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Biomedical subjects

M R Gold

Publications and source records attributed to M R Gold.

At least 109 records · Page 6Linked to original sources

Trends toward a national health care marketplace.

In recent years, the health care industry has experienced considerable growth in organizations that are national in focus-organizations that operate in multiple markets not all clustered in one geographic region. This study summarizes information on trends in ownership of various types of health care organizations (i.e., HMOs, PPOs, hospitals, physician practices) for purposes of assessing the growth rate of national companies and the overall significance of this phenomenon. This is followed by a synthesis of factors that encourage or impede the growth of national managed care companies, the sector that has exhibited the most pronounced growth of national companies. We discuss likely future directions and the degree to which national companies may enjoy long-term competitive advantages.

Economic Competition↗

B cell antigen receptor signaling induces the formation of complexes containing the Crk adapter proteins.

Crk proteins are Src homology (SH) 2/SH3-containing adapter proteins that can mediate the formation of signaling complexes. We show that engaging the B cell antigen receptor (BCR) on the RAMOS B cell line caused both Crk-L and Crk II to associate with several tyrosine-phosphorylated proteins. We identified two of these phosphoproteins as Cas and Cbl and showed that both bound to the Crk SH2 domain after BCR engagement. BCR ligation also increased the amount of Crk proteins in the particulate fraction of the cells and induced the formation of Crk.Cas and Crk.Cbl complexes in the particulate fraction. We propose that tyrosine phosphorylation of membrane-associated Cas and Cbl creates binding sites for the Crk SH2 domain and recruits Crk complexes to cellular membranes. Thus, Crk proteins may participate in BCR signaling by using their SH2 domains to direct the interactions and subcellular localization of proteins that bind to their SH3 domains. In RAMOS cells, we found that the SH3 domains of Crk-L and Crk II bound C3G. Since C3G activates Rap, a negative regulator of the Ras pathway, Crk proteins may participate in regulation of Ras signaling by the BCR.

Adaptor Proteins, Signal Transducing↗

Efficacy and safety of procainamide in preventing arrhythmias after coronary artery bypass surgery.

Arrhythmias are common after cardiac surgery and are associated with hemodynamic compromise, stroke, and prolonged hospitalization. Beta blockers prevent atrial fibrillation postoperatively, but there are few data regarding the prophylactic use of type 1 antiarrhythmic agents or the prevention of ventricular arrhythmias. Accordingly, we performed a randomized, double-blind, placebo-controlled study of the effects of oral procainamide on 100 patients undergoing elective coronary artery bypass surgery. Procainamide was received for 4 days; the dosage was adjusted for body weight. Patients receiving procainamide had a significant reduction in atrial fibrillation (16 vs 29 patient-days, p < 0.05) and ventricular tachycardia (2% vs 20%, p < 0.01). However, the incidence of atrial fibrillation was not significantly reduced (38% vas 26%). In the group achieving therapeutic serum procainamide levels, there was reduction in all measured postoperative arrhythmias. No serious cardiac or noncardiac adverse events were noted during procainamide therapy, although there was a significant increase in the incidence of nausea. We conclude that procainamide reduces arrhythmias in the early postoperative period after coronary artery bypass surgery, most prominently in patients who achieve therapeutic serum levels. This was associated with no serious cardiac adverse reactions.

Administration, Oral↗

Complications associated with pectoral cardioverter-defibrillator implantation: comparison of subcutaneous and submuscular approaches. Worldwide Jewel Investigators.

