Publications by authors named "Ninet Sinaii"

93 Publications

American Indian and Alaska Native Enrollment in Clinical Studies in the National Institutes of Health's Intramural Research Program.

Ethics Hum Res 2021 May;43(3):2-9

Neurologist at the National Institute of Neurological Disorders and Stroke (NINDS).

Clinical studies conducted by the National Institutes of Health's Intramural Research Program (NIH-IRP) provide eligible individuals with access to innovative research treatments that may not otherwise be available. The NIH-IRP's mission is to include all Americans, including American Indians and Alaska Natives, in its clinical research. This study is the first to provide data about inclusion of American Indians/Alaska Natives in NIH-IRP clinical studies. We analyzed data from the more than 1,800 NIH-IRP protocols active in 2014 and 2017. We found that the absolute number of American Indian/Alaska Native enrollees increased between 2014 and 2017 but remained at 1% of all participants, a disproportionately low level. The number of clinical studies that enrolled American Indian/Alaska Native individuals similarly did not change. NIH efforts to expand participation of American Indians/Alaska Natives in clinical studies has often focused on research within their communities or on health needs specific to these groups. Those efforts should expand to include processes and protections for the proportionate and ethical inclusion of American Indians and Alaska Natives who individually enroll in studies that are not specific to American Indians, Alaska Natives, or their tribal nations.
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http://dx.doi.org/10.1002/eahr.500090DOI Listing
May 2021

Cardiovascular Disease Risk Factors and Metabolic Morbidity in a Longitudinal Study of Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2021 Mar 2. Epub 2021 Mar 2.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Context: Patients with congenital adrenal hyperplasia (CAH) are exposed to hyperandrogenism and supraphysiologic glucocorticoids, both can increase risk of metabolic morbidity.

Objective: Our aim was to evaluate cardiovascular and metabolic morbidity risk in a longitudinal study of patients with CAH spanning both childhood and adulthood.

Design And Setting: Patients with classic CAH followed for a minimum of 5 years during both childhood and adulthood (n=57) at the National Institutes of Health were included and compared with the U.S. general population using NHANES data.

Main Outcome Measures: Obesity, hypertension, insulin resistance, fasting hyperglycemia and dyslipidemia.

Results: Compared to the U.S. population, patients with CAH had higher (P<0.001) prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia and low HDL during childhood and obesity (P=0.024), hypertension (P<0.001) and insulin resistance (P<0.001) during adulthood. In our cohort, obesity, hypertension, fasting hyperglycemia, and hypertriglyceridemia began prior to age 10. During childhood, increased mineralocorticoid dose was associated with hypertension (P=0.0015) and low HDL (P=0.0021). During adulthood, suppressed androstenedione was associated with hypertension (P=0.002), and high LDL (P=0.0039); while suppressed testosterone (P=0.003) was associated with insulin resistance. Elevated 17-hydroxyprogesterone, possibly reflecting poor disease control, was protective against high cholesterol (P=0.0049) in children. Children whose mothers were obese (maternal obesity) had increased risk of obesity during adulthood (P=0.0021). Obesity in turn contributed to the development of hypertension, insulin resistance, and hypertriglyceridemia in adulthood.

Conclusion: Patients with CAH develop metabolic morbidity at a young age associated with treatment-related and familial factors. Judicious use of glucocorticoid and mineralocorticoid is warranted.
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http://dx.doi.org/10.1210/clinem/dgab133DOI Listing
March 2021

11-Oxygenated Androgens Useful in the Setting of Discrepant Conventional Biomarkers in 21-Hydroxylase Deficiency.

J Endocr Soc 2021 Feb 11;5(2):bvaa192. Epub 2020 Dec 11.

Section on Congenital Disorders, National Institutes of Health Clinical Center, Bethesda, MD, USA.

Context: Serum 17-hydroxyprogesterone (17OHP) and androstenedione (A4) are the conventional biomarkers used to assess disease control in patients with 21-hydroxylase deficiency (21OHD). However, discrepancy between the two is not uncommon, limiting interpretation.

Objective: To evaluate 11-oxyandrogens in discriminating good versus poor disease control in 21OHD in the setting of discrepant 17OHP and A4.

Methods: Retrospective analysis of 2738 laboratory assessments obtained as part of Natural History Study of congenital adrenal hyperplasia (CAH) at the National Institutes Health Clinical Center. Patients with discrepant 17OHP and A4 and available sera were selected. A 15-steroid mass-spectrometry panel was performed in sera from patients with 21OHD and age- and sex-matched controls. Patients were categorized in "good" or "poor" control based on clinical assessment (bone age advancement, signs and symptoms of precocious puberty, menstrual irregularity, hirsutism, or hypogonadotrophic hypogonadism).

