Biomedical subjects
W J Hall
Publications and source records attributed to W J Hall.
Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry.
BACKGROUND: Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. METHODS AND RESULTS: Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QTc >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers (KVLQT1 on 11p15.5), 62 LQT2 carriers (HERG on 7q35-36), and 31 LQT3 carriers (SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8+/-7 versus 14+/-10 years, P<0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P<0.0001). Affected family members had similar findings. By Cox analysis adjusting for QTc duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 (P<0.001), and it was 1.87 (P=0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 (P<0.001) by age 15 years, and it was 3.25 (P<0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P=0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. CONCLUSIONS: Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.
The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial.
BACKGROUND: The recently reported Multicenter Automatic Defibrillator Implantation Trial (MADIT) showed improved survival in selected asymptomatic patients with coronary disease and nonsustained ventricular tachycardia. The economic consequences of defibrillator management in this patient population are unknown. METHODS AND RESULTS: Patients were followed up to quantify their use of healthcare services, including hospitalizations, physician visits, medications, laboratory tests, and procedures, during the trial. The costs of these services, including the costs of the defibrillator, were determined in patients randomized to defibrillator and nondefibrillator therapy. Incremental cost-effectiveness ratios were calculated by relating these costs to the increased survival associated with the use of the defibrillator. The average survival for the defibrillator group over a 4-year period was 3.66 years compared with 2.80 years for conventionally treated patients. Accumulated net costs were $97,560 for the defibrillator group compared with $75,980 for individuals treated with medications alone. The resulting incremental cost-effectiveness ratio of $27,000 per life-year saved compares favorably with other cardiac interventions. Sensitivity analyses showed that the incremental cost-effectiveness ratio would be reduced to approximately $23,000 per life-year saved if transvenous defibrillators were used instead of the older devices, which required thoracic surgery for implantation. CONCLUSIONS: An implanted cardiac defibrillator is cost-effective in selected individuals at high risk for ventricular arrhythmias.
Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators.
BACKGROUND: The effects of pregnancy on women with the hereditary long QT syndrome are currently unknown. The appropriate medical management of pregnant patients with the long QT syndrome has not been established. METHODS AND RESULTS: The study was a retrospective analysis of the 422 women (111 probands affected with the long QT syndrome and 311 first-degree relatives) enrolled in the long QT syndrome registry who had one or more pregnancies. The first-degree relatives were classified as affected (QTc >0.47), borderline (QTc=0.45 to 0.47), and unaffected (QTc <0.45). Cardiac events were defined as the combined incidence of long QT syndrome-related death, aborted cardiac arrest, and syncope. The incidence of cardiac events was compared during equal prepregnancy, pregnancy, and postpartum intervals (40 weeks each). Multivariate logistic regression analysis was performed by use of a mixed-effects model to identify independent predictors of cardiac events among probands. The pregnancy and postpartum intervals were not associated with cardiac events among first-degree relatives. The postpartum interval was independently associated with cardiac events among probands (odds ratio [OR], 40.8; 95% confidence interval [CI], 3.1 to 540; P=.01); the pregnancy interval was not associated with cardiac events. Treatment with beta-adrenergic blockers was independently associated with a decrease in the risk for cardiac events among probands (OR, 0.023; 95% CI, 0.001 to 0.44; P=.01). CONCLUSIONS: The postpartum interval is associated with a significant increase in risk for cardiac events among probands with the long QT syndrome but not among first-degree relatives. Prophylactic treatment with beta-adrenergic blockers should be continued during the pregnancy and postpartum intervals in probands with the long QT syndrome.
Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.
Malignant hyperthermia (MH) is an autosomal dominant genetic condition that presents in susceptible people undergoing general anaesthesia. The clinical disorder is a major cause of anaesthetic morbidity and mortality. The UK Malignant Hyperthermia Group has performed genetic linkage analysis on 20 large, well defined malignant hyperthermia families, using hypervariable markers on chromosome 19q13.1, including the candidate MH gene RYR1, the gene coding for the skeletal muscle ryanodine receptor protein. The results were analysed using LINKAGE to perform two point and multipoint lod scores, then HOMOG to calculate levels of heterogeneity. The results clearly showed genetic heterogeneity between MH families; nine of the families gave results entirely consistent with linkage to the region around RYR1 while the same region was clearly excluded in three families. In the remaining eight MHS families there were single recombinant events between RYR1 and MH susceptibility. HOMOG analysis was of little added benefit in determining the likelihood of linkage to RYR1 in these families. This confirmation of the presence of heterogeneity in the UK MH population, along with the possibility of the presence of two MH genes in some pedigrees, indicates that it would be premature and potentially dangerous to offer diagnosis of MH by DNA based methods at this time.
Transitional care: hospital to home.
