Clinical Composite Score Research Articles

Leadless left ventricular endocardial pacing for CRT upgrades in previously failed and high-risk patients in comparison with coronary sinus CRT upgrades.

AimsCardiac resynchronization therapy (CRT) upgrades may be less likely to improve following intervention. Leadless left ventricular (LV) endocardial pacing has been used for patients with previously failed CRT or high-risk upgrades. We compared procedural and long-term outcomes in patients undergoing coronary sinus (CS) CRT upgrades with high-risk and previously failed CRT upgrades undergoing LV endocardial upgrades.Method and resultsProspective consecutive CS upgrades between 2015 and 2019 were compared with those undergoing WiSE-CRT implantation. Cardiac resynchronization therapy response at 6 months was defined as improvement in clinical composite score (CCS) and a reduction in LV end-systolic volume (LVESV) ≥15%. A total of 225 patients were analysed; 121 CS and 104 endocardial upgrades. Patients receiving WiSE-CRT tended to have more comorbidities and were more likely to have previous cardiac surgery (30.9% vs. 16.5%; P = 0.012), hypertension (59.2% vs. 34.7%; P < 0.001), chronic obstructive airways disease (19.4% vs. 9.9%; P = 0.046), and chronic kidney disease (46.4% vs. 21.5%; P < 0.01) but similar LV ejection fraction (30.0 ± 8.3% vs. 29.5 ± 8.6%; P = 0.678). WiSE-CRT upgrades were successful in 97.1% with procedure-related mortality in 1.9%. Coronary sinus upgrades were successful in 97.5% of cases with a 2.5% rate of CS dissection and 5.6% lead malfunction/displacement. At 6 months, 91 WiSE-CRT upgrades and 107 CS upgrades had similar improvements in CCS (76.3% vs. 68.5%; P = 0.210) and reduction in LVESV ≥15% (54.2% vs. 56.3%; P = 0.835). ConclusionDespite prior failed upgrades and high-risk patients with more comorbidities, WiSE-CRT upgrades had high rates of procedural success and similar improvements in CCS and LV remodelling with CS upgrades.

Role of ultrasound for assessment of psoriatic arthritis patients with fibromyalgia

ObjectiveTo investigate whether ultrasonography (US), as an objective imaging modality, can optimise the evaluation of disease activity in psoriatic arthritis (PsA) patients with concomitant fibromyalgia syndrome (FMS).MethodsThe study population included...

The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.

The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities. The ADVANCE CRT registry (2013-2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P < 0.001), HF event rate was higher (67.0 ± 21.7 vs. 11.4 ± 3.7/100 pt-year, P < 0.001), and HF readmission within 30 days was more common [hazard ratio 7.06, 95% confidence interval (2.1-43.7)]. Inpatient hospitalization was the most common and most expensive event type in CRT-NR. Comorbid HF was increased by diabetes, hypertension, and pulmonary disorders. Over 2 years, compared to CRT responders, each CRT-NR resulted in excess cost of $6388 ($3859-$10 483) to Medicare (P = 0.015) or $10 197 ($6161-$17 394) to private insurances (P = 0.014). Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients.

Subacromial Balloon Spacer versus Partial Repair for Massive Rotator Cuff Tears: A Prospective, Randomized, Multi-center Trial

