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Objective Musculoskeletal pain conditions are a leading cause of pain and disability internationally and a common reason to seek health care. Accurate prediction of recurrence of health care seeking due to musculoskeletal conditions could allow for better tailoring of treatment. The aim of this project was to characterize patterns of recurrent physical therapy seeking for musculoskeletal pain conditions and to develop a preliminary prediction model to identify those at increased risk of recurrent care seeking. Design Retrospective cohort. Setting Ambulatory care. Subjects Patients (n = 578,461) seeking outpatient physical therapy (United States). Methods Potential predictor variables were extracted from the electronic medical record, and patients were placed into three different recurrent care categories. Logistic regression models were used to identify individual predictors of recurrent care seeking, and the least absolute shrinkage and selection operator (LASSO) was used to develop multivariate prediction models. Results The accuracy of models for different definitions of recurrent care ranged from 0.59 to 0.64 (c-statistic), and individual predictors were identified from multivariate models. Predictors of increased risk of recurrent care included receiving workers’ compensation and Medicare insurance, having comorbid arthritis, being postoperative at the time of the first episode, age range of 44–64 years, and reporting night sweats or night pain. Predictors of decreased risk of recurrent care included lumbar pain, chronic injury, neck pain, pregnancy, age range of 25–44 years, and smoking. Conclusion This analysis identified a preliminary predictive model for recurrence of care seeking of physical therapy, but model accuracy needs to improve to better guide clinical decision-making.

Redox balance and methylation are crucial to homeostasis and are linked by the methionine-homocysteine cycle. We examined whether differences in methylation potential, measured as plasma levels of S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), occur at baseline and during anti-oxidant therapy with the xanthine oxidase inhibitor allopurinol in patients with heart failure with reduced ejection fraction. We analyzed plasma samples collected at baseline and 24 weeks in the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) study, which randomized patients with heart failure with reduced ejection fraction to allopurinol or placebo. Associations between plasma levels of SAM, SAH, SAM/SAH ratio, and outcomes, including laboratory markers and clinical events, were assessed. Despite randomization, median SAM levels were significantly lower at baseline in the allopurinol group. SAH levels at 24 weeks, and change in SAM from baseline to week 24, were significantly higher in the group of patients randomized to allopurinol compared to the placebo group. A significant correlation was observed between change in SAH levels and change in plasma uric acid (baseline to 24-week changes) in the allopurinol group. There were no significant associations between levels of SAM, SAH, and SAM/SAH ratio and clinical outcomes. Our results demonstrate significant biological variability in SAM and SAH levels at baseline and during treatment with an anti-oxidant and suggest a potential mechanism for the lack of efficacy observed in trials of anti-oxidant therapy. These data also highlight the need to explore personalized therapy for heart failure.

Background In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin. Objectives The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes. Methods Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily). Results Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p Conclusions Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984)

Background The optimal anticoagulation strategy for patients with atrial fibrillation (AF) and bioprosthetic valve (BPV) replacement or native valve repair remains uncertain. Hypothesis We evaluated the safety and efficacy of apixaban vs warfarin in patients with AF and a history of BPV replacement or native valve repair. Methods Using data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (n = 18 201), a randomized trial comparing apixaban with warfarin in patients with AF, we analyzed the subgroup of patients (n = 251) with prior valve surgery. We contacted sites by telephone to obtain additional data about prior valve surgery. Full data were available for 156 patients. The primary efficacy endpoint was stroke/systemic embolism. The primary safety endpoint was major bleeding. Treatment groups were compared using a Cox regression model. Results In ARISTOTLE, 104 (0.6%) patients had a history of BPV replacement (n = 73 [aortic], n = 26 [mitral], n = 5 [mitral and aortic]) and 52 (0.3%) had a history of valve repair (n = 50 [mitral], n = 2 [aortic]). Among patients with BPVs, 55 were randomized to apixaban and 49 to warfarin. Among those with a history of native valve repair, 32 were randomized to apixaban and 20 to warfarin. Overall clinical event rates were low, with no significant differences between apixaban and warfarin for any outcomes. Conclusions In patients with AF and a history of BPV replacement or repair, the safety and efficacy of apixaban compared with warfarin was consistent with results from ARISTOTLE. These data suggest that apixaban may be reasonable for patients with BPVs or prior valve repair, though future larger randomized trials are needed. ClinicalTrials.gov NCT00412984.

