Clinical Endpoints In Patients Research Articles

Heart failure, recurrent vascular events and death in patients with ischemic stroke—results of the MonDAFIS study

Heart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse.We assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF) < 55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models. Overall, 410/2562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF < 55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95% CI 1.02–4.79), and all-cause death (HR 1.67; 95% CI 1.12–2.50), but not with major bleed (HR 1.93; 95% CI 0.73–5.06) or recurrent stroke/TIA (HR 1.08; 95% CI 0.75–1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization. Patients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar. Trial registration number Clinicaltrials.gov NCT02204267.

Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of thepatients, adherence to vericiguat was high as indicated by a medication possession ratio of ≥ 80%, and 67% of thepatients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

Efficacy of pre, pro, and synbiotic on clinical endpoint of acute pancreatitis: a systematic review and meta-analysis

Background: Acute pancreatitis (AP) commonly presents as gastrointestinal disease and can become a life-threatening condition. The pathophysiological process involves impairment in the gut barrier and bacterial translocation, mediating the infection of necrotic pancreatic tissue. Therefore, a strategy to maintain gut integrity is rational. The Probiotics in Pancreatitis Trial (PROPATRIA) found that probiotics had a harmful effect on severe AP. However, additional research revealed neither favorable nor unfavorable effects. This study aimed to analyze the efficacy of these medications on clinical endpoints in patients with AP. Methods: We performed a systematic search up to April 14, 2023. The study population in this review were patients with AP. The intervention consisted of prebiotic group, probiotic group, and synbiotic group. The effectiveness of each group in treating LoH was the main result, while infection complications were the secondary result. The analysis was conducted using a random effect model, and publication bias was found using a funnel plot. Results: 16 studies were used in this review and meta-analysis. A total of 1,044 acute pancreatitis patients and 779 patients were included for primary and secondary outcomes, respectively. The use of either pre-, pro-, and synbiotics reduces the LoH significantly (-3.32 days, p = 0.001). Subgroup analysis of the interventions revealed that probiotics (-3.02 days, p =0.02) and prebiotics (-3.9 days, p =0.02) reduce the LoH, but not for synbiotics (-4.37 days, p =0.18). As for secondary outcomes, the use of pre-, pro-, and synbiotics reduce the risk of infection in acute pancreatitis patients with odds ratio (OR) of 0.32 (p = 0.006). Conclusion: Additional medication of prebiotics, probiotics, and synbiotics as an adjunctive to standard therapy showed clinical benefits in AP patients. Therefore, its usage on acute pancreatitis patients could provide clinical benefit, albeit further studies are warranted.

Principle and design of clinical efficacy observation of extracorporeal cardiac shock wave therapy for patients with myocardial ischemia-reperfusion injury: A prospective randomized controlled trial protocol

Background Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life threatening event with a poor prognosis due to myocardial ischemia/reperfusion injury despite coronary revascularization. Extracorporeal cardiac shock wave (ECSW) is a safe, effective and non-invasive new method for the treatment of cardiovascular diseases. The current results show that extracorporeal cardiac shock wave provides a new treatment option for patients with severe and advanced coronary heart disease. However, there are relatively few clinical studies on the application of in vitro cardiac shock waves in patients with myocardial ischemia-reperfusion injury. We hypothesized that extracorporeal cardiac shock therapy would also be effective in reducing clinical endpoints in patients with STEMI reperfusion. Objective This study is order to provide a new therapeutic method for patients with myocardial ischemia-reperfusion injury and reveal the possible mechanism of ECSW for ischemia-reperfusion injury. Methods and materials CEECSWIIRI is a single-center, prospective randomized controlled trial that plans to enroll 102 eligible patients with acute ST-segment elevation myocardial infarction reperfusion. Eligible patients with STEMI reperfusion will be randomly divided into external cardiac shock therapy (ECSW) trial group and blank control group. The blank control group will receive optimal drug therapy, and the experimental group will receive optimal drug therapy combined with ECSW. The shock wave treatment plan will be 3-month therapy, specifically 1 week of treatment per month, 3 weeks of rest, 3 times of ECSW in each treatment week, respectively on the first day, the third day and the fifth day of the treatment week, lasting for 3 months and follow-up for 2 years. The primary endpoint will be to assess the 2-year improvement in all-cause death, re-hospitalization due to cardiovascular disease, major unintentional cerebrovascular events, including cardiogenic death, myocardial infarction, heart failure, arrhythmia, emergency coronary revascularization, and stroke in patients with STEMI reperfusion. Secondary endpoints will include improvements in angina pectoris, quality of life, cardiac structure and function, coronary microcirculation, and endothelial progenitor cell-derived miR-140-3p in relation to survival outcomes. Trial registration number ClinicalTrial.gov.org PRS:NCT05624203; Date of registration: November 12, 2022.