Objectives:Despite various treatment options, the successful management of irreparable, massive rotator cuff tears (MRCTs) remains challenging. Implantation of a biodegradable subacromial balloon spacer (InSpaceTM system; OrthoSpace, Caesarea, Isreal) has gained considerable interest for the treatment of MCRTs due to its ability to effectively recenter the humeral head within the glenoid. Despite promising results, investigations examining outcomes following balloon spacer implantation are limited to small case series and short-term prospective trials without comparison to other surgical modalities. The purpose of the present investigation was to prospectively evaluate the safety and efficacy of the arthroscopically deployed, subacromial spacer balloon compared to partial rotator cuff repair in patients with MRCTs at 24 month follow up.Methods:A non-inferiority, prospective, single-blinded, multicenter, randomized, controlled, pivotal study was conducted to compare the outcomes of arthroscopic subacromial balloon spacer implantation to partial repair in the treatment of MRCTs. Patients ≥ 40 years of age with symptomatic full thickness MRCTs (tears ≥ 5 cm or ≥ 2 tendons) that had failed non-operative management were included. Clinical outcome data, derived from subjective questionnaires and physical examination, were collected at baseline and follow-up intervals at Day 10, Week 6, Month 3, 6, 12 and 24. Postoperative magnetic resonance imaging (MRI) scans were obtained at 6 weeks and 12 months. The primary composite effectiveness endpoint was defined as achievement of the minimal clinically important difference (MCID) for the Western Ontario Rotator Cuff (WORC) score (275 points) and American Shoulder and Elbow Society (ASES) score (6.4 points) by week 6 and maintenance at month 12 without subsequent secondary surgical intervention (SSSI) or serious adverse device effects (SADEs). Secondary effectiveness endpoints included changes in individual and composite clinical outcome scores relative to baseline in addition to MRI findings. Intention-to-treat (ITT), per-protocol (PP), and safety analyses were performed separately.Results:A total of 20 sites were enrolled in the investigation. One hundred, eighty-four patients were randomized into the clinical study (n= 93 balloon spacer; n= 91 partial repair) and included in the safety population, of which 183 patients were included in the ITT analysis (n=93 balloon spacer; n= 90 partial repair) and 176 in the PP analysis (n= 88 balloon spacer; n= 88 partial repair). No significant difference in demographic characteristics based on mean age, sex, race or body mass index were appreciated between groups. Mean procedure duration was 44.6 ± 16.9 minutes for the balloon spacer group and 71.2 ± 30.1 minutes for the partial repair group. Significant improvement over time relative to baseline was observed in all WORC (Fig. 1) and ASES (Fig. 2) scores in both groups. The magnitude of improvement for subjects in the balloon spacer group was the same or better than for subjects in the partial repair group at 12 and 24 month follow up. At 12 months, 51% (n=45 of 88) of patients in the balloon spacer group and 35 patients 40% (n= 35 of 88) in the partial repair group had reached and maintained the primary composite endpoint, meeting the noninferiority criteria (non-inferiority margin 10%; p = 0.0049) and corresponding to an 11.4% mean advantage for the spacer implant group. Non-inferiority was similarly confirmed in the ITT population (p=0.0089). SSSI occurred in 6 subjects (n=3 balloon spacer; n=3 partial repair), with two subjects in each group requiring reverse shoulder arthroplasty and one subject in each group undergoing shoulder arthroscopy.Conclusions:Use of the balloon spacer was found to produce non-inferior outcomes when compared to partial rotator cuff repair for patients with MRCTs at 24 month follow up. Outcomes following balloon spacer device placement met non-inferiority criteria when compared to the partial repair group based on primary composite endpoints.

Clinical manifestations and long-term outcome of early Lyme neuroborreliosis according to the European Federation of Neurological Societies diagnostic criteria (definite versus possible) in central Europe. A retrospective cohort study.

The characteristics and long-term outcome of Lyme neuroborreliosis (LNB) according to diagnostic certainty (definite vs. possible) are incompletely understood. In this retrospective cohort study of adults with definite or possible LNB, clinical and microbiological characteristics and long-term outcome over 12 months were evaluated at a single medical center. Severity of acute disease and long-term outcome were assessed using a composite clinical score encompassing clinical findings and symptoms and by the probability of incomplete recovery. Amongst 311 adult patients enrolled from 2008 to 2017, 139 (44.7%) had definite LNB and 172 (55.3%) had possible LNB. The most frequent LNB manifestation was cranial neuropathy with or without meningitis (53.4%). Patients with definite LNB more often had Bannwarth syndrome (53.2% vs. 18.6%), more severe disease (6 points vs. 4 points), longer pre-treatment duration (median 21days vs. 13.5days), higher cerebrospinal fluid pleocytosis (median 139×106 /L vs. 11×106 /L) and higher rate of Borrelia seropositivity (84.2% vs. 68.6%) than those with possible LNB. Ceftriaxone was prescribed more often than oral doxycycline in definite LNB than in possible LNB (96.4% vs. 65.7%). Unfavorable outcomes decreased during follow-up, being higher in patients with more severe disease at enrollment and in those with possible LNB, but were not associated with antibiotic therapy. Early LNB, most often presenting as cranial neuropathy, was definitively diagnosed in less than half of cases. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty. In this retrospective cohort study of 311 adults with Lyme neuroborreliosis (LNB), allocated according to diagnostic certainty, early LNB was definitively diagnosed in less than half of cases and the most frequent LNB manifestation was cranial neuropathy with or without meningitis. Patients with definite LNB more often had Bannwarth syndrome, more severe disease, longer pre-treatment duration, higher cerebrospinal fluid pleocytosis and higher rate of Borrelia seropositivity than those with possible LNB. A better diagnostic approach is needed to confirm borrelial etiology. Ceftriaxone was not superior to doxycycline in the treatment of early LNB, regardless of diagnostic certainty.

Early Survival Prediction Framework in CD19-Specific CAR-T Cell Immunotherapy Using a Quantitative Systems Pharmacology Model.

