Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called "heterogeneity of treatment effect" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.
Ventricular repolarization components on the surface electrocardiogram (ECG) include J (Osborn) waves, ST-segments, and T- and U-waves, which dynamically change in morphology under various pathophysiologic conditions and play an important role in the development of ventricular arrhythmias. Our primary objective in this review is to identify the ionic and cellular basis for ventricular repolarization components on the body surface ECG under normal and pathologic conditions, including a discussion of their clinical significance. A specific attempt to combine typical clinical ECG tracings with transmembrane electrical recordings is made to illustrate their logical linkage. A transmural voltage gradient during initial ventricular repolarization, which results from the presence of a prominent transient outward K(+) current (I(to))-mediated action potential (AP) notch in the epicardium, but not endocardium, manifests as a J-wave on the ECG. The J-wave is associated with the early repolarization syndrome and Brugada syndrome. ST-segment elevation, as seen in Brugada syndrome and acute myocardial ischemia, cannot be fully explained by using the classic concept of an "injury current" that flows from injured to uninjured myocardium. Rather, ST-segment elevation may be largely secondary to a loss of the AP dome in the epicardium, but not endocardium. The T-wave is a symbol of transmural dispersion of repolarization. The R-on-T phenomenon (an extrasystole originating on the T-wave of a preceding ventricular beat) is probably due to transmural propagation of phase 2 re-entry or phase 2 early after depolarization that could potentially initiate polymorphic ventricular tachycardia or fibrillation.
Objective Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson’s disease (PD) but results are conflicting. Many studies do not account for confounding or reverse-causation. We sought to address these concerns by quantifying risk of PD after TBI compared to non-TBI trauma (NTT, defined as fractures). Methods Using inpatient/emergency department (ED) ICD-9 code data for California hospitals from 2005–2006, we identified patients age ≥55 with TBI (n=52,393) or NTT (n=113,406) and without baseline PD or dementia who survived hospitalization. Using Kaplan-Meier estimates and Cox proportional hazards models (adjusted for age, sex, race/ethnicity, income, comorbidities, healthcare use, trauma severity), we estimated risk of PD after TBI during follow-up ending in 2011. We also assessed interaction with mechanism of injury (fall vs. non-fall) and effect of TBI-severity (mild vs. moderate/severe) and TBI-frequency (1 TBI vs. >1 TBI). Results TBI patients were significantly more likely to be diagnosed with PD compared to NTT patients (1.7% versus 1.1%, p<0.001, adjusted hazard ratio (HR) 1.44, 95% CI 1.31–1.58). Risk of PD was similar for TBI sustained via falls versus non-falls (interaction p=0.6). Assessment by TBI-severity (mild TBI HR 1.24, 95% CI 1.04–1.48; moderate/severe TBI HR 1.50, 95% CI 1.35–1.66) and TBI-frequency (1 TBI HR 1.45, 95% CI 1.30–1.60; >1 TBI HR 1.87, 95% CI 1.58–2.21) revealed a dose-response. Interpretation Among patients age ≥55 presenting to inpatient/ED settings with trauma, TBI is associated with a 44% increased risk of developing PD over 5–7 years that is unlikely due to confounding or reverse-causation.
The limitations of subgroup analyses are well established—false positives due to multiple comparisons, false negatives due to inadequate power, and limited ability to inform individual treatment decisions because patients have multiple characteristics that vary simultaneously. In this article, we apply Bayes’s rule to determine the probability that a positive subgroup analysis is a true positive. From this framework, we derive simple rules to determine when subgroup analyses can be performed as hypothesis testing analyses and thus inform when subgroup analyses should influence how we practice medicine.
Key Points Question Does the risk of cognitive decline among US adults vary by sex? Findings In this cohort study using pooled data from 26 088 participants, women, compared with men, had higher baseline performance in global cognition, executive function, and memory. Women, compared with men, had significantly faster declines in global cognition and executive function, but not memory. Meaning These findings suggest that women may have greater cognitive reserve but faster cognitive decline than men.
