs with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Optum® De-Identified Electronic Health Record (EHR) data was used to perform separate propensity-score matched analyses of adult, oral anticoagulant (OAC)-naïve AAs with NVAF or acute VTE, respectively; who had a body mass index≥30kg/m 2 and ≥12-months EHR activity with ≥1-encounter before OAC initiation. Cox regression was performed and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). For the NVAF analysis, 1,969 rivaroxaban- and 1,969 warfarin-users were matched. Rivaroxaban was not associated with a difference in stroke/systemic embolism versus warfarin (HR = 0.88, 95%CI = 0.60-1.28), but less major bleeding (HR = 0.68, 95%CI = 0.50-0.94) was observed. Among 683 rivaroxaban-users with VTE, 1:1 matched to warfarin-users, rivaroxaban did not alter recurrent VTE (HR = 1.36, 95%CI = 0.79-2.34) or major bleeding (HR = 0.80, 95%CI = 0.37-1.71) risk versus warfarin at 6-months (similar findings observed at 3- and 12-months). Rivaroxaban appeared to be associated with similar thrombotic, and similar or lower major bleeding risk versus warfarin in these obese, AA cohorts.

Background Extended duration thromboprophylaxis (ET) for approximately 30 days can effectively and safely reduce venous thromboembolism (VTE) risk in appropriately selected medically ill patients. We sought to estimate the proportion of hospitalized medically ill patients potentially qualifying for ET and assess their post-discharge clinical and economic outcomes using a large claims database. Methods Using MarketScan claims from January 2012 to September 2018, we identified medically ill patients hospitalized with a primary diagnosis of heart failure, respiratory insufficiency, ischemic stroke, infection, or inflammatory disease and ≥1-additional risk factor for VTE. Patients 30 days, receiving oral anticoagulation prior to index hospitalization or having an indication for full-dose anticoagulation were excluded, as were patients deemed high-risk for bleeding due to active, in-hospital treated cancer, gastroduodenal ulcer or bleeding within the prior 3 months, bronchiectasis, pulmonary cavitation or hemorrhage, or dual antiplatelet therapy use. Results We identified 2,782,988 patients ≥40 years of age and admitted for a high-risk medical illness. Of these, 724,531 patients (26.0%) were identified as ET candidates. Patients' VTE risk appeared highest in the first 30 days post-discharge (1,532/724,531, 0.2%). Adjusted post-index hospitalization costs (2018 US$) for patients with a VTE within 30 days were higher than those without VTE (Δ = $32,623 at 30 days, Δ = $43,325 at 90 days, Δ = $53,668 at 365 days; p

Introduction A paucity of contemporary data examining bleeding-related hospitalization outcomes in atrial fibrillation (AF) patients exists. Methods Adults in the Nationwide Readmissions Database (January 2016–November 2016) with AF and hospitalized for intracranial hemorrhage (ICH), gastrointestinal, genitourinary, or other bleeding were identified. Association between bleed types and outcomes were assessed using multivariable regression (gastrointestinal defined as referent) and reported as crude incidences and adjusted odds ratios (ORs) or mean differences with 95% confidence intervals (CIs). Results In total, 196,878 index bleeding-related hospitalizations were identified in this AF cohort (CHA2DS2VASc score ≥2 in 95.1%), with 70.8% classified as gastrointestinal. The overall incidences of in-hospital mortality, need for post-discharge out-of-home care, and 30-day readmission were 4.9, 50.8, and 18.2%, respectively. Multivariable regression suggested traumatic and nontraumatic ICHs were associated with higher odds of in-hospital mortality (OR = 3.99, 95% CI = 3.79, 4.19; OR = 13.09, 95% CI = 12.24, 13.99) and need for post-discharge out-of-home care (OR = 2.92, 95% CI = 2.83, 3.01; OR = 2.74, 95% CI = 2.59, 2.90), and increases in mean index hospitalization length-of-stay (8.31 days, 95% CI = 8.03, 8.60, 6.27 days, 95% CI = 5.97, 6.57) versus gastrointestinal bleeding. Genitourinary and other bleeds were associated with lower mortality (OR = 0.37, 95% CI = 0.25, 0.55; OR = 0.59, 95% CI = 0.53, 0.64) and reduced length-of-stays (−2.84 days, 95% CI = − 2.91, −2.76; −2.06 days, 95% CI = − 2.11, −2.01) versus gastrointestinal bleeding. Genitourinary bleeds were also associated with a reduced need for post-discharge out-of-home care (OR = 0.86, 95% CI = 0.77, 0.97). Conclusion The burden of bleeding-related hospitalizations was notably driven by relatively rare but severe and life-threatening ICH, and less morbid but more frequent gastrointestinal bleeding. There is need for continued research on bleeding risk factors and mitigation techniques to avoid bleeding-related patient hospitalizations.

