Clinical Composite Score Research Articles

Long-term efficacy of cardiac resynchronization therapy with triple-site ventricular stimulation in heart failure patients

Abstract Background Cardiac resynchronization therapy (CRT) reduces cardiac electrical dyssyncrhony and improves clinical outcomes in selected symptomatic patients with left ventricular (LV) systolic dysfunction. However, patients after conventional CRT (Bi-V) have residual cardiac electrical dyssynchrony. CRT with multi-site pacing has gained attention to improve short-term outcome refractory to BiV. However, long-term follow up outcome is still uncertain. We evaluated the efficacy of CRT with triple-site ventricular stimulation (Tri-V), involving 2 LV lead in 2 anatomically separated veins and a single RV lead in RV apex for long-term follow up period. Methods Ninety-two consecutive patients with New York Heart Association class II-IV heart failure, LV ejection fraction <0.35, and QRS interval >120ms, who underwent CRT implantation between 2010 and 2016, were enrolled. Acute hemodynamic responses to temporary dual-site and triple-site ventricular pacing were evaluated, and patients were assigned to either the Bi-V or Tri-V group based on the results. The primary endpoint was the HF clinical composite score, which scores patients as improved, unchanged, or worsened. The secondary endpoint included cumulative survival from any cause of death and HF hospitalization. Results Tri-V was successfully implanted in 32 patients. Five patients were excluded during follow-up because of uncaptured pacing in one of the LV leads. One year post-implantation, the clinical composite score significantly improved in 84% of Tri-V patients compared to 57% in the Bi-V group (p=0.026). After a median follow-up of 12.0 years, there was no significant difference about all-cause mortality between Tri-V and Bi-V (p=0.147). However, Tri-V group showed significant lower HF hospitalization (p=0.005) than Bi-V group. The number of battery exchange was not significantly different between Tri-V than Bi-V group (1.4±0.7 vs. 1.2±0.8, p=0.361). Conclusion CRT with Tri-V, characterized by stable lead parameters, appears to offer greater long-term benefits than Bi-V in terms of clinical status without excessive battery exchanges.figure

EP.06B.07 CARE: Developing a Clinical Composite Score for mNSCLC and Co-Design Solutions to Bridge the Metropolitan vs Regional Gap

EP.06B.07 CARE: Developing a Clinical Composite Score for mNSCLC and Co-Design Solutions to Bridge the Metropolitan vs Regional Gap

Mechanical dyssynchrony as a selection criterion for cardiac resynchronization therapy: Design of the AMEND-CRT trial.

One third of patients do not improve after cardiac resynchronization therapy (CRT). Septal flash (SF) and apical rocking (ApRock) are deformation patterns observed on echocardiography in most patients eligible for CRT. These markers of mechanical dyssynchrony have been associated to improved outcome after CRT in observational studies and may be useful to better select patients. The aim of this trial is to investigate whether the current guideline criteria for selecting patients for CRT should be modified and include SF and ApRock to improve therapy success rate, reduce excessive costs and prevent exposure to device-related complications in patients who would not benefit from CRT. The AMEND-CRT trial is a multicentre, randomized, parallel-group, double-blind, sham-controlled trial with a non-inferiority design. The trial will include 578 patients scheduled for CRT according to the 2021 ESC guidelines who satisfy all inclusion criteria. The randomization is performed 1:1 to an active control arm ('guideline arm') or an experimental arm ('echo arm'). All participants receive a device, but in the echo arm, CRT is activated only when SF or ApRock or both are present. The outcome of both arms will be compared after 1year. The primary outcome measures are the average change in left ventricular end-systolic volume and patient outcome assessed using a modified Packer Clinical Composite Score. The findings of this trial will redefine the role of echocardiography in CRT and potentially determine which patients with heart failure and a prolonged QRS duration should receive CRT, especially in patients who currently have a class IIa or class IIb recommendation.

Heparin-Binding Protein Stratifies Mortality Risk Among Ugandan Children Hospitalized With Respiratory Distress.