Results: Discrepant 17OHP and A4 was found in 469 (17%) laboratory assessments. Of these, 403 (86%) had elevated 17OHP with A4 in reference range. Of 46 patients with available sera, 30 (65%) were in good control. Median fold elevation relative to controls was higher in patients with poor versus good control for 11-hydroxytestosterone (median [interquartile range], 2.82 [1.25-5.43] vs 0.91 [0.49- 2.07],  = .003), and 11-ketotestosterone (3.57 [2.11-7.41] vs 1.76 [1.24-4.00],  = .047). Fold elevation of 11-hydroxytestosterone between 3.48 (sensitivity 97%, specificity 47%) and 3.88 (sensitivity 100%, specificity 40%) provided the best discrimination between poor vs good control.

Conclusion: 11-Oxyandrogens, especially 11-hydroxytestosterone, may be useful in the management of CAH when conventional biomarkers are inconclusive.
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http://dx.doi.org/10.1210/jendso/bvaa192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796775PMC
February 2021

Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: A cross-sectional study.

Eur J Pain 2021 04 8;25(4):831-840. Epub 2021 Jan 8.

Rehabilitation Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Background: Chronic pelvic pain persists in some women with endometriosis even after lesion removal and optimized hormonal treatment.

Objective: Characterize the presence and distribution of pain, myofascial dysfunction and sensitisation beyond the pelvis in women with endometriosis-associated chronic pelvic pain.

Methods: Cross-sectional study of 30 women prior to participation in a clinical trial. Evaluation included pain-focused abdominopelvic gynaecologic examination with the identification of pelvic floor muscle spasm. Neuro-musculoskeletal examination assessed paraspinal allodynia and hyperalgesia bilaterally and myofascial trigger points in 13 paired muscles. Pressure-pain thresholds were measured over interspinous ligaments and trigger points. Women completed the body territories element of the Body Pain Index.

Results: All women had a pelvic floor muscle spasm that they self-identified as a major focus of pain. Twenty of 30 women described their pelvic pain as focal. However, all demonstrated widespread myofascial dysfunction with low pressure-pain thresholds and trigger points in over two-thirds of 26 assessed regions. Widespread spinal segmental sensitisation was present in 17/30, thoracic in 21/30 and lumbosacral/pelvic in 18/30. Cervical sensitisation manifested as low pressure-pain thresholds with 23/30 also reporting recurrent, severe headaches and 21/30 experiencing orofacial pain. Those reporting diffuse pelvic pain were more likely to have widespread (p = .024) and lumbosacral/pelvic (p = .036) sensitisation and report over 10 painful body areas (p = .009).

Conclusions: Women with endometriosis-associated chronic pelvic pain often have myofascial dysfunction and sensitisation beyond the pelvic region that may be initiated or maintained by on-going pelvic floor spasm. These myofascial and nervous system manifestations warrant consideration when managing pain in this population. Clinicaltrials.gov identifier: NCT01553201.

Significance: Women with endometriosis often have pelvic pain persisting after surgery despite hormonal therapies and these women have regional pelvic sensitisation and myofascial dysfunction. Pelvic floor muscle spasm is a major pain focus in this population. Sensitisation and myofascial dysfunction are widespread, beyond the pelvic region. On-going pelvic floor spasm may initiate or maintain sensitisation. Myofascial/sensitisation manifestations warrant consideration when managing pain in this population.
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http://dx.doi.org/10.1002/ejp.1713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979491PMC
April 2021

Neurofilament light chain levels correlate with clinical measures in CLN3 disease.

Genet Med 2021 04 26;23(4):751-757. Epub 2020 Nov 26.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.

Purpose: CLN3 disease is a neurodegenerative disorder with onset in childhood. It affects multiple functions at different developmental stages. Incomplete understanding of the pathophysiology hampers identification of cell and tissue biochemical compounds reflective of the disease process. As treatment approaches are being explored, more sensitive, objective, quantifiable, and clinically relevant biomarkers are needed.

Methods: We collected prospective biosamples from 21 phenotyped individuals with CLN3. We measured neurofilament light chain (NEFL) levels, a marker of neuronal damage, in cross-sectional CSF and serum samples from individuals with CLN3 and in pediatric non-CLN3 controls using two different assays.

