Pharmacy Benefit Managers in the Eye of the Storm: Growing Multipartite Scrutiny.

The high cost of prescription drugs in the U.S. remains an ongoing national challenge. A recurring focal point in discussions over this distressing steady state is the role(s) played by Pharmacy Benefit Managers (PBMs) who negotiate drug prices with pharmaceutical manufacturers, conduct drug utilization reviews, engage in disease management, and see to formulary creation. At their inception, the multiple newly established PBMs were arguably intent on constraining the rise of prescription drug prices. At the time of this writing, however, the lion share of a far less competitive PBM market is controlled by CVS Caremark, Express Scripts, and OptumRx. It is this evolving reality which could be interpreted to mean that the PBMs may have become part of the problem, rather than part of the solution. Expanded scrutiny of the PBMs by Federal and State authorities as well as by Professional Medical Associations must not be delayed with an eye toward affording the public with relief from the high cost of prescription drugs.

Factors affecting live birth rates in donor oocytes from commercial egg banks vs. program egg donors: an analysis of 40,485 cycles from the Society for Assisted Reproductive Technology registry in 2016-2018.

OBJECTIVE: To examine the differences in live birth rates (LBRs), with single embryo transfer (SET), using oocytes from program generated egg donors vs. commercial egg bank donors and other factors affecting LBRs using donor oocytes. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 40,485 in vitro fertilization cycles using donor oocytes reported to the Society for Assisted Reproductive Technology registry in 2016-2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rate and cumulative LBR for SET using donor oocytes. RESULT(S): Multivariate results from the first SET from 19,128 cycles, including 15,429 from program generated egg donors and 3,699 from commercial egg banks, showed, when controlling for all other variables, the following: the LBR in the first SET cycle using commercial egg banks was 53.3% compared with 55.4% using program recruited egg donors (odds ratio [OR], 0.92); a reduction in the LBR with increasing recipient age, ages 40-44 years (OR, 0.80), 45-49 years (OR, 0.77), and >49 years (OR, 0.65); a steady decline in the LBR with increases in recipient body mass index above normal; and a steady increase in the LBR in association with >16 oocytes retrieved. Double embryo transfer increased the LBR (SET, 52%, vs. double embryo transfer, 58%) but also significantly increased the multiple pregnancy LBR, with 43% twins and 0.9% triplets. Blastocyst transfer had a higher LBR than cleavage stage embryos (52.5% vs. 39.5%). Intracytoplasmic sperm injection vs. conventional insemination when using fresh oocytes from program donors had similar LBRs. CONCLUSION(S): When performing in vitro fertilization using donor oocytes with SET, the LBR is affected by oocyte source, recipient age, recipient body mass index, stage of embryo at transfer, and number of oocytes retrieved.

Development of an audit method to assess the prevalence of the ACGME's general competencies in an undergraduate medical education curriculum.

BACKGROUND: Despite the use of competency-based frameworks to evaluate physicians, the role of competency-based objectives in undergraduate medical education remains uncertain. PURPOSE: By use of an audit methodology, we sought to determine how the six Accreditation Council for Graduate Medical Education (ACGME) competencies, conceptualized as educational domains, would map onto an undergraduate medical curriculum. METHODS: Standardized audit forms listing required activities were provided to course directors, who were then asked to indicate which of the domains were represented in each activity. Descriptive statistics were calculated. RESULTS: Of 1,500 activities, there was a mean of 2.13 domains per activity. Medical Knowledge was the most prevalent (44%), followed by Patient Care (20%), Interpersonal and Communication Skills (12%), Professionalism (9%), Systems-Based Practice (8%), and Practice-Based Learning and Improvement (7%). There was considerable variation by year and course. CONCLUSIONS: The domains provide a useful framework for organizing didactic components. Faculty can also consider activities in light of the domains, providing a vocabulary for instituting curricular change and innovation.

Is a history of gestational diabetes related to risk factors for coronary heart disease?