Association of medical therapy with cardiovascular outcomes in patients with myocardial infarction with nonobstructive coronary arteries

Abstract Background Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a disease that has been poorly characterized with unclear clinical and therapeutic outcomes. The association of medical therapy with cardiovascular outcomes in patients with MINOCA has been inadequately assessed. The purpose of this meta-analysis is to evaluate the association of medical therapy with cardiovascular outcomes in patients with MINOCA. Methods A literature search was conducted for studies reporting on the association of medical therapy with clinical endpoints in patients with MINOCA. Clinical endpoints include all-cause mortality, recurrence of acute coronary syndrome (ACS), and major adverse cardiovascular events (MACE). Databases searched included Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. Results A total of 9 studies with 27731 MINOCA patients (17816 on medical therapy, 9915 not on medical therapy) met inclusion criteria. Mean follow-up duration was 56 months, mean age was 63 years old, 52% were men. Medical therapy did not significantly reduce risk of MACE compared to no medical therapy (OR 0.99, 95% CI 0.91-1.07; p=0.73). Subgroup analysis demonstrated no significant reduction in risk of MACE regardless of ACE inhibitors/ARBs, antiplatelet therapy, or beta blocker therapy (OR 1.03, 95% CI 0.91-1.17; p=0.62; OR 1.00, 95% CI 0.87-1.14; p=0.98; OR 0.92, 95% CI 0.79-1.06; p=0.22). However, there is a trend toward lower risk of MACE in MINOCA patients on beta blocker therapy. Analysis of MINOCA patients by presence of vasospasm did not demonstrate any significant reduction in risk of MACE with antiplatelet use in either subgroups (OR 1.03, 95% CI 0.71-1.49; p=0.89 without vasospasm; OR 0.92, 95% CI 0.74-1.14; p=0.44 with vasospasm). Use of antiplatelet therapy in patients with vasospasm did not significantly reduce risk of mortality or recurrent ACS (OR 0.80, 95% CI 0.37-1.75; p=0.58; OR 1.21, 95% CI 0.89-1.64; p=0.22). Conclusions Standard medical therapy using antiplatelet agents, beta blockers, or ACE inhibitors/ARBs are not associated with lower risk of cardiovascular outcomes in patients with MINOCA regardless of presence of vasospasm. However, there is a paucity in literature evaluating agents other than antiplatelet therapies. Additional high-quality studies are required to evaluate the utility of specific medication classes for treatment of specific etiologies of MINOCA.

Association of baseline and changes in health related quality of life with mortality following myocardial infarction: multicentre longitudinal linked cohort study

Abstract Background/Introduction Health related quality of life (HRQoL) for patients following myocardial infarction (MI) is frequently impaired and often deteriorates. However, the association between HRQoL and clinical endpoints in patients with MI is unknown. Purpose To investigate the association of baseline and temporal changes in HRQoL with long term all-cause mortality following MI. Methods This nationwide longitudinal linked health record study includes individuals with MI admitted to 77 hospitals in England between 1st November 2011 and 24th June 2015 in the EMMACE-3 and -4 studies. Self-reported HRQoL was collected using the EuroQol EQ-5D-3L (EuroQOL Visual Analogue Scale (EQ-VAS) and EuroQOL 5-Dimensional Classification (EQ-5D)) instrument during hospitalisation and at 1, 6 and 12-months following hospital discharge. Flexible parametric and multilevel survival models estimated associations of baseline and change in HRQoL with long term all-cause mortality. Results Of 9,474 individuals with MI, 25% (2,360) were women and 22.5% (2,135) participants died during the 9 years follow up period (median 6.9 years). There was an improvement in HRQoL over 12 months following MI (baseline mean, mean increase: EQ-5D 0.76, 0.003 per month; EQVAS 69.0, 0.5 per month). Better HRQoL at baseline was inversely associated with mortality (HR 0.55, 95% CI 0.47-0.63) (Figure 1A). At baseline, problems with self-care (HR 1.73, 95% CI 1.56-1.92), mobility (1.65, 1.50-1.81), usual activities (1.34, 1.23-1.47) and pain/discomfort (1.34, 1.22-1.46), were associated with increased mortality (Figure 1A). Improvements in EQ-5D (HR 0.69, 95% CI 0.60-0.80), but not EQ-VAS reduced the risk of death (Figure 1B). Deterioration in mobility, pain/discomfort, usual activities and self-care over 12 months increased the risk of death (HR 1.43, 95% CI 1.31-1.58; 1.21, 95% CI 1.11-1.32; 1.20, 95% CI 1.10-1.32; 1.44, 95% CI 1.30-1.59, respectively) (Figure 1B). Conclusions For patients with MI, poor HRQoL at baseline, its dimensions and deterioration over time are associated with mortality. Measuring HRQoL in routine clinical practice could delineate an at-risk group for targeted interventions to improve prognosis.Figure 1

