Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Drug Safety in Episodic Migraine Management in Adults Part 1: Acute Treatments.

PURPOSE OF REVIEW: The aim of this review is to aid in choosing safe options when assessing potential risks of acute migraine treatments based on known mechanisms of action and anticipated safety concerns. RECENT FINDINGS: Part 1 highlights safety issues associated with commonly used medications to treat acute migraine attacks. Strategies to mitigate cardiovascular and gastrointestinal risks of nonsteroidal anti-inflammatory drugs, evaluation of cardiovascular risks of triptan and ergot alkaloids, and precautions with use of antiemetics and the novel drugs gepants and ditans are discussed to help practitioners in clinical decision-making. When available, we included recommendations from professional societies and data from pharmacovigilance systems. While guidelines on efficacy are available, one must also consider the possible risks and adverse effects of a drug when creating treatment plans.

Drug Safety in Episodic Migraine Management in Adults. Part 2: Preventive Treatments.

PURPOSE OF REVIEW: The aim of this review is to aid in decision-making when choosing safe and effective options for preventive migraine medications. RECENT FINDINGS: In Part 2, we have compiled clinically relevant safety considerations for commonly used migraine prophylactic treatments. Preventive treatment of episodic migraine includes nonspecific and migraine-specific drugs. While medications from several pharmacological classes-such as anticonvulsants, beta-blockers, and antidepressants-have an established efficacy in migraine prevention, they are associated with a number of side effects. The safety of migraine-specific treatments such as anti-CGRP monoclonal antibodies and gepants are also discussed. This review highlights safety concerns of commonly used migraine prophylactic agents and offers suggestions on how to mitigate those risks.

Migraine diagnosis and treatment: A knowledge and needs assessment of women's healthcare providers.

BACKGROUND: Studies suggest that migraine is often underdiagnosed and inadequately treated in the primary care setting, despite many patients relying on their primary care provider (PCP) to manage their migraine. Many women consider their women's healthcare provider to be their PCP, yet very little is known about migraine knowledge and practice patterns in the women's healthcare setting. OBJECTIVE: The objective of this study was to assess women's healthcare providers' knowledge and needs regarding migraine diagnosis and treatment. METHODS: The comprehensive survey assessing migraine knowledge originally developed for PCPs was used in this study, with the addition of a section regarding the use of hormonal medications in patients impacted by migraine. Surveys were distributed online, and primarily descriptive analyses were performed. RESULTS: The online survey was completed by 115 women's healthcare providers (response rate 28.6%; 115/402), who estimated that they serve as PCPs for approximately one-third of their patients. Results suggest that women's healthcare providers generally recognize the prevalence of migraine, but experience some knowledge gaps regarding migraine management. Despite 82.6% (95/115) of survey respondents feeling very comfortable or somewhat comfortable with diagnosing migraine, only 57.9% (66/114) reported routinely asking patients about headaches during annual visits. Very few were familiar with the American Academy of Neurology guidelines on preventative treatment (6.3%; 7/111) and the Choosing Wisely Campaign recommendations on migraine treatment (17.3%; 19/110), and many prescribed medications known to contribute to medication overuse headache. In addition, only 24.3% (28/115) would order imaging for a new type of headache, 35.7% (41/115) for worsening headache, and 47.8% (55/115) for headache with neurologic symptoms; respondents cited greater tendency with sending patients to an emergency department for the same symptoms. Respondents had limited knowledge of evidence-based, non-pharmacological treatments for migraine (i.e., biofeedback or cognitive behavioral therapy), with nearly none placing referrals for these services. Most providers were comfortable prescribing hormonal contraception (mainly progesterone only) to women with migraine without aura (80.9%; 89/110) and with aura (72.5%; 79/109), and followed American College of Obstetricians and Gynecologists (ACOG) guidelines to limit combination hormonal contraception for patients with aura. When queried, 6.3% or less (5/79) of providers would prescribe estrogen-containing contraception for women with migraine with aura. Only 37.3% (41/110) of respondents reported having headache/migraine education. Providers indicated interest in education pertaining to migraine prevention and treatment (96.3%; 105/109), migraine-associated disability (74.3%; 81/109), and diagnostic testing (59.6%; 65/109). CONCLUSION: Women's healthcare providers appear to have several knowledge gaps regarding the management of migraine in their patients. These providers would likely benefit from access to a headache-specific educational curriculum to improve provider performance and patient outcomes.

