Bleeding risk from anticoagulant thromboprophylaxis in patients with multiple myeloma: a MarketScan analysis.

Background: Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is frequently recommended but underutilized partly due to the absence of studies assessing bleeding risk. Objectives: To determine the rate of severe (hospitalized) bleeding from thromboprophylaxis in patients treated for MM and identify clinical risk factors for bleeding in this population. Methods: Using the MarketScan database, we analyzed 6656 patients treated for MM between 2013 and 2021. Concomitant thromboprophylaxis was defined using prescription claims. Hospitalized bleeding was identified through the Cunningham algorithm. Bleeding rates were compared by thromboprophylaxis status, and Cox regression identified risk factors for bleeding. Results: Anticoagulant thromboprophylaxis was used in 6.6% (436) patients treated for MM. Patients on thromboprophylaxis had a higher rate of immunomodulatory-based therapy (63.8% vs 46.7%; P < .01) and lower rate of antiplatelet use (2.1% vs 4.7%; P < .01). Bleeding occurred in 1.4% of them during median follow-up of 1.3 years. Rate of severe bleeding was not different between those on prophylaxis (7.8 per 1000 person-years) and those not on prophylaxis (10.1 per 1000 person-years). No association was identified between thromboprophylaxis and bleeding. Factors associated with increased bleeding included age (hazard ratio [HR], 1.38 per 10 years increase in age), comorbidity index (HR, 1.18 per SD increase), history of bleeding (HR, 1.54), hypertension (HR, 1.87), and renal disease (HR, 1.56). Conclusion: Risk of serious bleeding from thromboprophylaxis in patients treated for MM was low, and concomitant anticoagulant therapy did not result in increased bleeding risk. Clinical risk factors for bleeding included age, comorbidity index, bleeding history, hypertension, and renal disease.

Percutaneous left atrial appendage occlusion and risk of stroke, hospitalized bleeding and death in Medicare beneficiaries.

PURPOSE: Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA2DS2-VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death. METHODS: Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA2DS2-VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used. RESULTS: Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years. CONCLUSION: In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications.

Comparative efficacy of ofatumumab versus oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons.

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.

SGLT2 Inhibitors Are Associated With Reduced Cardiovascular Disease in Patients With Type 2 Diabetes: An Analysis of Real-World Data.

OBJECTIVE: To assess the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and other second-line diabetes therapies with risk of cardiovascular disease (CVD), as well as conduct head-to-head comparisons between SGLT2 inhibitors. PATIENTS AND METHODS: Using data from the MarketScan databases (January 1, 2013, through December 31, 2019), SGLT2 inhibitor users were matched with up to five other second-line therapy users by age, sex, date of enrollment, and date of second-line therapy initiation. The primary composite outcome included stroke, atrial fibrillation, myocardial infarction, and heart failure. Hazard ratios were estimated, adjusting for demographics and a propensity score reflecting comorbidities and medications. RESULTS: In this study population of 313,396 patients (mean age 53±10 years; 47% female), 9787 incident CVD events occurred over a median follow-up of 1.36 years. After multivariable adjustments, SGLT2 inhibitor users had a lower risk of CVD than other second-line therapy users (HR, 0.66; 95% CI, 0.62 to 0.71). Significant associations were also observed when each CVD outcome was assessed separately. No differences were noted when comparing individual SGLT2 inhibitors. CONCLUSION: SGLT2 inhibitors were associated with a clinically meaningfully lower CVD risk in the real-world setting. In head-to-head comparisons, the different SGLT2 inhibitors were consistent in their protective associations with CVD. This suggests that as a class, SGLT2 inhibitors may have widespread benefit in preventing CVD among patients with type 2 diabetes.

Venous thromboembolism mortality and trends in older US adults, 2011-2019.