Current prognostic tools do not reliably and objectively identify children with pneumonia at risk of a severe or life-threatening episode. Heparin-binding protein (HBP) is a host immune protein that is released in response to infection. We hypothesized that measuring HBP concentrations at hospital admission could help risk-stratify children with pneumonia and identify those at higher risk of an adverse prognosis. We evaluated the prognostic accuracy of HBP for predicting in-hospital mortality among children with respiratory distress, and whether HBP could improve the accuracy of validated composite clinical severity scores. Of 778 Ugandan children under 5 years of age and presenting with clinically defined pneumonia, 60 (7.7%) died during hospital admission. HBP concentrations at presentation were significantly higher in children with fatal outcomes (median, 76 ng/mL [interquartile range {IQR}, 41-150]) compared to children who survived (median, 31 ng/mL [IQR, 18-57]) (P < .001). Children with HBP >41 ng/mL on admission had an elevated risk of death (hazard ratio, 5.3 [95% confidence interval {CI}, 2.9-9.5]; P < .0001). In receiver operating characteristic (ROC) curve analysis, HBP concentrations distinguished between fatal and nonfatal outcomes (area under the ROC curve, 0.75 [95% CI, .66-.84]) and significantly improved the prediction provided by the Respiratory Index of Severity in Children, a composite clinical severity score (P = .0026). Measuring HBP at presentation could help identify children at risk of severe and fatal pneumonia. Adding HBP to clinical scores could improve the recognition and triage of children with pneumonia at risk of death.

Lumbar Facet Arthroplasty Versus Fusion for Grade-I Degenerative Spondylolisthesis with Stenosis: A Prospective Randomized Controlled Trial.

The comparative effectiveness of decompression plus lumbar facet arthroplasty versus decompression plus instrumented lumbar spinal fusion in patients with lumbar spinal stenosis and grade-I degenerative spondylolisthesis is unknown. In this randomized, controlled, Food and Drug Administration Investigational Device Exemption trial, we assigned patients who had single-level lumbar spinal stenosis and grade-I degenerative spondylolisthesis to undergo decompression plus lumbar facet arthroplasty (arthroplasty group) or decompression plus fusion (fusion group). The primary outcome was a predetermined composite clinical success score. Secondary outcomes included the Oswestry Disability Index (ODI), visual analog scale (VAS) back and leg pain, Zurich Claudication Questionnaire (ZCQ), Short Form (SF)-12, radiographic parameters, surgical variables, and complications. A total of 321 adult patients were randomized in a 2:1 fashion, with 219 patients assigned to undergo facet arthroplasty and 102 patients assigned to undergo fusion. Of these, 113 patients (51.6%) in the arthroplasty group and 47 (46.1%) in the fusion group who had either reached 24 months of postoperative follow-up or were deemed early clinical failures were included in the primary outcome analysis. The arthroplasty group had a higher proportion of patients who achieved composite clinical success than did the fusion group (73.5% versus 25.5%; p < 0.001), equating to a between-group difference of 47.9% (95% confidence interval, 33.0% to 62.8%). The arthroplasty group outperformed the fusion group in most patient-reported outcome measures (including the ODI, VAS back pain, and all ZCQ component scores) at 24 months postoperatively. There were no significant differences between groups in surgical variables or complications, except that the fusion group had a higher rate of developing symptomatic adjacent segment degeneration. Among patients with lumbar spinal stenosis and grade-I degenerative spondylolisthesis, lumbar facet arthroplasty was associated with a higher rate of composite clinical success than fusion was at 24 months postoperatively. Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Longitudinal health outcomes in caregivers of military members with traumatic brain injury.

To examine longitudinal change in health-related quality of life (HRQOL) in caregivers of service members/veterans with traumatic brain injury and factors associated with clinically elevated symptoms. Caregivers (N = 220) completed nine HRQOL outcome measures and 10 risk factor measures at a baseline evaluation and follow-up evaluation 3 years later. Caregiver's responses on the nine HRQOL outcome measures were classified into four clinical change categories based on the presence/absence of clinically elevated T-scores (≥ 60 T) at baseline and follow-up: (a) Persistent (baseline ≥ 60T + follow-up ≥ 60 T), (b) Developed (baseline < 60 T + follow-up ≥ 60 T), (c) Improved (baseline ≥ 60 T + follow-up < 60 T), and (d) Asymptomatic (baseline < 60 T + follow-up < 60 T). A clinical change composite score was calculated by summing the number of Persistent or Developed HRQOL outcome measures and used to create three clinical change groups: (a) No Symptoms (n = 69, zero measures), (b) Some Symptoms (n = 88, one to three measures), and (c) Numerous Symptoms (n = 63, four to nine measures). Of the nine HRQOL outcome measures, Bodily Pain, Perceived Stress, Sleep-Related Impairment, and Fatigue were most frequently classified as Persistent or Developed from baseline to follow-up in the entire sample. A linear relationship was found between the vast majority of risk factors across the three clinical change groups at baseline and follow-up (Numerous > Some > None). The risk factors were correlated with the number of elevated HRQOL symptoms at baseline and follow-up. Most Asymptomatic or Persistent caregivers did not have meaningful change (≥ 1 SD) in HRQOL scores. A sizable proportion of Developed or Improved caregivers had either meaningful or no change in HRQOL scores. There is a need for ongoing clinical services for military caregivers. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The importance of ultrasound examination in care of juvenile idiopathic arthritis patients: 9 months follow-up study.