Patient-Reported Outcomes in Myotonic Dystrophy Type 2: Correlations with Motor and Cognitive Endpoints (S7.007)

<h3>Objective:</h3> To characterize patient-reported outcomes (PROs) and evaluate relationships between PROs and clinical endpoints in patients with myotonic dystrophy type 2 (DM2). <h3>Background:</h3> Although muscle weakness is the key feature in DM2, two-thirds of patients report that impaired cognition is among the most disabling symptoms and affects their quality of life. PROs of physical and mental status are extremely limited in DM2 but could serve as measures for clinical trial development. <h3>Design/Methods:</h3> Ten individuals with DM2 and ten age and gender-matched controls were enrolled. All participants underwent brain MRIs and a comprehensive battery of cognitive and motor measures. Additionally, they completed PROs, including the 36-Item Short Form (SF-36), PRO Measurement Information System (PROMIS-10), Beck Depression and Anxiety Inventory (BDI and BAI), and Apathy Evaluation Scale (AES). Paired t-test and Spearman’s correlation were used to determine group differences and correlations between PROs and clinical endpoints. <h3>Results:</h3> Of 20 participants (60% female), mean age and education were similar between groups. Compared to controls, the DM2 group showed a significant difference in BAI, AES, and SF-36 physical functioning (PF) subscale (<i>p</i>=0.004–0.024) and impaired PROMIS-Global Physical (GPH) and Mental Health (GMH). We found a strong correlation between SF-36 (PF) and PROMIS-GPH with a 6-minute walk test and gait speed (<i>rho</i>=0.68–0.75, <i>p</i>=0.02–0.04). Moderate correlations were observed between 1) BDI and verbal fluency test; 2) BAI and processing speed; 3) AES and a test of executive function and cerebral white matter integrity. <h3>Conclusions:</h3> Our pilot study demonstrates that changes in mental and physical health status are of significance for DM2 patient’s quality of life. The relationships between PROs (BAI, BDI, and AES) and cognitive endpoints suggest brain involvement. PROs, as measured by SF-36 and PROMIS-10, are associated with motor endpoints. These results support the use of PROs as a tool to measure disease burden in DM2. <b>Disclosure:</b> Dr. Jain has nothing to disclose. Dr. Olszewski has nothing to disclose. Dr. Flashman has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Archives of Clinical Neuropsychology. The institution of Dr. Flashman has received research support from NIH/NINDS. The institution of Dr. Flashman has received research support from Michael J Fox Foundation. Mrs. Burgos-Aguilar has nothing to disclose. Dr. Duncan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BrainQ Technologies. Dr. Duncan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Pittsburg Pepper Center. Dr. Duncan has stock in CareDirections. The institution of Dr. Duncan has received research support from PCORI. The institution of Dr. Duncan has received research support from NIA and NINDS. The institution of Dr. Duncan has received research support from AHRQ. Dr. Duncan has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Nopoulos has received personal compensation in the range of $500-$4,999 for serving as a Consultant for norvartis. The institution of Dr. Puwanant has received research support from Muscular Dystrophy Association. The institution of Dr. Puwanant has received research support from NIH/NINDS. The institution of Dr. Puwanant has received research support from NIH/NINDS.