Coronary heart disease (CHD) risk in 20 non-diabetic women with and 20 without a distant history of gestational diabetes (hGDM), matched on age, body mass index, and time since GDM-affected pregnancy, was compared in a case control study. Women with an hGDM had lower high-density lipoprotein cholesterol (HDL-c), p = .02, and higher triglycerides, p < or = .001, versus controls. The combination of high triglycerides and low HDL-c occurred in 25% of hGDM cases versus 0% of controls, p

Governance of Academic Health Centers and Systems: A Conceptual Framework for Analysis.

Health care has evolved from a cottage industry to a very complex one constituting nearly one-fifth of the U.S. economy. Large aggregated health care systems have evolved primarily for the purpose of optimizing financial performance by capturing greater market share and taking advantage of economies of scale in care delivery. With the noble intent of providing a broader base of support for the academic mission, academic health centers (AHCs) have followed suit by partnering with community hospitals and organizations with variable prior experience in the education and research arenas. Such a strategy makes good business sense, but it creates challenges for the academic mission. Singular emphasis on physicians' clinical productivity enhances financial margin but often reduces faculty time and effort dedicated to the academic mission. While individual AHC governance is varied, the leadership structure of large aggregated health systems built around an AHC is even more complex and heterogeneous. Yet, to ensure the prosperity of the academic mission, the governance structure of such health care systems is of critical importance. Preservation of academic oversight of the faculty practice plan, a unifying central focal point of organizational decision making, and genuine physician leadership are three overarching governance characteristics that strengthen the prosperity of the academic mission within large aggregated health systems. Despite the heterogeneous nature of academic health system governance, these critical components of organizational leadership structure facilitate support of a robust academic mission. Understanding these principles and objectives of governance is essential for critical faculty engagement in AHC leadership activities.

The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials.

CONTEXT: Polycystic ovary syndrome (PCOS) presents in adolescence, and obesity is a common finding. The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear. OBJECTIVE: We investigated the effects of metformin, oral contraceptives (OCs), and/or lifestyle modification in obese adolescent women with PCOS. DESIGN: Two small, randomized, placebo-controlled clinical trials were performed. PATIENTS AND PARTICIPANTS: A total of 79 obese adolescent women with PCOS participated. INTERVENTIONS: In the single treatment trial, subjects were randomized to metformin, placebo, a lifestyle modification program, or OC. In the combined treatment trial, all subjects received lifestyle modification and OC and were randomized to metformin or placebo. MAIN OUTCOME MEASURES: Serum concentrations of androgens and lipids were measured. RESULTS: Lifestyle modification alone resulted in a 59% reduction in free androgen index with a 122% increase in SHBG. OC resulted in a significant decrease in total testosterone (44%) and free androgen index (86%) but also resulted in an increase in C-reactive protein (39.7%) and cholesterol (14%). The combination of lifestyle modification, OC, and metformin resulted in a 55% decrease in total testosterone, as compared to 33% with combined treatment and placebo, a 4% reduction in waist circumference, and a significant increase in HDL (46%). CONCLUSIONS: In these preliminary trials, both lifestyle modification and OCs significantly reduce androgens and increase SHBG in obese adolescents with PCOS. Metformin, in combination with lifestyle modification and OC, reduces central adiposity, reduces total testosterone, and increases HDL, but does not enhance overall weight reduction.

Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome.