Juvenile idiopathic arthritis (JIA) is a group of rare musculoskeletal disorders with chronic inflammation of joints, typically manifesting before the age of 16 years. The assessment of disease activity remains pivotal in JIA treatment decisions, particularly during clinical remission. While musculoskeletal ultrasound (MSUS) has shown promise in detecting subclinical synovitis, longitudinal data on MSUS features in JIA remains limited. The aim of this study was to evaluate the prevalence of subclinical synovitis observed in MSUS over a follow-up period in JIA patients. Additionally, it sought to assess the consistency and correlation between clinical findings, standardized composite clinical score (JADAS10), and MSUS-detected synovitis during 9 months follow-up. a prospective single-center study was conducted, enrolling all consecutive JIA patients (excluding systemic JIA) seen at the study center in one year period. At three-months intervals over a 9 months period (M0, M3, M6 and M9), patients underwent clinical examination, laboratory tests, and MSUS assessment. Data on demographic characteristics, disease profile, and treatment were collected. Patients were categorized into active disease (ACT) or remission (REM) groups based on Wallace criteria and JADAS10 scores using previously validated thresholds. The ultrasound assessments adhered to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) pediatric group, covering 40 joints, were performed by two ultrasonographers at every visit. Subclinical synovitis was defined as synovitis detected exclusively by MSUS. Spearman's correlation coefficients (rs) were used to evaluate the association between MSUS, clinical data, and outcome measures, such as active joint count (ACJ), patient's/parent's global assessment of disease activity (PaGA), physician's global assessment of disease activity (PhGA) and JADAS10. subclinical synovitis was evident in 5.2% of all joints and in 80.6% of the patients at baseline. During the follow-up period, signs of subclinical synovitis decreased to 3.8% of joints, however, the proportion of affected patients remained high (67.7%), with the majority in REM group. Despite the consistent strong correlation between PaGA and PhGA throughout the study (rs > 0.895; p < 0.001), both measures displayed moderate (rs = 0.647; p < 0.001) to weak (rs = 0.377; p = 0.04) correlations with MSUS findings. Notably, PaGA remained significantly correlated with MSUS at the M9 visit (rs = 0.377, p = 0.04), while PhGA showed no correlation (p = 0.094). The study results indicate the persistence of subclinical inflammation detected by MSUS in a significant proportion of JIA patients, even during clinical remission. Moreover, the findings suggest that conventional measurements of JIA activity may be insufficient for assessing patients in clinical remission.

Increased Cardiometabolic Risk in Healthy Young Adults With Early Life Stress.

This study aimed to evaluate the relationship between early life stress (ELS) and metabolic risk in healthy young adults and assess the role of health behaviors. Young adults aged 18 to 40 years ( N = 190) with no medical conditions or medication usage were recruited from the community. Participants with ELS ( N = 113) had a history of childhood maltreatment, and most also experienced parental loss ( n = 88). Controls ( N = 77) had no history of maltreatment or parental loss. Standardized interviews and self-reports assessed demographics, adversity, medical/psychiatric history, and health behaviors. Blood pressure and anthropometrics were measured, and fasting plasma assayed for lipid profiles, glucose, insulin level, and hemoglobin A 1c . We calculated both a clinical cut-point and continuous composite metabolic risk score based on clinical risk factors and the mean of z scores of each measure, respectively. ELS was significantly associated with increased clinical cut-point ( β = 0.68, 95% confidence interval [CI] = 0.20-1.17, p = .006) and continuous ( β = 0.23, 95% CI = 0.08-0.038, p = .003) composite metabolic risk scores. On sensitivity analysis, the association of ELS with the continuous composite metabolic risk score was reduced to a trend after adjusting for a range of psychosocial and health predictors ( β = 0.18, 95% CI = 0.00-0.36, p = .053), with both diet and college graduate status significant in the model. Healthy young adults with a history of ELS have increased metabolic risk scores as compared with controls. This relationship may be partially due to health behaviors and socioeconomic factors. These findings underline that ELS is an early contributor to metabolic risk.