Association of Computed Tomography Measures of Muscle and Adipose Tissue and Progressive Changes throughout Treatment with Clinical Endpoints in Patients with Advanced Lung Cancer Treated with Immune Checkpoint Inhibitors

To investigate the association between skeletal muscle mass and adiposity measures with disease-free progression (DFS) and overall survival (OS) in patients with advanced lung cancer receiving immunotherapy, we retrospectively analysed 97 patients (age: 67.5 ± 10.2 years) with lung cancer who were treated with immunotherapy between March 2014 and June 2019. From computed tomography scans, we assessed the radiological measures of skeletal muscle mass, and intramuscular, subcutaneous and visceral adipose tissue at the third lumbar vertebra. Patients were divided into two groups based on specific or median values at baseline and changes throughout treatment. A total number of 96 patients (99.0%) had disease progression (median of 11.3 months) and died (median of 15.4 months) during follow-up. Increases of 10% in intramuscular adipose tissue were significantly associated with DFS (HR: 0.60, 95% CI: 0.38 to 0.95) and OS (HR: 0.60, 95% CI: 0.37 to 0.95), while increases of 10% in subcutaneous adipose tissue were associated with DFS (HR: 0.59, 95% CI: 0.36 to 0.95). These results indicate that, although muscle mass and visceral adipose tissue were not associated with DFS or OS, changes in intramuscular and subcutaneous adipose tissue can predict immunotherapy clinical outcomes in patients with advanced lung cancer.

A comprehensive meta-analysis comparing radiofrequency ablation versus pharmacological therapy for the treatment of atrial fibrillation in patients with heart failure

BackgroundAtrial fibrillation (AF) and heart failure (HF) are both associated with worse prognosis and often coexist in the same patients. Whether catheter ablation (CA) is superior to pharmacological therapy in reducing major clinical endpoints in patients with AF and HF is still unsettled. ObjectiveTo conduct a comprehensive meta-analysis comparing CA with medical therapy (MT) in this population. MethodsWe systematically searched for randomized and observational studies comparing clinical outcomes between patients with AF and HF treated with CA or MT. The studied outcomes were mortality, hospitalization, left ventricle ejection fraction (LVEF) and 6-min walking test (6MWT) improvement. ResultsA total of 12 studies counting 41,377 patients (3611 treated with CA and 37,766 with MT) were included in the analysis. The random-effect model revealed a clear trend in favor of CA in reducing unexpected HF hospitalization (RR 0.72; 95%CI 0.51–1.00; P = 0.05), all-cause death (RR 0.77; 95%CI 0.59–1.01; P = 0.06), all-cause hospitalization (RR 0.84; 95%CI 0.68–1.03; P = 0.09), and the composite of HF hospitalization and death (RR 0.77; 95%CI 0.58–1.02; P = 0.07), compared with MT. Patients treated with CA experienced a better improvement in LVEF (mean difference 6.17; 95%CI 2.98–9.37; P = 0.0002) and 6MWT (mean difference 13.70; 95%CI 3.95–23.45; P = 0.006).When the analysis was limited to randomized controlled trial, CA was found to significantly reduce all-cause death (RR 0.68; 95%CI 0.54–0.86; P = 0.001). ConclusionAs compared to MT, CA is associated with a better improvement in functional capacity and LVEF, and with a reduction in major clinical endpoints in patients with HF and AF.

Outcome of COVID-19 Patients Presented with Gastrointestinal and Hepatic Manifestations

Background. COVID-19 is rapidly spreading as a global pandemic disease that affects mortality, morbidity, and economic recession worldwide including Myanmar. This study is aimed at investigating the prevalence and temporal nature of gastrointestinal and hepatic manifestations as well as their association with composite clinical endpoints in patients with COVID-19. Method. This was a retrospective hospital-based cohort study conducted on confirmed COVID-19 patients who were admitted to two designated COVID-19 hospitals: DSLH and No. (22/100) MH, Yangon, Myanmar, from June 1, 2021, to August 31, 2021. Data related to patients’ demographics, clinical characteristics, and clinical outcomes were abstracted manually through individual hospital records. Results. Out of the 241 patients recruited, 68 (28.2%) of the patients had GI symptoms. Ageusia/hypogeusia and diarrhea are the most common symptoms at 41.3% and 28.3%, respectively. Abnormal liver chemistries at admission are found in 52.7% of total patients. Mortality is 12.9% (31/241). Patients with abnormal liver chemistry are older ( p &lt; 0.001 ), unvaccinated or incompletely vaccinated ( p = 0.04 ), associated comorbidities ( p = 0.019 ), leukocytosis ( p &lt; 0.001 ), lymphopenia ( p = 0.033 ), hypoalbuminemia ( p &lt; 0.001 ), higher INR ( p &lt; 0.001 ), and longer HDU stay ( p &lt; 0.001 ) and higher mortality ( p &lt; 0.001 ). Conclusion. COVID-19-infected patients with abnormal liver chemistry are found to have worse clinical outcomes, although no significant association is found in patients with digestive symptoms. More attention should be given to this group of patients in the next coming wave.