Introduction: A non-medical switch is a change to a patient’s medication regimen for reasons other than lack of clinical response, side-effects or poor adherence. Specialist physicians treat complex patients who may be vulnerable to non-medical switching. Objectives: To evaluate specialist physicians’ perceptions regarding the frequency of non-medical switch requests, and the impact on their patients’ outcomes and healthcare utilization. Methods: An online survey of randomly sampled physicians spending ≥10% of time providing patient care and having received ≥1 non-medical switch request during the prior 12-months. Results: Among 404 specialist physicians surveyed, non-medical switch requests were reported as very frequent or frequent by 35.0% of oncologists (for injectable cancer agents) and up to 80.3% of endocrinologists (for injectable anti-hyperglycemics). Respondents reported decreased medication effectiveness (25.0% of oncologists to 75.0% of dermatologists) and increased side-effects (32.5% of oncologists to 66.7% of psychiatrists). Most specialists reported very frequent or frequent increases in non-office visits (52.5% of oncologists to 75.3% of endocrinologists) and calls with pharmacies (57.5% of oncologists to 80.5% of rheumatologists) due to non-medical switching. Conclusions: Receipt of non-medical switching requests were common among specialist physicians. Non-medical switching may lead to negative effects on patient care and require increased healthcare utilization.

BACKGROUND:Physicians are in an ideal position to describe the impact of medication non-medical switching (switching commonly due to formulary changes by insurer for reasons unrelated to patient health) on their practice dynamics and patient care. We sought to examine physicians' openness to requests for non-medical switching and their experiences and opinions regarding the impact of non-medical switching on their practice, staff and patients. METHODS:An online survey of randomly-sampled physicians spending ≥10% of time providing patient care and having received ≥1 non-medical switch request during the prior 12-months. The impact of non-medical switching on clinical decision-making process; professional experience with clinical practice, patient-physician relationship, insurance process; and perceived impact on practice, staff and patients were assessed. Weighted percent responses were calculated. RESULTS:We sampled 1,010 physicians (response rate = 55.5%). Many responded being frequently not amenable (26.0%) or had reservations (41.8%) to non-medical switch requests; with >50% indicating patient stability on current therapy and suboptimal alternatives as factors frequently influencing amenability. Physicians agreed non-medical switching can create ethical concerns (clinical judgement, autonomy, ability to treat per guidelines; 74.8%, 82.3%, 53.5%, respectively), while forcing them to take responsibility for insurers' decisions (81.1%) and diverting their clinical time (84.3%). Most indicated non-medical switching increased practice burden (administrative, non-billable interactions, additional staffing, non-office patient contact, calls to/from the pharmacy; 85.0%, 72.5%, 62.2%, 64.2%, 69.5%, respectively). Physicians felt insurer processes discouraged non-medical switch challenges (76.7%) and required inconvenient lengths-of-time (76.1%) speaking to insurer representatives without proper expertise (62.0%). They believed non-medical switching negatively impacted aspects of care (effectiveness, side-effects, medication adherence and abandonment, out-of-pocket costs, medication errors; 46.5%, 53.2%, 50.6%, 49.4%, 59.6%, 54.5%, respectively). CONCLUSIONS:Physicians were frequently not amenable or had reservations regarding non-medical switching. They noted ethical concerns due to non-medical switching. Most felt non-medical switches burdened their practice and negatively impacted care.

Background There is a paucity of contemporary data estimating the incidence of major adverse cardiovascular events (MACE) in patients with established atherosclerotic disease or multiple risk factors managed in routine practice. We estimated 1‐ and 4‐year incidences of MACE and the association between MACE and vascular beds affected in these patients. Methods and Results Using US IBM MarketScan data from January 1, 2013 to December 31, 2017, we identified patients ≥45 years old with established coronary artery disease, cerebrovascular disease, peripheral artery disease, or the presence of ≥3 risk factors for atherosclerosis during 2013 with a minimum of 4 years of follow‐up. We calculated 1‐ and 4‐year incidences of MACE (cardiovascular death or hospitalization for myocardial infarction or ischemic stroke). A Cox proportional hazards regression model adjusted for age and sex was used to evaluate the association between vascular bed number/location(s) affected and MACE. We identified 1 302 856 patients with established atherosclerotic disease or risk factors for atherosclerosis. Coronary artery disease was present in 16.9% of patients, cerebrovascular disease in 7.6%, peripheral artery disease in 13.6%, and risk factors for atherosclerosis only in 66.0%. The 1‐ and 4‐year incidences of MACE were 1.4% and 6.9%, respectively. At 4 years, MACE was more frequent in patients with atherosclerotic disease in a single (hazard ratio=1.51, 95% CI=1.48–1.55), 2‐(hazard ratio=2.35, 95% CI=2.27–2.44), or all 3 vascular beds (hazard ratio=3.30, 95% CI=2.97–3.68) compared with having risk factors for atherosclerosis. Conclusions Patients with established atherosclerotic disease or who have multiple risk factors and are treated in contemporary, routine practice carry a substantial risk for MACE at 1‐ and 4‐ years of follow‐up. MACE risk was shown to vary based on the number and location of vascular beds involved.

Gordiids, or freshwater hairworms, are members of the phylum Nematomorpha that use terrestrial definitive hosts (arthropods) and live as adults in rivers, lakes, or streams. The genus Paragordius consists of 18 species, one of which was described from the Nearctic in 1851. More than 150 years later, we are describing a second Paragordius species from a unique habitat within the Nearctic; the Madrean Sky Island complex. The Madrean Sky Islands are a series of isolated high mountains in northern Mexico and the southwestern United States (Arizona and New Mexico), and are well known for their high diversity and endemicity. The new species is described based on both molecular data (COI barcoding) and morphological characters of the eggs, larvae, cysts, and adults. Adult females have unique small oblong mounds present on the interior of the trifurcating lobes with randomly dispersed long hairs extending from the furrows between the mounds. Marked genetic differences support observed morphological differences. This species represents the second new hairworm to be described from the Madrean Sky Islands, and it may represent the first endemic hairworm from this biodiversity hotspot.