OBJECTIVES: The aim of this study was to compare complications in a large cohort of patients undergoing pectoral cardioverter-defibrillator implantation with a subcutaneous or submuscular approach. BACKGROUND: Pectoral placement of implantable cardioverter-defibrillator (ICD) pulse generators is now routine because of downsizing of these devices. subcutaneous implantation has been advocated by some because it is a simple surgical procedure comparable to pacemaker insertion. Others have favored submuscular insertion to avoid wound complications. These surgical approaches have not been compared previously. METHODS: The subjects for this study were 1,000 consecutive patients receiving a Medtronic Jewel ICD at 93 centers worldwide. Cumulative follow-up for all patients was 633.7 patient-years, with 64.9% of patients followed up for > or = 6 months. The complications evaluated were erosion, pocket hematoma, seroma, wound infection, dehiscence, device migration, lead fracture and dislodgment. RESULTS: Subcutaneous implantation was performed in 604 patients and submuscular implantation in the remaining 396. The median procedural times were shorter for subcutaneous implantation (p = 0.014). In addition, the cumulative percentage of patients free from erosion was greater for subcutaneous implantations (p = 0.03, 100% vs. 99.1% at 6 months). However, lead dislodgment was more common with subcutaneous implantations (p = 0.019, 2.3% vs. 0.5% at 6 months) and occurred primarily during the first month postoperatively. Overall, there were no significant differences in cumulative freedom from complications between groups (4.1% vs. 2.5%, p = 0.1836). CONCLUSIONS: Subcutaneous pectoral implantation of this ICD can be performed safely and has a low complication rate. This approach requires a simple surgical procedure and, compared with the submuscular approach, is associated with shorter procedure times and comparable overall complication rates. However, early follow-up is important in view of the increased lead dislodgment rate.

Aged↗

Recommendations of the Panel on Cost-effectiveness in Health and Medicine.

OBJECTIVE: To develop consensus-based recommendations for the conduct of cost-effectiveness analysis (CEA). This article, the second in a 3-part series, describes the basis for recommendations constituting the reference case analysis, the set of practices developed to guide CEAs that inform societal resource allocation decisions, and the content of these recommendations. PARTICIPANTS: The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, was convened by the US Public Health Service (PHS). EVIDENCE: The panel reviewed the theoretical foundations of CEA, current practices, and alternative methods used in analyses. Recommendations were developed on the basis of theory where possible, but tempered by ethical and pragmatic considerations, as well as the needs of users. CONSENSUS PROCESS: The panel developed recommendations through 2 1/2 years of discussions. Comments on preliminary drafts prepared by panel working groups were solicited from federal government methodologists, health agency officials, and academic methodologists. CONCLUSIONS: The panel's methodological recommendations address (1) components belonging in the numerator and denominator of a cost-effectiveness (C/E) ratio; (2) measuring resource use in the numerator of a C/E ratio; (3) valuing health consequences in the denominator of a C/E ratio; (4) estimating effectiveness of interventions; (5) incorporating time preference and discounting; and (6) handling uncertainty. Recommendations are subject to the ¿rule of reason,¿ balancing the burden engendered by a practice with its importance to a study. If researchers follow a standard set of methods in CEA, the quality and comparability of studies, and their ultimate utility, can be much improved.

Cost-Benefit Analysis↗

Differential activation of the ERK, JNK, and p38 mitogen-activated protein kinases by CD40 and the B cell antigen receptor.

B cell antigen receptor (BCR)-induced apoptosis in the WEHI-231 B lymphoma cell line can be prevented by engaging CD40. We have used this cell line to investigate the role of mitogen-activated protein (MAP) kinases in integrating BCR and CD40 signaling. Each of the three types of MAP kinases, the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and p38, phosphorylates a distinct set of transcription factors. Thus, activating different combinations of MAP kinases could lead to distinct biological responses. We found that BCR engagement in WEHI-231 cells caused a 15- to 20-fold activation of ERK2 and a 2- to 3-fold stimulation of ERK1. CD40 did not activate either of these kinases, nor did it affect BCR-induced ERK activation. In contrast, CD40 engagement caused a 50- to 70-fold increase in JNK activity. BCR cross-linking caused a modest (4- to 8-fold) increase in JNK activity by itself and also potentiated CD40-induced JNK activation. Finally, CD40 caused strong activation of the p38 kinase as well as MAPKAP kinase-2, a downstream target of p38. BCR engagement caused only weak activation of the p38 pathway. In summary, the BCR strongly activates ERK2 and weakly activates ERK1, JNK, and p38, while CD40 markedly stimulates the JNK and p38 kinases. Thus, activation of only ERK2 correlates with apoptosis in WEHI-231 cells, whereas full activation of all three MAP kinase pathways correlates with cell survival. The role of MAP kinases in regulating these responses remains to be tested.

Animals↗

The role of cost-effectiveness analysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine.