The Hospital Recovery Scale: A clinically useful endpoint in patients hospitalized with influenza

Background: Currently, no single best primary endpoint exists for measuring the efficacy of treatments in seriously ill patients with respiratory infections, such as influenza, who require hospitalization. The Hospital Recovery Scale is an ordinal endpoint used to evaluate treatment outcomes in clinical studies of hospitalized patients infected with influenza.Methods: To determine whether Hospital Recovery Scale outcomes correspond to those for other clinical endpoints in patients hospitalized due to influenza, data from the phase 3 randomized, double-blind ZORO clinical trial (NCT01231620) were analyzed. Randomized influenza-infected patients were divided into subgroups of interest based on prespecified baseline and infection-related characteristics, as well as randomized treatment arms (intravenous zanamivir 300 mg or 600 mg, or oral oseltamivir 75 mg). Clinical endpoints relevant to this population were included to analyze differences in outcomes between the subgroups, and correspondence of these endpoints and hospital recovery endpoint was evaluated.Results: Data from 488 patients were analyzed. There were strong correlations (ρs > 0.8) between the Hospital Recovery Scale assessed on the day after completion of a 5-day antiviral therapy (Day 6) and both time to hospital discharge and time to intensive care unit discharge, and moderate to strong correlations (0.6 < ρs < 0.8) between the Hospital Recovery Scale on Day 6 and several other relevant clinical endpoints.Conclusions: The Hospital Recovery Scale is applicable as a primary endpoint in trials to evaluate new therapies for severely ill patients hospitalized due to influenza, and may have utility in other severe respiratory illnesses such as COVID-19.

Treatment planning computed tomography radiomics for predicting treatment outcomes and haematological toxicities in locally advanced cervical cancer treated with radiotherapy: A retrospective cohort study.

We evaluated whether radiomic features extracted from planning computed tomography (CT) scans predict clinical end points in patients with locally advanced cervical cancer (LACC) undergoing intensity-modulated radiation therapy and brachytherapy. A retrospective cohort study. Xiangya Hospital of Central South University, Changsha, Hunan, China. Two hundred and fifty-seven LACC patients who were treated with intensity-modulated radiotherapy from 2014 to 2017. Patients were allocated into the training/validation sets (3:1 ratio) using proportional random sampling, resulting in the same proportion of groups in the two sets. We extracted 254 radiomic features from each of the gross target volume, pelvis and sacral vertebrae. The sequentially backward elimination support vector machine algorithm was used for feature selection and end point prediction. Clinical end points include tumour complete response (CR), 5-year overall survival (OS), anaemia, and leucopenia. A combination of ten clinicopathological parameters and 34 radiomic features performed best for predicting CR (validation balanced accuracy: 80.8%). The validation balanced accuracy of 54 radiomic features was 85.8% for OS, and their scores can stratify patients into the low-risk and high-risk groups (5-year OS: 95.5% versus 36.4%, p < 0.001). The clinical and radiomic models were also predictive of anaemia and leucopenia (validation balanced accuracies: 71.0% and 69.9%). This study demonstrated that combining clinicopathological parameters with CT-based radiomics may have value for predicting clinical end points in LACC. If validated, this model may guide therapeutic strategy to optimise the effectiveness and minimise toxicity or treatment for LACC.

