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Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791, NCT00523341., Competing Interests: Declaration of competing interest S Ferrari has received research grants from Amgen, UCB Pharma, and Agnovos; has received consulting fees from Amgen, UCB Pharma, Eli Lilly, Agnovos, and LAbatec; and has given expert testimony for Novartis. EM Lewiecki has received research grants from Radius, Amgen, Mereo, and Bindex; has received consulting fees and served on the advisory board for Amgen, Radius, Alexion, Sandoz, and Samsung Bioepis; and has served on the speaker's bureau for Radius and Alexion. PW Butler, DB Crittenden, and N Pannacciulli are former employees and stockholders of Amgen Inc. DL Kendler has received research grants from Amgen and AstraZeneca; has received consulting fees from Amgen and Eli Lilly; and has served on the speaker's bureau for Amgen, Eli Lilly, and Pfizer. N Napoli has received consulting fees from Abiogen, Eli Lilly, and UCB Biopharma; and has served on the speaker's bureau for Eli Lilly. S Huang is an employee and stockholder of Amgen Inc. E Siris has received royalties from Up To Date as a peer reviewer for denosumab. N Binkley has received research grants from Radius, RTI Health Solutions, and GE Healthcare; and has received consulting fees/served on an Advisory Board for Amgen and Taurus., (Copyright © 2020. Published by Elsevier Inc.)

Context: Evidence for further nonvertebral fracture (NVF) reductions with long-term antiresorptive therapy in osteoporosis is lacking., Objective: To evaluate NVF risk reduction in subjects receiving ≤10 years of denosumab treatment., Design: Phase 3, randomized, placebo-controlled, 3-year Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (NCT00089791) and its open-label 7-year extension (NCT00523341)., Setting: One hundred seventy-two study centers worldwide., Patients: Women 60 to 90 years, lumbar spine or total hip bone mineral density T-scores <-2.5 (≥-4.0 at both)., Interventions: Subjects randomly assigned 1:1 denosumab 60 mg SC Q6M (long-term) or placebo (crossover) in FREEDOM; eligible subjects could enroll in the extension to receive denosumab 60 mg SC Q6M., Main Outcome Measures: NVF Exposure-adjusted subject incidence (per 100 subject-years) during denosumab treatment years 1 to 3 and 4 to 7 (all subjects) and years 4 to 10 (long-term only), and rate ratios (RRs) for years 4 to 7 or 4 to 10 vs 1 to 3., Results: Among 4074 subjects (2343 long-term, 1731 crossover), NVF rates (95% CI) in all subjects were 2.15 (1.90 to 2.43) during years 1 to 3 and 1.53 (1.34 to 1.75) during years 4 to 7 of denosumab treatment [RR (95% CI) = 0.72 (0.61 to 0.86); P < 0.001]; in long-term only were 1.98 (1.67 to 2.34) during years 1 to 3 and 1.44 (1.24 to 1.66) during years 4 to 10 [RR = 0.74 (0.60 to 0.93); P = 0.008]. combined osteonecrosis of the jaw and atypical femoral fracture rate was 0.06., Conclusions: Long-term denosumab treatment, >3 and ≤10 years, was associated with further reductions in NVF rates compared with the first 3 years., (Copyright © 2019 Endocrine Society.)

