JAMA. 2005;293:1367-1373.
The discovery of RNA interference (RNAi), an endogenous cellular gene-silencing mechanism, has already provided a powerful tool for basic science researchers to study gene function. The subsequent finding that RNAi also operates in mammalian cells has generated excitement regarding potential therapeutic applications. In this article we discuss the basic mechanism of RNAi and the therapeutic opportunities and obstacles for harnessing RNAi for therapy of human disease.
JAMA. 2008;300(13):1532-1543.
Context In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA). Objective To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (SQ) to intramuscular (IM) and omitting the week 2 dose from the licensed schedule. Design, Setting, and Participants Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002). Intervention Healthy adults received AVA by the SQ (reference group) or IM route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals. Main Outcome Measures Noninferiority at week 8 and month 7 of anti–protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4xR). Reactogenicity outcomes were proportions of injection site and systemic AEs. Results At week 8, the 4-IM group (GMC, 90.8 µg/mL; GMT, 1114.8; %4xR, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 µg/mL; GMT, 1315.4; %4xR, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4xR (GMC, 52.2 µg/mL; GMT, 650.6; %4xR, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs. Conclusions The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs. Trial Registration clinicaltrials.gov Identifier: NCT00119067
JAMA. 2004;291:599-604.
The use of complementary and alternative medicine (CAM) has grown dramatically in recent years, as has research on the safety and efficacy of CAM treatments. Minimal attention, however, has been devoted to the ethical issues relating to research on CAM. We argue that public health and safety demand rigorous research evaluating CAM therapies, research on CAM should adhere to the same ethical requirements for all clinical research, and randomized, placebo-controlled clinical trials should be used for assessing the efficacy of CAM treatments whenever feasible and ethically justifiable. In addition, we explore the legitimacy of providing CAM and conventional therapies that have been demonstrated to be effective only by virtue of the placebo effect.
JAMA. 2002;288:1775-1779.
The chronic care model is a guide to higher-quality chronic illness management within primary care. The model predicts that improvement in its 6 interrelated components—self-management support, clinical information systems, delivery system redesign, decision support, health care organization, and community resources—can produce system reform in which informed, activated patients interact with prepared, proactive practice teams. Case studies are provided describing how components of the chronic care model have been implemented in the primary care practices of 4 health care organizations.
JAMA. 2002;288:1097-1101.
Since family practice was first recognized as a specialty in the late 1960s, considerable intellectual and organizational change has occurred in medicine, especially during the 1990s. To reflect on and reconsider the role of family practice in US health care, this article reviews the development of family practice as a specialty, provides a current assessment of the status of family medicine in the United States, and comments on issues that are of ongoing importance to family practice.
JAMA. 2008;299(18):2188-2193.
A 19-year-old woman living with relatives in the United States who was admitted for elective cranial surgery for complications related to a congenital disorder developed an acute intracranial hemorrhage 10 days after surgery. The patient was declared dead following repeat negative apnea tests. The patient's father requested that the treating team administer an unverified traditional medicinal substance to the patient. Because of the unusual nature of this request, the treating team called an ethics consultation. The present article reviews this case and discusses other cases that share key features to determine whether and when it is appropriate to accommodate requests for interventions on patients who have been declared dead.
JAMA. 2004;292:1044-1050.
Conducting educational research in medical schools is challenging partly because interventional controlled research designs are difficult to apply. In addition, strict accreditation requirements and student/faculty concerns about educational inequality reduce the flexibility needed to plan and execute educational experiments. Consequently, there is a paucity of rigorous and generalizable educational research to provide an evidence-guided foundation to support educational effectiveness. "Educational epidemiology," ie, the application across the physician education continuum of observational designs (eg, cross-sectional, longitudinal, cohort, and case-control studies) and randomized experimental designs (eg, randomized controlled trials, randomized crossover designs), could revolutionize the conduct of research in medical education. Furthermore, the creation of a comprehensive national network of educational epidemiologists could enhance collaboration and the development of a strong educational research foundation.
JAMA. 2002;288:889-893.
This article—the first in a series on primary care—outlines the daunting challenges facing primary care today. Most people in the United States desire a primary care "home" to provide for and coordinate their health care needs. Yet primary care is endangered by physician stress, inadequate performance in managing chronic illness, and inability to provide prompt access and reliable continuity of care. Fundamental redesign is needed to improve access to and quality of care while easing physicians' workload without causing major increases in health care costs.