Impact of Apolipoprotein E Genotype on Neurocognitive Function in Patients With Brain Metastases: An Analysis of NRG Oncology's RTOG 0614

Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT. NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed longitudinal NCF testing, and included an optional blood draw for APOE analysis. NCF test results were compared at baseline and over time with mixed-effects models. A cause-specific Cox model for time to NCF failure was performed to assess the effects of treatment arm and APOE carrier status. APOE results were available for 45% of patients (n = 227/508). NCF did not differ by APOE e4 carrier status at baseline. Mixed-effects modeling showed that APOE e4 carriers had worse memory after WBRT compared with APOE e4 noncarriers (Hopkins Verbal Learning Test-Revised total recall [least square mean difference, 0.63; P = .0074], delayed recognition [least square mean difference, 0.75; P = .023]). However, APOE e4 carrier status was not associated with time to NCF failure (hazard ratio, 0.86; 95% CI, 0.60-1.23; P = .40). Memantine delayed the time to NCF failure, regardless of carrier status (hazard ratio, 0.72; 95% CI, 0.52-1.01; P = .054). APOE e4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, and the Clinical Trial Battery Composite score after treatment with WBRT (+/- memantine), without acceleration of onset of difference in time to NCF failure.

Inflammatory immune profiles associated with disease severity in pulmonary tuberculosis patients with moderate to severe clinical TB or anemia.

Immune control of Mycobacterium tuberculosis (Mtb) infection is largely influenced by the extensive disease heterogeneity that is typical for tuberculosis (TB). In this study, the peripheral inflammatory immune profile of different sub-groups of pulmonary TB patients was explored based on clinical disease severity, anemia of chronic disease, or the radiological extent of lung disease. Plasma samples were obtained from n=107 patients with active pulmonary TB at the time of diagnosis and after start of standard chemotherapy. A composite clinical TB symptoms score, blood hemoglobin status and chest X-ray imaging were used to sub-group TB patients into 1.) mild and moderate-severe clinical TB, 2.) anemic and non-anemic TB, or 3.) limited and extensive lung involvement. Plasma levels of biomarkers associated with inflammation pathways were assessed using a Bio-Plex Magpix 37-multiplex assay. In parallel, Th1/Th2 cytokines were quantified with a 27-multiplex in matched plasma and cell culture supernatants from whole blood stimulated with M. tuberculosis-antigens using the QuantiFERON-TB Gold assay. Clinical TB disease severity correlated with low blood hemoglobin levels and anemia but not with radiological findings in this study cohort. Multiplex protein analyses revealed that distinct clusters of inflammation markers and cytokines separated the different TB disease sub-groups with variable efficacy. Several top-ranked markers overlapped, while other markers were unique with regards to their importance to differentiate the TB disease severity groups. A distinct immune response profile defined by elevated levels of BAFF, LIGHT, sTNF-R1 and 2, IP-10, osteopontin, chitinase-3-like protein 1, and IFNα2 and IL-8, were most effective in separating TB patients with different clinical disease severity and were also promising candidates for treatment monitoring. TB patients with mild disease displayed immune polarization towards mixed Th1/Th2 responses, while pro-inflammatory and B cell stimulating cytokines as well as immunomodulatory mediators predominated in moderate-severe TB disease and anemia of TB. Our data demonstrated that clinical disease severity in TB is associated with anemia and distinct inflammatory immune profiles. These results contribute to the understanding of immunopathology in pulmonary TB and define top-ranked inflammatory mediators as biomarkers of disease severity and treatment prognosis.

Clinical markers for unfavorable course of multiple sclerosis

Objective. To study possible clinical markers associated with the unfavorable course of multiple sclerosis and its transition to a progressive subtype.&#x0D; Materials and methods. This prospective study included healthy volunteers and patients with relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS). For a comprehensive clinical evaluation, the participants completed the Timed 25-Foot Walk Test (T25-FW), Nine-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Fatigue test, and MSProDiscuss questionnaires. Then we compared the results between the groups.&#x0D; Results. We found significant differences between the groups in regard to most of the tests. Furthermore, we proposed a composite clinical score (CCS) based on T25-FW, SDMT, and 9-HPT results (for both hands).&#x0D; Discussion. Our CCS can be a useful clinical tool to determine the most likely course of multiple sclerosis at a certain timepoint.