GlycA and GlycB as Inflammatory Markers in Chronic Heart Failure

The role of inflammation in heart failure (HF) has been extensively described, but it is uncertain whether inflammation exerts a different prognostic influence according to etiology. We aimed to examine the inflammatory state in chronic HF by measuring N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB), evolving proton nuclear magnetic resonance biomarkers of systemic inflammation, and explore their prognostic value in patients with chronic HF. The primary end point was a composite of all-cause death and HF readmission. A total of 429 patients were included. GlycB correlated with interleukin-1 receptor-like 1 in the whole cohort (r2=0.14, p=0.011) and the subgroup of nonischemic etiology (r2=0.31, p <0.001). No association was found with New York Heart Association functional class or left ventricular ejection fraction. In patients with nonischemic HF (52.2%, n=224), GlycA and GlycB exhibited significant association with the composite end point (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.06 to 1.33, p=0.004 and HR 2.13, 95% CI 1.43 to 3.13, p <0.001; respectively) and GlycB with HF readmission after multivariable adjustment (HR 2.25, 95% CI 1.54 to 3.30, p <0.001). GlycB levels were also associated with a greater risk of HF-related recurrent admissions (adjusted incidence rate ratio 1.33, 95% CI=1.07 to 1.65, p=0.009). None of the markers were associated with the clinical end points in patients with ischemic HF. In conclusion, GlycA and GlycB represent an evolving approach to inflammation status with prognostic value in long-term outcomes in patients with nonischemic HF.

Spatial interplay patterns of cancer nuclei and tumor-infiltrating lymphocytes (TILs) predict clinical benefit for immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) show prominent clinical activity across multiple advanced tumors. However, less than half of patients respond even after molecule-based selection. Thus, improved biomarkers are required. In this study, we use an image analysis to capture morphologic attributes relating to the spatial interaction and architecture of tumor cells and tumor-infiltrating lymphocytes (TILs) from digitized H&E images. We evaluate the association of image features with progression-free (PFS) and overall survival in non–small cell lung cancer (NSCLC) (N = 187) and gynecological cancer (N = 39) patients treated with ICIs. We demonstrated that the classifier trained with NSCLC alone was associated with PFS in independent NSCLC cohorts and also in gynecological cancer. The classifier was also associated with clinical outcome independent of clinical factors. Moreover, the classifier was associated with PFS even with low PD-L1 expression. These findings suggest that image analysis can be used to predict clinical end points in patients receiving ICI.

Baseline platelet count in percutaneous coronary intervention: a dose–response meta-analysis

ObjectivesThe nature of the relationship between baseline platelet count and clinical outcomes following percutaneous coronary intervention (PCI) is unclear. We undertook dose–response and pairwise meta-analyses to better describe the prognostic...

Pilot Study of a Wearable Activity Monitor During Head and Neck Radiotherapy to Predict Clinical Outcomes.

Given the established associations between performance status and survival in a variety of cancers, there is significant interest in using a biometric wearable device (WD) to predict outcomes in the oncology population. In this pilot study, we investigated the ability of a WD to predict meaningful clinical end points in patients undergoing head and neck radiotherapy. Patients receiving head and neck definitive chemoradiotherapy or postoperative radiotherapy/chemoradiotherapy were enrolled in this pilot study, designed to show 90% compliance with using the device. Individuals were asked to wear the WD for 23 hours a day, and hospital admissions, pain medication usage, and FACT-G quality-of-life (QoL) score were prospectively recorded. Fifty-one patients were enrolled and started using the WD, but eight patients stopped wearing it, resulting in a compliance probability of only 84%. There were 15 hospital admissions, 13 of which were planned for feeding tube placement. There was no step count threshold that predicted the need for admission or more pain medications. However, among the 25 patients with a significant reduction in FACT-G score, the average reductions in daily steps during the week and weekend before the decline were 988 (P = .005) and 1,311 (P = .018), respectively, and the odds of a QoL reduction were more than 4-fold higher among patients experiencing a week-to-week reduction of at least 1,000 daily steps. There was no association between heart rate and any end point. Although not meeting the compliance goal, the majority of patients did use the WD. The WD signal could not identify patients requiring hospitalization or significantly more pain medication, but the finding of reduced step counts before a significant reduction in QoL is provocative.

Hydromethylthionine enhancement of central cholinergic signalling is blocked by rivastigmine and memantine.