Venous thromboembolism (VTE) affects 1.2 million people per year in the United States. With several clinical changes in diagnosis and treatment approaches in the past decade, we evaluated contemporary post-VTE mortality risk profiles and trends. Incident VTE cases were identified from the 2011-2019 Medicare 20% Sample, which is representative of nearly all Americans aged 65 and older. The social deprivation index was linked from public data; race/ethnicity and sex were self-reported. The all-cause mortality risk 30 days and 1 year after incident VTE was calculated in demographic subgroups and by prevalent cancer diagnosis status using model-based standardization. Risks for major cancer types, risk differences by age, sex, race/ethnicity, and socio-economic status (SES), and trends over time are also reported. The all-cause mortality risk among older US adults following incident VTE was 3.1% (95% CI 3.0-3.2) at 30 days and 19.6% (95% CI 19.2-20.1) at 1 year. For cancer-related VTE events, the age-sex-race-standardized risk was 6.0% at 30 days and 34.7% at 1 year. The standardized 30-day and 1-year risks were higher among non-White beneficiaries and among those with low SES. One-year mortality risk decreased 0.28 percentage points per year (95% CI 0.16-0.40) on average across the study period, with no trend observed for 30-day mortality risk. In sum, all-cause mortality risk following incident VTE has decreased slightly in the last decade, but racial and socio-economic disparities persist. Understanding patterns of mortality among demographic subgroups and in cancer-associated events is important for targeting efforts to improve VTE management.

Autoimmune disease and risk of postpartum venous thromboembolism.

Background: The risk of pregnancy-related mortality in the United States has nearly doubled since 1990, with venous thromboembolism (VTE) accounting for approximately 10% of these deaths. Objectives: The objective of this study was to assess whether preexisting autoimmune disease is a risk factor for postpartum VTE. Methods: Using the MarketScan Commercial and Medicare Supplemental administrative databases, a retrospective cohort study analyzed whether postpartum persons with autoimmune disease had a higher risk of postpartum VTE incidence than postpartum persons without autoimmune disease. Using International Classification of Diseases codes, we identified 757,303 individuals of childbearing age who had a valid delivery date with at least 12 weeks of follow-up. Results: Individuals were, on average, 30.7 years old (SD, 5.4), and 3.7% (N = 27,997 of 757,303) of them had evidence of preexisting autoimmune disease. In covariate-adjusted models, postpartum persons with preexisting autoimmune disease had higher rates of postpartum VTE than postpartum persons without autoimmune disease (hazard ratio [HR], 1.33; 95% CI, 1.07-1.64). When analyzed by individual autoimmune disease, those with systemic lupus erythematosus (HR, 2.49; 95% CI, 1.47-4.21) and Crohn's disease (HR, 2.49; 95% CI, 1.34-4.64) were at an elevated risk of postpartum VTE compared with those without autoimmune disease. Conclusion: Autoimmune disease was associated with a higher rate of postpartum VTE, with evidence that the association was most pronounced among individuals with systemic lupus erythematosus and Crohn's disease. These findings suggest that postpartum persons of childbearing age with autoimmune disease may require more monitoring and prophylactic care after delivery to prevent potentially fatal VTE events.

Effect of Chronic Digoxin Use on Mortality and Heart Failure Hospitalization in Pulmonary Arterial Hypertension.

Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic digoxin use in PAH are unclear. Methods and Results Data from the Minnesota Pulmonary Hypertension Repository were used. The primary analysis used likelihood of digoxin prescription. The primary end point was a composite of all-cause mortality or heart failure (HF) hospitalization. Secondary end points included all-cause mortality, HF hospitalization, and transplant-free survival. Multivariable Cox proportional hazards analyses determined the hazard ratios (HR) and 95% CIs for the primary and secondary end points. Among 205 patients with PAH in the repository, 32.7% (n=67) were on digoxin. Digoxin was more often prescribed to patients with severe PAH and right ventricular failure. After propensity score-matching, 49 patients were digoxin users, and 70 patients were nonusers; of these 31 (63.3%) in the digoxin group and 41 (58.6%) in nondigoxin group met the primary end point during a median follow-up time of 2.1 (0.6-5.0) years. Digoxin users had a higher combined all-cause mortality or HF hospitalization (HR, 1.82 [95% CI, 1.11-2.99]), all-cause mortality (HR, 1.92 [95% CI, 1.06-3.49]), HF hospitalization (HR, 1.89 [95% CI, 1.07-3.35]), and worse transplant-free survival (HR, 2.00 [95% CI, 1.12-3.58]) even after adjusting for patient characteristics and severity of PAH and right ventricular failure. Conclusions In this retrospective, nonrandomized cohort, digoxin treatment was associated with greater all-cause mortality and HF hospitalization, even after multivariate correction. Future randomized controlled trials should assess the safety and efficacy of chronic digoxin use in PAH.