# Background Rivaroxaban, a fixed-dose oral direct factor Xa inhibitor, does not require continuous monitoring and thus reduces the hospital stay and economic burden in low-risk pulmonary embolism (LRPE) patients. # Study Question What is the effectiveness of rivaroxaban versus the standard of care (SOC; low-molecular-weight heparin, unfractionated heparin, warfarin) among LRPE patients in the Veterans Health Administration? # Study Design Adult patients with continuous health plan enrollment for ≥12 months pre- and 3 months post-inpatient PE diagnosis (index date=discharge date) between October 1, 2011- June 30, 2015 and an anticoagulant claim during the index hospitalization were included. # Measures and Outcomes Patients scoring 0 points on the simplified Pulmonary Embolism Stratification Index were considered low-risk and were stratified into SOC and rivaroxaban cohorts. Propensity score matching (PSM) was used to compare hospital-acquired complications (HACs), PE-related outcomes (recurrent venous thromboembolism, major bleeding, and death), and healthcare utilization and costs between the rivaroxaban and SOC cohorts. # Results Among 6746 PE patients, 1918 were low-risk; of these, 73 were prescribed rivaroxaban, 1546 were prescribed SOC, and 299 were prescribed other anticoagulants during the index hospitalization. After 1:3 PSM, 64 rivaroxaban and 192 SOC patients were included. During the index hospitalization, rivaroxaban users (versus SOC) had similar inpatient length of stay (LOS; 7.0 vs 6.7 days, standardized difference [STD]=1.8) but fewer HACs (4.7% vs 10.4%; STD: 21.7). In the 90-day post-discharge period, PE-related outcome rates were similar between the cohorts (all p>0.05). However, rivaroxaban users had fewer outpatient (15.9 vs 20.4; p=0.0002) visits per patient as well as lower inpatient ($765 vs $2,655; p

Warfarin has been associated with renovascular calcification and worsening renal function, whereas rivaroxaban may provide a degree of renopreservation by decreasing vascular inflammation. We sought to compare rivaroxaban and warfarin’s impact on renal decline in patients with nonvalvular atrial fibrillation (NVAF) treated in routine practice. Using US MarketScan claims data from January 2012 to December 2017, we identified patients with NVAF newly initiated on rivaroxaban or warfarin with ≥12 months of continuous insurance coverage prior to initiation. Patients with stage 5 chronic kidney disease (CKD) or receiving hemodialysis at baseline were excluded. Outcomes included rates (events/100 person-years) of hospital or emergency department admission for acute kidney injury (AKI) or progression to stage 5 CKD or need for hemodialysis. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores (absolute standardized differences

Extended thromboprophylaxis with oral anticoagulation can reduce the risk of symptomatic venous thromboembolism (VTE) in high-risk patients. We sought to estimate the proportion of medically ill patients in the United States who might qualify for extended thromboprophylaxis according to the criteria used in the Medically-Ill Patient Assessment of Rivaroxaban versus Placebo in Reducing Post-Discharge Venous ThromboEmbolism Risk (MARINER) trial. We analyzed 2014 National Inpatient Sample (NIS) data that provide a 20% weighted annual sample of all discharges from US acute-care hospitals. Hospitalizations for acute medically ill patients were identified as those with a primary discharge diagnosis code for heart or respiratory failure, ischemic stroke, infection, or inflammatory diseases. Patients were excluded if they were 35-days, or were contraindicated to nonvitamin K antagonist oral anticoagulants. The modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE)-VTE score was used to stratify patients’ risk for postdischarge VTE, with a score of 2 to 3 suggesting patients were at moderate- and ≥4 as high-risk. Of the 35 358 810 hospitalizations in the 2014 NIS, 1 849 535 were medically ill patients admitted for heart failure (10.1%), respiratory failure (12.2%), ischemic stroke (8.8%), infection (58.5%), or inflammatory diseases (10.4%). The modified IMPROVE-VTE score classified 1 186 475 (64.1%) of these hospitalizations as occurring in moderate-risk and 407 095 (22.0%) in high-risk patients. This real-world study suggests a substantial proportion of acute medically ill patients might benefit from extended thromboprophylaxis using the modified IMPROVE-VTE score and clinical elements of the MARINER trial.