Objective: Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24., Methods: This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for <3 months (glucocorticoid-initiating) or for ≥3 months (glucocorticoid-continuing) before screening. All patients <50 years old had a history of osteoporotic fracture. Glucocorticoid-continuing patients ≥50 years old had T scores of -2.0 or less (or -1.0 or less with fracture history). Patients were randomized (1:1) to receive denosumab 60 mg subcutaneously Q6M or risedronate 5 mg orally QD for 24 months, with daily calcium and vitamin D., Results: Of 795 patients, 590 (74.2%) completed the study (in the glucocorticoid-initiating group, 109 of 145 patients treated with denosumab and 117 of 145 patients treated with risedronate; in the glucocorticoid-continuing group, 186 of 253 patients treated with denosumab and 178 of 252 patients treated with risedronate). Denosumab was superior to risedronate in increasing lumbar spine and total hip BMD at all time points assessed, among glucocorticoid-initiating patients (24-month lumbar spine: BMD increase of 6.2% versus 1.7%, respectively [P < 0.001]; 24-month total hip: BMD increase of 3.1% versus 0.0% [P < 0.001]) and among glucocorticoid-continuing patients (24-month lumbar spine: BMD increase of 6.4% versus 3.2% [P < 0.001]; 24-month total hip: BMD increase of 2.9% versus 0.5% [P < 0.001]). Adverse events, serious adverse events (including infections), and fractures were similar between treatment groups., Conclusion: Denosumab was superior to risedronate in terms of increases in spine and hip BMD through month 24, and the safety profile was similar between treatment groups. Denosumab may offer a new osteoporosis treatment option for glucocorticoid-treated patients., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Context: Antiresorptive therapy has been associated with osteonecrosis of the jaw (ONJ), an infrequent but potentially serious adverse event., Objective: To assess information on invasive oral procedures and events (OPEs)-dental implants, tooth extraction, natural tooth loss, scaling/root planing, and jaw surgery-during the 7-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Extension study and to present details of positively adjudicated ONJ cases., Design: Randomized, double-blind, placebo-controlled, 3-year trial (FREEDOM) followed by 7 years of open-label denosumab (FREEDOM Extension). At Extension Year 3, women were asked to record their history of invasive OPEs since the start of the Extension to Year 2.5 and oral events in the prior 6 months. The questionnaire was then administered every 6 months until the end of the Extension., Setting: Multicenter, multinational clinical trial., Patients: Postmenopausal women with osteoporosis., Interventions: Subcutaneous denosumab 60 mg or placebo every 6 months for 3 years, then 7 years of open-label denosumab., Main Outcome Measures: Self-reports of OPEs and adjudicated cases of ONJ., Results: Of respondents, 45.1% reported at least one invasive OPE. The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000 person-years. ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%)., Conclusions: Although invasive OPEs were common in these denosumab-treated women and were associated with an increased ONJ incidence, the overall rate of ONJ was low, and all cases with complete follow-up resolved with treatment., (Copyright © 2019 Endocrine Society.)

Purpose: In November, 2014, the State of Oklahoma enacted legislation potentially eliminating the provision of conditional confidential pediatric care. A consent form for treatment specific to adolescent confidential care was developed in response. This study examines parent/guardian response to the consent form., Methods: The consent to treatment form describes the clinical and developmental benefits of conditional confidential treatment of adolescent minors and asks parent/guardians to waive the right to: (1) access confidential portions of the medical record, (2) be present for the physical exam, (3) be present for risk behavior discussions, and (4) consent for hormonal contraception, if indicated., Results: Of 269parent/guardian respondents to the consent form, over 95% waived their rights for each of the four provisions., Conclusions: When provided with information on the rationale for provision of conditional confidential care, a diverse group of parent/guardians in a conservative state overwhelmingly agree to this standard of care., (Copyright © 2018 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Acromegaly resulting from the ectopic secretion of growth hormone-releasing hormone (GHRH) is rare. We present a case of acromegaly secondary to proven GHRH-secretion by a bronchial carcinoid tumor in a type 1 diabetic subject and document the clinical course pre- and post-resection of the tumor and of subsequent octreotide therapy. A 54-year-old Caucasian man was referred for evaluation of acromegalic symptoms and significantly increased insulin requirements. He had a history of left lung surgery 20 years prior for hemoptysis. Initial laboratory results indicated acromegaly. Fasting serum growth hormone (GH): 26.1 ng/mL (0-5 ng/mL), insulin-like growth factor 1 (IGF-1): 635 ng/mL (87-283 ng/mL), GH at 60 min post-ingestion of 75 grams of oral glucose during a glucose tolerance test: 8.3 ng/mL (normal <1 ng/mL). Pituitary magnetic resonance imaging (MRI) revealed diffuse pituitary enlargement without adenoma. A 4.4 cm left hilar mass was noted on chest computed tomography (CT) scan. Further evaluation for a suspected GHRH-secreting neuroendocrine tumor was pursued. Plasma GHRH level was elevated: 198 pg/mL (<50 pg/mL). Octreoscan showed radiolabelled-octreotide uptake in the left lung mass and pituitary gland. Surgical resection of the lung mass was performed. Immunohistochemical study of the tumor tissue indicated a neuroendocrine tumor secreting GHRH. Postoperatively, serum GHRH, GH and IGF-1 levels fell precipitously. At 10 months, IGF-1 levels were mildly elevated and 7 months of 10 mg long-acting octreotide therapy (Sandostatin(®) LAR(®)) was trialed. At 20 months, off octreotide, serum IGF-1 levels had normalized, acromegalic features were receding, and the patient's daily insulin requirements had decreased by 57%.

