Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

The 2015 Pediatric Endocrine Society Ethics Symposium: Controversies Regarding 'Gender Verification' of Elite Female Athletes - Sex Testing to Hyperandrogenism.

An overview of the Pediatric Endocrine Society's Ethics Symposium held in April 2015 at the annual meeting of the Pediatric Academic Societies is provided by the panel moderators with a summary of efforts by international athletic governing bodies over several decades to 'verify' the eligibility of athletes to compete in female only events, culminating in the hyperandrogenism policies that were the focus of the panel debate. This history was extensively reviewed in the symposium's opening presentation by Alan Rogol, in collaboration with Lindsay Pieper. Two sharply divergent views were then conveyed. David Allen's, in support, is provided in his article which follows. The opposing case, provided by Katrina Karkazis, is extensively summarized herein and reflected in her Science essay with Rebecca Jordan-Young which appeared shortly after the meeting. The subsequent ruling by the international Court of Arbitration for Sport to suspend the hyperandrogenism rule is noted with some speculation regarding the implications if it is upheld.

Creating a new structure for research on health care effectiveness.

Effectiveness research (a term we use in preference to the more confining and difficult health services or outcomes research) evaluates the clinical setting and the health care system on which it depends. It uses a variety of health care assessment techniques and the practical clinical trial to inform clinical practice, quality interventions, and health policy decisions. Effectiveness research had not had sufficient public or private funding to produce the information needed to facilitate evidence-based health care improvement. However, recent trends, such as the likelihood for continued substantial increases in health care costs and concern regarding the quality and safety of the US health care system, are among the important arguments for increasing its funding and capacity. We propose a new entity, a public-private consortium to expand and offer new capability and resources in this area. The consortium would consist of all relevant public and private entities. It would be organized into an executive committee, which would identify research priorities and panels to design requests for proposals. Competitive peer-reviewed proposals, transparency and balance of forces in choice of topics, conduct of research, and interpretation of results would be important features. Metrics for success would be use of the data derived from consortium projects in medical decision making and benefit design. The consortium would provide balance and potential mediation of conflicting or competing interests in which all stakeholders will be present to establish the rules. Broad representation of all interests would serve to avoid the economic, policy, and political issues that have bedeviled past efforts. Models for the consortium include the Health Effectiveness Institute, the Centers for Education and Research on Therapeutics, and the Transportation Research Board.

Gender verification of female Olympic athletes.

Gender verification of female athletes has long been criticized by geneticists, endocrinologists, and others in the medical community. Problems include invalid screening tests, failure to understand the problems of intersex, the discriminatory singling out of women based only on laboratory results, and the stigmatization and emotional trauma experienced by individuals screened positive. Genuine sex-impostors have not been uncovered by laboratory-based genetic testing; however, gender verification procedures have resulted in substantial harm to a number of women athletes born with relatively rare genetic abnormalities. Individuals with sex-related genetic abnormalities raised as females have no unfair physical advantage and should not be excluded or stigmatized, including those with 5-alpha-steroid-reductase deficiency, partial or complete androgen insensitivity, and chromosomal mosaicism. In 1990, the International Amateur Athletics Federation (IAAF) called for ending genetic screening of female athletes and in 1992 adopted an approach designed to prevent only male impostors from competing. The IAAF recommended that the "medical delegate" have the ultimate authority in all medical matters, including the authority to arrange for the determination of the gender of the competitor if that approach is judged necessary. The new policy advocated by the IAAF, and conditionally adopted by the International Olympic Committee, protects the rights and privacy of athletes while safeguarding fairness of competition, and the American Medical Association recommends that it become the permanent approach.

Translating clinical research into practice: practice-based research networks--a promising solution.

Greater effort is needed to translate research discoveries into clinical practice and to ensure that proven treatments are routinely implemented by physicians. Practice-based research networks are an undervalued resource in the endeavor to bring research results to bear in patient care. These networks are groups of practicing health care providers who have organized to address research questions of primary importance to their patients. Existing practice-based research networks have addressed a wide range of issues, including improvement of preventive service delivery, reliability of diagnostic measures, practice variation, disease prevention, and systems of care coordination. Several deficiencies in the current system prevent practice-based research networks from reaching their full potential as mechanisms of translating clinic research into practice. For practice-based research networks to flourish, they need increased funding for practice-based research networks; information systems to facilitate research by practicing physicians; training programs for health care providers; and communication networks between providers, clinical researchers, professional societies, and academic health centers.

Clinical research in the United States at a crossroads: proposal for a novel public-private partnership to establish a national clinical research enterprise.

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.

Overcoming burdens in the regulation of clinical research in children. Proceedings of a consensus conference, in historical context.