**Background:** Increased hospital length of stay is an important cost driver in hospitalized low-risk pulmonary embolism (LRPE) patients, who benefit from abbreviated hospital stays. We sought to measure length-of-stay associated predictors among Veterans Health Administration LRPE patients. **Methods:** Adult patients (aged ≥18 years) with ≥1 inpatient pulmonary embolism (PE) diagnosis (index date = discharge date) between 10/2011-06/2015 and continuous enrollment for ≥12 months pre- and 3 months post-index were included. PE patients with simplified Pulmonary Embolism Stratification Index score 0 were considered low risk; all others were considered high risk. LRPE patients were further stratified into short (≤2 days) and long length of stay cohorts. Logistic regression was used to identify predictors of length of stay among low-risk patients. **Results:** Among 6746 patients, 1918 were low-risk (28.4%), of which 688 (35.9%) had short and 1230 (64.1%) had long length of stay. LRPE patients with computed tomography angiography (Odds ratio [OR]: 4.8, 95% Confidence interval [CI]: 3.82-5.97), lung ventilation/perfusion scan (OR: 3.8, 95% CI: 1.86-7.76), or venous Doppler ultrasound (OR: 1.4, 95% CI: 1.08-1.86) at baseline had an increased probability of short length of stay. Those with troponin I (OR: 0.7, 95% CI: 0.54-0.86) or natriuretic peptide testing (OR: 0.7, 95% CI: 0.57-0.90), or more comorbidities at baseline, were less likely to have short length of stay. **Conclusion:** Understanding the predictors of length of stay can help providers deliver efficient treatment and improve patient outcomes which potentially reduces the length of stay, thereby reducing the overall burden in LRPE patients.

Background: Non-medical switching (NMS) is defined as switching to a clinically similar but chemically distinct medication for reasons apart from lack of effectiveness, tolerability or adherence. Objective: To update a prior systematic review evaluating the impact of NMS on outcomes. Data sources: An updated search through 10/1/2018 in Medline and Web of Science was performed. Study selection: We included studies evaluating ≥25 patients and measuring the impact of NMS of drugs on ≥1 endpoint. Data extraction: The direction of association between NMS and endpoints was classified as negative, positive or neutral. Data synthesis: Thirty-eight studies contributed 154 endpoints. The direction of association was negative (n = 48; 31.2%) or neutral (n = 91; 59.1%) more often than it was positive (n = 15; 9.7%). Stratified by endpoint type, NMS was associated with a negative impact on clinical, economic, health-care utilization and medication-taking behavior in 26.9%,41.7%,30.3% and 75.0% of cases; with a positive effect seen in 3.0% (resource utilization) to 14.0% (clinical) of endpoints. Of the 92 endpoints from studies performed by the entity dictating the NMS, 88.0%were neutral or positive; whereas, only 40.3%of endpoints from studies conducted separately from the interested entity were neutral or positive. Conclusions: NMS was commonly associated with negative or neutral endpoints and was seldom associated with positive ones.

Introduction: Numerous real-world studies have compared non-vitamin K antagonist oral anticoagulants (NOACs) with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF). A meta-analysis was performed to synthesize the available evidence. Methods: Systematic searches were performed through 12/2016 to identify non-randomized NVAF studies comparing NOACs with VKAs, and reporting effectiveness, safety, or persistence. Results: Of 562 citations identified, 49, 79, and 18 compared rivaroxaban, dabigatran, and apixaban, respectively, with VKAs and were included. Compared with VKAs, rivaroxaban was associated with a reduced risk of ischemic stroke (IS) (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.75–0.93), intracranial haemorrhage (ICH) (HR = 0.69, 95% CI = 0.52–0.90), and non-persistence (HR = 0.62, 95% CI = 0.60–0.65). Dabigatran was associated with a significantly lower risk of IS (HR = 0.80, 95% CI = 0.65–0.98) and ICH (HR = 0.45, 95% CI = 0.36–0.58), but not for non-persistence (HR = 0.91, 95% CI = 0.53–1.55), compared with VKAs. Apixaban was associated with a lower risk of ICH than VKAs (HR = 0.41, 95% CI = 0.28–0.60), but was not different to VKAs in terms of IS (HR = 1.01, 95% CI = 0.87–1.17) or non-persistence (HR = 1.08, 95% CI = 0.81–1.45). Conclusion: NOACs appear to be at least as effective and safe as VKAs for stroke prevention in patients with NVAF.

Abstract Background Low-risk pulmonary embolism (PE) patients may be candidates for outpatient treatment or abbreviated hospital stay. There is a need for a claims-based prediction rule that payers/hospitals can use to risk stratify PE patients. We sought to validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule for in-hospital and 30-day outcomes. Methods We used the Optum Research Database from 1/2008-3/2015 and included adults hospitalized for PE (415.1x in the primary position or secondary position when accompanied by a primary code for a PE complication) and having continuous medical and prescription coverage for ≥6-months prior and 3-months post-inclusion or until death. In-hospital and 30-day mortality and 30-day complications (recurrent venous thromboembolism, rehospitalization or death) were assessed and prognostic accuracies of IMPACT with 95 % confidence intervals (CIs) were calculated. Results In total, 47,531 PE patients were included. In-hospital and 30-day mortality occurred in 7.9 and 9.4 % of patients and 20.8 % experienced any complication within 30-days. Of the 19.5 % of patients classified as low-risk by IMPACT, 2.0 % died in-hospital, resulting in a sensitivity and specificity of 95.2 % (95 % CI, 94.4–95.8) and 20.7 % (95 % CI, 20.4–21.1). Only 1 additional low-risk patient died within 30-days of admission and 12.2 % experienced a complication, translating into a sensitivity and specificity of 95.9 % (95 % CI, 95.3–96.5) and 21.1 % (95 % CI, 20.7–21.5) for mortality and 88.5 % (95 % CI, 87.9–89.2) and 21.6 % (95 % CI, 21.2–22.0) for any complication. Conclusion IMPACT had acceptable sensitivity for predicting in-hospital and 30-day mortality or complications and may be valuable for retrospective risk stratification of PE patients.