TIPS-15 NEUROCOGNITIVE FUNCTION AND NEUROCOGNITIVE CONCERNS IN AN ONGOING PHASE III TRIAL OF PRE-OPERATIVE SRS VERSUS POST-OPERATIVE SRS FOR BRAIN METASTASES

Abstract In our ongoing phase III randomized trial (NCT03741673) evaluating risk of leptomeningeal disease (LMD) in patients with brain metastasis, patients are stratified by tumor size, location, and histology, and randomized to pre-operative SRS versus post-operative SRS. The primary endpoint is 1-year LMD-free rate, and exploratory endpoints include neurocognitive function (NCF). NCF is assessed prior to treatment and longitudinally (1.5, 6, and 12 months from the start of treatment) with the HVLT-R, TMT, and COWA yielding the Clinical Trial Battery Composite score (CTB COMP). Patients also complete the MDASI-BT, which includes a Cognitive Factor measuring patient reported cognitive concerns. Currently, 41 patients completed pre-treatment NCF baseline. Characteristics of patients with pre-treatment NCF baseline include mean (SD): age 60.0+/-11.7 years, 2.6+/-2.2 metastases, 15.2+/-10.1 cc brain metastases volume, median KPS 90 (range: 70-100), 83% white, 52% male, and 50% received AEDs at time of surgery. The most common primary cancers among this cohort were: 31% NSCLC, 19% RCC, 14% melanoma, 7% breast, 2% thyroid, and 26% other. Mean (SD) NCF z-scores ranged from z= -0.09 (1.08) to -3.09 (6.13), CTB COMP z=-1.13 (1.65), and the mean (SD) MDASI-BT Cognitive Factor score was 1.1 (1.3). Using multivariable linear regression including CTB COMP, MDASI-BT Cognitive and Affective Factor, KPS, number of and intracranial volume of metastases, only intracranial volume of metastases was statistically significantly associated with CTB COMP (B=-.058, p=.034) and only the MDASI-BT Affective Factor was statistically significantly associated with the MDASI-BT Cognitive Factor (B=.305, p=&amp;lt;.001). At baseline, disease factors such as tumor burden appear to be the primary driver of objectively measured neurocognitive dysfunction and mood factors appear to be the primary driver of subjective patient reported neurocognitive concerns. This has important implications for interpretation of these different clinical outcome assessments in clinical trials measuring objective neurocognitive function and subjective neurocognitive concerns.

PO-02-016 PHYSIOLOGIC SIGNALS FROM CRT DEVICES ARE INDICATIVE OF CRT RESPONSE IN SMART-MSP STUDY

Cardiac resynchronization therapy (CRT) is a well-established treatment for some heart failure patients with reduced ejection fraction, but a subset of these patients does not respond to CRT. Multi-site pacing (MSP) is proposed to improve clinical response to CRT, but it is unclear which CRT subset would benefit from MSP. Physiologic sensor data from CRT devices may provide insights into this question. To determine whether device based physiologic parameters are indicative of CRT response/non-response and thus identify potential candidates for MSP. SMART-MSP study evaluated 6-month CRT response, defined by improved Clinical Composite Score, in patients with CRT defibrillators (CRT-D). Device parameters considered for this analysis included third (S3) and first (S1) heart sounds, thoracic impedance (ITTI), respiration rate, rapid shallow breathing index (RSBI), activity, and the multi-sensor HeartLogic index. From a randomly selected 60% development set of patients (183 CRT responders and 40 non-responders) with at least 150 days of data, the following statistical measures were calculated for each parameter based on the first 60- and 150-day epoch after CRT-D implant: mean (μ), standard deviation (σ) and change from first 30-day mean to last 30-day mean (Δ). To evaluate the effect of each measure on CRT response, odds ratios were calculated and tested for significance via univariable and multivariable logistic regression. The 60-day analysis (Fig 1A) shows that increases in σ60 for S3, S3/S1, RSBI, respiration rate, and HeartLogic index as well as μ60 for RSBI were significantly associated with reduced odds of CRT response in the univariable model. The only signal to survive multivariate elimination was respiration rate σ60. The 150-day analysis (Fig 1B) shows the same indications and that increases in μ150 for RSBI and HeartLogic index were associated with reduced odds while increases in μ150 and Δ150 for activity were associated with increased odds of CRT response. Both respiration rate σ150 and activity Δ150 survived multivariate elimination. Multiple device-based physiologic parameters significantly differed between CRT responders versus non-responders in the SMART-MSP study. 60-day results indicate that there is potential for device-based parameters to identify patients who may benefit from switching to MSP sooner. However, while useful parameters are apparent early on (60-day window), more parameters become significant over a longer follow-up (150 days).

