National Institutes Of Health Conference Research Articles

Scaling genetic resources: New paradigms for diagnosis and treatment of rare genetic disease.

Development of genetic tests for rare genetic diseases has traditionally focused on individual diseases. Similarly, development of new therapies occurred one disease at a time. With >10,000 rare genetic diseases, this approach is not feasible. Diagnosis of genetic disorders has already transcended old paradigms as whole exome and genome sequencing have allowed expedient interrogation of all relevant genes in a single test. The growth of newborn screening has allowed identification of diseases in presymptomatic babies. Similarly, the ability to develop therapies is rapidly expanding due to technologies that leverage platform technology that address multiple diseases. However, movement from the basic science laboratory to clinical trials is still hampered by a regulatory system rooted in traditional trial design, requiring a fresh assessment of safe ways to obtain approval for new drugs. Ultimately, the number of nucleic acid-based therapies will challenge the ability of clinics focused on rare diseases to deliver them safely with appropriate evaluation and long-term follow-up. This manuscript summarizes discussions arising from a recent National Institutes of Health conference on nucleic acid therapy, with a focus on scaling technologies for diagnosis of rare disorders and provision of therapies across the age and disease spectrum.

Pragmatic trials and improving long-term care: Recommendations from a national institutes of health conference

Pragmatic trials and improving long-term care: Recommendations from a national institutes of health conference

Acute gastrointestinal bleeding: proposed study outcomes for new randomised controlled trials.

Acute gastrointestinal bleeding (GIB) remains a common cause of hospitalisation. However, interpretation and comparisons of published studies in GIB have been hampered by disparate study methodology. To make recommendations about outcome measures to be used in future randomised controlled trials (RCTs) of patients with acute bleeding from any GI source (nonvariceal UGI, variceal, small bowel, or colon) and suggest new RCTs in acute GIB for future peer-reviewed funding. As part of a National Institutes of Health conference entitled "Hemostatic Outcomes in Clinical Trials", a group of GIB experts performed targeted critical reviews of available evidence with the goal of proposing a bleeding outcome that could potentially be applied to different disciplines. In addition, the panel sought to develop a clinically meaningful primary endpoint specifically for acute GIB, potentially allowing a more contemporary regrouping of clinically relevant outcomes. The primary endpoint proposed was a composite outcome of further bleeding within 30days after randomisation leading to red blood cell transfusion, urgent intervention (repeat endoscopy; interventional radiology or surgery), or death. Secondary outcomes may include the individual components of the primary outcome, length of hospitalisation, serious adverse events, and health care resource utilisation. The proposed endpoint may help move the GIB field forward by focusing on the most clinically relevant outcomes for patients with acute GIB of all types and informing study design and importance of sample size determination for future RCTs in GIB.

“Just Birth”: Childbirth Advocacy and the Rhetoric of Feminist Health Justice

I examine writing produced in an online community of childbirth advocacy during a 2010 National Institutes of Health Conference convened to develop a consensus resolution on best practices regarding vaginal birth after cesarean (VBAC). Through an analysis of blog posts and comment threads written in response to the conference proceedings, I find that participants in the feminist counterpublic of birth advocacy utilize three primary strategies: they redefine VBAC as “just birth” rather than a medical “procedure;” they recontextualize the biomedical use of “risk” to include other factors outside of the immediate context of the hospital; and they reframe VBAC as a right rather than a preference. Together, these strategies work together to demonstrate the incommensurability of “shared doctor–patient decision making” within the current biomedical model of care. This move, toward a rights-based framework within a more highly contextualized systemic critique of health care, positions VBAC to be an issue that could link birth advocacy to a larger feminist health justice movement.