Objective: Type 2 deiodinase gene (DIO2) polymorphisms have been associated with changes in pituitary-thyroid axis homeostasis. The -258A/G (SNP rs12885300) polymorphism has been associated with increased enzymatic activity, but data are conflicting. To characterize the effects of -258A/G polymorphism on intrathyroidal thyroxine (T(4)) to triiodothyronine (T(3)) conversion and thyroid hormone (TH) secretion pattern, we studied the effects of acute, TRH-mediated, TSH stimulation of the thyroid gland., Design: Retrospective analysis., Methods: The TH secretion in response to 500  μg i.v. TRH injection was studied in 45 healthy volunteers., Results: Twenty-six subjects (16 females and ten males, 32.8 ± 10.4 years) were homozygous for the ancestral (-258A/A) allele and 19 (11 females and eight males, 31.1 ± 10.9 years) were carriers of the (-258G/x) variant. While no differences in the peak TSH and T(3) levels were observed, carriers of the -258G/x allele showed a blunted rise in free T(4) (FT(4); P<0.01). The -258G/x92Thr/Thr haplotype, compared with the other groups, had lower TSH values at 60  min (P<0.03). No differences were observed between genotypes in baseline TH levels., Conclusions: The -258G/x DIO2 polymorphism variant is associated with a decreased rate of acute TSH-stimulated FT(4) secretion with a normal T(3) release from the thyroid gland consistent with a shift in the reaction equilibrium toward the product. These data indicate that the -258G DIO2 polymorphism causes changes in the pattern of hormone secretion. These findings are a proof of concept that common polymorphisms in DIO2 can subtly affect the circulating levels of TH and might modulate the TH homeostasis.

Background: The common Thr92Ala D2 polymorphism has been associated with changes in pituitary-thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)-mediated TSH stimulation of the thyroid gland., Methods: Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes., Results: No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 ± 2.67 vs. 21.07 ± 2.86 ng/dL, p = 0.029). Thr/Ala subjects showed an intermediate response. Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 ± 6.84 vs. 69.56 ± 6.06 minutes, p = 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups., Conclusions: The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSH-stimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis.