Incidence and Risk Factors of Pulmonary Hypertension After Venous Thromboembolism: An Analysis of a Large Health Care Database.

Background Pulmonary hypertension (PH) is a devastating potential complication of pulmonary embolism, a manifestation of venous thromboembolism (VTE). The incidence of and risk factors for PH in those with prior VTE are poorly characterized. Methods and Results International Classification of Diseases (ICD) codes from inpatient and outpatient medical claims from MarketScan administrative databases for years 2011 to 2018 were used to identify cases of VTE, comorbidities before the VTE event, and PH occurring subsequent to the VTE event. Cumulative incidence and hazard ratios (HR), and their 95% CI, were calculated. The 170 021 VTE cases included in the analysis were on average (±SD) 57.5±15.8 years old and 50.5% were female. A total of 5943 PH cases accrued over an average follow-up of 1.94 years. Two years after incident VTE, the cumulative incidence (95% CI) of PH was 3.5% (3.4%-3.7%) overall. It was higher among older individuals, among women (3.9% [3.8%-4.1%]) than men (3.2% [3.0%-3.3%]), and among patients presenting with pulmonary embolism (6.2% [6.0%-6.5%]) than those presenting with deep vein thrombosis only (1.1% [1.0%-1.2%]). Adjusting for age and sex, risk of PH was higher among patients with VTE with underlying comorbidities. Using the Charlson comorbidity index, there was a dose-response relationship, whereby greater scores were associated with increased PH risk (score ≥5 versus 0: HR, (2.50 [2.30-2.71])). When evaluating individual comorbidities, the strongest associations were observed with concomitant heart failure (HR, 2.17 [2.04-2.31]), chronic pulmonary disease (2.01 [1.90-2.14]), and alcohol abuse (1.66 [1.29-2.13]). Conclusions In this large, real-world population of insured people with VTE, 3.5% developed PH in the 2 years following their initial VTE event. Risk was higher among women, with increasing age, and in those with additional comorbidities at the time of the VTE event. These data provide insights into the burden of PH and risk factors for PH among patients with VTE.

Root-Specific Expression of Vitis vinifera VviNPF2.2 Modulates Shoot Anion Concentration in Transgenic Arabidopsis.

Grapevines (Vitis vinifera L., Vvi) on their roots are generally sensitive to salt-forming ions, particularly chloride (Cl-) when grown in saline environments. Grafting V. vinifera scions to Cl--excluding hybrid rootstocks reduces the impact of salinity. Molecular components underlying Cl--exclusion in Vitis species remain largely unknown, however, various anion channels and transporters represent good candidates for controlling this trait. Here, two nitrate/peptide transporter family (NPF) members VviNPF2.1 and VviNPF2.2 were isolated. Both highly homologous proteins localized to the plasma membrane of Arabidopsis (Arabidopsis thaliana) protoplasts. Both were expressed primarily in grapevine roots and leaves and were more abundant in a Cl--excluding rootstock compared to a Cl--includer. Quantitative PCR of grapevine roots revealed that VviNPF2.1 and 2.2 expression was downregulated by high [NO3 -] resupply post-starvation, but not affected by 25 mM Cl-. VviNPF2.2 was functionally characterized using an Arabidopsis enhancer trap line as a heterologous host which enabled cell-type-specific expression. Constitutive expression of VviNPF2.2 exclusively in the root epidermis and cortex reduced shoot [Cl-] after a 75 mM NaCl treatment. Higher expression levels of VviNPF2.2 correlated with reduced Arabidopsis xylem sap [NO3 -] when not salt stressed. We propose that when expressed in the root epidermis and cortex, VviNPF2.2 could function in passive anion efflux from root cells, which reduces the symplasmic Cl- available for root-to-shoot translocation. VviNPF2.2, through its role in the root epidermis and cortex, could, therefore, be beneficial to plants under salt stress by reducing net shoot Cl- accumulation.