The Chiropractic Vertebral Subluxation Part 8: Terminology, Definitions, and Historicity From 1966 to 1980

ObjectiveThe purpose of this paper is to review and discuss the history of chiropractic vertebral subluxation (CVS) between the years 1966 and 1980, with an emphasis on consensus models and terminology. DiscussionThe consensus models on CVS during this time were an outgrowth of previous model building, research, and practice methods. The first consensus models were developed by the radiology diplomates of the American Chiropractic Board of Radiology. Later work was used to develop Medicare standards. Research and theory were influenced by the 1975 National Institutes of Health conference on spinal manipulation in 1975 and the workshops that followed that meeting. A new historical consciousness about the CVS, developed at the National Institutes of Health conference, which was a turning point for the profession in the use of terminology and the focus on functional pathophysiology associated with CVS. The historical view of CVS developed by Watkins, Haldeman, and Janse led to new integrative and historical developments in the profession. ConclusionTheories during this period included consensus efforts as well as new distinctions about CVS theory and terminology.

Vaginal birth after cesarean: an effective method to reduce cesarean.

Cesarean deliveries represent almost one third of US births. Given that repeat cesarean is the most common single indication for cesarean, trial of labor after cesarean (TOLAC) with subsequent vaginal birth after cesarean (VBAC) is an important mechanism to reduce the overall cesarean rate. The 2010 National Institutes of Health Conference found that one of the biggest barriers to VBAC is the lack of patient access to TOLAC. Many women who currently deliver by repeat cesarean would be candidates for a TOLAC. This manuscript will summarize the evidence on VBAC to help clinicians identify candidates, provide evidence-based counseling, and guide management of TOLAC.

Re-Evaluating “Transitional Neonatal Hypoglycemia”: Mechanism and Implications for Management

A Committee of the Pediatric Endocrine Society was recently asked by xxx to develop guidelines for evaluation and management of hypoglycemia in neonates, infants, and children. To aid in formulating recommendations for neonates, in this review, we analyzed available data on the brief period of hypoglycemia which commonly is observed in normal newborns during the transition from fetal to extrauterine life, hereafter referred to as transitional neonatal hypoglycemia in normal newborns. The goal was to better understand the mechanism underlying this phenomenon in order to formulate recommendations for recognizing neonates requiring diagnosis and treatment during the first days of life for disorders causing severe and persistent hypoglycemia. It has long been known that plasma glucose concentrations are lower in the first 1–3 days of life in normal newborn infants than at later ages. Not until the 1960s was it appreciated that hypoglycemia in neonates could sometimes be symptomatic and, as in older infants and children, cause seizures or permanent brain damage (1, 2). Although studies in laboratory animals have demonstrated postnatal developmental changes in specific enzymes involved in hepatic gluconeogenesis and ketogenesis (3, 4), it is unclear that such changes adequately explain transitional neonatal hypoglycemia in human newborns or if other mechanisms may be involved (5, 6). A National Institutes of Health conference outlined many of the “gaps in knowledge” about neonatal hypoglycemia and lamented the lack of a rational basis for defining hypoglycemia in neonates (7). For this re-evaluation of transitional neonatal hypoglycemia in normal newborns, we used the strategy routinely employed by pediatric endocrinologists for evaluation of hypoglycemia in older infants and children. This strategy, based on an examination of the major metabolic fuel and hormone responses to hypoglycemia, makes it possible to discover the mechanism of hypoglycemia and to make a specific diagnosis of the underlying cause (Figure; available at www.jpeds.com) (8). We reviewed published data in normal newborns on metabolic fuel and hormone responses during the period of transitional neonatal hypoglycemia. We focused on mean responses as being most likely representative of normal newborns, recognizing the possibility of heterogeneity, particularly with regard to peri-partum stresses and feeding practices. We found that transitional neonatal hypoglycemia most closely resembles known genetic forms of congenital hyperinsulinism, which cause a lowering of the plasma glucose threshold for suppression of insulin secretion. This conclusion is based on strong evidence supported by two or more independent reports and provides a novel perspective on both the diagnosis and management of hypoglycemia in the first several days after birth. Figure Hypoglycemia diagnosis based on plasma metabolic fuel responses. Measurement of major fuels (lactate as a gluconeogenic substrate, FFA from adipose tissue lipolysis, and beta-hydroxybutyrate as the major ketone from hepatic ketogenesis) at a time of hypoglycemia ...

Treatment of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases workshop.