The prevention of tau protein aggregations is a therapeutic goal for the treatment of Alzheimer's disease (AD), and hydromethylthionine (HMT) (also known as leucomethylthioninium-mesylate [LMTM]), is a potent inhibitor of tau aggregation in vitro and in vivo. In two Phase 3clinical trials in AD, HMT had greater pharmacological activity on clinical endpoints in patients not receiving approved symptomatic treatments for AD (acetylcholinesterase (AChE) inhibitors and/or memantine) despite different mechanisms of action. To investigate this drug interaction in an animal model, we used tau-transgenic L1 and wild-type NMRI mice treated with rivastigmine or memantine prior to adding HMT, and measured changes in hippocampal acetylcholine (ACh) by microdialysis. HMT given alone doubled hippocampal ACh levels in both mouse lines and increased stimulated ACh release induced by exploration of the open field or by infusion of scopolamine. Rivastigmine increased ACh release in both mouse lines, whereas memantine was more active in tau-transgenic L1mice. Importantly, our study revealed a negative interaction between HMT and symptomatic AD drugs: the HMT effect was completely eliminated in mice that had been pre-treated with either rivastigmine or memantine. Rivastigmine was found to inhibit AChE, whereas HMT and memantine had no effects on AChE or on choline acetyltransferase (ChAT). The interactions observed in this study demonstrate that HMT enhances cholinergic activity in mouse brain by a mechanism of action unrelated to AChE inhibition. Our findings establish that the drug interaction that was first observed clinically has a neuropharmacological basis and is not restricted to animals with tau aggregation pathology. Given the importance of the cholinergic system for memory function, the potential for commonly used AD drugs to interfere with the treatment effects of disease-modifying drugs needs to be taken into account in the design of clinical trials.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study)

Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n= 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p= 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p= 0.992 and HR 1.058; 95% CI 0.727-1.548; p= 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Evaluation of ocrelizumab in older progressive multiple sclerosis patients

BackgroundSeminal trials evaluating anti-CD20 therapy in progressive MS primarily found benefit in younger, less-disabled patients with more inflammatory disease activity. The risks and benefits of ocrelizumab use in older patients with progressive froms of MS are not known. MethodsRetrospective chart review was performed for patients older than 55 with primary or secondary progressive MS at the time of ocrelizumab initiation. Clinical endpoints from 2 years prior to anti-CD20 therapy served as a within-subject control. ResultsData was reviewed for 56 patients older than the age of 55 at the time of ocrelizumab initiation. Of 37 patients with 2-years of follow up on ocrelizumab, 40%(n=15) experienced confirmed disability progression (CDP) while 60% (n=22) remained stable or improved. 24 patients had data available for the within-subject control; for these patients, median age was 67, baseline EDSS 6.3, and disease duration 20.5 years. Prior to anti-CD20 therapy, 58% (n=14) of patients remained stable and 42% (n=10) experienced CDP. After ocrelizumab initiation, 71% (n=17) remained stable and 29% (n=7) experienced CDP. There was no difference between CDP (p=0.54) or change in EDSS (p=0.09) between time periods. Ocrelizumab was well tolerated and no difference in infection rate was seen using the within-subject control. ConclusionsWe found no difference in clinical endpoints for patients on ocrelizumab compared to prior to anti-CD20 therapy; however, we could not exclude a modest effect given our sample size. Larger trials are needed to evaluate ocrelizumab use in this understudied MS subpopulation.

Exercise-Based Cardiac Rehabilitation and All-Cause Mortality Among Patients With Atrial Fibrillation.

BackgroundThere is limited evidence of long‐term impact of exercise‐based cardiac rehabilitation (CR) on clinical end points for patients with atrial fibrillation (AF). We therefore compared 18‐month all‐cause mortality, hospitalization, stroke, and heart failure in patients with AF and an electronic medical record of exercise‐based CR to matched controls.Methods and ResultsThis retrospective cohort study included patient data obtained on February 3, 2021 from a global federated health research network. Patients with AF undergoing exercise‐based CR were propensity‐score matched to patients with AF without exercise‐based CR by age, sex, race, comorbidities, cardiovascular procedures, and cardiovascular medication. We ascertained 18‐month incidence of all‐cause mortality, hospitalization, stroke, and heart failure. Of 1 366 422 patients with AF, 11 947 patients had an electronic medical record of exercise‐based CR within 6‐months of incident AF who were propensity‐score matched with 11 947 patients with AF without CR. Exercise‐based CR was associated with 68% lower odds of all‐cause mortality (odds ratio, 0.32; 95% CI, 0.29–0.35), 44% lower odds of rehospitalization (0.56; 95% CI, 0.53–0.59), and 16% lower odds of incident stroke (0.84; 95% CI, 0.72–0.99) compared with propensity‐score matched controls. No significant associations were shown for incident heart failure (0.93; 95% CI, 0.84–1.04). The beneficial association of exercise‐based CR on all‐cause mortality was independent of sex, older age, comorbidities, and AF subtype.ConclusionsExercise‐based CR among patients with incident AF was associated with lower odds of all‐cause mortality, rehospitalization, and incident stroke at 18‐month follow‐up, supporting the provision of exercise‐based CR for patients with AF.