Direct Oral Anticoagulants and Warfarin for Atrial Fibrillation Treatment: Rural and Urban Trends in Medicare Beneficiaries.

BACKGROUND: Data are needed on the use of oral anticoagulation in patients with atrial fibrillation (AF) in rural versus urban areas, including the initiation of direct oral anticoagulants (DOACs). OBJECTIVE: We used Medicare data to examine rural/urban differences in anticoagulation use in patients with AF. METHODS: We identified incident AF in a 20% sample of fee-for-service Medicare beneficiaries (aged ≥ 65 years) from 2011 to 2016 and collected ZIP code and covariates at the time of AF. We identified the first anticoagulant prescription filled, if any, following AF diagnosis. We categorized beneficiaries into four rural/urban areas using rural-urban commuting area codes and used Poisson regression models to compare anticoagulant use. RESULTS: We included 447,252 patients with AF (mean age 79 ± 8 years), of which 82% were urban, 9% large rural, 5% small rural, and 4% isolated. The percentage who initiated an anticoagulant rose from 34% in 2011 to 53% in 2016, paralleling the uptake of DOACs. In a multivariable-adjusted analysis, those in rural areas (vs. urban) were more likely to initiate an anticoagulant. However, rural beneficiaries (vs. urban) were less likely to initiate a DOAC; those in isolated areas were 17% less likely (95% confidence interval [CI] 13-20), those in small rural areas were 12% less likely (95% CI 9-15), and those in large rural areas were 10% less likely (95% CI 8-12). CONCLUSION: Among Medicare beneficiaries with AF, anticoagulation use was low but increased over time with the introduction of DOACs. Rural beneficiaries were less likely to receive a DOAC.

Inpatient Versus Outpatient Acute Venous Thromboembolism Management: Trends and Postacute Healthcare Utilization From 2011 to 2018.

Background Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases (ICD) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]). Conclusions Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.

Claims-Based Score for the Prediction of Bleeding in a Contemporary Cohort of Patients Receiving Oral Anticoagulation for Venous Thromboembolism.

Background Current scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data. Methods and Results We selected patients with incident VTE initiating oral anticoagulation in the 2011 to 2017 MarketScan databases. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use before oral anticoagulation initiation as potential predictors of bleeding using stepwise selection of variables in Cox models run on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165 434 patients with VTE and initiating oral anticoagulation, of whom 2294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% CI, 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95% CI, 0.67-0.69). For comparison, the c-statistic of the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly (>65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score in this population was 0.62 (95% CI, 0.61-0.63). Conclusions We have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.

Venous thrombosis recurrence risk according to warfarin versus direct oral anticoagulants for the secondary prevention of venous thrombosis.