This is the second of a two-part summary of a National Institutes of Health conference on fecal incontinence (FI) that summarizes current treatments and identifies research priorities. Conservative medical management consisting of patient education, fiber supplements or antidiarrheals, behavioral techniques such as scheduled toileting, and pelvic floor exercises restores continence in up to 25% of patients. Biofeedback, often recommended as first-line treatment after conservative management fails, produces satisfaction with treatment in up to 76% and continence in 55%; however, outcomes depend on the skill of the therapist, and some trials are less favorable. Electrical stimulation of the anal mucosa is ineffective, but continuous electrical pulsing of sacral nerves produces a ≥50% reduction in FI frequency in a median 73% of patients. Tibial nerve electrical stimulation with needle electrodes is promising but remains unproven. Sphincteroplasty produces short-term clinical improvement in a median 67%, but 5-year outcomes are poor. Injecting an inert bulking agent around the anal canal led to ≥50% reductions of FI in up to 53% of patients. Colostomy is used as a last resort because of adverse effects on quality of life. Several new devices are under investigation but not yet approved. FI researchers identify the following priorities for future research: (1) trials comparing the effectiveness, safety, and cost of current therapies; (2) studies addressing barriers to consulting for care; and (3) translational research on regenerative medicine. Unmet patient needs include FI in special populations (e.g., neurological disorders and nursing home residents) and improvements in behavioral treatments.

What do we know about metabolic syndrome in adolescents with PCOS?

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women that manifests itself with a variety of features. For this reason, three different diagnostic criteria have been introduced. For adults, the National Institutes of Health Conference (NIH) criteria, which consists of hyperandrogenism and oligo-anovulation, is the most widely used. Symptoms of PCOS usually start with puberty and may overlap with normal pubertal development. Hormonal fluctuations during this period make the diagnosis of PCOS more difficult. Until now, there is no validated diagnostic criteria for PCOS in adolescents. Although menstrual disorders and cosmetic problems are the most common complaints of adolescents with PCOS, patients should also be evaluated for the potential risk for insulin resistance, obesity, subclinical atherosclerosis, diabetes, metabolic syndrome and cardiovascular disease. Obesity is the most prominent predictor of metabolic syndrome. As the incidence of obesity is increasing both in childhood and adolescence, governments will be faced with a social and economic burden in the future. Adolescents with PCOS are more obese than normal adolescents and have an increased risk of metabolic syndrome. It is suggested that abdominal adiposity increases the risk of metabolic syndrome by inducing various cytokine secretions. Although there is no consensus on metabolic syndrome criteria in the adolescent period, International Diabetes Federation (IDF) criteria may be used for children older than 10 years. Various clinical and metabolic markers are investigated for the prediction of metabolic syndrome in the literature. Waist circumference, serum triglycerides and androgens are the suspected predictors of metabolic syndrome. The prevention of abdominal adiposity and the early diagnosis of PCOS in adolescence should be the main target for the prevention of metabolic syndrome. Clinicians should investigate adolescents with PCOS for metabolic and cardiovascular risks and take preventive action. A Mediterranean diet, low in fat and high in fruits and vegetables, along with moderate-intensity exercise and smoking cessation are the recommended interventions for especially obese adolescents with PCOS. Metformin may be the treatment of choice when lifestyle modifications are ineffective.

Family History in Primary Care Pediatrics

The family history has been called the first genetic test; it was a core element of primary care long before the current wave of genetics technologies and services became clinically relevant. Risk assessment based on family history allows providers to personalize and prioritize health messages, shifts the focus of health care from treatment to prevention, and can empower individuals and families to be stewards of their own health. In a world of rising health care costs, the family history is an important tool, with its primary cost being the clinician's time. However, a recent National Institutes of Health conference highlighted the lack of substantive evidence to support the clinical utility of family histories. Annual collection of a comprehensive 3-generation family history has been held up as the gold standard for practice. However, interval family histories targeted to symptoms and family histories tailored to a child's life stage (ie, age-based health) may be important and underappreciated methods of collecting family history that yield clinically actionable data and supplement existing family history information. In this article, we review the various applications, as well as capabilities and limitations, of the family history for primary care providers.

