James S. Hodges

Natural History and Expansive Clinical Profile of Stress (Tako-Tsubo) Cardiomyopathy

OBJECTIVES This study was designed to define more completely the clinical spectrum and consequences of stress cardiomyopathy (SC) beyond the acute event. BACKGROUND Stress cardiomyopathy is a recently recognized condition characterized by transient cardiac dysfunction with ventricular ballooning. METHODS Clinical profile and outcome were prospectively assessed in 136 consecutive SC patients. RESULTS Patients were predominantly women (n = 130; 96%), but 6 were men (4%). Ages were 32 to 94 years (mean age 68 +/- 13 years); 13 (10%) were <or=50 years of age. In 121 patients (89%), SC was precipitated by intensely stressful emotional (n = 64) or physical (n = 57) events, including 22 associated with sympathomimetic drugs or medical/surgical procedures; 15 other patients (11%) had no evident stress trigger. Twenty-five patients (18%) were taking beta-blockers at the time of SC events. Three diverse ventricular contraction patterns were defined by cardiovascular magnetic resonance (CMR) imaging, usually with rapid return to normal systolic function, although delayed >2 months in 5%. Right and/or left ventricular thrombi were identified in 5 patients (predominantly by CMR imaging), including 2 with embolic events. Three patients (2%) died in-hospital and 116 (85%) have survived, including 5% with nonfatal recurrent SC events. All-cause mortality during follow-up exceeded a matched general population (p = 0.016) with most deaths occurring in the first year. CONCLUSIONS In this large SC cohort, the clinical spectrum was heterogeneous with about one-third either male, <or=50 years of age, without a stress trigger, or with in-hospital death, nonfatal recurrence, embolic stroke, or delayed normalization of ejection fraction. Beta-blocking drugs were not absolutely protective and SC was a marker for increased noncardiac mortality. These data support expanded management and surveillance strategies including CMR imaging and consideration for anticoagulation.

Rating the quality of evidence for clinical practice guidelines.

This article describes the system for rating the quality of medical evidence developed and used during creation of the Agency for Health Care Policy and Research-sponsored heart failure guideline. Previous approaches to rating evidence were not designed for use in the setting of clinical practice guidelines. The present system is based on the tenet that flaws in research design are serious to the extent they threaten the validity of the results of studies. A taxonomy of major and minor flaws based on that tenet was developed for randomized controlled trials and for cohort and medical registry studies. The use of the system is described in the context of two difficult clinical issues considered by the Panel: the role of coronary artery revascularization and the use of metoprolol.

Comparison of U.S. and Italian experiences with sudden cardiac deaths in young competitive athletes and implications for preparticipation screening strategies.

Controversy has evolved over the most practical and effective strategy for preparticipation cardiovascular screening of competitive athletes to detect unsuspected cardiovascular disease and prevent sudden death on the athletic field. Athlete screening in the Veneto region of Italy is part of a national program (with 12-lead electrocardiography) that has reported the detection of previously undiagnosed hypertrophic cardiomyopathy and a decrease in the cardiovascular death rate in young athletes. In this study, over time periods of similar length, cardiovascular-related mortality rates in Veneto athletes were compared with those of a demographically similar region of the United States (Minnesota) in which screening is limited to history and physical examination. There were 55 sudden cardiovascular deaths reported in Veneto over 26 years (2.1/year), compared with 22 deaths in 23 years (0.96/year) in Minnesota. Over the recent and comparable 11-year period, 1993 to 2004, 12 deaths were reported in Veneto and 11 in Minnesota. When analyzed as deaths per 100,000 person-years, Veneto exceeded Minnesota for all years combined (1.87 for 1979 to 2004 vs 1.06 for 1985 to 2007, respectively, p = 0.006), although the 2 regions did not differ significantly for 1993 to 2004 (0.87 vs 0.93, respectively, p = 0.88) or most recently for 2001 to 2004 (0.43 vs 0.90, respectively, p = 0.38). In conclusion, sudden cardiovascular deaths in young competitive athletes occurred at a low rate in both Veneto and Minnesota. Despite different preparticipation screening strategies, athlete sudden death rates in these demographically similar regions of the United States and Italy have not differed significantly in recent years. These data do not support a lower mortality rate associated with preparticipation screening programs involving routine electrocardiography and examinations by specially trained personnel.

Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter

BACKGROUND We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection. METHODS A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed. RESULTS After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine only (P=0.24). As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10). Survival was similar in the three groups. In a subgroup analysis, combination therapy delayed disease progression or death in patients who had previously received zidovudine for 12 months or less. Therapy with zidovudine plus didanosine resulted in more gastrointestinal adverse effects, and treatment with zidovudine plus zalcitabine, more neuropathy. The mean increases in CD4 cell counts at two months were higher with combination therapy than with zidovudine alone. CONCLUSIONS In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.