BACKGROUND: Venous thromboembolism (VTE) affects nearly 1 million Americans annually, and many benefit from continued anticoagulation after the initial 3- to 6-month treatment period (secondary prevention). OBJECTIVES: To determine whether warfarin, apixaban, or rivaroxaban is associated with reduced recurrent VTE hospitalization in the secondary prevention of VTE. PATIENTS/METHODS: We performed a retrospective cohort study of participants enrolled in the MarketScan Insurance Database between 2013 and 2017 in those with an incident VTE. In those individuals who continued oral anticoagulation (warfarin, apixaban, or rivaroxaban) beyond 6 months, we determined the relative rate of recurrent VTE hospitalization. RESULTS: Among 119 964 individuals with VTE, 25 419 remained on anticoagulation after 6 months and were matched successfully by age, sex, and date. After adjusting for a propensity score, apixaban versus rivaroxaban (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45-0.94) and apixaban versus warfarin (HR, 0.68; 95% CI, 0.47-1.00) had a reduced risk of recurrent VTE hospitalization, and rivaroxaban versus warfarin (HR, 1.12; 95% CI, 0.94-1.33) had equivalent rates. For the rivaroxaban versus warfarin comparison there was a significant interaction by renal function (P < .01) where rivaroxaban was associated with a lower risk of recurrent VTE hospitalization (HR, 0.65; 95% CI, 0.41-1.03) in those with kidney disease and increased risk in those without kidney disease (HR, 1.24; 95% CI, 1.02-1.50). CONCLUSIONS: These data suggest that apixaban has a lower recurrent VTE hospitalization rate than rivaroxaban during the secondary prevention of VTE, and further study of diverse patient populations, especially by kidney function, is warranted.

Impact of oral anticoagulant choice for the secondary prevention of venous thromboembolism on the risk of inpatient bleeding.

BACKGROUND: Randomized trials suggest that direct oral anticoagulants (DOACs) are at least as effective as warfarin for primary treatment of VTE and that bleeding risk may be lower for some DOACs relative to warfarin. However, there is very little information regarding potential bleeding risks for DOACs versus warfarin in secondary prevention of VTE. OBJECTIVE: The aim of this study was to compare rates of bleeding events resulting in inpatient admissions between individuals taking apixaban, rivaroxaban, and warfarin for secondary prevention of VTE during the period 2013-2017. METHODS: We used the IBM MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database (IBM Watson Health, Ann Arbor, MI) to establish a retrospective cohort. Initial venous thrombolism events were defined from medical claims, and follow-up for this cohort began 6 months after the initial event. Bleeding events resulting in inpatient admission were identified from claims data over the subsequent year of secondary prevention. RESULTS: A total of 69 264 individuals were identified for the cohort, with 567 bleeding events. The crude rate of bleeding was highest among warfarin users (1.47/100 person-years; 95% confidence interval [CI], 1.24-1.74) and lower among those on either apixaban (1.00/100 person-years; 95% CI, 0.65-1.54) or rivaroxaban (0.84/100 person-years; 95% CI, 0.66-1.08). In multivariable adjusted Cox models, those on apixaban (hazard ratio [HR], 0.80; 95% CI, 0.50-1.29) and rivaroxaban (HR, 0.81; 95% CI, 0.59-1.09) had somewhat lower rates of bleeding events relative to those on warfarin. CONCLUSIONS: We found modest evidence of decreased risk of bleeding for apixaban and rivaroxaban. These estimates were relatively imprecise.

A multicenter prospective audit to investigate the current management of patients undergoing anti-reflux surgery in the UK: Audit & Review of Anti-Reflux Operations & Workup.

BACKGROUND: There are a variety of surgical and endoscopic interventions available to treat gastroesophageal reflux disease. There is, however, no consensus on which approach is best.The aim of this national audit is to describe the current variation in the UK clinical practice in relation to anti-reflux surgery (ARS) and to report adherence to available clinical guidelines. METHODS: This national audit will be conducted at centers across the UK using the secure online web platform ALEA. The study will comprise two parts: a registration questionnaire and a prospective multicenter audit of ARS. All participating centers will be required to complete the registration questionnaire comprising details regarding pre-, peri-, and post-operative care pathways and whether or not these are standardized within each center. Following this, a 12-month multicenter prospective audit will be undertaken to capture data including patient demographics, predominant symptoms, preoperative investigations, surgery indication, intraoperative details, and postoperative outcomes within the first 90 days.Local teams will retain access to their own data to facilitate local quality improvement. The full dataset will be reported at national and international scientific congresses and will contribute to peer-reviewed publications and national quality improvement initiatives. CONCLUSIONS: This study will identify and explore variation in the processes and outcomes following ARS within the UK using a collaborative cohort methodology. The results generated by this audit will facilitate local and national quality improvement initiatives and generate new possibilities for future research in anti-reflux interventions.