Translating Current Knowledge Into Dementia Prevention

Considerable knowledge has been gained from epidemiologic studies and randomized clinical trials regarding risk factors for dementia, including Alzheimer disease (AD) and vascular dementia (VaD). Most identified risk factors for dementia are similar to vascular disease risk factors for heart disease and stroke. In 2010, the National Institutes of Health Conference concluded that there are no validated modifiable factors to reduce the incidence of AD or to change its course. This research perspective specifically concerning AD disregards the fact that in community-dwelling elderly, the most common forms of dementia involve the cerebral macrovasculature and microvasculature, manifesting as VaD and mixed dementia (the combination of VaD and AD) in autopsy-confirmed cases. Thus, prevention of dementia in clinical practice should be considered from this broader and more relevant view and not just a research perspective on "pure" AD. Practicing clinicians can reasonably state to patients that, although more definitive research is clearly needed, the management and treatment of vascular disease risk factors are likely beneficial not only to prevent heart disease and stroke, but also common forms of dementia in the community.

Helping to address the over treatment of prostate cancer: tools to differentiate lethal and non-lethal phenotype in prostate cancer

Helping to address the over treatment of prostate cancer: tools to differentiate lethal and non-lethal phenotype in prostate cancer

Calculated NIH Response Correlates with Changes in Patient-Reported Symptoms but Not with Quality of Life: Results From the Chronic Gvhd Consortium

Abstract 1988Background: In 2005, the National Institutes of Health (NIH) Consensus Conference recommended measurement tools to capture clinician or patient-assessed chronic GVHD manifestations. The NIH Conference also proposed a set of provisional definitions to calculate response using these measures. The correlation of the calculated NIH responses with patient-reported quality of life (QOL) or symptoms has not been examined. Ideally, improvement according to NIH response criteria would be associated with better QOL and fewer symptoms compared to patients who have stable disease or progress. Patients and methods: We studied 274 patients with chronic GVHD requiring systemic treatment who were enrolled in a multi-center, prospective, longitudinal, observational cohort. Treatment of chronic GVHD was not uniform for this study. 256 patients had follow-up visits at 6 months after enrollment. The 6 month time point was chosen to be consistent with many earlier phase II studies. Responses were classified according to the calculated NIH response algorithm (BBMT 2006;12:491) as complete, partial, stable or progression, separately in skin, eye, mouth, lung, liver and gastrointestinal (GI) tract as well as overall by comparing organ manifestations reported at the follow-up visit to the enrollment visit. Complete or partial response was considered “response”, and stable disease or progression as “no response”. QOL measures included the SF-36, FACT-BMT and Human Activities Profile (HAP) score. Symptom measures included the Lee symptom scale and 10-point global rating of symptoms. Linear regression models were used to estimate the change in measures associated with response vs. no response, adjusting for case type (incident vs. prevalent), donor/patient gender and NIH global severity at enrollment. Results: Patients with a median age of 52 years were enrolled at a median of 13 months from transplant. Of 274 patients, 247 (90%) had mobilized blood cell transplant, 132 (48%) had HLA-matched related donors, 138 (50%) had unrelated donors, and 153 (56%) had myeloablative conditioning. At 6 months, overall response rates were 10 (4%) CR, 72 (28%) PR, 14(6%) SD, and 157(62%) PD, for a CR+PR rate of 32%. Organ-specific CR+PR response rates were 31% for skin, 16% for eye, 26% for mouth, 23% for GI, and 31% for liver. Compared with no response, overall response was associated with improved overall symptom burden measures, but not with changes in QOL measures. For example, the Lee overall score was estimated to be 4.6 points lower in responders than in non-responders (Table 1). Organ-specific analyses showed that organ response was associated with improved symptom burden in skin, eye, mouth and GI except for mouth dryness (Table 2). Conclusion: The calculated organ-specific and overall NIH responses by the provisional algorithm correlated with corresponding organ-specific and overall changes in patient-reported symptom burden, but calculated overall response did not correlate with changes in patient-reported QOL. Our results suggest that the calculated NIH response is a surrogate measure for patient symptom burden in clinical trials.Table 1Estimated change in QOL and symptom measures associated with overall responseOutcomeClinically meaningful change1R vs. NR Estimated change (95% CI)PSF-36 PCS4.80.8 (−1.9–3.5).57SF-36 MCS5.20.1 (−2.7–2.9).93FACT-BMT102.7 (−1.8–7.1).24HAP MAS6.20.7 (−3.2–4.6).73HAP AAS8.41.6 (−2.6–5.8).45Lee symptom overall score6.2−4.6 (−7.3–−1.9).001Patient-rated overall symptoms2−0.9 (−1.6–−0.3).003R, response; NR, no response; PCS, physical component score; MCS, mental component score; MAS, maximum activity score; AAS, adjusted activity score.1Half-standard deviation of baseline score or 2-point change on a 10-point scale.Table 2Estimated change in symptom measures for each organ associated with organ responseOrganClinically meaningful changeR vs. NR Estimated change (95% CI)PLee symptom scaleSkin10.4−7.3 (−14–−0.8).03Eye14.8−16 (−27–−4.7).005Mouth13.8−16 (−24–−7.6)<.001GI (nutrition)6.2−7.1 (−13–−1.1).02Patient-rated symptomsSkin itching2−1.0 (−1.8–−0.1).03Eye problem2−1.3 (−2.4–−0.2).03Mouth dryness2−0.1 (−1.1–0.8).81Mouth pain2−1.1 (−1.9–−0.2).02Mouth sensitivity2−1.0 (−1.9–−0.1).03R, response; NR, no response. Disclosures:No relevant conflicts of interest to declare.