At the University of Bristol, we established a novel dissection course to complement our anatomy degree. Students enrolled in this undergraduate course are trained as comparative anatomists, with equal time given to both human and veterinary anatomy. Historically, students opted to dissect either human or veterinary donors as part of the course. To fully reflect the comparative nature of the degree, the dissection course was redesigned so students could dissect both human and veterinary specimens as part of the same course. This facilitated a wide-ranging experience of anatomy, encouraging detailed knowledge of a multitude of species and allowing for multifaceted anatomy graduates to be ready for employment in a wide and competitive job market. Across three iterations of the amended version of the course, median marks ranged from 58.7% to 62.0%, with between 22 and 39 students enrolled. In comparison to the course prior to the introduction of the change, median marks ranged from 59.8% to 62.8%, with between 16 and 24 students enrolled. There was no significant difference between marks before or after the introduction of the concurrently comparative aspect. This paper describes the course, with learning materials and assessments considered, along with some reflection on its value. The course offers benefits to students by widening their perspective on anatomical knowledge and making them more equipped for the job market. It also broadens their understanding of form-function relationships. However, student feedback implied that having the choice between human or veterinary dissection was preferable, and this may outweigh the perceived benefits of the course.

The establishment and maintenance of pluripotency depend on precise coordination of gene expression. We establish serine-arginine-rich splicing factor 3 (SRSF3) as an essential regulator of RNAs encoding key components of the mouse pluripotency circuitry, SRSF3 ablation resulting in the loss of pluripotency and its overexpression enhancing reprogramming. Strikingly, SRSF3 binds to the core pluripotency transcription factor Nanog mRNA to facilitate its nucleo-cytoplasmic export independent of splicing. In the absence of SRSF3 binding, Nanog mRNA is sequestered in the nucleus and protein levels are severely downregulated. Moreover, SRSF3 controls the alternative splicing of the export factor Nxf1 and RNA regulators with established roles in pluripotency, and the steady-state levels of mRNAs encoding chromatin modifiers. Our investigation links molecular events to cellular functions by demonstrating how SRSF3 regulates the pluripotency genes and uncovers SRSF3-RNA interactions as a critical means to coordinate gene expression during reprogramming, stem cell self-renewal and early development.

BackgroundFrailty predicts poorer outcomes and decreased anticoagulation use in patients with nonvalvular atrial fibrillation. We sought to assess the effectiveness and safety of apixaban, dabigatran and rivaroxaban versus warfarin in frail nonvalvular atrial fibrillation patients. Methods and ResultsUsing US MarketScan claims data from November 2011 to December 2016, we identified frail oral anticoagulant‐naïve nonvalvular atrial fibrillation patients with ≥12 months of continuous insurance coverage before oral anticoagulant initiation. Frailty status was determined using the Johns Hopkins Claims‐based Frailty Indicator score (≥0.20 indicating frailty). Users of apixaban, dabigatran, or rivaroxaban were separately 1:1 matched to warfarin users via propensity‐scores, with residual absolute standardized differences

Randomized controlled trials (RCTs) have compared mechanical endovascular therapy (MET) in addition to intravenous tissue plasminogen activator (IVtPA) to IVtPA alone for the management of acute ischemic stroke (AIS). Direct comparative studies between individual METs are not available. In lieu of head-to-head randomized control trials, we performed an adjusted indirect treatment comparison (ITC) meta-analysis to assess the comparative efficacy and safety of different METs, Solitaire+IVtPA and Penumbra+IVtPA in AIS patients.We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from January 1, 2005 through April 1, 2017 for RCTs in AIS patients, comparing a single MET+IVtPA to IVtPA alone and reporting shift in ordinal modified Rankin Scale (mRS) score at 90 days. Secondary endpoints included 90 day mortality and symptomatic intracranial hemorrhage (sICH). Endpoints were pooled using traditional random effects meta-analysis methods, producing odds ratios and 95% confidence intervals. Adjusted ITCs using pooled estimates were then performed. Three studies (SWIFT PRIME, EXTEND-IA, THERAPY) were included; two evaluating the Solitaire stent retriever and one the Penumbra system. Traditional meta-analysis demonstrated that each MET+IVtPA resulted in increased odds of improving ordinal mRS score vs. IVtPA alone, but did not alter the odds of death or sICH. Adjusted ITC showed no significant difference between the METs for any outcome.No significant difference in efficacy or safety between the Solitaire and Penumbra devices was observed.

Several tidal power schemes have been proposed for the River Severn Estuary between the South West of England and Wales. An indicative technology assessment has been undertaken in order to evaluate the so-called ‘Shoots Barrage’ over its foreseen lifespan of 120 years in terms of its cradle-to-site, operation and maintenance requirements. It would be located just upriver of the Severn road crossings in the United Kingdom (UK), involve an estimated cost of L3.2 bn to construct, and could potentially generate around 2.7 TWh per year (or a little under 1% of UK electricity demand). This scheme is favoured by environmental groups, because to its more benign environmental impacts compared with the much larger, Cardiff-Weston scheme. The present analysis suggests that the proposed Shoots Barrage would yield relatively attractive ‘figures of merit’ in terms of its net energy and carbon emissions, although its financial performance is poorer than alternative power generators.