Simple SummaryTreatment with chimeric antigen receptor (CAR)-T cells has improved the prognosis of patients with non-Hodgkin lymphoma (NHL) substantially. Yet, as up to 60% of patients eventually relapse, insights into factors determining treatment response are highly warranted. We used mathematical modeling to characterize typical and individual concentration–time profiles of four different CAR-T cell subtypes and tumor burden in 19 NHL patients and investigated patient-/therapy-related factors associated with poor survival. A low CAR-T cell maximum expansion capacity and no previous autologous stem cell transplantation were associated with a poor prognosis. We next translated our most important model parameter into a clinical composite score, which leverages but does not require the use of the model. Based on our clinical data, we propose a clinical composite score cut-off value for early survival prediction. Additional data will be needed to update and refine the developed model and the proposed clinical composite score cut-off value.Chimeric antigen receptor (CAR)-T cell therapy has revolutionized treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). However, since 36–60% of patients relapse, early response prediction is crucial. We present a novel population quantitative systems pharmacology model, integrating literature knowledge on physiology, immunology, and adoptive cell therapy together with 133 CAR-T cell phenotype, 1943 cytokine, and 48 metabolic tumor measurements. The model well described post-infusion concentrations of four CAR-T cell phenotypes and CD19+ metabolic tumor volume over 3 months after CAR-T cell infusion. Leveraging the model, we identified a low expansion subpopulation with significantly lower CAR-T cell expansion capacities amongst 19 NHL patients. Together with two patient-/therapy-related factors (autologous stem cell transplantation, CD4+/CD8+ T cells), the low expansion subpopulation explained 2/3 of the interindividual variability in the CAR-T cell expansion capacities. Moreover, the low expansion subpopulation had poor prognosis as only 1/4 of the low expansion subpopulation compared to 2/3 of the reference population were still alive after 24 months. We translated the expansion capacities into a clinical composite score (CCS) of ‘Maximum naïve CAR-T cell concentrations/Baseline tumor burden’ ratio and propose a CCSTN-value > 0.00136 (cells·µL−1·mL−1 as predictor for survival. Once validated in a larger cohort, the model will foster refining survival prediction and solutions to enhance NHL CAR-T cell therapy response.

Clinical effectiveness of a dedicated cardiac resynchronization therapy pre-assessment clinic incorporating cardiac magnetic resonance imaging and cardiopulmonary exercise testing on patient selection and outcomes.

BackgroundPre-procedural assessment of patients undergoing cardiac resynchronization therapy (CRT) is heterogenous and patients implanted with unfavorable characteristics may account for non-response. A dedicated CRT pre-assessment clinic (CRT PAC) was developed to standardize the review process and undertake structured pre-procedural evaluation. The aim of this analysis was to determine the effectiveness on patient selection and outcomes.MethodsA prospective database of consecutive patients attending the CRT PAC between 2013 and 2018 was analyzed. Pre-operative assessment included cardiac magnetic resonance (CMR) and cardiopulmonary exercise testing (CPET). Patients were considered CRT responders based on improvement in clinical composite score (CCS) and/or reduction in left ventricular end-systolic volume (LVESV) ≥ 15% at 6-months follow-up.ResultsOf 252 patients reviewed in the CRT PAC during the analysis period, 192 fulfilled consensus guidelines for implantation. Of the patients receiving CRT, 82% showed improvement in their CCS and 57% had a reduction in LVESV ≥ 15%. The presence of subendocardial scar on CMR and a peak VO2 ≤ 12 ml/kg/min on CPET predicted CRT non-response. Two patients were unsuitable for CRT as they had end-stage heart failure and died during follow-up. The majority of patients initially deemed unsuitable for CRT did not suffer from unexpected hospitalization for decompensated heart failure or died from cardiovascular disease; only 8 patients (13%) received CRT devices during follow-up because of symptomatic left ventricular systolic impairment.ConclusionA dedicated CRT PAC is able to appropriately select patients for CRT. Pre-procedural investigation/imaging can identify patients unlikely to respond to, or may not yet be suitable for CRT.

Rheumatoid Arthritis Relapse and Remission - Advancing Our Predictive Capability Using Modern Imaging.

Clinical remission has become an achievable target for the majority of patients with rheumatoid arthritis, but subclinical inflammation as assessed by ultrasound and magnetic resonance imaging (MRI) has been demonstrated to be frequent in patients in clinical remission. Subclinical synovitis has been shown to be linked to both subsequent structural damage progression and a risk of flare, demonstrating that subclinical synovitis represents incomplete suppression of inflammation and questions whether it is appropriate only to use clinical composite scores as treatment target in clinical practice. Maintaining a state of remission has proven important as sustained clinical remission impacts long-term outcome regarding joint damage progression, physical function and quality of life. Treating subclinical inflammation has been attempted and has led to more frequent strict clinical remission and better physical function, but also to more adverse events. Thus, an overall benefit of incorporating imaging goals in treat-to-target strategies has not been documented. However, in patients in clinical remission on biological disease-modifying anti-rheumatic drugs, both ultrasound and MRI may aid in the clinical decision regarding whether drug tapering or even discontinuation should be attempted.

Paced or sensed conduction time to determine programming with cardiac resynchronization therapy: The PASED-CRT Trial.

Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with drug refractory heart failure. This study sought to compare the longest RVsense to LVsense activation time (sLAT) versus the longest RVpace to LVsense activation time (pLAT) as the programmed site for left ventricular (LV) pacing in CRT patients with quadripolar LV leads at 3 months. This single site, double-blinded, prospective trial, randomized patients 1:1 into the sLAT or pLAT group to determine response. LV pacing was programmed at implant and maintained through 3 months of follow-up. The 6-minute hall walk (6MHW) test, NYHA, Minnesota living with heart failure, and clinical composite score (CCS) at the 3 months was compared. N=92 patients (73M:19F age 66 ± 11.3 years) were randomized implanted and programmed per protocol. Baseline characteristics were comparable. N=39 sLAT and N=34 pLAT completed the 3-month visit for final analysis. Significant improvement from baseline to 3 months was seen in the sLAT group from 253.9 (+/-11.5) to 323.1 (+/-11.9) P=.001. Similarly, the pLAT group improved from 274.9 (+/-16.15) to 343.9 (+/-15.9) P=.003. The difference between these groups, however, did not reach significance (P=.86). The pLAT group demonstrated a higher responder rate of (71%) versus the sLAT group (64%) based on the CCS although not reaching significance (P=.56). Use of both the pLAT and sLAT method of programming demonstrated significant improvement in 6MHW distance at 3 months with pLAT demonstrating a slightly higher responder rate based on CCS (P=.56). pLAT should be considered at minimum as equivalent in patients with no intrinsic conduction.

688 Pediatric Obstructive Sleep Apnea (OSA) and COVID-19-Related Adverse Clinical Outcomes

IntroductionThe relationship of OSA and human coronavirus (COVID-19) in the pediatric population is unknown. We postulate that OSA is associated with SARS-CoV-2 positivity and with adverse COVID-19 outcomes in children.MethodsA retrospective review of 120 consecutive patients (<18 years) with prior polysomnogram (PSG) and COVID-19 testing from the Cleveland Clinic COVID-19 registry was conducted. Using a case control design of SARS-CoV-2 positive and negative pediatric patients, we examined COVID-19 and pre-existing OSA (dichotomized AHI≥1) using logistic (OR,95%CI) regression and as continuous measures: AHI, oxygen(SpO2) nadir, %time SpO2<90%) using linear regression(beta+/-SE). In those positive for SARS-CoV-2(cases only), we assessed the association of OSA and World Health Organization(WHO) COVID-19 clinical outcome composite score (hospitalization, requiring supplemental oxygen, non-invasive ventilation/high-flow oxygen, invasive ventilation/ECMO or death) using Wilcoxon rank sum test for ordinal data.ResultsCases (n=36) were 11.8±4.4 years, 61% male, 27.8% black and 88.9% with OSA, while 85.7% of controls (n=84) had OSA. OSA was not associated with increased SARS-CoV-2 positivity: OR=1.33(0.40, 4.45,p=0.64). No significant difference between cases and controls for mean AHI 3.7(1.5,6.0) vs 3.5(1.5,7.1),p=0.91,SpO2 nadir 88.6±5.4 vs 89.1±4.4,p=0.58,%time SpO2<90% 0.05[0.00,1.00) vs 0.10 (0.00,1.00, p=0.65) respectively was noted. WHO-7 COVID-19 clinical outcome did not meet statistical significance in relation to OSA due to the low event frequency (p=0.49). Of note, those with OSA vs without OSA had a higher WHO-7 outcome score of 2 vs 0 and prevalence of hospitalization: 12.5 vs 0% respectively. Of hospitalized patients, the following was observed: 23% had moderate/severe OSA vs 4.3% mild OSA, 50% required supplemental oxygen and 25% required intubation/invasive ventilation. No deaths or readmissions were reported. High risk conditions included: 75% obesity, 50% asthma, 25% sickle cell disease and 25% hypoplastic left heart.ConclusionIn this first report of which we are aware focused on COVID-19 in pediatric OSA, we use a case control design leveraging COVID-19 and sleep laboratory registries. Albeit not statistically significant, pediatric patients with OSA had a higher percentage of worse clinical outcomes. Larger network studies are needed to clarify whether poorer COVID-19 outcomes may be attributable to OSA or modulated via high risk health conditions.Support (if any):

Clinical health markers in dogs fed raw meat-based or commercial extruded kibble diets.