BACKGROUND: Many investigators are concerned that the modes of implementation and enforcement of the federal regulations designed to protect children are unduly impeding pediatric clinical research. OBJECTIVE: To assess regulatory impediments to clinical research involving children and to develop recommendations to ameliorate them. PARTICIPANTS: The Pediatric Endocrine Society and The Endocrine Society convened a consensus conference involving experts and stakeholders in patient-oriented research involving children and adolescents in 2008. CONSENSUS PROCESS: Following presentations that reviewed problematic issues around key regulations, participants divided into working groups to develop potential solutions that could be adopted at local and federal levels. Presentations to the full assembly were then debated. A writing committee then drafted a summary of the discussions and main conclusions, placing them in historical context, and submitted it to all participants for comment with the aim of developing consensus. CONCLUSIONS: Recommendations designed to facilitate the ethical conduct of research involving children addressed the interpretation of ambiguous regulatory terms such as "minimal risk" and "condition" and called for the development by professional societies of best practice primers for common research procedures that would be informative to both investigators and institutional review boards. A call was issued for improved guidance from the Office for Human Research Protections and Food and Drug Administration as well as for the development by professional societies of a process to monitor progress in improving human subject research regulation. Finally, a need for systematic research to define the nature and extent of institutional obstacles to pediatric research was recognized.

Pharmacologic management of insomnia in children and adolescents: consensus statement.

OBJECTIVE: The purpose of this work was to develop a consensus statement on the current status and future role for pharmacologic management of insomnia in children and adolescents. METHOD: The National Sleep Foundation, in collaboration with Best Practice Project Management, Inc, convened expert representatives involved in the study and treatment of pediatric insomnia and conducted a 2-day conference to examine the role of pharmacologic management of pediatric insomnia and to make recommendations regarding the development of clinical trials in this area. After a series of presentations providing background on the current knowledge of pediatric insomnia and its treatment alternatives, workgroups provided recommendations for the evaluation of pharmacologic treatment of insomnia in specific populations of children and adolescents and developed guidelines for the core methodologic issues relevant to the design of clinical trials. The group developed consensus recommendations for clinical trials in this area encompassing: (1) high-priority patient populations for research, (2) inclusion/exclusion criteria, (3) outcome measures, (4) ethical considerations unique to clinical trials involving children and adolescents, and (5) priorities for future research that will enhance the understanding of pediatric insomnia. RESULTS: Conference participants unanimously agreed that there is a need for pharmacologic management of pediatric insomnia. Furthermore, the widespread use of "hypnotic" and psychotropic medications for children in the absence of safety and efficacy data indicates a knowledge gap about the best pharmacologic practices for management of pediatric insomnia. Attendees reached consensus on methodologic issues in the study of pharmacologic treatment of pediatric insomnia including agreeing on a definition of pediatric insomnia as "repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in daytime functional impairment for the child and/or family." It was agreed that priority should be given to insomnia studies in children with attention-deficit/hyperactivity disorder and those with pervasive developmental disorders/autism spectrum disorder. There was also agreement on the need for pharmacokinetic and pharmacodynamic studies to determine appropriate dose levels and to evaluate safety with a wide range of doses. CONCLUSIONS: The treatment of pediatric insomnia is an unmet medical need. Before appropriate pharmacologic management guidelines can be developed, rigorous, large-scale clinical trials of pediatric insomnia treatment are vitally needed to provide information to the clinician on the safety and efficacy of prescription and over-the-counter agents for the management of pediatric insomnia.

The physician's role in discussing organ donation with families.

Federal Conditions of Participation from the Health Care Financing Administration (now the Centers for Medicare and Medicaid Services) introduced in 1998 require that all families be presented the option of organ and tissue donation when death is imminent. The perception that physicians were being excluded from participating in this process led to a resolution at the American Medical Association House of Delegates meeting in December 1999, calling on the American Medical Association Council on Scientific Affairs to review the Conditions of Participation "to ensure that there is no prohibition of physician involvement in the organ donation process..." The number of organs procured for transplantation in the United States is insufficient to meet needs. Families' hospital experiences significantly affect their decisions to donate organs. Discussing severe brain injury, brain death, and organ donation after brain death with families is a specialized form of end-of-life decision-making and care in the intensive care unit; however, the knowledge, skills, and attitudes necessary for physicians and nurses to promote good end-of-life decision-making are widely variable. The federal Conditions of Participation require that those making requests of families for organ donation receive specific training. They do not prohibit physician involvement in initiating organ donation requests, provided these individuals are properly trained. Physicians have an important role in caring for patients and families in these circumstances, and the care they provide is enhanced through training, attention to the special issues involved, and collaboration with organ procurement organization personnel.