Clinical guidelines recommend early discharge of patients with low-risk pulmonary embolism (LRPE). This study measured the overall impact of early discharge of LRPE patients on clinical outcomes and costs in the Veterans Health Administration population. Adult patients with ≥1 inpatient diagnosis for pulmonary embolism (PE) (index date) between 10/2011-06/2015, continuous enrollment for ≥12 months pre- and 3 months post-index date were included. PE risk stratification was performed using the simplified Pulmonary Embolism Stratification Index. Propensity score matching (PSM) was used to compare 90-day adverse PE events (APEs) [recurrent venous thromboembolism, major bleed and death], hospital-acquired complications (HACs), healthcare utilization, and costs among short (≤2 days) versus long length of stay (LOS). Net clinical benefit was defined as 1 minus the combined rate of APE and HAC. Among 6,746 PE patients, 95.4% were men, 22.0% were African American, and 1,918 had LRPE. Among LRPE patients, only 688 had a short LOS. After 1:1 PSM, there were no differences in APE, but short LOS had fewer HAC (1.5% vs 13.3%, 95% CI: 3.77-19.94) and bacterial pneumonias (5.9% vs 11.7%, 95% CI: 1.24-3.23), resulting in better net clinical benefit (86.9% vs 78.3%, 95% CI: 0.84-0.96). Among long LOS patients, HACs (52) exceeded APEs (14 recurrent DVT, 5 bleeds). Short LOS incurred lower inpatient ($2,164 vs $5,100, 95% CI: $646.8-$5225.0) and total costs ($9,056 vs $12,544, 95% CI: $636.6-$6337.7). LRPE patients with short LOS had better net clinical outcomes at lower costs than matched LRPE patients with long LOS.

Intraoperative neurophysiological monitoring during endoscopic, endonasal approaches to the skull base is both feasible and safe. Numerous reports have recently emerged from the literature evaluating the efficacy of different neuromonitoring tests during endonasal procedures, making them relatively well-studied. The authors report on a comprehensive, multimodality approach to monitoring the functional integrity of at risk nervous system structures, including the cerebral cortex, brainstem, cranial nerves, corticospinal tract, corticobulbar tract, and the thalamocortical somatosensory system during endonasal surgery of the skull base. The modalities employed include electroencephalography, somatosensory evoked potentials, free-running and electrically triggered electromyography, transcranial electric motor evoked potentials, and auditory evoked potentials. Methodological considerations as well as benefits and limitations are discussed. The authors argue that, while individual modalities have their limitations, multimodality neuromonitoring provides a real-time, comprehensive assessment of nervous system function and allows for safer, more aggressive management of skull base tumors via the endonasal route.

A retrospective cohort analysis of the US MarketScan claims databases was performed to compare persistence and discontinuation rates between the vitamin K antagonist warfarin and the non-vitamin K antagonist oral anticoagulants rivaroxaban and dabigatran in patients with non-valvular atrial fibrillation. The analysis included adult patients with non-valvular atrial fibrillation newly initiated on rivaroxaban, dabigatran, or warfarin between November 1, 2011 and December 31, 2013, with a baseline CHA2DS2-VASc score ≥2, two or more non-valvular atrial fibrillation diagnosis codes (427.31), and ≥6 months' continuous medical and pharmacy benefit enrollment before oral anticoagulant initiation. Propensity score matching was performed to match patients receiving rivaroxaban with those receiving dabigatran (1:1) and warfarin (1:1). Patients were followed until the first event of inpatient death, end of continuous enrollment, or end of study period. Medication persistence was defined as absence of a refill gap of >60 days. Discontinuation was defined as no additional refill for >90 days and through to end of follow-up. Hazard ratios (HRs) of oral anticoagulant persistence and discontinuation were estimated using Cox proportional hazard models. In total, 3,2634 patients were included (n = 10878/oral anticoagulant group). Rivaroxaban was associated with better persistence than both dabigatran (HR 0.64, 95% confidence interval [CI] 0.62-0.67) and warfarin (HR 0.62, 95% CI 0.59-0.64) and lower discontinuation than dabigatran (HR 0.61, 95% CI 0.58-0.64) and warfarin (HR 0.65, 95% CI 0.62-0.68). Real-world analysis of oral anticoagulant use may reveal whether the relatively high persistence/low discontinuation demonstrated for rivaroxaban translates into lower rates of stroke.