Background: Among patients with atrial fibrillation (AF), women are less likely to receive catheter ablation and may have more complications and less durable results. Most information about sex-specific differences after ablation comes from observational data. We prespecified an examination of outcomes by sex in the 2204-patient CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). Methods: CABANA randomized patients with AF age ≥65 years or Results: CABANA randomized 819 (37%) women (ablation 413, drug 406) and 1385 men (ablation 695, drug 690). Compared with men, women were older (median age, 69 years versus 67 years for men), were more symptomatic (48% Canadian Cardiovascular Society AF Severity Class 3 or 4 versus 39% for men), had more symptomatic heart failure (42% with New York Heart Association Class ≥II versus 32% for men), and more often had a paroxysmal AF pattern at enrollment (50% versus 39% for men) ( P P =0.043), and complications from treatment were infrequent in both sexes. For the primary outcome, the hazard ratio for those who underwent ablation versus drug therapy was 1.01 (95% CI, 0.62–1.65) in women and 0.73 (95% CI, 0.51–1.05) in men (interaction P value=0.299). The risk of recurrent AF was significantly reduced in patients undergoing ablation compared with those receiving drug therapy regardless of sex, but the effect was greater in men (hazard ratio, 0.64 [95% CI, 0.51–0.82] for women versus hazard ratio, 0.48 [95% CI, 0.40–0.58] for men; interaction P value=0.060). Conclusions: Clinically relevant treatment-related strategy differences in the primary and secondary clinical outcomes of CABANA were not seen between men and women, and there were no sex differences in adverse events. The CABANA trial results support catheter ablation as an effective treatment strategy for both women and men. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00911508.

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy. Dr. Fudim is supported by an American Heart Association Grant, 17MCPRP33460225; he consults for Coridea, AxonTherapies, Galvani, and Daxor. Dr. Greene has received research support from a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis, Amgen, Bristol-Myers Squibb and Novartis; and serves on an advisory board for Amgen. Dr. Sharma has received research support from the Fonds de la recherche en sante du Quebec (FRSQ)-Junior 1, Jean Roy award in Cardiology (McGill University), Akcea, Pharma, Solutions, Alberta Innovates Health Solutions, Bayer-Canadian Cardiovascular Society, Boehringer-Ingelheim, Roche Diagnostics, and Takeda. Dr. Verbrugge was supported by a Fellowship of the Belgian American Educational Foundation. Dr. Martens has received consultancy fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Novartis, and Vifor Pharma and an unrestricted research grant from Vifor Pharma. Dr. Grodin receives research support from the Texas Health Resources Clinical Scholars fund and has received consultancy fees from Pfizer, Inc. Dr. Hernandez receives Grant/Research Support; Company Relationship; AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold Pharmaceuticals, Merck, Novartis. Honoraria; Company Relationship; Bayer, Boston Scientific, Novartis. Dr. Felker has received research funding from Otsuka, Novartis, Roche Diagnostics, Amgen, Merck, American Heart Association, and the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis, Roche Diagnostics, Amgen, Trevena, Cytokinetics, Madeliene, Myokardia, Bristol-Myers Squibb, Stealth Biotherapeutics, and GlaxoSmithKline. Dr. Mentz receives research support from the National Institutes of Health (U01HL125511-01A1, U10HL110312, and R01AG045551-01A1), Akros, Amgen, AstraZeneca, Bayer, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck, Novartis, Otsuka, and ResMed; honoraria from Abbott, AstraZeneca, Bayer, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, and ResMed; and has served on an advisory board for Amgen, Luitpold, Merck, and Boehringer Ingelheim. The remaining authors have no disclosures to report. Fudim, M (corresponding author), 2301 Erwin Rd, Durham, NC 27713 USA. marat.fudim@gmail.com

Introduction: The VICTORIA (Vericiguat Global Study in Subjects with HF with Reduced EF) trial included 5050 patients in 3 discrete subgroups reflecting their index worsening heart failure (HF) event: Methods: We compared primary composite (CV death and HFH) and secondary (all-cause death and HFH) outcomes across index event subgroups, both before and after adjusting for clinical covariates (HF duration, NYHA class, medical history, heart rate, HF medications and laboratory values including baseline NT-proBNP), as well as their response to vericiguat. Results: Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow up of 10.8 months, the absolute primary event rates were high in all subgroups (20.5 - 42.5 per 100 patient-years, Figure). Compared to the IV diuretic group highest relative risk was in HFH Conclusions: Among patients with worsening chronic HF, those within a 3 month window of HFH had almost a 1.5 times risk of CV death or HFH compared to those requiring IV diuretics but not HFH , irrespective of age or clinical risk factors. Vericiguat added to standard therapy was associated with similar benefit across the spectrum of risk in worsening HF.