Contemporary acute hospital care of older adults must include special attention to the transitional, or peridischarge, phase of hospitalization. This article reviews the evidence from outcomes data and economic factors that demonstrate that precise transitional planning is a critical element in the care of older hospitalized adults. Some of the promising initiatives being explored around the country are reviewed.
Smooth non-parametric receiver operating characteristic (ROC) curves for continuous diagnostic tests.
Receiver operating characteristic (ROC) curves have seen increasing use to assess the accuracy of diagnostic tests that yield continuous test results. We can calculate a fully non-parametric ROC curve from the empirical false positive rate (FPR) and true positive rate (TPR) at each possible decision threshold, but it may be quite jagged. We can obtain a smooth ROC curve by directly fitting a parameteric model, for example, binormal or bilogistic, to the actual test results, but substantial lack-of-fit may result if the distributional assumptions are not valid. A recently proposed alternative algorithm 'LABROC4' is insensitive to such departures, but is not fully flexible in that the form of the resulting ROC curve is restricted to be binormal. We propose a smooth non-parametric ROC curve derived from kernel density estimates of the two test result distributions. We obtain pointwise standard errors for the estimated TPR at each FPR and use them to construct pointwise confidence intervals for the ROC curve, using a logit transformation. We also obtain standard errors for the estimated TPR and FPR at given thresholds and use them to construct confidence rectangles in (FPR, TPR)-space that correspond to a specific threshold. We adapt existing methods for the unsmoothed non-parametric ROC curve to obtain the area under the ROC curve and its standard error; we also give partial areas and corresponding standard errors. We have created a FORTRAN algorithm 'ROC-&-ROL', available upon request. We compare ROC curves and areas obtained by applying our methods and its competitors to two data sets, one of which is fit well by parametric methods and LABROC4, the other of which is not.
Medical oncology and geriatric medicine: is it time for fellowship integration?
Although training programs exist in both medical oncology and geriatrics (approved by the American Board of Internal Medicine), neither is adequate to ensure an appropriate supply of physicians to assume a leadership role in the treatment of the increasing number of geriatric patients who have or will develop a malignancy. A proposal for offering a 3-4 year program leading to dual certification is under consideration. A careful review of both the medical oncology training program and added qualifications in geriatrics has identified key components of each that can serve as a basis for a combined program. Such a program can encourage research into behavior modification of existing biases in referring geriatric oncology patients for treatment as well as a better understanding of the biology of aging, addressing in particular the pharmacology of anticancer agents in this unique population. It is anticipated that pilot projects will be undertaken to develop common pathways for developing combined programs in medical oncology and geriatrics. The second phase will include recruitment of selected candidates who are interested in an academic career in geriatric oncology. A need for additional academic-based geriatric oncologists has been identified that can address the anticipated increase in the incidence and presence of cancer in an aging population. Such a cadre of specialists will be in an excellent position to recommend changes in the current (mostly negative) approach to the management of cancer in patients age > 65 years.
Clinical implications of silent versus symptomatic exercise-induced myocardial ischemia in patients with stable coronary disease.
OBJECTIVES: This study was undertaken to better understand the functional and prognostic significance of silent relative to symptomatic ischemia. BACKGROUND: Previous studies have reached conflicting conclusions as to whether painless ischemia identified during noninvasive cardiac testing is related to a lesser extent of myocardial ischemia or a different prognosis than ischemia accompanied by angina, or both. METHODS: Nine hundred thirty-six clinically stable patients 1 to 6 months after an acute coronary event, either myocardial infarction or unstable angina, underwent ambulatory monitoring, exercise treadmill testing and stress thallium-201 scintigraphy. They were then followed up prospectively for a mean of 23 months for recurrent cardiac events (cardiac death, nonfatal myocardial infarction or unstable angina). RESULTS: Compared with patients with symptomatic ischemia during testing (n = 125), those with silent ischemia (n = 378) demonstrated less severe and extensive reversible defects on stress thallium scintigraphy (p = 0.0008), less functional impairment during treadmill testing manifested by longer exercise duration (640 +/- 173 vs. 529 +/- 190 s, p = 0.002) and longer time to ST segment depression (530 +/- 215 vs. 419 +/- 205 s, p = 0.0001) and less frequent ST segment depression during ambulatory monitoring (9% vs. 19%, p = 0.005). Patients with symptomatic ischemia had a significantly (p = 0.004) increased number of subsequent recurrent cardiac events (28.8%) versus those with silent (18.0%) or no (17.3%) ischemia. Adverse outcomes were especially concentrated in the subgroup with symptomatic ischemia and poor exercise tolerance. The difference in cardiac event rates between patients with silent versus symptomatic ischemia persisted after adjustment for baseline clinical characteristics by Cox regression analysis. CONCLUSIONS: Patients with painless ischemia during exercise testing 1 to 6 months after recovery from a coronary event have less jeopardized ischemic myocardium and fewer recurrent cardiac events than patients with symptomatic ischemia.