Perioperative management of patients with Mucolipidosis II and III: Lessons from a case series.

Mucolipidosis (ML) II and III are complex lysosomal storage disorders characterized by progressive multisystem pathology which can pose challenges to the anesthetist and increase the risks associated with general anesthesia. We sought to review the management of patients with ML II and III undergoing anesthesia in our institution in order to better define recommendations for the preoperative assessment and optimization of these children. We further elected to analyze the conduct of anesthesia, intraoperative management, and perioperative complications that our patients had experienced in order to allow improved informed consent and anesthetic planning. We performed a retrospective examination of the medical notes of those patients who had undergone anesthesia in our institution to identify their clinical features, anesthetic technique, airway management, and perioperative complications. Five children underwent 11 episodes of anesthesia. Fiber-optic or videolaryngoscopy was utilized in six out of seven intubations, with four out of seven requiring a change from the method initially chosen to enable intubation. Four of the five patients had an abnormal echocardiogram. Three patients had radiological evaluation of their cervical spine, with two demonstrating abnormalities. One patient had changes suggesting instability at the atlantoaxial junction. Children and babies with ML II and III present multisystem challenges to the anesthetist. Multidisciplinary planning and assessment, followed by a discussion of risk, should proceed any elective surgery. These complex children should undergo elective anesthesia delivered by an experienced (pediatric) anesthetist in an appropriate tertiary center with on-site pediatric ENT and critical care support.

Comparison of first-line and second-line use of fingolimod in relapsing MS: The open-label EARLIMS study.

BACKGROUND: Treatment of MS often begins with low-efficacy injectable disease-modifying therapy (iDMT). OBJECTIVES: To compare the effect of fingolimod 0.5 mg/day on clinical, MRI, patient-reported, and safety outcomes, in treatment-naïve and previously treated (≥1 iDMT) patients with early MS. METHODS: EARLIMS was a multicentre, open-label, non-randomized, parallel-group phase 3 b/4 study in Australia and Spain. Patients with relapsing-remitting MS, Expanded Disability Status Scale (EDSS) score <4.0, and ≥1-5 years since diagnosis, received daily fingolimod for 48 weeks. The primary endpoint was annualized relapse rate (ARR). RESULTS: Of 347 patients enrolled at 51 sites (treatment-naïve, 200 [57.6%]; previously treated, 147 [42.4%]), 320 completed the study (treatment-naïve, 184 [92.0%]; previously treated, 136 [92.5%]), but the study remained underpowered (planned enrolment, n = 432). Fingolimod reduced ARR to similar levels in both treatment-naïve (mean ARR [95% confidence interval], 0.21 [0.14, 0.29]) and previously treated groups (0.30 [0.20, 0.41]; p = 0.1668). There were no new safety signals. CONCLUSIONS: Fingolimod appeared equally effective as first- or second-line therapy in relapsing MS. There was a trend for better outcomes with fingolimod in treatment-naïve patients than in those previously treated with >1 iDMT.

Impact of oral anticoagulation choice on healthcare utilization for the primary treatment of venous thromboembolism.

Little is known about the impact of oral anticoagulation (OAC) choice on healthcare encounters during venous thromboembolism (VTE) primary treatment. Among anticoagulant-naïve patients with VTE, we tested the hypotheses that healthcare utilization would be lower among users of direct OACs (DOACs; rivaroxaban or apixaban) than among users of warfarin. MarketScan databases for years 2016 and 2017 were used; healthcare utilization was identified in the first 6 months after initial VTE diagnoses. The 23,864 patients with VTE had on average 0.2 ± 0.5 hospitalizations, spent 1.3 ± 5.2 days in the hospital, had 5.7 ± 5.1 outpatient encounters, and visited an emergency department 0.4 ± 1.1 times. As compared to warfarin, rivaroxaban and apixaban were associated with fewer hospitalizations, days hospitalized, outpatient office visits, and emergency department visits after accounting for age, sex, comorbidities, and medications. Hospitalization rates were 24% lower (incidence rate ratio (IRR): 0.76; 95% CI: 0.69, 0.83) with rivaroxaban and 22% lower (IRR: 0.78; 95% CI: 0.71, 0.87) with apixaban, as compared to warfarin (IRR: 1.00 (reference)). Healthcare utilization was similar between apixaban and rivaroxaban users. Patients with VTE prescribed rivaroxaban and apixaban had lower healthcare utilization than those prescribed warfarin, while there was no difference when comparing apixaban to rivaroxaban. These findings complement existing literature supporting the use of DOACs over warfarin.