Cardiovascular (CV) outcome studies of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shifted the paradigm of type 2 diabetes management given their benefits regarding a reduction in major adverse CV events. However, the relationship between GLP-1 RAs and coronary revascularization remains poorly understood. In this EXSCEL post-hoc analysis, we used univariate Cox proportional models and Kaplan Meier survival analysis to evaluate the effect of once-weekly exenatide (EQW) on a composite outcome of hospitalization for acute coronary syndrome (ACS) or coronary revascularization. Similar models were utilized to evaluate the relationship between significant participant characteristics within the entire study population and the composite outcome. Of the 14,736 participants in EXSCEL with complete follow-up data, 1642 (11.1%) experienced an ACS or coronary revascularization event during a median follow-up of 3.3 years (interquartile range, 2.3-4.4). EQW had no effect on hospitalization for ACS or coronary revascularization (HR 1.00, 95% CI 0.91-1.10). Among EXSCEL participants, enrollment in Latin America (HR 0.51, 95% CI 0.43-0.60) and a history of peripheral artery disease (HR 0.79, 95% CI 0.70-0.90) were associated with a reduced risk for coronary revascularization, whereas enrollment in North America (HR 1.92, 95% CI 1.74-2.12), a history of CV disease (HR 3.24, 95% CI 2.78-3.78), and a previous myocardial infarction (HR 1.54, 95% CI 1.39-1.71) were associated with increased risk for study end points. EQW had no association with hospitalization for ACS or coronary revascularization. Participant enrollment location and CV disease burden may play a role in the variable CV efficacy of GLP-1 RAs that has been observed in trials thus far.

We appreciate Dr. Landau’s interest in the effects of apixaban dose adjustment in patients with the combination of low body weight and advanced age in the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) trial ([1][1]). Apixaban dose should be

Background In ARISTOTLE, patients with atrial fibrillation and ≥2 dose-reduction criteria [age ≥80 years, weight ≤60 kg, and creatinine ≥1.5 mg/dL (133 μmol/L)] were randomized to apixaban 2.5 mg twice daily (b.i.d) or warfarin. Purpose To determine whether the apixaban dose adjustment in ARISTOTLE resulted in similar efficacy and safety compared to warfarin. Methods The effects of apixaban 2.5 mg b.i.d versus warfarin on stroke or systemic embolism, major bleeding and death in ARISTOTLE patients with ≥2 dose-reduction criteria were compared with the effects of apixaban 5 mg b.i.d in patients with 0 or 1 dose-reduction criterion. Results Of 751 (4.1%) patients with ≥2 dose-reduction criteria, 386 were assigned to apixaban 2.5 mg b.i.d and 365 to warfarin. Compared to patients with 0 or 1 dose reduction criteria (n=17,322), these patients had a higher risks of stroke/systemic embolism (HR =1.78; 95% CI [1.24–2.57]), major bleeding (HR =1.73; 95% CI [1.28–2.32]) and death (HR=3.21; 95% CI [2.69–3.83]), irrespective of whether they were assigned to apixaban or warfarin. The benefits of apixaban 2.5 mg b.i.d compared with warfarin on stroke or systemic embolism, major bleeding, and death in patients with ≥2 dose-reduction criteria were consistent with that of apixaban 5 mg b.i.d in patients with either 0 or 1 dose-reduction criteria (Figure). Conclusions While they are at higher overall risk, patients with appropriate dose reduction criteria have consistent benefits with apixaban 2.5 mg b.i.d. over warfarin. Additional analyses investigating the relationship between apixaban dose and both apixaban plasma concentrations and levels of thrombosis biomarkers are underway. Acknowledgement/Funding Bristol-Myers Squibb and Pfizer, Inc.

Importance: The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.Objective: To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial.Design, Setting, and Participants: Analysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (Intervention: Vericiguat titrated to 10 mg daily vs placebo.Main Outcomes and Measures: The primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH.Results: Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.Conclusions and Relevance: Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.Trial Registration: ClinicalTrials.gov Identifier: NCT02861534.