OBJECTIVE: To develop consensus-based recommendations guiding the conduct of cost-effectiveness analysis (CEA) to improve the comparability and quality of studies. The recommendations apply to analyses intended to inform the allocation of health care resources across a broad range of conditions and interventions. This article, first in a 3-part series, discusses how this goal affects the conduct and use of analyses. The remaining articles will outline methodological and reporting recommendations, respectively. PARTICIPANTS: The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, was convened by the US Public Health Service (PHS). EVIDENCE: The panel reviewed the theoretical foundations of CEA, current practices, and alternative procedures for measuring and assigning values to resource use and health outcomes. CONSENSUS PROCESS: The panel met 11 times during 2 1/2 years with PHS staff and methodologists from federal agencies. Working groups brought issues and preliminary recommendations to the full panel for discussion. Draft recommendations were circulated to outside experts and the federal agencies prior to finalization. CONCLUSIONS: The panel's recommendations define a "reference case" cost-effectiveness analysis, a standard set of methods to serve as a point of comparison across studies. The reference case analysis is conducted from the societal perspective and accounts for benefits, harms, and costs to all parties. Although CEA does not reflect every element of importance in health care decisions, the information it provides is critical to informing decisions about the allocation of health care resources.

Advisory Committees↗

Increased Monday incidence of life-threatening ventricular arrhythmias. Experience with a third-generation implantable defibrillator.

BACKGROUND: Examination of the timing of cardiac events provides important pathophysiological information. Previous studies have shown that the onset of acute myocardial infarction occurs most frequently on Monday. The septadian (day of the week) pattern of occurrence of sudden cardiac death and lethal ventricular arrhythmias has not been examined previously. METHODS AND RESULTS: We examined the septadian distribution of life-threatening (cycle length < 280 ms) ventricular arrhythmias in 683 consecutive patients receiving a Ventak PRx, a third-generation implantable defibrillator with an event recorder. There was a prominent Monday peak, with a midweek decline and a secondary peak later in the week. A marked trough is apparent on both weekend days. The observed pattern was independent of age, sex, ejection fraction, NYHA functional class, type of heart disease, and the use of antiarrhythmic drugs but was not observed in patients receiving beta-blockers. CONCLUSIONS: Potentially lethal arrhythmias are not random events but occur in a daily pattern suggesting a relationship to the beginning and end of the work week. The absence of a Monday peak in patients receiving beta-blockers suggests that the pattern may be influenced by beta-blockers. This information may be useful in devising strategies to prevent sudden cardiac death.

Aged↗

Effects of an active pectoral-pulse generator shell on defibrillation efficacy with a transvenous lead system.

Transvenous lead systems have become routine for defibrillator implantation. A reduction of pulse generator size has made pectoral placement possible and enabled the pulse generator shell to become an active part of the defibrillation pathway. To directly assess the effect of the addition of an active generator on defibrillation thresholds to a transvenous lead system, we prospectively measured paired, randomized defibrillation thresholds (DFTs) in 21 patients undergoing defibrillator implantation. A dual coil lead (Endotak C, Cardiac Pacemakers, Inc., Guidant Corp., St. Paul, Minnesota) was used with the distal coil as the cathode for all shocks. The DFT was 8.4 +/- 3.2 J with the active shell, compared with 13.1 +/- 6.9 J with the lead alone (p < 0.01). This reduction was greatest in those patients with higher thresholds with the lead-alone configuration and resulted in DFT < or = 15 J with the active shell configuration in all patients. Shock impedance was reduced from 49 +/- 5 to 42 +/- 4 ohms (p < .001), but peak current at defibrillation threshold was unaffected by the addition of the active pectoral shell. We conclude that the addition of an active pectoral shell to a 2-coil transvenous lead system resulted in a marked reduction of defibrillation energy requirements. The uniformly low DFT ( < or = 15 J) observed suggests that an active pulse generator with a 25 J maximum output could be implanted in most patients while maintaining an adequate defibrillation safety margin.

Aged↗

Chronic rise in defibrillation threshold with a hybrid lead system.

