2 Minute Medicine Rewind December 30, 2019

Association of Intrinsic Brain Architecture With Changes in Attentional and Mood Symptoms During Development

1. Resting-state functional connectivity between several brain regions may serve as a useful biomarker to predict future neuropsychiatric symptoms such as attention deficits, anxiety, and depression in children.

Evidence Rating Level: 2 (Good)

Neurodevelopment has become an important area of focus as it relates to mapping psychiatric and neurocognitive trajectories. There is also increasing interest in biomarkers that may allow for prediction of and early intervention for attention difficulties, anxiety, depression, and other conditions. Many cognitive processes are top-down, such that the prefrontal cortex (PFC) and higher-order regions inform other areas, notably the dorsolateral PFC (DLPFC) and anterior cingulate cortex (ACC) through their connections, resting-state networks and connectivity, rather than localization, are the critical components for determining outcomes. In this cohort study, 94 children who were enrolled in another developmental longitudinal study related to the prediction of reading disabilities were studied to assess whether specific brain connectivity patterns are associated with longitudinal changes in scores on the Child Behavior Checklist (CBCL), a parental-report assessment used to screen for emotional, behavioral, and social problems and to predict psychiatric illnesses. As part of the study, resting-state fMRI (rs-fMRI) connectivity at seven years of age was measured, and reassessed yearly for four years. After four years of follow-up, data was available for 54 of the original 94 children. Researchers found that reduced positive coupling between the medial PFC and DLPFC at 7 years of age was associated with a decrease in attention symptoms four years later (p=0.01, β=0.32). Further, reduced coupling between the subgenual ACC and DLPFC at 7 years of age was associated with increased mood symptoms (i.e. anxiety and depression) within the following four years (p=0.01, β=0.30). Interestingly, subgenual ACC-DLPFC connectivity was a stronger predictor of symptoms transitioning from subclinical to clinical levels than baseline CBCL scores. The findings of this study therefore highlight the importance of functional connectivity in not only predicting future symptoms but determining those who may be at-risk and in need of early intervention.

Coronary Sinus Neuropeptide Y Levels and Adverse Outcomes in Patients With Stable Chronic Heart Failure

1. In patients with stable heart failure, adrenergic co-transmitter neuropeptide Y (NPY) levels can identify patients at risk of adverse outcomes related to hyperadrenergic activation

Evidence Rating Level: 2 (Good)

The adrenergic co-transmitter neuropeptide Y (NPY) is one of the neurotransmitters released by cardiac sympathetic nerve terminals, and may represent an important biomarker in the prognostication of patients with chronic heart failure (CHF). This prospective cohort study investigated coronary sinus (CS) NPY levels in 105 patients with stable CHF at the time elective cardiac resynchronization therapy (CRT) device implantation to determine the role of NPY levels in predicting adverse outcomes, including chronic heart failure hospitalization, death, orthotopic heart transplantation and ventricular assist device placement. The mean left ventricular ejection fraction (LVEF) of the sample was 26% (SD 7%). Patients were optimized with beta-blockers (90%), angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or nitrate/hydralazine combination (95%), and/or aldosterone antagonist (25%) prior to treatment. Researchers found that for patients with CS NPY levels greater than 130 pg/mL, the hazard ratio for event-free survival was increased (HR 9.5, 95% CI 2.92 to 30.5, p<0.001). Eight deaths and 28 heart failure hospitalizations were reported. Following CRT device implantation and follow-up, 59 patients were considered CRT responders at six-months post-treatment. Baseline NPY levels were not significantly different between responders and non-responders (difference = – 2.2 pg/mL, p = 0.76). Following molecular analyses of CHF patients and organ donor controls, NPY levels were associated with eGFR (rs = -0.36, p<0.001), N-terminal-pro hormone brain natriuretic peptide (rs = 0.33, p = 0.004), and left ventricular diastolic dimension (rs = -0.35, p<0.001), but not LVEF, functional status, age, or CRT response. Adjusting for LVEF, eGFR, and age to determine event-free (left ventricular assist device, cardiac transplant, death) survival for CS NPY levels greater than 130 pg/mL suggested similar findings to the previous analyses. Significantly reduced mean (SD) NPY protein was noted in cardiomyopathy (13.7 [7.6]) compared to controls (31.4 [3.7]; p<0.001) in stellate ganglia neurons and, with similar mRNA levels between these groups, suggests that CHF patients experience increased release from stellate ganglia neurons. This study therefore suggests that CS NPY levels may be associated with outcomes in stable CHF patients undergoing CRT, where elevated neuronal activity may serve as a mediating mechanism in these patients.

Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer

1. Compared to standard photon therapy, proton chemoradiotherapy resulted in significantly reduced reduction in adverse events without changing disease-free or overall survival rates

Evidence Rating Level: 2 (Good)

The standard of care for many cancers is concurrent chemoradiotherapy, which can be associated with significant morbidity. The administration of proton therapy as opposed to photon therapy, may result in reduced toxicity and improved outcomes through differences in radiation dose to surrounding tissues. This non-randomized, retrospective, comparative effectiveness study of 1,483 adult patients with non-metastatic, locally advanced cancer was conducted from 2011 through 2016 to determine differences between concurrent proton (n=391) and photon (n=1,092) chemoradiotherapy. Critical outcome data included 90-day adverse events associated with hospitalizations (CTCAEv4 grade >=3), performance status decline during treatment established by Eastern Cooperative Oncology Group (ECOG), and 90-day adverse events of at least CTCAEv4 grade 2 limiting activities of daily living (ADLs), and disease-free and overall survival. Researchers found that patients receiving proton therapy were significantly older than those undergoing photon therapy (p<0.01), exhibited less favorable Charlson-Deyo comorbidity scores (median difference 3.0, p<0.01), and had lower integral radiation dose to non-target tissues (mean volume difference –5.0 cGy/CC x 107, p<0.01). Baseline toxicity and ECOG performance status were not significantly different between treatment groups. Following propensity score weighted-analyses, proton therapy was found to be associated with a significant reduction in relative risk of grade 3 or worse adverse events during the 90-day time frame (RR 0.31, 95% CI 0.15 to 0.66, p = 0.002), grade 2 adverse events (RR 0.78, 95% CI 0.65 to 0.93, p=0.006), and reduced ECOG performance during treatment (RR 0.51, 95% CI 0.37 to 0.71, p<0.001). There were no significant differences in disease-free and overall survival rates. Nonetheless, this study found that proton chemoradiotherapy reduced acute adverse events leading to unplanned hospitalizations. As such, further studies are warranted to replicate these findings, as the results of this study suggest that proton therapy may be less harmful than conventional photon therapy.

Mortality and Health Care Utilization Among Medicare Patients Undergoing Emergency General Surgery vs Those With Acute Medical Conditions

1. Older adults who undergo emergency general surgeries face similar rates of hospital use, days away from home and work, and one-year mortality rates compared to other acute medical patients

Evidence Rating Level: 2 (Good)

Pneumonia, myocardial infarction, and heart failure are common acute medical conditions that result in hospitalization, post-discharge hospital use, and days at home. However, emergency general surgery (EGS) accounts for 11% of hospitalizations and nearly 50% of these are patients are older adults at an increased risk of mortality and readmission following EGS. This retrospective, population-based cohort study utilizing Medicare claims data sought to determine whether or not these older adult EGS patients face similar outcomes compared to other medical patients. This study investigated a total of 481,417 matched patient pairs (mean 78.9 years, 56.6% female). Patients were admitted for one of the top five high-burden EGS procedures: partial colectomy, small-bowel resection, peptic ulcer disease surgery, lysis of adhesions, laparotomy; or an acute medical condition: pneumonia, heart failure, myocardial infarction. Researchers found that following in the 30 days post-discharge, EGS patients faced higher mortality (p<0.001) than acute medical patients. However, EGS patients faced a lower one-year mortality rate (p<0.001) than the matched medical patients. Regarding post-discharge hospital encounters, acute medical patients experienced higher rates (incidence rate ratio 1.31, 95% CI 1.30 to 1.32) but groups were similar in terms of mean days spent at home (incident rate ratio 1.004, 95% CI 1.004 to 1.004). This study therefore highlights the importance of considering older-adult EGS patients in quality improvement efforts, as they not only face similar outcomes to matched medical patients, but have a higher risk of mortality 30 days post-discharge.

Clinician vs Patient Reporting of Baseline and Post-Baseline Symptoms for Adverse Event Assessment in Cancer Clinical Trials

1. Across 26 cancer clinical trials, researchers detected fewer baseline symptoms than those reported by patients, suggesting that adjustments to baseline determinations in clinical trials should consider patient reports as reliable data points.

Evidence Rating Level: 2 (Good)

Baseline symptoms are an important consideration in oncologic clinical trials. Currently, the standard process of determining adverse events (AEs) is the Common Terminology Criteria for Adverse Events (CTCAE), however, this does not account, in a clear manner, events attributable to baseline symptoms and those arising during clinical trials. As such, it is important to account for patient-reported baseline symptoms to adjust analyses of adverse events that are specific to the trials themselves. This retrospective study of legacy clinical trials supported by the National Cancer Institute aimed to analyze clinician CTCAE as well as patient-reported outcome (PRO) questionnaires both at baseline and throughout the clinical trials. A total of 26 cancer clinical trials between 1996 and 2015 were identified, with 24 unique AEs captured with the PRO questionnaires and other specific symptom scales. Baseline scores were significantly higher on patient reports compared to clinicians (83% of symptoms differed). Worst-case postbaseline symptom rates, independent of baseline adjustments, were different between patients and clinicians in 88% of reported symptoms, 76% of which were higher according to the patients. Importantly, approximately 67% of reported symptoms were significantly different between patients and clinicians when accounting for baseline symptoms, only 56% of which were rated higher by patients. This study highlights that nearly 75% of patients report a higher number of baseline symptoms than clinicians, such that misattribution of symptoms to trial effects may be overestimated. However, if sufficient patient reports are obtained and adjustment methods are utilized in accordance with this study, this discrepancy is reduced to roughly 50% disagreement and may reduce error in determining trial effects and AEs.

Image: PD

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