Fosgonimeton Provides Congruent Improvements on Neurodegeneration Biomarkers, Significantly Correlating With Composite Clinical Score of Cognition and Function in Alzheimer’s Disease (S26.008)

<h3>Objective:</h3> To evaluate changes from baseline in plasma biomarkers in subjects with mild-to-moderate Alzheimer’s disease (AD) treated with fosgonimeton, a small-molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, compared with placebo and to assess multifactorial correlations with the global statistical test (GST), a composite score informed by both ADAS-Cog11 and activities of daily living (ADCS-ADL23). <h3>Background:</h3> Despite the multifactorial nature of AD, research has primarily targeted proteotoxicity; approaches addressing other contributory factors are needed. Fosgonimeton was evaluated in the randomized, double-blind, placebo-controlled, phase 2 ACT-AD study (NCT04491006); biomarker results are reported here. <h3>Design/Methods:</h3> Blood samples were collected at baseline (N=77) and week 26 of treatment. Biomarkers assessed include neurofilament light chain (NfL; indicates ongoing neurodegeneration), GFAP (indicates microglial activation), YKL-40 (indicates neuroinflammation), and amyloid beta 40 and 42 (Aβ40, Aβ42). Results are represented for pooled active arms versus placebo, without background therapy. <h3>Results:</h3> Baseline biomarker levels were similar between treatments. A statistically significant change from baseline versus placebo in NfL (−7.9 pg/mL; SE, 2.7; <i>P</i>=0.0059) and directionally favorable improvements in GFAP (−29.3 pg/mL; SE, 28.6; <i>P</i>=0.312), YKL-40 (−34.9 ng/mL; SE, 26.5; <i>P</i>=0.195), and Aβ42/40 ratio (0.0066; SE, 0.0035; <i>P</i>=0.064) were observed in fosgonimeton-treated subjects. ApoE4 genotype, baseline Mini-Mental State Examination score, sex, or age did not affect these results. In an analysis to confirm correlation of biomarkers and clinical outcomes, the composite endpoint GST proved to be highly correlated with changes in NfL (r=0.46; <i>P</i>=0.0011) and GFAP (r=0.30; <i>P</i>=0.0394). <h3>Conclusions:</h3> In this first-ever, randomized, placebo-controlled trial of fosgonimeton, a statistically significant reduction in NfL and descriptive, congruent GFAP and YKL-40 plasma concentration improvements were observed, which would be consistent with a neuroprotective effect and multimodal mechanism of action of fosgonimeton. The significant correlation of NfL and GFAP reduction with the composite clinical endpoint further supports clinical relevance. <b>Disclosure:</b> Dr. Moebius has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Athira Pharma, Inc.. Dr. Moebius has stock in Athira Pharma, Inc.. Ms. Ooi has received personal compensation for serving as an employee of Athira Pharma Inc. Ms. Ooi has stock in Athira Pharma Inc. Dr. Hale has received personal compensation for serving as an employee of Athira Pharma. Dr. Hale has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Takeda. Dr. Hale has stock in Amgen. Dr. Setti has received personal compensation for serving as an employee of Athira Pharma. Dr. Setti has stock in Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Alpine Immune Sciences. Mrs. Kleist has stock in Athira Pharma. Mrs. Kleist has stock in Alpine Immune Sciences. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Optina. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Corium. Dr. Bernick has stock in Aurora. The institution of Dr. Bernick has received research support from UFC. The institution of Dr. Bernick has received research support from Top Rank Promotions. The institution of Dr. Bernick has received research support from Haymon Boxing.

Return to the Emergency Department Within 3 Months Following Pediatric Acute Concussion.

To determine the proportion of concussed children returning to the emergency department (ED) for a concussion-related reason within 3 months of initial presentation and to determine which clinical composite score (5P or Post-Concussion Symptom Inventory) best predicts a return visit. We combined a secondary analysis of data from the prospectively collected 5P study with a retrospective medical record review of children aged 5 to 18 years who returned to the Children's Hospital of Eastern Ontario (CHEO) ED for a concussion-related reason within 3 months of an acutely diagnosed concussion. Among 770 eligible participants, 632 children (median age: 11.8 [interquartile range (IQR), 9.0-14.5] years; 58.9% male) were included in the study. The primary outcome was the number of patients who returned to CHEO ED for a concussion-related reason within 3 months of an acute concussion diagnosed at CHEO ED. The secondary outcome was number of patients who returned within 14 days. Forty-seven children (7.4%; 95% confidence interval [CI]: 5.6-9.7) had a concussion-related return to the ED within 3 months, the majority of which occurred in the first 14 days (29/47; 61.7%; 95% CI: 47.4-74.2). History of migraines (21.3% vs 9.7%; P = .03) were more common in those with a return visit. Headache was the most frequently reported symptom (87.2%) on revisit. Females aged 13 to 18 years had the highest return rate (survival rate: 85.8% [95% CI: 79.8-92.3]) compared with males and younger age groups. In multivariable Cox hazards regression modeling, inclusion of risk scores improved prognostication (pseudo R2 = 8%). The difference in pseudo R2 between 5P and Post-Concussion Symptom Inventory is small. Most children and adolescents do not return to the ED following an acute concussion. Female youth with medium to high 5P scores at the index concussion visit may benefit from early referral to interdisciplinary specialty concussion care to guide treatment in anticipation of prolonged symptoms. By identifying these risk factors at the initial ED visit, healthcare and patient burden may be reduced.