Despite the type I insulin-like growth factor receptor (IGF-IR) being highly expressed in more than 80% of human lung tumors, a transgenic model of IGF-IR overexpression in the lung has not been created. We produced two novel transgenic mouse models in which IGF-IR is overexpressed in either lung type II alveolar cells (surfactant protein C [SPC]-IGFIR) or Clara cells (CCSP-IGFIR) in a doxycycline-inducible manner. Overexpression of IGF-IR in either cell type caused multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas. These tumors expressed thyroid transcription factor 1 and Kruppel-like factor 5 in most tumor cells. Similar to our previous work with lung tumors that developed in the mouse mammary tumor virus-IGF-II transgenic mice, the lung tumors that develop in the SPC-IGFIR and CCSP-IGFIR transgenic mice expressed high levels of the cyclic adenosine monophosphate response element binding protein that was localized primarily to the nucleus. Although elevated IGF-IR expression can initiate lung tumor development, tumors can become independent of IGF-IR signaling as IGF-IR down-regulation in established tumors produced tumor regression in some, but not all, of the tumors. These findings implicate IGF-IR as an important initiator of lung tumorigenesis and suggest that the SPC-IGFIR and CCSP-IGFIR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.

When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone.A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3-12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥ 1500 mg daily or maximally tolerated dose for ≥ 4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI).Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00-11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15-2.26 kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19-2.44 kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88-5.43 mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16-8.03).Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.

Background: Intravenous magnesium reduces the QTc interval of patients receiving ibutilide. Whether oral magnesium can reduce the QTc interval associated with oral sotalol and dofetilide is not known. This study was undertaken to evaluate the impact of oral magnesium on the QTc interval and whether an inherent intracellular magnesium deficiency exists among patients with arrhythmias. Methods: Participants receiving sotalol or dofetilide for atrial or ventricular arrhythmias were randomized to receive magnesium l‐lactate (504 mg elemental magnesium daily, Niche Pharmaceuticals, Roanoke, TX) or placebo for 48 hours. A 12‐lead electrocardiogram (ECG) was obtained at baseline, 3 hours, and 51 hours after dosing to correspond to the Tmax after oral ingestion. The QTc interval was measured from the ECGs and compared between groups. Intracellular magnesium concentrations were determined by energy‐dispersive x‐ray analysis at baseline and 51 hours after dosing (Intracellular Diagnostics, Inc., Foster City, CA). Results: The QTc interval reductions from baseline were greater in the magnesium group than placebo at 3 and 51 hours (P = 0.015 and P < 0.001, respectively). Sixty‐three percent of patients (regardless of experimental group) had baseline intracellular magnesium concentrations below the normal reference range of 33.9–41.9 mEq/IU, with an average level of 32.6 ± 2.2 mEq/IU. Conclusions: Oral magnesium l‐lactate raises intracellular magnesium concentrations and lowers the QTc interval of patients receiving sotalol or dofetilide.

In the framework of the European Copernicus programme, the European Space Agency (ESA) has launched the Sentinel-2 (S2) Earth Observation (EO) mission which provides optical high spatial resolution imagery over land and coastal areas. As part of this mission, a tool (named S2-RUT, from Sentinel-2 Radiometric Uncertainty Tool) has been developed. The tool estimates the radiometric uncertainty associated with each pixel in the top-of-atmosphere (TOA) reflectance factor images provided by ESA. This paper describes the design and development process of the initial version of the S2-RUT tool. The initial design step describes the S2 radiometric model where a set of uncertainty contributors are identified. Each of the uncertainty contributors is specified by reviewing the pre- and post-launch characterisation. The identified uncertainty contributors are combined following the guidelines in the ‘Guide to Expression of Uncertainty in Measurement’ (GUM) model and this combination model is further validated by comparing the results to a multivariate Monte Carlo Method (MCM). In addition, the correlation between the different uncertainty contributions and the impact of simplifications in the combination model have been studied. The software design of the tool prioritises an efficient strategy to read the TOA reflectance factor images, extract the auxiliary information from the metadata in the satellite products and the codification of the resulting uncertainty image. This initial version of the tool has been implemented and integrated as part of the Sentinels Application Platform (SNAP).

The net effect of pollen production on fecundity in plants can range from negative--when self-pollen interferes with fecundity due to incompatibility mechanisms, to positive--when pollen availability is associated with increased pollinator visitation and fecundity due to its utilization as a reward. We investigated the responses of bees to pollen and nectar rewards, and the effects of these rewards on pollen deposition and fecundity in the hermaphroditic succulent shrub Aloe tenuior. Self-pollinated plants failed to set fruit, but their ovules were regularly penetrated by self-pollen tubes, which uniformly failed to develop into seeds as expected from ovarian self-incompatibility (or strong early inbreeding depression). Bees consistently foraged for pollen during the morning and early afternoon, but switched to nectar in the late afternoon. As a consequence of this differential foraging, we were able to test the relative contribution to fecundity of pollen- versus nectar-collecting flower visitors. We exposed emasculated and intact flowers in either the morning or late afternoon to foraging bees and showed that emasculation reduced pollen deposition by insects in the morning, but had little effect in the afternoon. Despite the potential for self-pollination to result in ovule discounting due to late-acting self-sterility, fecundity was severely reduced in artificially emasculated plants. Although there were temporal fluctuations in reward preference, most bee visits were for pollen rewards. Therefore the benefit of providing pollen that is accessible to bee foragers outweighs any potential costs to fitness in terms of gender interference in this species.