CONTEXT: Adults with polycystic ovary syndrome (PCOS) may be at increased risk for metabolic syndrome (MBS) and related cardiovascular disease. It is not clear whether PCOS diagnosed in adolescence increases the risk of MBS in this age group. OBJECTIVE: The aim was to compare the prevalence and related characteristics of MBS in obese adolescents with and without PCOS. DESIGN: We conducted a cross-sectional study of overweight and obese PCOS adolescents and BMI matched controls. PATIENTS AND PARTICIPANTS: A total of 74 subjects, 43 with PCOS and 31 controls, participated in the study. INTERVENTIONS: Each subject underwent a physical examination and laboratory evaluation for a diagnosis of MBS. Regional fat distribution was determined by computerized tomography scan in the PCOS adolescents. MAIN OUTCOME MEASURES: We measured the prevalence of MBS and its components in adolescent subjects and controls. RESULTS: The PCOS group had larger ovarian volume and higher measures of total testosterone and free androgen index than controls, but there were no differences in waist circumference, fasting glucose, blood pressure, or lipids. PCOS adolescents demonstrated more glucose abnormalities and higher plasminogen activator inhibitor-1. By pediatric criteria, 53% of the PCOS and 55% of the control adolescents had MBS. By adult criteria, 26% of PCOS and 29% of controls met diagnostic criteria for MBS. CONCLUSIONS: Obese adolescent women have a high prevalence of MBS, and PCOS does not add additional risk for MBS. There appears to be an association between MBS and visceral adiposity. PCOS is associated with increased incidence of glucose intolerance and increased plasminogen activator inhibitor-1. Our results reinforce the importance of obesity counseling in adolescents to recognize the possible risk of future cardiovascular disease in these young women.

Governance of Academic Medical Centers Is Indeed a Complex and Unique Operation.

As academic medical centers (AMCs) have extended their operations into their communities, partnered with new organizations, and developed new modes of operation to achieve their missions, new governance approaches are required. Chari and colleagues, in this issue of Academic Medicine, describe the development and application of criteria to evaluate governance options for the University of California (UC), which has a number of public AMCs, almost all of which are components of individual UC universities. Although many of these criteria may also be applicable to smaller AMCs, a more individual approach to governance is required-that is, one must step back and first ask about the organization, structure, and goals of the entities to be governed. The major nonfederal and nonspecialty teaching hospitals in the United States are about evenly split between those that are university owned or controlled and those having an independent relationship with their associated medical school. However, the challenges, obstacles, and desired end points are similar. The development of a successful governance structure will require identifying and appreciating many factors.

Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial.

OBJECTIVE: To assess the effect of low-dose mifepristone on quality of life, pain, bleeding, and uterine size among women with symptomatic leiomyomata. METHODS: Forty-two women with symptomatic uterine leiomyomata and uterine volume of 160 mL or more were randomized to mifepristone, 5 mg daily, or placebo for 26 weeks. Quality of life (Uterine Fibroid Symptoms Quality of Life Questionnaire and Medical Outcomes Study 36-Item Short Form survey) and uterine and leiomyoma size (ultrasonography) were assessed at baseline, and at 1 month, 3 months, and 6 months of treatment. Bleeding (daily logs and pictorial charts) and pain (McGill Pain Questionnaire) were assessed monthly. Endometrial pathology was assessed at baseline and 6 months. RESULTS: Forty-two women were randomized; 37 women completed all 6 months. Women randomized to mifepristone showed an improvement in leiomyoma-specific quality of life. Forty-one percent became amenorrheic, rates of anemia improved, and adjusted uterine size was reduced by 47%. Compared with the placebo group, improvements in these outcomes in the treatment group were significantly greater (P<.05 to .001). There were no significant differences in adverse effects between the groups. No endometrial hyperplasia was noted in any participant. CONCLUSION: Low-dose mifepristone improves leiomyoma-specific quality of life and reduces leiomyoma size among women with symptomatic leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00133705 LEVEL OF EVIDENCE: I.

Pelvic organ prolapse in nulliparous women and their parous sisters.

OBJECTIVE: To investigate the role of vaginal delivery and familial factors in the development of pelvic organ prolapse by comparing the prevalence of this condition in nulliparous women and their parous sisters. METHODS: Pairs of nulliparous and parous postmenopausal sisters were recruited for assessment of pelvic organ prolapse. One hundred one sister pairs underwent clinical evaluation. Pelvic organ prolapse was recorded using the Pelvic Organ Prolapse Quantification System. RESULTS: The majority of women had no pelvic organ prolapse. By compartment there was a 74.3% to 91.1% concordance in prolapse stage within sister pairs. In discordant sister pairs, the parous sister was found to have the more advanced prolapse 88% of the time. CONCLUSION: High concordance of pelvic organ prolapse in nulliparous and parous sister pairs suggests a familial predisposition toward developing this condition. However, vaginal delivery does appear to confer a risk for more advanced pelvic organ prolapse. LEVEL OF EVIDENCE: II-2.

Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial.

OBJECTIVE: To compare the efficacy of gabapentin, estrogen, and placebo in the treatment of hot flushes. METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 postmenopausal women to assess the efficacy of estrogen and gabapentin in the treatment of moderate-to-severe hot flushes. Participants were randomly assigned to receive either 0.625 mg/d of conjugated estrogens (n = 20), placebo (n = 20), or gabapentin titrated to 2,400 mg/d (n = 20) for 12 weeks. Participants recorded frequency and severity of baseline hot flushes on a hot flush diary for 2 weeks before randomization and for 12 weeks after randomization. The primary outcome measure was the weekly hot flush composite score, which takes into account both severity and frequency of hot flushes. Secondary outcome measures were differences in pre- and posttreatment scores pertaining to depression (Zung Depression Scale) and other climacteric symptoms (Greene Climacteric Scale). RESULTS: Intention-to-treat analysis showed that the reduction in the hot flush composite score for both estrogen (72%, P = .016) and gabapentin (71%, P = .004) was greater than the reduction associated with placebo (54%) at the conclusion of the 12th week. The extent of reduction in hot flush composite score, however, was not significantly different between estrogen and gabapentin (P = .63). No differences were seen between groups in the Zung Depression Scale, or in any of the Greene Climacteric subscales except for the Somatic Symptom cluster, which was significantly greater in the gabapentin arm than in the placebo arm. Despite a lack of group differences in adverse events, the Headache, Dizziness, and Disorientation cluster appeared with greater frequency in the gabapentin group. Estimation of the number needed to harm in this cluster suggests that these symptoms may occur with every fourth patient treated with gabapentin. CONCLUSION: Despite the small scale of this study, gabapentin appears to be as effective as estrogen in the treatment of postmenopausal hot flushes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT 00276081. LEVEL OF EVIDENCE: I.

Urinary incontinence in nulliparous women and their parous sisters.

OBJECTIVE: To investigate the role of vaginal delivery and familial factors in the development of urinary incontinence by comparing the prevalence of this condition in nulliparous women and their parous sisters. METHODS: A sample of 143 pairs of nulliparous/parous postmenopausal sisters completed a comprehensive questionnaire regarding symptoms of pelvic floor disorders. Of these, 101 pairs underwent clinical evaluation of urinary incontinence and genital prolapse. RESULTS: Among this sample of biological sisters, urinary incontinence was reported by 47.6% of nulliparous women and by 49.7% of parous women (P = .782). We found no difference in the severity or type of urinary incontinence between these 2 groups. There was a high concordance in continence status, however, within biological sisters. CONCLUSION: Vaginal birth does not seem to be associated with urinary incontinence in postmenopausal women. Considering the high concordance in continence status between sister pairs, and considering that the majority of parous women are continent, an underlying familial predisposition toward the development of urinary incontinence may be present.

Evaluating the efficacy of intervention.