Questionnaires or Serum Immunoglobulin G Testing in the Diagnosis of Hypersensitivity Pneumonitis among Patients with Interstitial Lung Disease.

Rationale: Hypersensitivity pneumonitis (HP) results from exposure to a variety of stimuli, which are challenging to identify. Questionnaires and serum immunoglobulin G (IgG) testing are methods to identify potentially causative exposures.Objectives: To perform a systematic review to determine the usefulness of questionnaires and serum IgG testing in identifying exposures that may have caused HP.Methods: This systematic review informed an international, multidisciplinary panel that developed a clinical practice guideline on the diagnosis of HP for the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax. MEDLINE, the Cochrane Library, and EMBASE were searched from January 1946 to October 2019 for studies that used a questionnaire or serum IgG testing to identify exposures that may have caused HP. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to appraise the quality of the evidence.Results: Searches identified 1,141 and 926 potentially relevant articles for questionnaires and serum IgG testing, respectively. The full texts of 32 and 49 articles, respectively, were reviewed. Two observational studies for questionnaires and 15 accuracy studies for serum IgG testing were selected. Questionnaires were better at detecting potentially relevant exposures than clinical history (100% vs. 26%; risk ratio [RR], 3.80; 95% confidence interval [95% CI], 1.79-8.06) and serum IgG testing (100% vs. 63%; RR, 1.58; 95% CI, 1.12-2.23) but did not differ from serum IgG testing plus bronchial challenge testing (59% vs. 65%; RR, 0.90; 95% CI, 0.65-1.24). Longer, detailed questionnaires were more likely to lead to identification of potential exposures. Only 70% of potential exposures identified by questionnaires were subsequently confirmed by environmental testing. Serum IgG testing distinguished HP from healthy exposed and unexposed control subjects with high sensitivity (90% and 92%, respectively) and high specificity (91% and 100%, respectively) but did not distinguish HP as effectively from interstitial lung diseases (ILDs; sensitivity of 83% and specificity of 68%).Conclusions: Using a questionnaire may help clinicians identify potentially relevant exposures when evaluating a patient with newly identified ILD for HP. Serum IgG testing may also lead to identification of potentially relevant exposures, but its usefulness for distinguishing HP from other types of ILD is poor.

Transbronchial Biopsy and Cryobiopsy in the Diagnosis of Hypersensitivity Pneumonitis among Patients with Interstitial Lung Disease.

Rationale: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) with a diagnosis based on clinical, radiological, and pathological findings. The evidence supporting transbronchial forceps lung biopsy (TBBx) and transbronchial lung cryobiopsy (TBLC) as sampling techniques to diagnose HP in patients with newly detected ILD has not been reviewed systematically.Objectives: A systematic review was performed to assess the diagnostic yield and complication rates of TBBx or TBLC in patients with newly detected ILD whose differential diagnosis includes HP and to inform the development of the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax clinical practice guidelines on the diagnosis of HP.Methods: Medline, Excerpta Medica Database, and the Cochrane Library were searched through October 2019. Studies that enrolled patients with ILD and reported the diagnostic yield of TBBx or TBLC were selected for inclusion. Data related to diagnostic yield and safety outcomes were extracted and then pooled across studies via meta-analysis. The quality of the evidence was appraised using the grading of recommendations, assessment, development, and evaluation (GRADE) approach.Results: The histopathologic diagnostic yields (number of procedures that yielded a histopathologic diagnosis divided by the total number of procedures performed) of TBBx and TBLC were 37% (95% confidence interval [CI], 32-42%) and 82% (95% CI, 78-86%), respectively, among patients with ILD. Among those diagnosed by TBBx, the proportion with HP could not be determined. However, among those diagnosed by TBLC, 13.4% had HP. TBBx was complicated by moderate to severe bleeding, severe bleeding, and pneumothorax in 4% (95% CI, 0-8%), 0% (95% CI, 0-1%), and 7% (95% CI, 2-13%) of patients, respectively. TBLC was complicated by any bleeding, severe bleeding, and pneumothorax in 11% (95% CI, 7-15%), 0% (95% CI, 0-1%), and 11% (95% CI, 9-14%) of patients, respectively. The quality of the evidence was very low because of the uncontrolled study designs, lack of consecutive enrollment, and inconsistent results.Conclusions: Very low-quality evidence indicated that TBLC had a higher diagnostic yield than TBBx among patients with ILD, although complications were similar.

Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. METHODS: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. RESULTS: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. CONCLUSIONS: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.

Primary Empty Sella.

Primary empty sella (PES) syndrome is a misnomer as it is not a syndrome but a radiological finding with possible endocrine abnormalities. No specific headache type has been shown to be caused by PES. Endocrine screening may be considered for asymptomatic persons with PES.

Bronchoalveolar Lavage Lymphocytes in the Diagnosis of Hypersensitivity Pneumonitis among Patients with Interstitial Lung Disease.

Rationale: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) characterized by inflammation and/or fibrosis in response to an inhalational exposure.Objectives: To determine the value of bronchoalveolar lavage (BAL) fluid lymphocyte cellular analysis in the detection of HP among patients with newly detected ILD.Methods: This systematic review was undertaken in the context of development of an American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax clinical practice guideline. The clinical question was, "should patients with newly detected ILD undergo BAL fluid lymphocyte analysis to diagnose HP?" MEDLINE, EMBASE, and the gray literature were searched through October 2019. Studies that reported the percentage of BAL fluid lymphocytes for various ILDs were selected for inclusion. Meta-analyses compared the mean percentage of BAL fluid lymphocytes among patients with HP with that among patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. The sensitivity and specificity by which various percentages of BAL fluid lymphocytes distinguish HP from IPF and sarcoidosis were also evaluated.Results: Eighty-four articles were selected. No randomized trials or observational studies were identified that compared BAL fluid lymphocyte analysis with no BAL fluid lymphocyte analysis in patients with ILD. Included studies were case series describing BAL fluid cell differentials in patients with various ILDs. The percentage of BAL fluid lymphocytes was significantly higher in both fibrotic and nonfibrotic HP compared with IPF. Similarly, the percentage of BAL fluid lymphocytes was significantly higher in both fibrotic and nonfibrotic HP compared with sarcoidosis. A threshold of 20% BAL fluid lymphocytes distinguished fibrotic HP from IPF with a sensitivity and specificity of 69% and 61%, respectively, and nonfibrotic HP from IPF with a sensitivity and specificity of 95% and 61%, respectively. It distinguished fibrotic HP from sarcoidosis with a sensitivity and specificity of 69% and 26%, respectively, and nonfibrotic HP from sarcoidosis with a sensitivity and specificity of 95% and 26%, respectively.Conclusions: The percentage of BAL fluid lymphocytes is higher in HP than IPF or sarcoidosis. However, a threshold that distinguishes HP from IPF or sarcoidosis with both high sensitivity and high specificity was not identified.

Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.

Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.Methods: Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.Results: The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.

Inferior vena cava filters do not increase the risk of blood stream infections in patients with newly diagnosed VTE.

BACKGROUND: The association between inferior vena cava (IVC) filter presence and subsequent bloodstream infection (BSI) is unknown. We hypothesized among patients with a new diagnosis of venous thromboembolism (VTE), incidence of BSI after 1 year would be higher in patients who had presence of an IVC filter. METHODS: We performed a retrospective cohort study of patients with newly diagnosed VTE but no IVC filter (N = 4,053) and patients with IVC filter (N = 635) admitted to a metropolitan hospital system from 2006 to 2009 comparing incidence of BSI within 1 year of inclusion. Multivariable regression modeling was used to evaluate the association of IVC filter placement with BSI 1 year after placement. RESULTS: Patients with an IVC filter placed were more likely to be older with higher Charlson co-morbidity score (median 4 vs 1; P < .001). The incidence of BSI was not different between the group with IVC filter and the group without (10.7% vs 8.8%; P = .12). There was no association with IVC filter placement and BSI before or after multivariable adjustment. CONCLUSIONS: In patients newly diagnosed with VTE, we found no association between IVC filter placement and increased incidence of BSI after 1 year.