Nursing home-acquired pneumonia: avoiding the hospital.
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The "common cold" in frail older persons: impact of rhinovirus and coronavirus in a senior daycare center.
OBJECTIVE: To evaluate the incidence and impact of rhinovirus and coronavirus infections in older persons attending daycare. DESIGN: Prospective descriptive study. SETTING: Three senior daycare centers in Rochester, New York. PATIENTS: Frail older persons and staff members of the daycare centers who developed signs or symptoms of an acute respiratory illness. MEASUREMENTS: Demographic, medical, and physical findings were recorded on subjects at baseline and during respiratory illness. Nasopharyngeal specimens for viral culture as well as acute and convalescent sera for coronavirus 229E enzyme immunoassay (EIA) were obtained for all illnesses. RESULTS: During the 44 months of study, 352 older persons experienced 522 illnesses. Thirty-five (7%) of 522 cultures were positive for rhinovirus and 37 (8%) of 451 serologies were positive for coronavirus 229E infection. The clinical syndromes associated with rhinovirus and coronavirus infection were similar and characterized by nasal congestion, cough, and constitutional symptoms. No patient died or was hospitalized, but approximately 50% had evidence of lower respiratory tract involvement. The average illness lasted 14 days. During the same period, 113 staff developed 338 respiratory illnesses. Eight percent were identified as coronavirus and 9% as rhinovirus. Cough, sputum production, and constitutional symptoms were significantly more common among older persons. CONCLUSIONS: Rhinovirus and coronavirus 229E are common causes of moderately debilitating acute respiratory illnesses among older persons attending daycare.
Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
BACKGROUND: Unsustained ventricular tachycardia in patients with previous myocardial infarction and left ventricular dysfunction is associated with a two-year mortality rate of about 30 percent. We studied whether prophylactic therapy with an implanted cardioverter-defibrillator, as compared with conventional medical therapy, would improve survival in this high-risk group of patients. METHODS: Over the course of five years, 196 patients in New York Heart Association functional class I, II, or III with prior myocardial infarction; a left ventricular ejection fraction < or = 0.35; a documented episode of asymptomatic unsustained ventricular tachycardia; and inducible, nonsuppressible ventricular tachyarrhythmia on electrophysiologic study were randomly assigned to receive an implanted defibrillator (n = 95) or conventional medical therapy (n=101). We used a two-sided sequential design with death from any cause as the end point. RESULTS: The base-line characteristics of the two treatment groups were similar. During an average follow-up of 27 months, there were 15 deaths in the defibrillator group (11 from cardiac causes) and 39 deaths in the conventional-therapy group (27 from cardiac causes) (hazard ratio for overall mortality, 0.46; 95 percent confidence interval, 0.26 to 0.82; P=0.009). There was no evidence that amiodarone, beta-blockers, or any other antiarrhythmic therapy had a significant influence on the observed hazard ratio. CONCLUSIONS: In patients with a prior myocardial infarction who are at high risk for ventricular tachyarrhythmia, prophylactic therapy with an implanted defibrillator leads to improved survival as compared with conventional medical therapy.
Marked reduction in long-term cardiac deaths with aspirin after a coronary event. Multicenter Myocardial Ischemia Research Group.
OBJECTIVES: We sought to assess the role of aspirin in a precisely defined cohort with coronary disease receiving current therapy. BACKGROUND: Prior results suggest that aspirin modestly decreases cardiac mortality in patients with coronary disease. However, these findings reflect heterogeneous study conditions and earlier management strategies. METHODS: We utilized findings from the Multicenter Study of Myocardial Ischemia, which enrolled 936 subjects 1 to 6 months after an acute myocardial infarction (n = 651 [70%]) or unstable angina (n = 285 [30%]). The follow-up period averaged 23 months, with treatment determined by referring physicians. RESULTS: At enrollment, 751 patients (80%) took aspirin regularly, usually 250 to 325 mg/day. Before enrollment, 291 patients (31%) had thrombolysis, and 352 (38%) had coronary angioplasty. During follow-up, cardiac death occurred in 22 patients, all-cause mortality in 31 and cardiac death or nonfatal myocardial infarction in 70. Each of these outcomes was significantly less frequent among aspirin users. Cardiac death rate was markedly reduced: 1.6% for aspirin users and 5.4% for nonusers (p = 0.005). These differences were not explained by imbalances in predictors of postinfarction risk or therapy other than aspirin (Cox hazard ratio 0.37, p = 0.023). They persisted at least 2 years after enrollment. The difference in mortality rate was particularly prominent after thrombolysis: 0.9% for aspirin users and 8.8% for nonusers (p = 0.004). CONCLUSIONS: Reduction in cardiac deaths among aspirin users is substantially greater than that reported previously. Although derived secondarily, our findings suggest that current practice leads to situations in which aspirin exerts a long-term, life-protecting action, particularly after thrombolysis.