The interest and demand for healthy and less processed foods for human consumption have been mirrored in the pet industry, with an explosion of alternative diets available. Several nontraditional feeding methodologies including raw meat-based diets (RMBDs) are believed by many dog owners to be superior to traditional extruded commercial dog foods. Despite the strong opinions, limited data are available comparing objective health measures among healthy dogs fed using different methods of diet preparation. Therefore, we compared health markers in client-owned dogs fed an RMBD to markers in dogs fed a high-quality extruded kibble. We hypothesized that healthy adult dogs fed RMBD would show differences in biochemical and hematological parameters and improved clinical health scores (e.g., dental, external ear canal, and integument scores) compared with dogs fed a kibble diet. A cross-sectional observational study was performed comparing hematology, serum biochemistry, urinalysis management history, and clinical health scores in healthy client-owned dogs reported as fed RMBD (n = 28) or kibble (n = 27) for >1 yr. Dental, external ear canal, and integument health scores were assigned by a single veterinary evaluator blinded to feed group, using a scale where 0 was normal and 3 was most severely affected. Spearman correlation coefficient (rs) was calculated to assess the strength and direction of the relationship of biochemical outcomes with age and body condition score (BCS), while analysis of variance was used to determine if biochemical analytes differed by breed or gender. Biochemical data were analyzed using multiple linear regression models, adjusting for the covariates gender, breed, age, and BCS. A composite clinical health score, (CCS) = 9 - (dental score + otitis score + integument score), was compared between feeding groups using Mann-Whitney test. Serum alkaline phosphatase activity (P < 0.001) and globulin concentration (P < 0.001) were lower, while lymphocyte count (P < 0.05) was higher in dogs fed RMBD. No differences were found in urinalysis between diet groups. Dogs fed RMBD showed a slight improvement in CCS compared with kibble-fed dogs (CCS: P = 0.03). Owner management significantly differed with a greater likelihood of management interventions including dietary supplements and sporting activities in the RMBD group. Further work is needed to specifically determine the impact of diet processing and nutrient content on canine health.

CarDiac magnEtic Resonance for prophylactic Implantable-cardioVerter defibrillAtor ThErapy in Non-Ischaemic dilated CardioMyopathy: an international Registry

The aim of this registry was to evaluate the additional prognostic value of a composite cardiac magnetic resonance (CMR)-based risk score over standard-of-care (SOC) evaluation in a large cohort of consecutive unselected non-ischaemic cardiomyopathy (NICM) patients. In the DERIVATE registry (www.clinicaltrials.gov/registration: RCT#NCT03352648), 1000 (derivation cohort) and 508 (validation cohort) NICM patients with chronic heart failure (HF) and left ventricular ejection fraction <50% were included. All-cause mortality and major adverse arrhythmic cardiac events (MAACE) were the primary and secondary endpoints, respectively. During a median follow-up of 959 days, all-cause mortality and MAACE occurred in 72 (7%) and 93 (9%) patients, respectively. Age and >3 segments with midwall fibrosis on late gadolinium enhancement (LGE) were the only independent predictors of all-cause mortality (HR: 1.036, 95% CI: 1.0117-1.056, P < 0.001 and HR: 2.077, 95% CI: 1.211-3.562, P = 0.008, respectively). For MAACE, the independent predictors were male gender, left ventricular end-diastolic volume index by CMR (CMR-LVEDVi), and >3 segments with midwall fibrosis on LGE (HR: 2.131, 95% CI: 1.231-3.690, P = 0.007; HR: 3.161, 95% CI: 1.750-5.709, P < 0.001; and HR: 1.693, 95% CI: 1.084-2.644, P = 0.021, respectively). A composite clinical and CMR-based risk score provided a net reclassification improvement of 63.7% (P < 0.001) for MAACE occurrence when added to the model based on SOC evaluation. These findings were confirmed in the validation cohort. In a large multicentre, multivendor cohort registry reflecting daily clinical practice in NICM work-up, a composite clinical and CMR-based risk score provides incremental prognostic value beyond SOC evaluation, which may have impact on the indication of implantable cardioverter-defibrillator implantation.

Redefining the Classifications of Response to Cardiac Resynchronization Therapy: Results From the REVERSE Study.

This study sought to assess the impact of a more detailed classification of response on survival. Cardiac resynchronization therapy (CRT) improves functional status and outcomes in selected populations with heart failure (HF). However, approximately 30% of patients do not improve with CRT by various metrics, and they are traditionally classified as nonresponders. REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) was a randomized trial of CRT among patients with mild HF. Patients were classified as Improved, Stabilized, or Worsened using prespecified criteria based on the clinical composite score (CCS) and change in left ventricular end-systolic volume index (LVESVi). All-cause mortality across CRT ON subgroups at 5 years was compared. Of the 406 subjects surviving 1 year, 5-year survival differed between CCS subgroups (p=0.03), with increased mortality in the Worsened response group. Of the 353 subjects with adequate echocardiograms, survival differed significantly between response groups (p<0.001), also due to increased mortality in the Worsened group. When combining CCS and LVESVi results, the lowest survival was observed among subjects who worsened for both measures, whereas the highest survival occurred in subjects who did not worsen by either endpoint. Multivariate analysis showed that LVESVi worsening with CRT at 6months, baseline LVESVi, and gender were independent predictors of survival. For both CCS and reverse remodeling, patients who worsen with CRT have a high mortality, although remodeling was the more important endpoint. Patients who stabilize early with CRT have a much better prognosis than previously recognized, suggesting that the current convention of nonresponder classification should be modified. (REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction]; NCT00271154).