Nonthoracotomy leads have become standard for implantable cardioverter-defibrillators (ICD) because of low perioperative morbidity, mortality, and expense. Reported increases in defibrillation thresholds (DFTs) with these lead systems, however, have raised the possibility of an eventual loss of defibrillation efficacy. The mechanism of this increase is unknown. In contrast, defibrillation efficacy of traditional epicardial lead systems has been demonstrated to remain relatively stable. In the present study, we examined the implantation and chronic DFTs in 45 patients with a hybrid system (a high right atrial coil and an extrapericardial patch) that combines elements from both the thoracotomy and nonthoracotomy approach. The mean threshold increased from 11.7 +/- 3.0 to 15.8 +/- 10.0 J (p < 0.001) and mean impedance increased from 37.0 +/- 7.7 to 48.8 +/- 9.0 ohms (p < 0.0001). There was a marked (> or = 10 J) increase in DFT in 11 patients (24%) including 4 who required reoperation to obtain an adequate safety margin. The increase in DFT was unrelated to any of the analyzed variables. We conclude that the presence of an extrapericardial patch does not prevent the increase in DFT reported with nonthoracotomy lead systems. This increase is unpredictable and occurs in almost 25% of patients.

Aged↗

Effects of waveform and polarity on defibrillation thresholds in humans using a transvenous lead system.

Minimizing defibrillation thresholds is important to allow for implantation of downsized pulse generators with reduced outputs while maintaining an adequate defibrillation safety margin. Recent studies have demonstrated a significant reduction in monophasic defibrillation thresholds with a transvenous lead when the polarity was reversed (proximal coil = cathode). However, conflicting data exist concerning the effect of polarity reversal on biphasic defibrillation thresholds. The present study was designed to evaluate prospectively the effect of waveform shape and polarity on defibrillation thresholds in humans. The group studied consisted of 26 patients undergoing cardioverter-defibrillator implantation for standard indications. All data were obtained with a transvenous lead alone configuration. Defibrillation thresholds were determined using a step-down protocol with the initial waveform and polarity randomized. Reversing polarity significantly decreased the delivered energy at defibrillation threshold with monophasic waveforms (14.8 +/- 7.1 vs 20.4 +/- 8.9 J; p < 0.001), but had no effect on the overall efficacy of biphasic waveforms (11.1 +/- 5.5 vs 12.2 +/- 6.5 J). In the subgroup of patients with high biphasic defibrillation thresholds (> or = 15 J), reversing polarity decreased the defibrillation threshold from 18.2 +/- 5.1 to 13.3 +/- 5.8 J (p < 0.001). Similarly, the improvement in defibrillation thresholds with reversing polarity of monophasic waveforms was confined to the subgroup of patients with higher defibrillation thresholds. Therefore, the lack of group effect of polarity on biphasic defibrillation thresholds may be simply due to the overall lowering of defibrillation thresholds by this waveform.

Adult↗

Electrophysiologic effects and predictors of success of combination therapy with class Ia and Ib antiarrhythmic drugs for sustained ventricular arrhythmias.

Antiarrhythmic drugs remain the first line of therapy in patients with sustained ventricular arrhythmias. Although success with class Ia antiarrhythmic medications has been limited, there is evidence that the addition of a class Ib agent may improve results. A total of 110 consecutive patients referred for electrophysiologic evaluation who had inducible sustained ventricular arrhythmias resistant to a class Ia agent underwent repeat electrophysiologic study after the addition of a class Ib drug. Patients with ejection fraction >40% and ventricular fibrillation inducible in the baseline study had an 80% response rate, whereas those with inducible ventricular tachycardia and ejection fraction < or = 40% responded 11% of the time. Responders demonstrated marked prolongation of ventricular refractoriness and slight shortening of the QRS, whereas nonresponders had QRS prolongation and a more modest increase in ventricular refractoriness. Thus, the efficacy of class Ia/Ib combination therapy in patients with inducible sustained ventricular arrhythmias refractory to a class Ia drugs alone can be predicted by baseline variables. Marked prolongation of ventricular refractoriness in the absence of QRS prolongation appears to be a key factor in the success of this combination.

Aged↗

Reconstitution of B cell antigen receptor-induced signaling events in a nonlymphoid cell line by expressing the Syk protein-tyrosine kinase.