Unrecognized challenges of treating status migrainosus: An observational study.

BACKGROUND: Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic. MATERIAL AND METHODS: Patients with episodic and chronic migraine who experienced continuous and prolonged attacks for more than 72 hours were treated with dexamethasone (4 mg orally twice daily for 3 days), ketorolac (60 mg intramuscularly), bilateral nerve blocks (1-2% lidocaine, 0.1-0.2 ml for both supraorbital and supratrochlear nerves, 1 ml for both auriculotemporal nerves, and 1 ml for both greater occipital nerves), or naratriptan (2.5 mg twice daily for 5 days). Hourly (for the first 24 hours) and daily (for first 30 days) change in headache intensity was documented using appropriate headache diaries. RESULTS: Fifty-four patients provided eligible data for 60 treatment attempts. The success rate of rendering patients pain free within 24 hours and maintaining the pain-free status for 48 hours was 4/13 (31%) for dexamethasone, 7/29 (24%) for nerve blocks, 1/9 (11%) for ketorolac and 1/9 (11%) for naratriptan. These success rates depended on time to remission, as the longer we allowed the treatments to begin to work and patients to become pain free (i.e. 2, 12, 24, 48, 72, or 96 hours), the more likely patients were to achieve and maintain a pain-free status for at least 48 hours. DISCUSSION: These findings suggest that current treatment approaches to terminating status migrainosus are not satisfactory and call attention to the need to develop a more scientific approach to define a treatment response for status migrainosus.

Current Treatment Options: Headache Related to Menopause-Diagnosis and Management.

PURPOSE OF REVIEW: Menopause is a life-changing event in numerous ways. Many women with migraine hold hope that the transition to the climacteric state will coincide with a cessation or improvement of migraine. This assumption is based mainly on common lay perceptions as well as assertions from many in the healthcare community. Unfortunately, evidence suggests this is far from the rule. Many women turn to a general practitioner or a headache specialist for prognosis and management. A natural instinct is to manipulate the offending agent, but in some cases, this approach backfires, or the concern for adverse events outweighs the desire for a therapeutic trial, and other strategies must be pursued. Our aim was to review the frequency and type of headache syndromes associated with menopause, to review the evidence for specific treatments for headache associated with menopause, and to provide management recommendations and prognostic guidance. RECENT FINDINGS: We reviewed both clinic- and population-based studies assessing headache associated with menopause. Headache in menopause is less common than headache at earlier ages but can present a unique challenge. Migraine phenotype predominates, but presentations can vary or be due to secondary causes. Other headache types, such as tension-type headache (TTH) and cluster headache (CH) may also be linked to or altered by hormonal changes. There is a lack of well-defined diagnostic criteria for headache syndromes associated with menopause. Women with surgical menopause often experience a worse course of disease status than those with natural menopause. Hormonal replacement therapy (HRT) often results in worsening of migraine and carries potential for increased cardiovascular and ischemic stroke risk. Estrogen replacement therapy (ERT) in patients with migraine with aura (MA) may increase the risk of ischemic stroke; however, the effect is likely dose-dependent. Some medications used in the prophylaxis of migraine may be useful in ameliorating the vasomotor and mood effects of menopause, including venlafaxine, escitalopram, paroxetine, and gabapentin. Other non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga may also be helpful in reducing headache and/or vasomotor symptoms associated with menopause. The frequency and type of headache associated with menopause is variable, though migraine and TTH are most common. Women may experience a worsening, an improvement, or no change in headache during the menopausal transition. Treatment may be limited by vascular risks or other medical and psychiatric factors. We recommend using medications with dual benefit for migraine and vasomotor symptoms including venlafaxine, escitalopram, paroxetine, and gabapentin, as well as non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga. If HRT is pursued, continuous (rather than cyclical) physiological doses should be used, transdermal route of administration is recommended, and the patient should be counseled on the potential for increased risk of adverse events (AEs). Concomitant use of a progestogen decreases the risk of endometrial hyperplasia with ERT. Biological mechanisms are incompletely understood, and there is a lack of consensus on how to define and classify headache in menopause. Further research to focus on pathophysiology and nuanced management is desired.