Abstract PS10-01: 6-year absolute invasive disease-free survival (IDFS) benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A STEPP analysis of the APHINITY (BIG 4-11) trial

Abstract Background: The primary analysis of the randomized, double-blind, placebo-controlled APHINITY trial, published in 2017, including 4804 patients (pts) with HER2-positive, early breast cancer with 45.4 months' median follow-up, demonstrated that adjuvant pertuzumab (P) added to trastuzumab and chemotherapy, statistically significantly improved invasive disease-free survival (IDFS) compared with placebo (Pla) added to trastuzumab and chemotherapy overall and for pts with node-positive (N+) disease. In 2019, updated descriptive analyses of IDFS with 74.1 months' median follow-up, demonstrated sustained benefit of adding P both overall (HR, 0.76; 95% CI, 0.64-0.91), and for N+ disease (HR, 0.72; 95% CI, 0.59-0.87), while confidence intervals remained wide for the node-negative (N-) cohort (HR, 1.02; 95% CI, 0.69-1.53). There is great interest to explore how these significant overall results translate into absolute treatment benefits for different patient subpopulations. Methods: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. Four continuous covariates of interest are considered for defining subpopulations in this report: i) a clinical composite risk score (see below), ii) TILs percentage, iii) HER2 FISH copy number, and iv) a clinical-biological composite risk score combining the previous three factors. Pts with lowest values for the covariate comprise the extreme left STEPP subpopulation, and pts with highest values comprise the extreme right subpopulation. The clinical composite risk score for IDFS based on the overall cohort was calculated using a Cox regression model including the following prespecified clinical characteristics: number of positive nodes, tumor size, age, and centrally-reviewed hormone receptor status. Composite risk scores were scaled between 0 and 100 with higher scores reflecting higher risk of an IDFS event. An example of low clinical risk factors would be T1N0 and aged 40-64; while high risk would be T3N2 or higher and ages &amp;lt;40 or ≥65. At 74.1 months' median follow-up, the composite risk of an IDFS event did not depend on hormone receptor status. Differences in Kaplan-Meier estimates of 6-year IDFS percents (P minus Pla) were used as estimates of treatment effect for each subpopulation. The overall analyses (N=4804) used 9 overlapping subpopulations with ~1000 pts in each, the N- analyses (N=1799) used 5 subpopulations with ~500 pts in each, and the N+ analyses (N=3005) used 7 subpopulations with ~750 pts in each. Intermediate (middle) subpopulations were the 5th, 3rd, and 4th, respectively. Results: Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts. For each analysis, results are shown for the two subpopulations at either extreme of the STEPP (i.e. lowest and highest risk or values) as well as the intermediate STEPP subpopulation. Conclusions: Based on the two extreme and one intermediate subpopulations of the STEPP analyses shown in the table, the intermediate clinical composite risk subpopulation and the highest TILs percentages had the largest absolute improvements in 6-year IDFS percents for P compared with Pla. Table of 6-year IDFS percents (%) from Aphinity STEPPs, Overall and for N- and N+ cohorts.6-year IDFS %Overall (N=4804)Node-Negative (N=1799)Node-Positive (N=3005)PPlaΔ±SEPPlaΔ±SEPPlaΔ±SEOverall Average Results90.687.82.8±0.995.094.90.1±1.187.983.44.5±1.2Clinical composite riskLowest risk (0 - 21)95.396.2-0.9±1.396.196.5-0.4±1.5---Intermediate (39 - 63)92.687.35.3±1.995.091.04.0±3.093.686.76.9±2.3Highest risk (81 - 100)80.575.84.7±2.8---79.475.44.0±3.2TILs percentageLowest values (0-9)90.487.82.6±2.094.795.2-0.5±2.087.282.64.6±2.7Intermediate (13-21)89.487.71.7±2.194.294.10.1±2.285.484.80.6±2.7Highest values (≥31)95.689.36.3±1.798.194.93.2±1.792.384.97.4±2.4HER2 copy numberLowest values (1-8)87.186.40.7±2.292.794.8-2.1±2.284.182.12.0±2.8Intermediate (9.5-11)91.889.02.8±1.994.996.1-1.3±1.990.783.37.4±2.5Highest values (13-32)90.588.91.6±2.096.095.10.9±2.087.785.32.4±2.6Clinical-biological composite riskLowest risk (0-21)96.796.40.3±1.298.295.72.5±1.6---Intermediate (40-60)93.489.53.9±1.991.792.7-1.0±2.594.288.85.4±2.2Highest risk (79-100)80.175.94.2±2.7---79.575.24.3±3.2 Citation Format: Richard D. Gelber, Xin Victoria Wang, Bernard F. Cole, David Cameron, Fatima Cardoso, Vivianne Tjan-Heijnen, Ian Krop, Sherene Loi, Roberto Salgado, Astrid Kiermaier, Elizabeth Frank, Debora Fumagalli, Carmela Caballero, Evandro de Azambuja, Marion Procter, Emma Clark, Eleonora Restuccia, Sarah Heeson, Jose Bines, Sibylle Loibl, Martine Piccart-Gebhardt. 6-year absolute invasive disease-free survival (IDFS) benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A STEPP analysis of the APHINITY (BIG 4-11) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-01.