Taking a Family History of Hypertension: Is There Patient Care Benefit?

Taking a Family History of Hypertension: Is There Patient Care Benefit?

Update: The Clinical Pharmacist as Principal Investigator

This paper summarizes the history of the clinical pharmacist as a principal investigator across a wide range of research venues and disciplines. Clinical pharmacists have served as principal investigators on a wide range of grants and contracts from all available funding sources, including peer‐reviewed funding from the National Institutes of Health (NIH). The NIH Conference on Pharm.D. Pathways to Biomedical Research in 2006 (http:www.nigms.nih.govTrainingPharm.D) is a strong endorsement of current and future opportunities for clinical pharmacist‐directed research. Both research funding and resultant scholarship have increased during the past decade, primarily in academic settings. Through an American Association of Colleges of Pharmacy database, the number of faculty with a Pharm.D. as their terminal degree who received NIH funding increased from 5 in 1998 to 24 in 2007. Use of www.ClinicalTrials.gov provided a stronger picture of clinical pharmacist research, with 523 studies performed by those with a Pharm.D. degree when searched in 2009. Because of the lack of a central database, it is difficult to discern the true number and extent of clinical pharmacist research funding and scholarship. Scientific efforts are still required to completely understand the impact of research and scholarship by clinical pharmacists. Most important, clinical pharmacist development needs to be an academic and practice priority to ensure an adequate supply of clinical pharmacists as principal investigators to continue making substantial and meaningful contributions in meeting the needs of patients, improving public health, and expanding the roles of clinical pharmacists.

Proceedings from the Conference on Reproductive Problems in Women of Color

The purpose of the National Institutes of Health conference on Reproductive Problems in Women of Color that convened on July 25, 2009 was to bring investigators together to examine data related to reproductive health care access and ethnic disparities in reproductive problems, fertility treatments, and pregnancy outcomes. One of the goals discussed at this conference was to initiate a research network of investigators interested in studying these problems through the development of an American Society of Reproductive Medicine special interest group and Society of Assisted Reproductive Technology writing groups.