Objectives Chronic pain affects 50 million Americans and is often treated with non-pharmacologic approaches like physical therapy. Developing a no-show prediction model for individuals seeking physical therapy care for musculoskeletal conditions has several benefits including enhancement of workforce efficiency without growing the existing provider pool, delivering guideline adherent care, and identifying those that may benefit from telehealth. The objective of this paper was to quantify the national prevalence of no-shows for patients seeking physical therapy care and to identify individual and organizational factors predicting whether a patient will be a no-show when seeking physical therapy care. Design Retrospective cohort study. Setting Commercial provider of physical therapy within the United States with 828 clinics across 26 states. Participants Adolescent and adult patients (age cutoffs: 14–117 years) seeking non-pharmacological treatment for musculoskeletal conditions from January 1, 2016, to December 31, 2017 (n = 542,685). Exclusion criteria were a primary complaint not considered an MSK condition or improbable values for height, weight, or body mass index values. The study included 444,995 individuals. Primary and secondary outcome measures Prevalence of no-shows for musculoskeletal conditions and predictors of patient no-show. Results In our population, 73% missed at least 1 appointment for a given physical therapy care episode. Our model had moderate discrimination for no-shows (c-statistic:0.72, all appointments; 0.73, first 7 appointments) and was well calibrated, with predicted and observed no-shows in good agreement. Variables predicting higher no-show rates included insurance type; smoking-status; higher BMI; and more prior cancellations, time between visit and scheduling date, and between current and previous visit. Conclusions The high prevalence of no-shows when seeking care for musculoskeletal conditions from physical therapists highlights an inefficiency that, unaddressed, could limit delivery of guideline-adherent care that advocates for earlier use of non-pharmacological treatments for musculoskeletal conditions and result in missed opportunities for using telehealth to deliver physical therapy.

Copeptin is a known predictor of mortality and re-hospitalization in patients with heart failure. We sought to investigate the relationship between copeptin levels, diuretic responsiveness, and various heart failure phenotypes in the setting of acute heart failure (AHF). Using patients enrolled in

Introduction The study involved preparing and implementation a model of complex screening programme for adolescents and comparison of anthropometric examinations between the population of the SOPKARD-Junior programme and representative sample of Polish children in the same age. Material and methods The screening programme in 14-15 year old pupils (n = 282) included: anthropometric, blood pressure, echocardiographic, electrocardiographic, carotid arteries, kidney and thyroid ultrasound examinations, as well as respiratory, dental and masticatory system, orthopaedic, psychological and psychiatric assessment. Blood and urine tests were also performed. The results of anthropometric examinations from the SOPKARD-Junior and OLAF programmes were used for comparative analysis. Results Statistically significant (p < 0.001) differences between young people from Sopot and their peers in the general Polish population were found in height (+3.61 cm for boys), body mass (+5.19 kg for boys and +3.99 kg for girls), body mass index (+0.99 kg/m2 for boys and +1.33 kg/m2 for girls), waist circumference (+4.52 cm for boys and +4.52 cm for girls) and hip circumference (+2.51 cm for boys). The highest attendance rate was achieved for examinations performed in school (e.g. anthropometric and blood pressure measurements - n = 268; 95%) and the lowest for the echocardiograpy performed in local hospital (n = 133; 47%). The mean score of the programme quality (scale 1-6) assessed by children was 4.63. Conclusions The SOPKARD-Junior programme represents an attempt to develop a model of screening assessments for teenagers in Poland. Preliminary results of the SOPKARD-Junior programme indicate small differences in the biological development of Sopot youth in comparison with their peers from Polish population of the OLAF programme. The high attendance rate on research conducted at the school indicate that proposed health examinations in adolescents are acceptable and feasible.

Selected biologically active non-nutrient components (BANS) were determined in broad bean seeds of fine-size and large-size seed varieties and in pea seeds for comparison. Among the analysed biologically active substances the broad bean seeds of fine-size and large-size seed varieties were differentiated mainly by phenolic compounds (including flavanols and proantocyanidines) which appear in twice as large quantities in large-size seed varieties. It was shown that in comparison to pea, broad bean seeds are characterised by a higher content of phenolic compounds, phytates as well as a higher activity of inhibitors of trypsin and amylases. Moreover, it was found that phenolic compounds accumulate mainly in the dark-colored seed coats of large-size broad bean and this fact is related to higher activity inhibiting α-amylases of methanol extracts from this fraction of seeds.