Objectively characterizing Huntington\u2019s disease using a novel upper limb dexterity test

BackgroundThe Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington’s, that is not reliant on clinical expertise for administration.MethodsOne-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington’s disease completed the Unified Huntington’s Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman’s R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures.ResultsBaseline C3t scores predicted baseline clinical scores to within 9–13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small (Omega ≤ 0.15) and mirrored the change in clinical scores.ConclusionThe C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington’s disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington’s disease.

Real-world outcomes in cardiac resynchronization therapy patients: design and baseline demographics of the SMART- Registry.

AimsThe SMART (Strategic MAnagement to optimize response to cardiac Resynchronization Therapy) Registry was designed to assess real‐world outcomes for patients receiving a cardiac resynchronization therapy defibrillator (CRT‐D) and to better understand which programming and optimization techniques are used and how effective they are.Methods and resultsThe SMART Registry is a global, multicentre, prospective, observational, post‐market CRT‐D registry with a planned enrolment of 2000 subjects from a maximum of 200 sites in Europe, North America, and Asia‐Pacific region. Each subject will be followed up for a minimum of 12 months. The primary endpoint of CRT response rate at 12 months is defined by a clinical composite score of all‐cause mortality, heart failure events, New York Heart Association Class, and quality of life as assessed by a patient global assessment instrument. A subgroup composed of the first 103 consecutive European subjects implanted with an NG4 device will have left ventricular multisite pacing feature enabled at any time during the initial 12 months of follow‐up. The primary endpoint for this sub‐analysis will be the NG4 PG‐related complication‐free rate at 36 months.ConclusionsThe SMART Registry achieved its recruitment target in August 2019, with 2014 patients enrolled. The baseline demographics demonstrated that patients were generally older, with greater co‐morbidity, and on more contemporary medical therapy than in the key CRT trials. The results of the SMART Registry will determine which programming and optimization techniques are effective in this real‐world population.

Mortality and risk factors on admission in toxic epidermal necrolysis: A cohort study of 59 patients

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening disorders characterized by widespread epidermal necrosis of the skin and mucosa. The severity-of-illness scoring system for TEN (SCORTEN) was widely used since 2000 as a standard prognostic tool consisting of seven clinical values. MethodsTo evaluate the prognosis using current treatments and risk factors for mortality, we retrospectively analyzed 59 cases of TEN, including SJS/TEN overlap treated in two university hospitals from January 2000 to March 2020. ResultsThe mortality rate of TEN was 13.6% (8/59). All patients treated with high-dose steroid administration in combination with plasma exchange and/or immunoglobulin therapy recovered. Logistic regression analysis showed nine clinical composite scores, namely: heart rate (≧120 bpm), malignancy present, percentage of body surface area with epidermal detachment (>10%), blood urea nitrogen (>28 mg/dL), serum bicarbonate level (<20 mEq/L), serum glucose level (>252 mg/dL), age (≧71 years), the interval between disease onset and treatment initiation at the specialty hospital (≧8 days), and respiratory disorder within 48 h after admission. The receiver operating characteristic curves confirmed a high potential for predicting the prognosis of TEN. ConclusionsRecent developments in treatment strategies have contributed to the improved prognosis of TEN patients. A modified severity scoring model composed of nine scores may be helpful in the prediction of TEN prognosis in recent patients. Further large-scale studies are needed to confirm mortality findings to improve prognostication in patients with TEN.

79 Clinical health markers in dogs fed raw meat based or commercial extruded kibble diets

Abstract Anecdotal reports of health benefits of raw meat-based diets (RMBD) for dogs include cleaner teeth, improved integument, and general health. However, little to no evidence is present in the scientific literature to support assertions of improved clinical outcomes in RMBD-fed dogs. We hypothesized that healthy dogs fed diets which have undergone less processing will show a clinical benefit and improved general health markers compared to dogs fed a highly processed diet. Enrollment criteria included healthy, client-owned adult dogs fed either RMBD or extruded kibble (EK) for &amp;gt; 1 year (RMBD n = 28; EK n = 27). Management history, clinical examination, hematology, urinalysis and serum biochemistry measures were collected for each dog. Dental, ear and coat scores were assigned by a blinded veterinary observer and a clinical composite score (CCS) calculated. Dogs fed RMBD showed an improved CCS and coat score compared to EK dogs (CCS: Mann Whitney test, P = 0.03; Coat: Fisher Exact Test, P = 0.04). Differences in blood analytes between feeding group were observed (Table 1). For each significant difference found by univariate analysis, forward stepwise linear regression was performed with age, breed, gender, and body condition score as independent factors. Serum alkaline phosphatase activity was 50% lower in dogs fed RMBD than those fed EK (P = 0.001). BUN was higher (P &amp;lt; 0.01) in RMBD dogs, while glucose concentration (P &amp;lt; 0.05) was lower in RMBD dogs compared to EK dogs. Platelet count was greater in RMBD dogs relative to EK group (P &amp;lt; 0.001). Owner management differed, with greater likelihood of management interventions and sporting activities in the RMBD group. RMBD may have mild clinical benefits and significant effects on blood analytes compared to EK, even when management was considered. Further work is needed to determine the impact of owner practices, diet processing, and nutrient content on health outcomes.