Objective To determine trends in ischemic stroke incidence among Mexican Americans and non-Hispanic whites. Methods We performed population-based stroke surveillance from January 1, 2000 to December 31, 2010 in Corpus Christi, Texas. Ischemic stroke patients 45 years and older were ascertained from potential sources, and charts were abstracted. Neurologists validated cases based on source documentation blinded to ethnicity and age. Crude and age-, sex-, and ethnicity-adjusted annual incidence was calculated for first ever completed ischemic stroke. Poisson regression models were used to calculate adjusted ischemic stroke rates, rate ratios, and trends. Results There were 2,604 ischemic strokes in Mexican Americans and 2,042 in non-Hispanic whites. The rate ratios (Mexican American:non-Hispanic white) were 1.94 (95% confidence interval [CI] = 1.67–2.25), 1.50 (95% CI = 1.35– 1.67), and 1.00 (95% CI = 0.90–1.11) among those aged 45 to 59, 60 to 74, and 75 years and older, respectively, and 1.34 (95% CI = 1.23–1.46) when adjusted for age. Ischemic stroke incidence declined during the study period by 35.9% (95% CI = 25.9–44.5). The decline was limited to those aged ≥60 years, and happened in both ethnic groups similarly (p > 0.10), implying that the disparities seen in the 45- to 74-year age group persist unabated. Interpretation Ischemic stroke incidence rates have declined dramatically in the past decade in both ethnic groups for those aged ≥60 years. However, the disparity between Mexican American and non-Hispanic white stroke rates persists in those <75 years of age. Although the decline in stroke is encouraging, additional prevention efforts targeting young Mexican Americans are warranted.
Objective: To estimate the ability of bedside information to risk stratify stroke in acute dizziness presentations.Methods: Surveillance methods were used to identify patients with acute dizziness and nystagmus or imbalance, excluding those with benign paroxysmal positional vertigo, medical causes, or moderate to severe neurologic deficits. Stroke was defined as acute infarction or intracerebral hemorrhage on a clinical or research MRI performed within 14 days of dizziness onset. Bedside information comprised history of stroke, the ABCD 2 score (age, blood pressure, clinical features, duration, and diabetes), an ocular motor (OM)-based assessment (head impulse test, nystagmus pattern [central vs other], test of skew), and a general neurologic examination for other CNS features. Multivariable logistic regression was used to determine the association of the bedside information with stroke. Model calibration was assessed using low (,5%), intermediate (5% to ,10%), and high ($10%) predicted probability risk categories. 05-4.57). No stroke cases were in the model's low-risk probability category (0/86, 0%), whereas 9 were in the moderate-risk category (9/94, 9.6%) and 20 were in the high-risk category (20/92, 21.7%). Results Conclusion:In acute dizziness presentations, the combination of ABCD 2 score, general neurologic examination, and a specialized OM examination has the capacity to risk-stratify acute stroke on MRI. Neurology ® 2015;85:1869-1878 GLOSSARY ABCD 2 5 age, blood pressure, clinical features, duration, diabetes; CI 5 confidence interval; HINTS 5 head impulse, nystagmus pattern, test of skew; HIT 5 head impulse test; ICH 5 intracerebral hemorrhage; OM 5 ocular motor; OR 5 odds ratio.Patients with dizziness from stroke are challenging to identify because they often lack typical stroke warning signs or symptoms. [1][2][3][4][5][6] Prior studies have been performed to assess bedside decision support tools that could help to discriminate stroke from other causes of acute dizziness.3,4,7 The ABCD 2 score (age, blood pressure, clinical features, duration, and diabetes) may also be useful in discriminating vascular from nonvascular events. [8][9][10] When assessed in a retrospective study of emergency department dizziness presentations, the visits with a low-risk ABCD 2 score (ABCD 2 , 4) had a stroke frequency of 1% (5/512 patients) compared with 8.1% (32/395) in the high-risk group (ABCD 2 $ 4). 3 Another tool that has been developed to identify cases of dizziness-stroke is the HINTS assessment (head impulse, nystagmus pattern, test of skew), which is based on a specialty bedside ocular motor (OM) examination.4 HINTS has shown promising results, superior to the ABCD 2 score (sensitivity/ specificity: ABCD 2 , 61%/62%; HINTS, 96.5%/84.4%) in a prospective study of acute dizziness. 4 In this study, we expand on this prior work by evaluating the ability of the combination of bedside predictors of stroke-including both the ABCD 2 score and the specialized OM examination-to stratify stroke risk using an MR...
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