Inhaled drug therapy development for the treatment of migraine.

INTRODUCTION: The inhalation of substances, both medicinally and recreationally, is a commonly used method of drug administration but has been underutilized in the treatment of neurologic disorders such as migraine. Three drugs have been studied as potential inhalable treatments for acute migraine: dihydroergotamine (MAP0004), prochlorperazine (Staccato prochlorperazine), and loxapine (Staccato loxapine). AREAS COVERED: This review discusses the available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, Staccato prochlorperazine and Staccato loxapine, including data from Phase II and Phase III clinical trials. EXPERT OPINION: Inhaled DHE offers rapid absorption with a pharmacokinetic profile similar to IV administration. Improved side effect profile results from more selective binding at antimigraine serotonergic receptors 5-HT1B and 5-HT1D. Inhaled prochlorperazine is rapidly absorbed and resulted in statistically significant migraine pain relief at 2 hours compared to placebo but is not currently being pursued by the manufacturer as a potential migraine abortive. Inhaled loxapine is also rapidly absorbed into systemic circulation but Phase IIb trials did not show statistically improved pain relief or pain freedom compared to placebo. MAP0004 will likely provide a good alternative to patients seeking rapid relief without the need for injection or other invasive routes.

Ice Pick Headache.

Ice pick headache, also called idiopathic or primary stabbing headache, is a unique headache type associated with ultra-brief stabs of pain, most commonly in the frontal or temporal area. It occurs predominantly in women and is estimated to affect 2-35% of the population. Unlike other headache types of short duration, such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), ice pick headache is not associated with any cranial autonomic symptoms but has been known to occur with nausea, vomiting, photophobia, and dizziness. It exists in two forms: primary and secondary, with examples of secondary causes being herpes zoster meningoencephalitis, meningiomas, stroke, and multiple sclerosis. Ice pick headache is one of the "indomethacin responsive headaches," but up to 35% of patients fail to show significant benefit with that treatment. Other treatment options include gabapentin, cyclooxygenase-2 inhibitors, melatonin, and external hand warming.

Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome.

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75-80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only approximately 30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/- mice and in individuals with CdLS.

Exercise-induced amenorrhea and bone health in the adolescent athlete.

Female participation in high school athletics has increased 800% in the last 30 years. The problem of exercise-induced amenorrhea was initially thought to be analogous to hypoestrogenism, but recent studies suggest that nutritional issues underlie most of the pathophysiology and that the mechanism is different from that seen in the primary hypogonadal state. Exercise-induced amenorrhea can be an indicator of an energy drain, and the presence of the other components of the female athlete triad-bone density loss and eating disorders-must be determined as well. Addressing skeletal problems related to nutritional and hormonal deficiencies in this population is of very high priority.

Appropriate use of estrogen replacement therapy in adolescents and young adults with Turner syndrome and hypopituitarism in light of the Women's Health Initiative.

Adolescents and young adult females who are hypoestrogenic need gonadal hormone therapy for sexual development, enhancement of growth, and maintenance of reproductive tissues, cyclic menses, and psychosocial health. In addition, prevention of chronic disease, specifically bone loss and possibly early heart disease, needs to be addressed in these patients. The etiology of hypopituitarism should also be considered when evaluating therapeutic options. The issues concerning estrogen replacement therapy (ERT), including the doses used and the length of therapy, are different for young patients than for postmenopausal women. The highly publicized findings of the Women's Health Initiative have identified risks of combined progestin-estrogen therapy; these risks, found in much older women, have raised questions regarding the appropriateness of ERT in adolescents with hypopituitarism and Turner syndrome. It is therefore appropriate to examine the relative risks and benefits of ERT in these populations.