Objective: Resting energy expenditure (EE) is a major contributor to the total EE and thus plays an important role in body weight regulation. Adaptive thermogenesis is a major component of EE in rodents, but little is known on the effects of exposure of humans to mild and sustainable reduction in environmental temperature., Design: To characterize the dynamic changes in continuously measured resting EE, substrate utilization, and hormonal axes simultaneously in response to mild reduction in environmental temperature, we performed a cross-over intervention., Methods: Twenty-five volunteers underwent two 12-h recordings of EE in whole room indirect calorimeters at 24 and 19 °C with simultaneous measurement of spontaneous movements and hormonal axes., Results: Exposure to 19 °C resulted in an increase in plasma and urine norepinephrine levels (P<0.0001), and a 5.96% (P<0.001) increase in EE without significant changes in spontaneous physical activity. Exposure to the lower temperature resulted in a significant increase in free fatty acid levels (P<0.01), fasting insulin levels (P<0.05), and a marginal decrease in postprandial glucose levels. A small but significant (P<0.002) increase in serum free thyroxine and urinary free cortisol (P<0.05) was observed at 19 °C., Conclusions: Our observations indicate that exposure to 19 °C, a mild and tolerable cold temperature, results in a predictable increase in EE driven by a sustained rise in catecholamine and the activation of counter-regulatory mechanisms.

During the past decade, there has been a growing interest in competency-based performance systems for enhancing both individual and organizational performance in health professions education and the varied healthcare industry sectors. In 2003, the Institute of Medicine's report Health Professions Education: A Bridge to Quality called for a core set of competencies across the professions to ultimately improve the quality of healthcare in the United States. This article reviews the processes and outcomes associated with the development of the Health Leadership Competency Model (HLCM), an evidence-based and behaviorally focused approach for evaluating leadership skills across the professions, including health management, medicine, and nursing, and across career stages. The HLCM was developed from extensive academic research and widespread application outside healthcare. Early development included behavioral event interviewing, psychometric analysis, and cross-industry sector benchmarking. Application to healthcare was supported by additional literature review, practice analysis, expert panel inputs, and pilot-testing surveys. The model addresses three overarching domains subsuming 26 behavioral and technical competencies. Each competency is composed of prescriptive behavioral indicators, or levels, for development and assessment as individuals progress through their careers from entry-level to mid-level and advanced stages of lifelong development. The model supports identification of opportunities for leadership improvement in both academic and practice settings.

In line with the current interest in leadership development across many industries today, a number of competency-based educational programming initiatives have been launched in professional education. As well, the National Summit on the Future of Education and Practice in Health Management and Policy in 2001 called for the documentation of learning outcomes for continual educational improvement in health management and policy. The National Center for Healthcare Leadership (NCHL) subsequently launched a comprehensive, multi-stage process for identifying the competencies salient to distinguishing outstanding leadership performance in health management. This article describes the plan and the processes associated with NCHL's specification of a preliminary model of core competencies for leadership in health management, as well as the continued methods for refinement and validation of the model with both educators and practitioners in the field. The initial version of the NCHL Competency Model has facilitated field-wide dialogue regarding outcomes-based learning and assessment for both educational and professional development program planning. Subsequent development of the model will continue to stimulate open exchanges regarding pedagogical practice, as well as facilitate the design of leadership assessments for individuals, programs, organizations, and the field at large.

The direct costs of residency training in the United States are over $1 billion per year. These educational programs have been organized predominantly around hospital services and supported by hospital revenues. Pressure has been increasing to reduce the rate of increase in hospital expenditures or costs or both. This article describes alternative methods for financing graduate medical education. Debate over the current sources of financing reveals several troublesome issues: the presence of residents allegedly decreases the productivity of professionals and leads to overusage of ancillary services, proposed methods to pay for faculty salaries and services have created confusion and concern, and the financing of ambulatory-care training has been insufficient and poorly coordinated. The medical-education community must resolve these professional and educational problems so that financing issues can be debated and properly defended.

This series of articles explores the bottom line of patient classification systems--their ability to measure the consumption and the quality of healthcare services. In these articles, the use of clinical profiles, severity measures, and nursing dependency factors are discussed as methods of measurement to help healthcare organizations manage the cost and quality of their services.