First-phase ejection fraction predicts response to cardiac resynchronization therapy and adverse outcomes

Abstract Background Cardiac Resynchronization Therapy (CRT) is an important therapeutic treatment for chronic heart failure. However, even in carefully selected cases up to 40% of patient fail to respond. First-phase ejection fraction (EF1), the ejection fraction up to the time of maximal ventricular contraction, is a novel and more sensitive echocardiographic measure of early systolic function. Purpose We examined the value of EF1, to predict response to CRT and clinical outcomes after CRT. Methods We analysed echocardiograms from 197 patients who underwent CRT between 2009 and 2018 and were followed to determine clinical outcomes. Results Volumetric response rate (reduction in end-systolic volume ≥15%) was 92.3% vs. 12.1%, for those with EF1 in the highest vs. lowest tertiles (p&amp;lt;0.001). A cut-off value of 11.9% for EF1 had &amp;gt;85% sensitivity and specificity for prediction of response to CRT; on multivariate logistic regression analysis incorporating previously defined predictors, EF1 was the strongest predictor of response (OR: 1.563, 95% CI: 1.371–1.782, p&amp;lt;0.001) (table 1). EF1 was also the strongest predictor of a clinical composite score (OR: 1.115, 95% CI: 1.044–1.191, p=0.001). Improvement in EF1 at 6 months after CRT implantation (6.5±5.8% vs 1.8±4.3% in responders vs. non-responders, p&amp;lt;0.001) was the best predictor of heart failure re-hospitalization and death after median follow-up of 29.2 months (HR: 0.819, 95% CI:0.765–0.876, p&amp;lt;0.001). Conclusion EF1 is a promising marker to identify patients likely to respond to CRT and most likely provides a measure of myocardial viability that determines response. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, Wellcome/EPSRC Centre for Medical Engineering

Coronary vasomotor dysfunction is associated with worse outcomes in patients with inflammatory disease

Abstract Background Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis (PsO) are common inflammatory conditions with excess cardiovascular (CV) risk compared to the general population. This excess CV risk is associated with traditional risk factors, glucocorticoid treatment, and systemic inflammation. Systemic inflammation perturbs endothelial function and has been linked to coronary vasomotor dysfunction. It is not clear if coronary vasomotor dysfunction would be associated with worse clinical outcomes in systemic autoimmune inflammatory conditions. Purpose We tested the hypothesis that impaired coronary flow reserve (CFR), which in the absence of flow-limiting obstructive coronary artery disease (CAD) reflects vasomotor dysfunction, among patients with SLE, RA, and PsO is associated with worse clinical outcomes. Methods We included patients with RA, SLE, and PsO who underwent clinically indicated rest/stress myocardial perfusion positron emission tomography (PET) at a large academic medical center from 2006 to 2019. Patients with an abnormal myocardial perfusion study (summed stress score &amp;gt;3) or left ventricular ejection fraction &amp;lt;40% were excluded. CFR was calculated as the ratio of myocardial blood flow (MBF, ml/min/g) at peak stress compared to the MBF at rest and adjusted for baseline heart rate and blood pressure. Results Among the 175 patients (median age 65.1 years, 80% female) in the cohort, 24% had SLE, 35% PsO, and 41% RA. There was no difference in mean CFR between patients with RA, SLE, or PsO. Over a median follow-up of 8.5 years after PET, there were 47 deaths. Patients in the lowest and middle tertile (CFR &amp;lt;2.18) had a higher all-cause mortality when compared with the highest (Figure 1), and this association remained significant after adjusting for age and a composite clinical score incorporating sex, symptoms, and CV risk factors (lowest vs. highest tertile: HR 2.8; 95% confidence interval 1.2–6.5; p=0.01). CV risk factors such as diabetes, hypertension, obesity, tobacco use, and a family history of CAD were not significantly different across CFR tertiles, suggesting that inflammatory-disease specific risk factors may contribute to coronary vasomotor dysfunction. Conclusions In patients with systemic inflammatory disease, coronary vasomotor dysfunction was associated with worse outcomes independent of traditional CV risk factors and may have utility as a marker of CV risk among patients with inflammatory disease. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. 5T32HL094301-02 NIH T32 Training Grant, “Noninvasive Cardiovascular Imaging Research Training Program”