B cell antigen receptor (BCR) cross-linking activates both Src family and Syk tyrosine kinases, resulting in increased cellular protein-tyrosine phosphorylation and activation of several downstream signaling enzymes. To define the role of Syk in these events, we expressed the BCR in the AtT20 mouse pituitary cell line. These nonlymphoid cells endogenously expressed the Src family kinase Fyn but not Syk. Anti-IgM stimulation of these cells failed to induce most of the signaling events that occur in B cells. BCR-expressing AtT20 transfectants were generated that also expressed Syk. Syk expression reconstituted several signaling events upon anti-IgM stimulation, including Syk phosphorylation and association with the BCR, tyrosine phosphorylation of numerous proteins including Shc, and activation of mitogen-activated protein kinase. In contrast, Syk expression did not reconstitute anti-IgM-induced inositol phosphate production. A catalytically inactive Syk mutant could associate with the BCR and become tyrosine phosphorylated but could not reconstitute downstream signaling events. Expression of the Src family kinase Lck instead of Syk also did not reconstitute signaling. Thus, wild type Syk was required to reconstitute several BCR-induced signaling events but was not sufficient to couple the BCR to the phosphoinositide signaling pathway.

Amino Acid Sequence↗

Effects of the growth of managed care on academic medical centers and graduate medical education.

The author offers insights into how the proliferation of competitive health care financing and service delivery systems based on managed care affects the financial support available to academic medical centers (AMCs), especially to their programs in graduate medical education (GME). The paper is based largely on case studies of AMCs conducted by the author in the summer of 1994 in the health care markets of San Diego, California, Minneapolis-St. Paul, Minnesota, and Washington, D.C., complemented by a review of the literature. In sum, the investigator found consensus among all parties that in the current market, managed care plans neither are willing nor feel able to pay much, if any, premium for the services of AMCs, particularly when established, respected alternatives exist, as they typically do for most services in major urban markets. Relatively few short-term adverse effects on AMCs were found from the growth of competitive systems, but AMCs are nevertheless very concerned that managed care will put them at a disadvantage. They are thus seeking ways to position themselves for the future. The AMCs are concerned that at some point, the cost reductions they are making will hinder the fulfillment of their unique traditional mission, since they believe that the costs of their GME programs can be reduced only so far without harming residents' training. Many managed care plans, however, question the AMC mission, taking issue particularly with the training AMCs provide and its relevance to current needs for primary and ambulatory care. The investigators also found considerable support for pooled funding for GME among diverse parties, but no consensus on how this funding should be structured, who should receive it, or what it should support. Potential conflicts were also identified between national, state, and market objectives for provider supply and specialty distribution because these objectives can embody different criteria for assessing the handling and locations of specialists' training. In addition, the findings indicate that it could be unwise to consider AMC policy independent of workforce objectives; doing so could create conflicts about the kinds of physicians who should be trained. The author concludes with a list of approaches to future research that may be constructive.

Academic Medical Centers↗

Transvenous defibrillation lead systems.

The use of the implantable cardioverter defibrillator has grown dramatically over the past 10 years. One of the major advances in defibrillation technology is the development of transvenous lead systems. Compared with traditional epicardial lead systems, transvenous defibrillation leads reduce perioperative mortality, hospitalization, and costs. Transvenous lead systems provide reliable sensing of ventricular tachyarrhythmias, although redetection of ventricular fibrillation can be prolonged, especially with integrated lead systems. Both ramp and burst adaptive pacing are equally effective for the termination of ventricular tachycardia and are successful in up to 90% of spontaneous events. Defibrillation thresholds are higher with transvenous leads than with epicardial patches. These thresholds are reduced with the use of multiple transvenous leads, subcutaneous patches, or with reversing shock polarity. However, the development of biphasic waveforms has made the largest impact on the efficacy of these lead systems, allowing dual coil transvenous systems to be effective in about 90% of patients. Defibrillation efficacy is further enhanced and implantation simplified by the incorporation of an active pulse generator located in the left pectoral region. Active pectoral pulse generators with biphasic waveforms will be the primary lead system for new implants.

Defibrillators, Implantable↗

Thoracoscopic versus laparoscopic placement of defibrillator patches.