JAMA. 2003;289:1042-1046.
The advanced access model of patient scheduling is based on the core principle that if the capacity to provide patient appointments balances the demand for appointments, patients calling to see their physician are offered an appointment the same day. The accompanying article in the series "Innovations in Primary Care" presents the theory behind advanced access scheduling. In this article we describe 4 case studies of primary care practices that successfully implemented advanced access and 3 examples of practices that were unable to achieve advanced access despite considerable efforts. The lessons of these case studies should be useful for primary care practices desiring to improve timely access to care and wishing to avoid the pitfalls that can derail this innovation.
JAMA. 2008;299(24):2877-2883.
Context Changes over time in epigenetic marks, which are modifications of DNA such as by DNA methylation, may help explain the late onset of common human diseases. However, changes in methylation or other epigenetic marks over time in a given individual have not yet been investigated. Objectives To determine whether there are longitudinal changes in global DNA methylation in individuals and to evaluate whether methylation maintenance demonstrates familial clustering. Design, Setting, and Participants We measured global DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA sampled at 2 visits on average 11 years apart in 111 individuals from an Icelandic cohort (1991 and 2002-2005) and on average 16 years apart in 126 individuals from a Utah sample (1982-1985 and 1997-2005). Main Outcome Measure Global methylation changes over time. Results Twenty-nine percent of Icelandic individuals showed greater than 10% methylation change over time (P < .001). The family-based Utah sample also showed intra-individual changes over time, and further demonstrated familial clustering of methylation change (P = .003). The family showing the greatest global methylation loss also demonstrated the greatest loss of gene-specific methylation by a separate methylation assay. Conclusion These data indicate that methylation changes over time and suggest that methylation maintenance may be under genetic control.
JAMA. 1998;279:1984-1991.
Objectives.— To review current knowledge of the biology and clinical implications of human immunodeficiency virus (HIV) resistance to antiretroviral drugs, describe assays for measuring resistance, and assess their use in clinical practice. Participants.— The International AIDS Society-USA assembled a panel of 13 physicians with expertise in basic science, clinical research, and patient care relevant to HIV resistance to antiretroviral drugs. Evidence.— We reviewed available data from published reports and presented at national and international research conferences. Basic science research, clinical trial results, and expert opinions were used to form the basis of this report. Data on methods for and characteristics of specific genotypic and phenotypic assays were obtained from manufacturers and service providers. Consensus Process.— The panel met regularly between October 1997 and April 1998. Panel subgroups developed and discussed different sections of the report before discussing them with the entire panel. Conclusions and suggested approaches to the use of resistance testing were determined by group consensus. Conclusions.— Plasma HIV RNA level and CD4+ cell count are the primary values that should be used to guide the initiation of antiretroviral therapy and subsequent changes in therapy. Possible causes of treatment failure other than development of drug resistance that should be considered are adherence, drug potency, and pharmacokinetic issues. Genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may prove useful for individual patient management. Assays under development need validation, standardization, and a clearer definition of their clinical roles. Possible current roles of resistance testing for choosing an initial regimen or changing antiretroviral therapy, as well as possible implications of the presence or absence of phenotypic resistance and genotypic changes, are discussed.
JAMA. 2005;293:90-95.
Discovery that the hormone erythropoietin (EPO) and its receptor play a significant biological role in tissues outside of the hematopoietic system has fueled significant interest in EPO as a novel cytoprotective agent in both neuronal and vascular systems. Erythropoietin is now considered to have applicability in a variety of disorders that include cerebral ischemia, myocardial infarction, and chronic congestive heart failure. Erythropoietin modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. As a result, cellular protection by EPO is robust and EPO inhibits the apoptotic mechanisms of injury, including the preservation of cellular membrane asymmetry to prevent inflammation. As the investigation into clinical applications for EPO that maximize efficacy and minimize toxicity progresses, a deeper appreciation for the novel roles that EPO plays in the brain and heart and throughout the entire body should be acquired.
JAMA. 2002;288:1909-1914.
This article reviews research evidence showing to what extent the chronic care model can improve the management of chronic conditions (using diabetes as an example) and reduce health care costs. Thirty-two of 39 studies found that interventions based on chronic care model components improved at least 1 process or outcome measure for diabetic patients. Regarding whether chronic care model interventions can reduce costs, 18 of 27 studies concerned with 3 examples of chronic conditions (congestive heart failure, asthma, and diabetes) demonstrated reduced health care costs or lower use of health care services. Even though the chronic care model has the potential to improve care and reduce costs, several obstacles hinder its widespread adoption.