The standard for reaching a verdict in civil trials is "the preponderance of the evidence." This is a valid standard to apply to evaluating the medical literature as well. Every published report should be given weight based on physicians' judgment of its reliability. Larger-scale studies should be weighted more heavily than smaller-scale studies, randomized trials more heavily than observation studies, rigorously designed trials more heavily than studies that may be biased. If there seems to be a relationship between a factor and an outcome, this does not necessarily imply that the factor caused the outcome. The association could be a result of chance variation between individuals. Statistical testing allows researchers to exclude chance as a likely cause of the relationship, but this is the only explanation ruled out by a significance test. The relationship could be a result of bias: bias in the selection of individuals for the study, bias in measurement of the factor or the outcome, or bias in differential loss to follow-up. A thorough analysis of the data is necessary to identify and exclude other possible explanations of the association. A government agency dealing with environmental regulations experimented with replacing administrative law judges with scientists. It was believed that scientists were better qualified to make the necessary technical evaluations. The experiment was not considered successful because, as one observer remarked, "Judges are used to having to reach a verdict within a short period of time based on whatever evidence is presented--scientists just can't seem to make decisions." This illustrates a similar difference between the role of the researcher and the role of the physician. The physician must decide the best treatment for each patient based only on whatever evidence is available. There is little question, however, what the patient would decide if allowed to choose between receiving the standard therapy today or waiting 5 years until conclusive scientific evidence has been obtained about whether an alternative treatment is better. Few patients would choose to wait. Yet the decisions a physician makes today will be criticized in 5 years, especially by those who never have had to make similar decisions themselves. Some decisions will turn out to be wrong when additional data are available, but physicians must make choices based on the best data currently available. The choice of medicine as a profession implies the acceptance of a life sentence to jury duty: the evidence will never stop accumulating, and the verdict must be continually reevaluated.

Polycystic ovary syndrome.

Women with polycystic ovarian syndrome have chronic anovulation and androgen excess not attributable to another cause. This condition occurs in approximately 4% of women. The fundamental pathophysiologic defect is unknown, but important characteristics include insulin resistance, hyperandrogenism, and altered gonadotropin dynamics. Inadequate follicle-stimulating hormone is hypothesized to be a proximate cause of anovulation. Obesity frequently complicates polycystic ovarian syndrome but is not a defining characteristic. The diagnostic approach should be based largely on history and physical examination, thus avoiding numerous laboratory tests that don't contribute to clinical management. Women with polycystic ovarian syndrome typically present because of irregular bleeding, hirsutism, and/or infertility. These conditions can be treated directly with oral contraceptives, oral contraceptives plus spironolactone, and ovulation induction, respectively. However, women with polycystic ovarian syndrome also have a substantially higher prevalence of diabetes and increased risk factors for cardiovascular disease. They should also be screened, therefore, for these conditions and followed closely if any risk factors are uncovered. For obese women with polycystic ovarian syndrome, behavioral weight management is a central component of the overall treatment strategy.

Low-dose mifepristone for uterine leiomyomata.

OBJECTIVE: To compare the effect of 5 and 10 mg of mifepristone on uterine leiomyoma size and symptoms, and to measure side effects. METHODS: Forty premenopausal women with large, symptomatic leiomyomata were randomized to receive either 5 or 10 mg of mifepristone daily for 6 months in an open-label study. Uterine volume was measured at bimonthly intervals by sonography. Serum concentrations of hemoglobin levels, follicle-stimulating hormone, and liver enzymes were obtained, and endometrial samples, symptoms, and menstrual bleeding were also assessed. RESULTS: Nineteen of 20 subjects taking 5 mg and all 20 subjects taking 10 mg completed all 6 months of the study. Mean uterine volume shrank by 48% (P <.001) in the 5-mg group and 49% (P <.001) in the 10-mg group, a nonsignificant difference. Leiomyoma-related symptoms were comparably reduced in both groups. Amenorrhea occurred in 60-65% of both groups. Hemoglobin levels increased by 2.5 g/dL in anemic subjects. The incidence of hot flashes increased significantly over baseline in the 10-mg group but not in the 5-mg group. Simple endometrial hyperplasia occurred in 28% of all subjects, with no difference between groups. No atypical hyperplasia was noted. CONCLUSION: Mifepristone in doses of 5 mg or 10 mg results in comparable leiomyoma regression, improvement in symptoms, and few side effects. Further study is needed to assess the long-term safety and efficacy of low-dose mifepristone.

For now, one well-timed intrauterine insemination is the way to go.

Two articles on pregnancy rates from superovulation and IUI in relation to the IUI protocol were reviewed. Results from a meta-analysis of IUI number (one vs. two) and from a randomized trial of IUI timing (33 hours vs. 39 hours after hCG administration) suggest that one well-timed insemination within several hours of ovulation represents a reasonable balance between efficacy and cost.