A possible easy way to predict response to cardiac resynchronization therapy: The role of QRS Index

Background: Some studies have evaluated the role of QRS duration (QRSd) as predictor of response to Cardiac Resynchronization Therapy (CRT). However, their results are still not entirely clear. The goal of our study was to determine the correlation between the relative change in QRS narrowing index (QI) compared to clinical outcome and prognosis in patients who underwent CRT implantation. Methods: We collected clinical and echocardiographic data of 115 patients in whome a CRT device was implanted in accordance with current guidelines. QRS duration before and after CRT implantation and QI were measured. Results: After 6 months, a significant improvement in all echocardiographic parameters was detected. QI was correlated to reverse remodelling (r = +0.19; 95% CI: 0.006 to 0.35, p = 0,049). The value of QI that predicted best LV reverse remodelling after 6 months of CRT was 12.25% (sensitivity = 65,5%, specificity = 75%, area under the curve = 0.737, p = 0,001). Independent predictors of QI are sex, serum creatinine and eGFR measured at baseline and LVEF pre-CRT performed by echocardiography. We observed an betterment in their HF clinical composite score and NYHA class at 12 months. We have also investigated the clinical outcomes and the possible sex differences related to QI. Conclusions: Patients with a larger QI after CRT initiation showed greater echocardiographic reverse remodelling and better outcome from death or cardiovascular hospitalization. QI seems to be an easy-to- measure variable that could be used or evaluated to predict CRT response but further studies are needed.

NCOG-03. IMPACT OF THE RATE OF RADIOGRAPHIC RESPONSE (RR) OF BRAIN METASTASES (BM) TO WHOLE BRAIN RADIATION THERAPY (WBRT) ON NEUROCOGNITIVE FUNCTION (NCF) ON NRG-CC001

Abstract BACKGROUND The assessment of BM response to WBRT and its impact on NCF in clinical trials has been limited by lack of standardized imaging protocols. NRG-CC001 is a randomized clinical trial requiring pre-specified MRI protocols at baseline and 6-months, providing a uniform dataset to investigate if RR correlates with NCF changes. METHODS NRG-CC001 randomized patients with BM to hippocampal avoidance WBRT (HA-WBRT) or WBRT. NCF was analyzed using 6-month standardized change scores and deterioration, defined using the reliable change index. Chi-square and t-tests were used for pretreatment characteristic comparisons. Inter-rater reliability between central and institutional assessment of RR was assessed with weighted kappa, κ. Linear regression was used to test trends in NCF change scores across types of response and multivariable logistic regression was used to test the association of RR to NCF deterioration. RESULTS 149 and 135 patients were evaluable for RR and NCF assessment, respectively. Pretreatment characteristics were well-balanced, except for post-high school education (70.6% HA-WBRT vs. 52.5% WBRT, p=0.023). Inter-rater reliability between central and institutional assessment of RR was fair (κ=0.36). There was no difference between arms in RR (p=0.41) with overall rates of 14.1% CR, 42.2% PR, 17% SD, and 26.7% PD. Patients with CR had improved 6-month NCF change as measured by HVLT-R Total Recall (p=0.0005), HVLT-R Delayed Recall (p=0.0003), HVLT-R Delayed Recognition (p=0.011), TMT-B (p=0.033), COWA (p=0.016), and Clinical Trial Battery Composite score (p=0.0011). Multivariable analysis demonstrated less deterioration in HVLT-R Delayed Recall for CR (p=0.019) and PR (p=0.0086) vs. SD/PD and HVLT-R Recognition for PR (p=0.031) vs. SD/PD. CONCLUSIONS HA-WBRT and WBRT result in similar RR at 6-months. CR or PR is associated with better NCF preservation. This suggests investigation into treatment escalation for patients with SD/PD may provide further NCF benefit along with HA-WBRT and memantine.Grant support from NCI-UG1CA189867 and U24CA180803.