Results: Cerebrospinal fluid (CSF) and serum NEFL levels are significantly higher in CLN3 (CSF: 2096 ± 1202; serum: 29.0 ± 18.0 pg/mL) versus similarly aged non-CLN3 (CSF: 345 ± 610; serum: 6.7 ± 3.2 pg/mL) samples. NEFL levels correlate with Unified Batten Disease Rating Scale and adaptive behavior composite scores, and magnetic resonance (MR) spectroscopy markers. NEFL levels from CSF and serum are strongly correlated (r = 0.83; p < 0.0001).

Conclusion: CSF and serum NEFL levels increase in multiple neurologic conditions. Here, we show that CSF and serum NEFL levels also increase in CLN3 (versus non-CLN3) and correlate with other disease-relevant measures. These findings suggest NEFL as a relevant and feasible biomarker for applications in CLN3 clinical trials and management.
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http://dx.doi.org/10.1038/s41436-020-01035-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035240PMC
April 2021

Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring.

Kidney Int 2021 01 9;99(1):227-237. Epub 2020 Nov 9.

Department of Medicine, Renal Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels.
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http://dx.doi.org/10.1016/j.kint.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833801PMC
January 2021

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease.

JAMA Netw Open 2020 10 1;3(10):e2019169. Epub 2020 Oct 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated.

Objective: To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD.

Design, Setting, And Participants: This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020.

Exposure: Diagnosis of ECD.

Main Outcomes And Measures: Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction.

Results: A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050).

Conclusions And Relevance: In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.19169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596581PMC
October 2020

Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1.

JAMA Neurol 2020 Dec;77(12):1564-1568

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

Importance: Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally.

Objective: To determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1.

Design, Setting, And Participants: Patients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019.

Exposures: Oral miglustat at baseline and at follow-up.

Main Outcomes And Measures: Oropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively.

Results: Overall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29).

Conclusions And Relevance: These data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.
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http://dx.doi.org/10.1001/jamaneurol.2020.3241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489403PMC
December 2020

Effect of a Brief Mindfulness-Based Program on Stress in Health Care Professionals at a US Biomedical Research Hospital: A Randomized Clinical Trial.

JAMA Netw Open 2020 08 3;3(8):e2013424. Epub 2020 Aug 3.

Clinical Center, National Institutes of Health, Bethesda, Maryland.

Importance: Stress among health care professionals is well documented. The use of mindfulness-based interventions to reduce stress has shown promising results; however, the time commitment of typical programs can be a barrier to successful implementation in health care settings.

Objective: To determine the efficacy and feasibility of a brief mindfulness-based program to reduce stress during work hours among health care professionals.

Design, Setting, And Participants: This intent-to-treat randomized clinical trial was conducted among full-time health care professionals at the Clinical Center at the National Institutes of Health in Bethesda, Maryland, between September 2017 and May 2018. Participants were randomized to receive mindfulness-based self-care (MBSC) training or life-as-usual control. Data were analyzed from June 2018 to January 2020.

Interventions: The MBSC intervention included 5 weekly, 1.5-hour in-class mindfulness practice sessions.

Main Outcomes And Measures: Stress level was the primary outcome, assessed with the Perceived Stress Scale 10-Item version. Secondary outcomes included anxiety, burnout, positive and negative affect, mindfulness (trait and state), and self-care. Assessments were taken at baseline and at the end of the intervention (week 5) in the intervention and control groups, and at follow-up (week 13) in the intervention group to test for a maintenance effect. A postprogram evaluation was also obtained.

Results: Of 82 randomized participants, 78 who completed the study at week 5 were included in the modified intent-to-treat analysis (median [interquartile range] age, 32 [23-48] years; 65 [83%] women), including 43 participants in the MBSC group and 35 participants in the control group. At the end of the intervention, compared with the control group, the MBSC group had reduced levels of stress (mean [SD] score, 17.29 [5.84] vs 18.54 [6.30]; P = .02) and anxiety (mean [SD] score, 2.58 [1.52] vs 4.23 [1.73]; P < .001), and improved positive affect (mean [SD] score, 35.69 [7.12] vs 31.42 [7.27]; P < .001), state mindfulness (mean [SD] score, 3.74 [1.18] vs 2.78 [1.16]; P < .001), and mindful self-care (mean [SD] score, 7.29 [2.44] vs 5.54 [2.77]; P < .001). Burnout, negative affect, and trait mindfulness levels did not differ between groups. Changes within the MBSC group through follow-up included sustained reductions in stress (change, -6.14; 95% CI, -7.84 to -4.44; P < .001), anxiety (change, -1.46; 95% CI, -1.97 to -0.94; P < .001), trait mindfulness (change, 0.63; 95% CI, 0.36 to 0.90; P < .001), and state mindfulness (change, 1.89; 95% CI, 1.39 to 2.39; P < .001).