Two decades ago teaching hospitals were a relatively small number of large, urban facilities. They were located near medical schools; were recipients of substantial support from local government appropriations and philanthropic donations; were providers of a large volume of ambulatory care to the indigent population; and were the centers for advancing medical research and technology. Since 1960, changes in medical education and the socioeconomic environment have resulted in a dramatic increase in the number and types of hospitals that formally participate in medical education. The traditional characterization of teaching hospitals still applies to some institutions, but hospitals newly affiliated with medical schools have very diverse characteristics. Unfortunately, third parties, regulators, and hospitals often attach the term "teaching hospital" to all of these hospitals as if they were a homogeneous set of institutions. Additional discussion and documentation of similarities and differences among teaching hospitals could benefit both hospitals and regulators when health policies are being formulated.

The number and types of patients treated by a hospital is referred to as the patient case mix. One classification approach--Diagnosis Related Groups--is being used in New Jersey and Maryland to determine hospital reimbursement rates. In this article, the authors define the concept of the patient case mix, describe DRGs, and forecast the impact they may have on hospital laboratory operations.

Medicare prospective payment by diagnosis-related groups (DRGs) has intensified the debate over the use and costs of medical technology. In this study, we examine the financial impact of DRG payment for medicare patients receiving medical intensive care. During a one-year period, payment for 446 Medicare patients receiving medical intensive care at a large teaching hospital was calculated to be +4.7 million below costs, representing an average loss per discharge of +10,567. Patients stayed an average of 21.6 days including an average of 5.0 days in the medical intensive-care unit--23 percent of the total stay. Twenty-eight percent of the MICU patients died during hospitalization. For this group, the average payment per discharge was projected to be +21,651 below the average per discharge cost. We conclude that the results send strong financial messages to hospitals providing medical intensive care to severely ill, elderly patients. Further exploration and research must occur to ensure hospital responses will be consistent with public policy expectations.

Much concern has been expressed about the Medicare Prospective Payment System's impact on access to care. In this study, we examine the financial impact of diagnosis-related group (DRG) payment for chronic ventilator-dependent Medicare patients. During a one-year period, payment for 95 Medicare patients who received a minimum of three days of continuous ventilator treatment and who spent no time in surgical intensive care at Rush-Presbyterian-St. Luke's Medical Center, was calculated to be $2.2 million below costs, representing an average loss per discharge of $23,129. Patients stayed an average of 26.6 days, of which 14.2 days were spent on a ventilator. We conclude that the results suggest a financial bias against chronic ventilator-dependent patients exists in the DRG system which could present access problems. We recommend three approaches to recognizing the cost of care for such patients in the DRG payment system and encourage those in public policy-making positions to use our results as the basis for a larger scale analysis of the impact of Medicare DRG payment on chronic ventilator-dependent patients.

Approximately two-thirds of all U.S. and Canadian medical schools have provisions for the evaluation of their departments on a periodic or ad hoc basis. Most of these institutions have initiated the departmental review process since 1970. It appears that use of the practice is increasing and is becoming an important tool in providing guidance for departmental activities, programs, and leadership. Departmental review may be conducted in a variety of ways with varying levels of intensity, flexibility, and skill, depending on the environment, resources, dean, department chairmen, faculty, and attitudes of university administrators. Departmental review may be employed to identify, elaborate, document, and/or contribute to the resolution of current and potential organizational concerns. When carefully administered, the process can be a stabilizing rather than a disruptive force; however, by itself, it does not solve major institutional problems.

Plasma fluorogenic corticosteroid and immunoreactive growth hormone levels rose significantly after the intravenous administration of methylamphetamine to healthy young men at various times of the day. The rise in corticosteroids was most pronounced in the evening and was accompanied by an increase in circulating levels of immunoreactive corticotrophin. Oral dexamphetamine also resulted in significant rises in plasma corticosteroids but not in growth hormone. These hormonal changes were accompanied by evidence of mild central stimulation. Though they may be part of an associated and non-specific response, it is more likely that they represent specific effects of amphetamines on centres in the hypothalamus or midbrain controlling secretion of corticotrophin and growth hormone releasing factors.