NIH Conference on the Future of Telehealth: Essential Tools and Technologies for Clinical Research and Care—A Summary

Major government efforts to widen the use of health information technology and speed the translation of biomedical research discoveries into clinical practice are converging with the rapid growth of the Internet to create unprecedented opportunities to use telehealth networks to broaden access to high-quality healthcare and expand the scope and reach of clinical and translational research. Recognizing the dual potential of telehealth networks to improve health outcomes and reduce barriers to participation in research, particularly in medically underserved communities, the National Center for Research Resources (NCRR), part of the National Institutes of Health (NIH), convened a national conference at the NIH on June 25-26, 2009, titled "Future of Telehealth: Essential Tools and Technologies for Clinical Research and Care," in collaboration with experts from the Health Resources and Services Administration, the Indian Health Service, the Department of Veterans Affairs, Internet2, and the NIH National Library of Medicine, National Institute of Biomedical Imaging and Bioengineering, and National Center for Minority Health and Health Disparities. The conference brought together over 400 subject matter experts from government, academia, and industry to discuss a wide range of issues in telehealth research and development. Its primary outcome is a set of short papers reporting on recommendations from thematic breakout sessions and some overarching recommendations that can, taken together, stimulate and help guide further research through new multi-agency, interdisciplinary collaborations.

How to Write an NIH R13 Conference Grant Application

The purpose of this article is to provide recommendations for writing a successful R13 conference grant proposal for the National Institutes of Health (NIH). The authors reviewed successful NIH conference grant proposal abstracts. They also reflect on their own experience in writing an NIH conference grant proposal and implementing a successful annual conference on research methods in the area of psychological trauma. The key to a strong proposal is linkage among all of its sections, from the specific aims to the budget. The specific aims should be justified by the need for the conference and articulated in the background and significance section, and the aims, in turn, should drive the content and format of the conference. Conferences can be an important way to promote NIH scientific goals, by disseminating new findings, facilitating collaborations, and stimulating new lines of research.

Reply to Mathews: Misplaced focus on experimental detail

Mathews, who represents the plastic industry, presents the industry “spin” on the issue of human bisphenol A (BPA) exposure (1), stating that BPA is subject to very rapid first-pass metabolism with the implication that there should be no BPA detected in human biomonitoring studies and thus that no threat to human health is posed by BPA. The evidence from science not funded by the chemical industry challenges this assumption (2, 3). BPA levels in blood are in the low parts per billion range (2), which is above levels that cause adverse effects in animal and human tissues (4). These findings predicted that BPA would be related to diabetes and cardiovascular disease in adults (5). There are thus potentially many non-oral sources of BPA exposure, which has led to the suggestion that the best approach to model continuous exposure of humans to BPA is administration via a continuous-release capsule, such as that used in our study (6). There is an extensive body of evidence that led the U.S. National Toxicology Program and experts from a National Institutes of Health conference on BPA (3) to express concern that BPA causes damage to the brain in animals and thus is likely to pose a threat to humans. The focus of Mathews on our method of administering a very low dose of BPA rather than on the significant damage to the brain is reminiscent of the response of tobacco industry product protection firms to scientific publications showing harm from cigarettes.

Overview of the conference “Vitamin D and Health in the 21st Century: an Update”

We summarize the key findings, strength of the evidence, and research needs identified in the National Institutes of Health conference “Vitamin D and Health in the 21st Century: an Update,” which was held in September 2007; a systematic evidence-based review; and a National Institutes of Health roundtable discussion held after the conference by scientists with relevant expertise. The evidence-based review addressed 5 questions on 25-hydroxyvitamin D [25(OH)D] and functional outcomes across the life cycle and response to exposure, bone health outcomes of supplementation, risks and benefits of sun exposure, and adverse outcomes. These questions also framed the conference and roundtable discussions. Researchers have made considerable progress in understanding the relation of 25(OH)D to bone health outcomes in the elderly and in postmenopausal women, but we know less about its impact on other stages of the life cycle and in racial and ethnic groups. Limitations of the existing data include the failure of many studies to control for important confounders [baseline 25(OH)D concentration, skin pigmentation, body mass index, compliance, etc], sparse data on key vulnerable populations (dark-skinned persons, reproducing women, infants, children, and adolescents), problems of accuracy and excessive variability in measuring 25(OH)D, lack of established relation of 25(OH)D with functional outcomes except in the elderly, and limited information on the effects of vitamin D independent of calcium, magnesium, and phosphate. Future research should determine and validate across the life cycle relevant functional outcomes for bone and other health factors as well as adverse outcomes for the biomarker of exposure, 25(OH)D, to enable assessment of the role of vitamin D status in health maintenance and disease prevention.