Strategic management to optimize response to cardiac resynchronization therapy registry

Abstract Background Cardiac resynchronization therapy (CRT) is guideline-recommended for the treatment of symptomatic heart failure (HF) in patients (pts) with reduced LVEF and prolonged QRS. Clinical trials report Clinical Composite Score (CCS) response rates from 60 to 75%. However, patients with common comorbidities, such as atrial fibrillation, are often under-represented in clinical trials. The Strategic MAnagement to optimize response to cardiac Resynchronization Therapy (SMART) Registry (NCT03075215) was designed to examine outcomes in CRT patients in the real world. Methods The SMART Registry was a global, multicenter, prospective, clinical registry that enrolled subjects undergoing a de novo CRT-D implant or upgrade from pacemaker to CRT-D using a quadripolar LV lead. CCS was assessed at 12 months post-implant. Results For study design and CCS outcomes see Figure 1. CCS at 12 months showed that 58.8% of pts improved and 20.1% stabilized. Of the 21.1% of pts that worsened, 8.4% were due to death, 7.8% non-fatal heart failure event, and 5% worsening of NYHA or patient global assessment. Notably, this registry had a high prevalence of pts with NYHA I/II (51%), Non-LBBB (50%), AF (37%), diabetes (35%), and bradycardia (31%) at baseline. Age (&amp;gt;65), diabetes, ischemia, non-LBBB, atrial fibrillation (AF) and renal dysfunction correlated with worsened CCS outcomes. NYHA III/IV patients had significantly higher HF hospitalization (HFH) rates than NYHA I/II (P-value &amp;lt;0.001) (Figure 2a) and patients with AF had higher HFH rates than those without (P-value &amp;lt;0.001) (Figure 2b). Similar effects of NYHA score and AF were seen on mortality. The use of ACE/ARB, or ARNI, and MRA correlated with better outcomes, whereas diuretics and anticoagulants correlated with poorer outcomes. Conclusions In this large registry, clinical outcomes across important sub-populations are in line with expectations, with older age, ischemia, renal dysfunction, AF, non-LBBB, and diabetes associated with a lower likelihood of response to CRT. By including these patients, this study provides a clearer picture of the effectiveness of CRT in the real world. Future studies should examine optimization approaches to facilitate CRT effectiveness in these under studied patient populations. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This registry was funded by Boston Scientific (BSC)

Anemia Is a Strong Predictor of Wasting, Disease Severity, and Progression, in Clinical Tuberculosis (TB).

A typical trait of chronic tuberculosis (TB) is substantial weight loss that concurs with a drop in blood hemoglobin (Hb) levels, causing anemia. In this observational study, we explored Hb levels in 345 pulmonary TB patients. They were divided into anemic or non-anemic groups which related to clinical symptoms, anthropometric measurements, and immune status. Data was obtained in a randomized controlled trial that we previously conducted using nutritional supplementation of TB patients in Ethiopia. A post hoc analysis demonstrated that anemic patients have a higher composite clinical TB score at baseline than non-anemic patients. Consequently, Hb values were significantly lower in underweight patients with moderate to severe disease and/or cavitary TB compared to normal weight patients with mild disease or non-cavitary TB. Anemia was associated with a low body mass index (BMI), low mid-upper arm circumference (MUAC), lower peripheral CD4 and CD8 T cells counts and IFN-γ levels, and a higher erythrocyte sedimentation rate (ESR). Chronic inflammation and TB disease progression appeared to be driven by elevated systemic levels of pro-inflammatory IL-6 in anemic patients. Multivariable modeling confirmed that a low Hb and a low BMI were key variables related to an unfavorable TB disease status. Although Hb levels increased with successful chemotherapy, anemic TB patients maintained a slower clinical recovery compared to non-anemic patients during the intensive phase treatment (two months). In conclusion, anemia is a strong predictor of wasting, disease severity, inflammation, and slower recovery in patients with pulmonary TB.

Six versus 2 weeks treatment with doxycycline in European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blinded, randomised and placebo-controlled trial

BackgroundThere is limited evidence regarding optimal duration of antibiotic treatment in neuroborreliosis. We aimed to compare efficacy and safety of oral doxycycline for 2 and 6 weeks in European Lyme...