JAMA. 2004;292:1474-1479.
Many 21st-century observers explain international efforts to control infectious diseases as a function of globalization and recent transformations in international commerce, transportation, and human migration. However, these contemporary global health initiatives can be more fully understood by also exploring the origins of international health organizations and regulations, which were initially dedicated exclusively to stemming the tide of infectious epidemics. This article reviews 3 eras of international approaches to controlling infectious diseases (1851-1881, 1881-1945, and 1945 to the present) and concludes by assessing how nations have a strong fiscal and humanitarian incentive to invest in infectious disease control programs and infrastructures in and beyond their own borders.
JAMA. 2005;294:2618-2622.
The National Institute for Health and Clinical Excellence (NICE) was established as a part of the British National Health Service in 1999 to set standards for the adoption of new health care technologies and the management of specific conditions. In doing so it was required explicitly to take into account both clinical effectiveness and cost-effectiveness. This article describes how NICE has responded to the challenge and considers whether its experience of balancing quality, innovation, and value for money holds policy lessons for the United States.
JAMA. 2005;293:855-862.
Molecular imaging is an emerging field that aims to integrate patient-specific and disease-specific molecular information with traditional anatomical imaging readouts. The information provided by this field may ultimately allow for noninvasive or minimally invasive molecular diagnostic capabilities, better clinical risk stratification, more optimal selection of disease therapy, and improved assessment of treatment efficacy. In this update, we first provide an overview of clinically relevant molecular imaging technologies and imaging agents. Next, their applications to disease detection, drug discovery, and biomedical research are discussed. To specifically demonstrate the potential of molecular imaging, we highlight recent advances in clinical and preclinical molecular imaging of cancer and atherosclerosis.
JAMA. 2007;297:2112-2120.
Public concerns about the perils associated with incomplete or delayed reporting of results from clinical trials has heightened interest in trial registries and results databases. Here we review the current status of trial registration efforts and the challenges in developing a comprehensive system of trial registration and reporting of results. ClinicalTrials.gov, the largest trial registry with 36 249 trials from approximately 140 countries, has procedures in place to help ensure that records are valid and informative. Key challenges include the need to minimize inadvertent duplicate registrations, to ensure that interventions have unambiguous names, and to have a search engine that identifies all trials that meet a user's specifications. Recent policy initiatives have called for the development of a database of trial results. Several issues confound the implementation of such a database, including the lack of an accepted format or process for providing summaries of trial results to the public and concerns about disseminating data in the absence of independent scientific review.
JAMA. 2008;299(11):1277-1290.
Context Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. Objective To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. Design and Setting Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. Main Outcome Measures Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. Results The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10–8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10–9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10–5) and 8 mg/cm2 (P = 5.0 x 10–6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. Conclusions Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10–7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
JAMA. 2003;289:2113-2119.
Cessation of life-support treatment is an appropriate option for situations in which the burdens of therapy substantially outweigh the benefits. Decisions to withdraw dialysis now precede 1 in 4 deaths of patients who have end-stage renal disease. Guidelines have been recently published to assist clinicians in making these complex and emotionally charged determinations, and they include: relying on shared decision making by all participants, obtaining informed consent, estimating the prognosis on dialysis, adopting a systematic approach for conflict resolution of disagreements, honoring advance directives, and ensuring the provision of palliative care. These principles are discussed in relation to an elderly man with dementia whose family decided to terminate maintenance hemodialysis.
JAMA. 2004;291:1120-1126.
The clinical research infrastructure of the United States is currently at a critical crossroads. To leverage the enormous biomedical research gains made in the past century efficiently, a drastic need exists to reengineer this system into a coordinated, safe, and more efficient and effective enterprise. To accomplish this task, clinical research must be transformed from its current state as a cottage industry to an enterprise-wide health care pipeline whose function is to bring the novel research from both government and private entities to the US public. We propose the establishment of a unique public-private partnership termed the National Clinical Research Enterprise (NCRE). Its agenda should consist of informed public participation, supportive information technologies, a skilled workforce, and adequate funding in clinical research. Devoting only 0.25% of the budgets from all health care stakeholders to support the NCRE would permit adequate funding to build the infrastructure required to address these problems in an enterprise fashion. All participants in the US health care delivery system must come together to focus on system-wide improvements that will benefit the public.