The grapevine NaE sodium exclusion locus encodes sodium transporters with diverse transport properties and localisation.

Grapevine (Vitis vinifera L.) is a valuable crop for human consumption and wine production, and is prone to suffering from salinity stress in arid regions or when exposed to low quality irrigation water. A previous study identified a quantitative trait locus (QTL) NaE, containing six High-affinity Potassium Transporter 1 genes, that was associated with shoot Na+ exclusion in grapevine. While HKT1;1 was predicted to be the most likely gene within this QTL to encode for this important salinity tolerance sub-trait, four other HKTs within the QTL remained uncharacterised; VviHKT1;2 encodes a truncated transcript unlikely to form a functional transporter. In this study, two allelic variants for each of VviHKT1;6, VviHKT1;7 and VviHKT1;8 from the heterozygous grapevine variety Cabernet Sauvignon were functionally characterised. Using the Xenopus laevis oocyte heterologous expression system, as well as transient expression in tobacco leaves, we found that the VviHKT1;6 and VviHKT1;7 alleles encoded plasma membrane localised proteins that facilitated significant non-rectifying Na+ transport. Conversely, proteins encoded by the VviHKT1;8 alleles were inwardly-rectifying, weak Na+ transporters that localised to intracellular organelles. Mining of previous RNA-seq gene expression data suggested that VviHKT1;6-8 are weakly expressed in grapevine roots, flower buds, and seeds under normal conditions and different nutrient regimes. We propose that VviHKT1;6 and VviHKT1;7 are likely to have a less significant role in grapevine leaf Na+ exclusion than VviHKT1;1, and that VviHKT1;8 is involved in endomembrane Na+ transport.

Vital sign monitoring during out-of-hospital pediatric advanced airway management.

OBJECTIVE: To evaluate physiologic monitoring in pediatric patients undergoing out-of-hospital advanced airway management. METHODS: Retrospective case series of pediatric patients (<18 years) with advanced airways placed in the out-of-hospital setting. Patients given cardiopulmonary resuscitation (CPR) or defibrillation before the first advanced airway attempt were excluded. Reviewers abstracted physiologic data from the patient monitor files and patient care reports. The primary outcome was the proportion of time pulse oximetry was in place during airway management. Other outcomes included the proportion of time ECG monitoring and waveform end-tidal capnography were in place as well as the incidence of oxygen desaturation events. RESULTS: We evaluated 23 pediatric patients with a mean age of 10.7 years (SD 6.5). Eleven of 18 (61%) children with medication-facilitated intubation had pulse oximetry in place when the first medication was documented as given. Eight of 18 (44%) had ECG monitoring, 12 of 18 (66%) had waveform capnography, and 5 of 18 (28%) had a blood pressure check within the 3 minutes before receiving the first medication. In the 3-minute preoxygenation phase, pulse oximetry was in place for an average of 1.4 minutes (47%, SD 0.37) and a visible photoplethysmogram (PPG) waveform obtained from the pulse oximeter was present for 0.6 minutes (20%, SD 0.34). During airway device placement, pulse oximetry was in place 73% (SD 0.39) of the time and 30% (SD 0.41) of the time there was a visible PPG waveform. CONCLUSIONS: Pediatric patients had critical deficits in physiologic monitoring during advanced airway management.