Nonthoracotomy lead systems have been developed to reduce the morbidity associated with cardioverter/defibrillator implantation. Total endocardial lead systems are effective in only about 50% of patients with standard monophasic waveforms; so patch placement is frequently required. We developed a new patch design and surgical techniques for thoracoscopic patch placement over the left ventricle and laparoscopic placement under the diaphragm. To compare the efficacy of these approaches, patches were placed in both locations in pigs acutely with a right ventricular coil serving as the anode for defibrillation. Defibrillation testing was performed, alternating between patches. The energies associated with 50% (DF50) and 90% (DF90) probability of successful defibrillation with biphasic shocks with determined. Defibrillator thresholds were significantly lower with intrathoracic than with subdiaphragmatic patches. Animal autopsy following more than 30 shocks from each patch revealed no gross damage to the lung or diaphragm in any animal.

Animals↗

Use of care and subsequent mortality: the importance of gender.

OBJECTIVE: In light of recent discussions on access that have emphasized the need to relate access measures to outcomes, we examined the relationship between three self-reported utilization and access to care measures and the risk of subsequent mortality. DATA SOURCES AND DESIGN: A nationally representative sample from the first National Health and Nutrition Examination Survey that included adults 25-64 years of age without publicly funded health insurance was followed prospectively from initial interview in 1971 through 1975. DATA COLLECTION: Complete baseline and follow-up information was obtained on 4,491 persons (90 percent). Baseline access and use was assessed with answers to three questions: having a usual source of care, obtaining a general checkup, and not obtaining needed care (or forgone care). The relationships between the access and use measures and mortality by 1987 in men and women were examined using survival analyses. The analyses adjusted for race, and for baseline age, education, income, residence, insurance status, employment status, the presence of morbidity on examination, self-rated health, smoking status, leisure exercise, alcohol consumption, and obesity. PRINCIPAL FINDINGS: After adjusting for all other baseline variables, not obtaining a general checkup was associated with higher mortality in women (hazard ratio = 1.64 [95% confidence interval = 1.16, 2.32]), but not in men (hazard ratio = 1.07 [95% confidence interval = 0.80, 1.42]). Reporting a usual source of care and forgone care were not related to subsequent mortality in either women or men. CONCLUSIONS: Reporting a general checkup is an outcome-related utilization measure in women only. Further development of access and use indicators should address gender differences in health care use.

Adult↗

A national survey of the arrangements managed-care plans make with physicians.

BACKGROUND: Despite the growth of managed care in the United States, there is little information about the arrangements managed-care plans make with physicians. METHODS: In 1994 we surveyed by telephone 138 managed-care plans that were selected from 20 metropolitan areas nationwide. Of the 108 plans that responded, 29 were group-model or staff-model health maintenance organizations (HMOs), 50 were network or independent-practice-association (IPA) HMOs, and 29 were preferred-provider organizations (PPOs). RESULTS: Respondents from all three types of plan said they emphasized careful selection of physicians, although the group or staff HMOs tended to have more demanding requirements, such as board certification or eligibility. Sixty-one percent of the plans responded that physicians' previous patterns of costs or utilization of resources had little influence on their selection; 26 percent said these factors had a moderate influence; and 13 percent said they had a large influence. Some risk sharing with physicians was typical in the HMOs but rare in the PPOs. Fifty-six percent of the network or IPA HMOs used capitation as the predominant method of paying primary care physicians, as compared with 34 percent of the group or staff HMOs and 7 percent of the PPOs. More than half the HMOs reported adjusting payments according to utilization or cost patterns, patient complaints, and measures of the quality of care. Ninety-two percent of the network or IPA HMOs and 61 percent of the group or staff HMOs required their patients to select a primary care physician, who was responsible for most referrals to specialists. About three quarters of the HMOs and 31 percent of the PPOs reported using studies of the outcomes of medical care as part of their quality-improvement programs. CONCLUSIONS: Managed-care plans, particularly HMOs, have complex systems for selecting, paying, and monitoring their physicians. Hybrid forms are common, and the differences between group or staff HMOs and network or IPA HMOs are less extensive than is commonly assumed.

Capitation Fee↗