Although breast cancer typically develops in women over the age of 40, it remains unclear when breast cancer initiating events occur or whether the mammary gland is particularly susceptible to oncogenic transformation at a particular developmental stage. Using MTB-IGFIR transgenic mice that overexpress type I insulin-like growth factor receptor (IGF-IR) in a doxycycline-inducible manner, mammary tumorigenesis was initiated at different developmental stages. Tumor multiplicity was significantly increased while tumor latency was significantly decreased when the IGF-IR transgene was expressed during pubertal development compared to post-pubertal transgene expression. Moreover, metastatic spread of mammary tumors to the lungs was approximately twice as likely when IGF-IR was overexpressed in pubertal mice compared to post-pubertal mice. In addition, engraftment of pubertal MTB-IGFIR mammary tissue into cleared mammary fat pads of pubertal hosts produced tumors more frequently and faster than engraftment into adult hosts. These experiments show that the mammary microenvironment created during puberty renders mammary epithelial cells particularly susceptible to transformation.

ObjectiveTo conduct a systematic review of economic models of newer anticoagulants for stroke prevention in atrial fibrillation (SPAF).Patients and methodsWe searched Medline, Embase, NHSEED and HTA databases and the Tuft's Registry from January 1, 2008 through October 10, 2012 to identify economic (Markov or discrete event simulation) models of newer agents for SPAF.ResultsEighteen models were identified. Each was based on a lone randomized trial/new agent, and these trials were clinically and methodologically heterogeneous. Dabigatran 150 mg, 110 mg and sequentially-dosed were assessed in 9, 8, and 9 models, rivaroxaban in 4 and apixaban in 4. Warfarin was a first-line comparator in 94% of models. Models were conducted from United States (44%), European (39%) and Canadian (17%) perspectives. Models typically assumed patients between 65-73 years old at moderate-risk of stroke initiated anticoagulation for/near a lifetime. All models reported cost/quality-adjusted life-year, 22% reported using a societal perspective, but none included indirect costs. Four models reported an incremental cost-effectiveness ratio (ICER) for a newer anticoagulant (dabigatran 110 mg (n = 4)/150 mg (n = 2); rivaroxaban (n = 1)) vs. warfarin above commonly reported willingness-to-pay thresholds. ICERs vs. warfarin ranged from $3,547-$86,000 for dabigatran 150 mg, $20,713-$150,000 for dabigatran 110 mg, $4,084-$21,466 for sequentially-dosed dabigatran and $23,065-$57,470 for rivaroxaban. Apixaban was found economically-dominant to aspirin, and dominant or cost-effective ($11,400-$25,059) vs. warfarin. Indirect comparisons from 3 models suggested conflicting comparative cost-effectiveness results.ConclusionsCost-effectiveness models frequently found newer anticoagulants cost-effective, but the lack of head-to-head trials and the heterogeneous characteristics of underlying trials and modeling methods make it difficult to determine the most cost-effective agent.

OBJECTIVES:To conduct a meta-analysis to quantify the real-world incidence of in-hospital or 30-day death or myocardial infarction (MI), and angiographically-confirmed ST-related treatment costs. BACKGROUND:The short-term clinical and economic consequences of coronary stent thrombosis (ST) are thought to be significant. METHODS:We searched MEDLINE, Embase and Scopus from January 2000-July 2012 to identify observational/registry studies that evaluated a cohort of ≥ 25 patients experiencing angiographically-confirmed thrombosis of a drug-eluting or bare-metal stent, required the use of dual-antiplatelet therapy for guideline-recommended durations, and reported incidences of in-hospital or 30-day death or MI and/or ST-related treatment costs. Incidences and costs from each study were pooled using random-effects meta-analysis. RESULTS:Twenty-three studies were included. Of the 13 studies reporting in-hospital outcomes, 12 (N=8,832 STs) reported mortality data, with the pooled incidence rate estimated to be 7.9%, 95%CI=5.4%-11.3%, I(2)=86%. Ten studies (N=1,294 STs) reported 30-day death, with a pooled incidence of 11.6%, 95%CI=8.8%-15.1%, I(2)=55%. Patients experiencing early ST (within 30-days of implant) had higher in-hospital and 30-day mortality than those experiencing very-late ST (interaction p

This study was conducted to estimate the indirect costs and health-related quality of life (HRQoL) (utilities) of multiple sclerosis (MS) patients in the United States (US), and to determine the impact of worsening mobility on these parameters. In collaboration with the North American Research Committee on Multiple Sclerosis (NARCOMS) registry we conducted a cross-sectional study of participants who completed the biannual update and supplemental spring 2010 survey. Demographic, employment status, income, mobility impairment, and health utility data were collected from a sample of registry participants who met the study criteria and agreed to participate in the supplemental Mobility Study. Mean annual indirect costs per participant in 2011US$ and mean utilities for the population and for cohorts reporting different levels of mobility impairment were estimated. Analyses included 3,484 to 3,611 participants, based on survey completeness. Thirty-seven percent of registrants were not working or attending school and 46.7% of these reported retiring early. Indirect costs per participant per year, not including informal caregiver cost, were estimated at $30,601±31,184. The largest relative increase in indirect costs occurred at earlier mobility impairment stages, regardless of the measure used. Participants' mean utility score (0.73±0.18) was lower than that of a similarly aged sample from the general US population (0.87). As with indirect costs, larger decrements in utility were seen at earlier mobility impairment stages. These results suggest that mobility impairment may contribute to increases in indirect costs and declines in HRQoL in MS patients.