Evaluation of four methods for the diagnosis of respiratory syncytial virus infection in older adults.
OBJECTIVE: To evaluate four methods of rapid diagnosis of respiratory syncytial virus (RSV) infection in older adults and to compare sensitivities with serologic analysis. DESIGN: Prospective comparative analysis. SETTING: Two adult daycenters. PATIENTS: Frail older persons attending the daycenter who developed signs or symptoms of acute respiratory illness between the months of December and February. MEASUREMENTS: Viral cultures performed by standard technique and bedside inoculation: antigen detection by indirect immunofluorescence assay (IFA) and Directigen enzyme immunoassay (EIA) on nasal brush samples; serologic analysis of acute and convalescent sera using EIA. RESULTS: RSV infection was documented by serology in 11 of 54 (20%) subjects during the study period. Bedside viral cultures were the most sensitive assay and were positive in 6/9 infections. Standard viral culture detected 5/11 cases. Both methods of rapid antigen detection were found to be insensitive, with 1/11 detected by IFA and 0/11 detected by EIA. CONCLUSION: Rapid antigen tests for the diagnosis of RSV in older persons should be used with caution.
ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome.
BACKGROUND: The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome. METHODS AND RESULTS: Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QTonset-c, QTpeak-c, QTc, and Tduration-c, in milliseconds) and the absolute height of the T wave (Tamplitude, in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n = 47), 7 (n = 30), and 11 (n = 76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected members of all six families had longer QT intervals (QTonset-c, QTpeak-c, or QTc) than unaffected family members (P < .01). Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features. Among affected individuals, the QTonset-c was unusually prolonged in those individuals with mutations involving the cardiac sodium channel gene SCN5A on chromosome 3 (lead II QTonset-c [mean +/- SD]: chromosome 3, 341 +/- 42 ms; chromosome 7, 290 +/- 56 ms; chromosome 11, 243 +/- 73 ms; P < .001); Tamplitude was generally quite small in the chromosome 7 genotype (lead II Tamplitude, mV: chromosome 3, 0.36 +/- 0.14; chromosome 7, 0.13 +/- 0.07; chromosome 11, 0.37 +/- 0.17; P < .001); and Tduration was particularly long in the chromosome 11 genotype (lead II Tduration-c: chromosome 3, 187 +/- 33 ms; chromosome 7, 191 +/- 51 ms; chromosome 11, 262 +/- 65 ms; P < .001). Similar ECG findings were observed in leads aVF and V5. A considerable variability exists in the quantitative repolarization parameters associated with each genotype, with overlap in the T-wave patterns among the three genotypes. CONCLUSIONS: Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.
Risk of cardiac events in family members of patients with long QT syndrome.
OBJECTIVES: This study sought to identify risk factors for cardiac events (syncope, aborted cardiac arrest or sudden cardiac death) in family members of patients with the long QT syndrome. BACKGROUND: Patients with the long QT syndrome are known to be at high risk for cardiac events. Whenever the first member of a family is identified as having the long QT syndrome (proband), there is concern regarding the likelihood of cardiac events in other family members. METHODS: A multivariate logistic regression model was used to evaluate the risk of cardiac events in 637 family members who were first- and second-degree relatives of 151 probands with the long QT syndrome and in a subset of 513 family members who were not receiving beta-adrenergic blocking agents. There were 293 first-degree (46%) and 344 second-degree relatives (54%) (293 men [46%], 344 women [54%]). Fifteen percent of the family members had a corrected QT interval (QTc) > 0.44 s, and relative tachycardia and bradycardia were observed in 12% and 25%, respectively. RESULTS: The risk of cardiac events occurring before age 40 in family members not taking beta-blockers was influenced by the QTc interval (odds ratio [OR] 1.18/0.01 increase in QTc value; 95% confidence interval [CI] 1.12 to 1.24), relative tachycardia (OR 2.21, 95% CI 0.97 to 5.02) or bradycardia (OR 2.24, 95% CI 1.10 to 4.56) and an interaction term combining gender and closeness of the relationship to the proband (OR for female first-degree relative 3.23 vs. all second-degree relatives, 95% CI 1.67-6.22). CONCLUSIONS: Female first-degree relatives of patients with the long QT syndrome have a higher risk of cardiac events than male first- or second-degree relatives, independent of recorded electrocardiographic findings. Not only bradycardia, but also tachycardia increases risk of cardiac events in family members of patients with the long QT syndrome.