Adding Spatially-Correlated Errors Can Mess Up the Fixed Effect You Love

Many statisticians have had the experience of fitting a linear model with uncorrelated errors, then adding a spatially-correlated error term (random effect) and finding that the estimates of the fixed-effect coefficients have changed substantially. We show that adding a spatially-correlated error term to a linear model is equivalent to adding a saturated collection of canonical regressors, the coefficients of which are shrunk toward zero, where the spatial map determines both the canonical regressors and the relative extent of the coefficients’ shrinkage. Adding a spatially-correlated error term can also be seen as inflating the error variances associated with specific contrasts of the data, where the spatial map determines the contrasts and the extent of error-variance inflation. We show how to avoid this spatial confounding by restricting the spatial random effect to the orthogonal complement (residual space) of the fixed effects, which we call restricted spatial regression. We consider five proposed interpretations of spatial confounding and draw implications about what, if anything, one should do about it. In doing so, we debunk the common belief that adding a spatially-correlated random effect adjusts fixed-effect estimates for spatially-structured missing covariates. This article has supplementary material online.

Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest Evaluation of a Regional System to Increase Access to Cooling

Background— Therapeutic hypothermia (TH) improves survival and confers neuroprotection in out-of-hospital cardiac arrest (OHCA), but TH is underutilized, and regional systems of care for OHCA that include TH are needed. Methods and Results— The Cool It protocol has established TH as the standard of care for OHCA across a regional network of hospitals transferring patients to a central TH-capable hospital. Between February 2006 and August 2009, 140 OHCA patients who remained unresponsive after return of spontaneous circulation were cooled and rewarmed with the use of an automated, noninvasive cooling device. Three quarters of the patients (n=107) were transferred to the TH-capable hospital from referring network hospitals. Positive neurological outcome was defined as Cerebral Performance Category 1 or 2 at discharge. Patients with non–ventricular fibrillation arrest or cardiogenic shock were included, and patients with concurrent ST-segment elevation myocardial infarction (n=68) received cardiac intervention and cooling simultaneously. Overall survival to hospital discharge was 56%, and 92% of survivors were discharged with a positive neurological outcome. Survival was similar in transferred and nontransferred patients. Non–ventricular fibrillation arrest and presence of cardiogenic shock were associated strongly with mortality, but survivors with these event characteristics had high rates of positive neurological recovery (100% and 89%, respectively). A 20% increase in the risk of death (95% confidence interval, 4% to 39%) was observed for every hour of delay to initiation of cooling. Conclusions— A comprehensive TH protocol can be integrated into a regional ST-segment elevation myocardial infarction network and achieves broad dispersion of this essential therapy for OHCA.Background— Therapeutic hypothermia (TH) improves survival and confers neuroprotection in out-of-hospital cardiac arrest (OHCA), but TH is underutilized, and regional systems of care for OHCA that include TH are needed. Methods and Results— The Cool It protocol has established TH as the standard of care for OHCA across a regional network of hospitals transferring patients to a central TH-capable hospital. Between February 2006 and August 2009, 140 OHCA patients who remained unresponsive after return of spontaneous circulation were cooled and rewarmed with the use of an automated, noninvasive cooling device. Three quarters of the patients (n=107) were transferred to the TH-capable hospital from referring network hospitals. Positive neurological outcome was defined as Cerebral Performance Category 1 or 2 at discharge. Patients with non–ventricular fibrillation arrest or cardiogenic shock were included, and patients with concurrent ST-segment elevation myocardial infarction (n=68) received cardiac intervention and cooling simultaneously. Overall survival to hospital discharge was 56%, and 92% of survivors were discharged with a positive neurological outcome. Survival was similar in transferred and nontransferred patients. Non–ventricular fibrillation arrest and presence of cardiogenic shock were associated strongly with mortality, but survivors with these event characteristics had high rates of positive neurological recovery (100% and 89%, respectively). A 20% increase in the risk of death (95% confidence interval, 4% to 39%) was observed for every hour of delay to initiation of cooling. Conclusions— A comprehensive TH protocol can be integrated into a regional ST-segment elevation myocardial infarction network and achieves broad dispersion of this essential therapy for OHCA. # Clinical Perspective {#article-title-40}

Six (or so) things you can do with a bad model

Many models used in policy or systems analysis either cannot be validated in any fully adequate sense, such as by comparing them with actual data, or could adequately be validated but have not been. For example, in the area of combat analysis, the central models are arguably almost entirely unvalidated and most will never be susceptible to adequate validation. Nevertheless, such models are often used and can be used fruitfully, even though we have no theory for how to use them or how to interpret and place value on the results they produce. This paper takes a step toward providing such a theory by focusing on the logic that should govern the use of inadequately validated models and the costs and benefits of using them. To this end, it identifies and evaluates six legitimate uses to which such models can be put.

Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms

&NA; Previous studies in our laboratory have demonstrated that cannabinoids administered intravenously attenuate the duration of nocifensive behavior and block the development of hyperalgesia produced by intraplantar injection of capsaicin. In the present study, we extended these observations and determined whether cannabinoids attenuate capsaicin‐evoked pain and hyperalgesia through spinal and peripheral mechanisms, and whether the antihyperalgesia was receptor mediated. Separate groups of rats were pretreated 7 min before capsaicin with an intrathecal injection of vehicle or the cannabinoid receptor agonist WIN 55,212‐2 at doses of 0.1, 1.0 or 10 &mgr;g in 10 &mgr;l. Although the intrathecal application of WIN 55,212‐2 did not alter nocifensive behavior following capsaicin, it produced a dose‐dependent decrease in hyperalgesia to heat and mechanical stimuli. Intrathecal pretreatment with the CB1 receptor antagonist SR141716A (10 &mgr;g) blocked the antihyperalgesia produced by WIN 55,212‐2. The ability of intrathecal administration of WIN 55,212‐2 to attenuate hyperalgesia was not due to motor deficits since the highest dose of WIN 55,212‐2 did not alter performance on the rota‐rod test. To investigate whether cannabinoids attenuated capsaicin‐evoked hyperalgesia through peripheral mechanisms, separate groups of rats were pretreated with an intraplantar injection of WIN 55,212‐2 at doses of 0.1, 1.0, 10 or 30 &mgr;g in 100 &mgr;l 5 min before capsaicin. Intraplantar pretreatment with WIN 55,212‐2 produced a dose‐dependent attenuation of hyperalgesia to heat, but did not attenuate mechanical hyperalgesia or the duration of nocifensive behavior. The inactive enantiomer WIN 55,212‐3 did not alter the development of hyperalgesia. SR141716A (100 &mgr;g) co‐injected with WIN 55,212‐2 (30 &mgr;g) partially attenuated the effects of WIN 55,212‐2 on hyperalgesia to heat. Intraplantar injection of the highest dose of WIN 55,212‐2 did not interfere with the development of hyperalgesia following capsaicin injection into the contralateral paw. These data show that cannabinoids possess antihyperalgesic properties at doses that alone do not produce antinociception, and are capable of acting at both spinal and peripheral sites.

Crack propensity of porcelain laminate veneers: A simulated operatory evaluation

STATEMENT OF PROBLEM Anterior teeth are especially subject to the thermal variations of ingested food and drinks. Postoperative cracks of porcelain laminates are considered a possible consequence of polymerization shrinkage, function, and thermocycling. PURPOSE This investigation was conducted to define the parameters associated with the development of cracks in porcelain veneers using cyclic thermal fatigue. MATERIAL AND METHODS Twenty-seven maxillary incisors were restored with porcelain laminate veneers and subjected to thermocycling (5 degrees C to 50 degrees C) for 1000 cycles. Ceramic cracks were reported for 11 of the 27 specimens. Teeth were sectioned and prepared for SEM analysis. Measurements of the ceramic and the luting composite thicknesses were performed for each specimen at different restoration locations (facial, incisal, and proximal). RESULTS No significant differences in the ceramic or the luting composite thicknesses were observed between cracked and uncracked specimens. However, significant differences were observed in the ratio of the ceramic and luting composite thicknesses. Most cracked samples exhibited a ratio at the facial location below 3.0 (2.6 +/- 0.35), whereas most noncracked specimens were above this value (3.9 +/- 0.19). Incisal and especially proximal measurements alone were not significantly different between cracked versus uncracked specimens. Ceramic was slightly thinner in the facial aspect than in the proximal aspect, which was also thinner than the incisal aspect. Composite in the facial aspect was thinner in the cervical area than in the incisal third of the tooth. CONCLUSIONS Significant cyclic temperature changes can induce the development of flaws in porcelain veneers. Control of tooth reduction and the application of die spacers during laboratory procedures undoubtedly represent key elements; a sufficient and even thickness of ceramic combined with a minimal thickness of luting composite will provide the restoration with a favorable configuration with regard to crack propensity, namely, a ceramic and luting composite thickness ratio above 3.

Long-term survival in patients with refractory angina

AIMS An increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascularization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history and predictors of adverse outcome, these patients have been considered at high risk for early mortality. METHODS AND RESULTS The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200 patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4% prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died (20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0-16, 14.7% over 9). By Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all-cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF. CONCLUSION Long-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life.