Conclusions And Relevance: This randomized clinical trial found that this brief mindfulness-based intervention was an effective and feasible means to reduce stress in health care professionals. Larger studies are needed to assess the effects on clinical care and patient outcomes.

Trial Registration: ClinicalTrials.gov Identifier: NCT03781336.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448827PMC
August 2020

Telomere Length Changes in Children With Cushing Disease: A Pilot Study.

J Endocr Soc 2020 Jul 7;4(7):bvaa067. Epub 2020 Jun 7.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

Context: Changes in telomere length (TL) have been linked to certain diseases. Studies on the effect of cortisol on TL have not led to conclusive results.

Objective: To determine whether TL is affected in pediatric patients with Cushing disease (CD) through an exploratory study.

Design: We studied 10 pediatric patients [mean age: 13.3 (2.6) years, 7 females], diagnosed and treated successfully for CD. TL was measured before and approximately 1 year after treatment. TL was compared with controls adjusting for age, and associations with disease characteristics were assessed.

Results: Adjusting for age, total lymphocyte TL of patients did not differ from controls during active disease ( = 0.13) but was shorter than controls at follow-up ( = 0.031). Total lymphocyte TL during active CD and at follow-up did not correlate with markers of hypercortisolemia. There was strong inverse correlation between TL during active disease and at follow-up with triglyceride levels at active disease (adjusted [Adj] R = 0.64; = 0.02 and Adj R = 0.5; = 0.036, respectively), suggesting that the higher the triglycerides, the shorter the TL in patients with CD. The change of TL between active disease and follow-up was positively correlated with systolic blood pressure (Adj R = 0.76; = 0.006).

Conclusions: In this pilot study, TL is shorter in children with hypercortisolemia, a difference that becomes detectable only after cure of CD. Triglycerides and blood pressure appear to be factors that are associated with TL in these patients. Further studies are required to confirm these results.
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http://dx.doi.org/10.1210/jendso/bvaa067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343236PMC
July 2020

Hypothalamic-Pituitary-Adrenal Axis Responses in Women with Endometriosis-Related Chronic Pelvic Pain.

Reprod Sci 2020 10 22;27(10):1839-1847. Epub 2020 Jun 22.

Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Room 7-4647, 10 Center Dr., Bethesda, MD, 20892, USA.

Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 μg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.
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http://dx.doi.org/10.1007/s43032-020-00201-xDOI Listing
October 2020

Attitudes Toward Fertility Preservation Among Transgender Youth and Their Parents.

J Adolesc Health 2020 10 29;67(4):583-589. Epub 2020 Apr 29.

Division of Adolescent Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: While gender-affirming hormones (GAH) may impact the fertility of transgender and gender diverse (TGGD) youth, few pursue fertility preservation (FP). The objective of this study is to understand youth and parent attitudes toward FP decision-making.

Methods: This study is a cross-sectional survey of youth and parents in a pediatric, hospital-based gender clinic from April to December 2017. Surveys were administered electronically, containing 34 items for youth and 31 items for parents regarding desire for biological children, willingness to delay GAH for FP, and factors influencing FP decisions.

Results: The mean age of youth (n = 64) was 16.8 years, and 64% assigned female at birth; 46 parents participated. Few youth (20%) and parents (13%) found it important to have biological children or grandchildren, and 3% of youth and 33% of parents would be willing to delay GAH for FP. The most common factor influencing youth FP decision-making was discomfort with a body part they do not identify with (69%), and for the parents, whether it was important to their child (61%). In paired analyses, youth and their parents answered similarly regarding youth desire for biological children and willingness to delay GAH for FP.

Conclusions: The majority of TGGD youth and parents did not find having biological offspring important and were not willing to delay GAH for FP. Discomfort with reproductive anatomy was a major influencing factor for youth FP decision-making and their child's wishes was a major factor for parents. Future qualitative research is needed to understand TGGD youth and parent attitudes toward FP and to develop shared decision-making tools.
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http://dx.doi.org/10.1016/j.jadohealth.2020.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508908PMC
October 2020

Neonatal Severe Hyperparathyroidism: Novel Insights From Calcium, PTH, and the CASR Gene.

J Clin Endocrinol Metab 2020 04;105(4)

Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD.

Context: Neonatal severe hyperparathyroidism (NSHPT) is rare and potentially lethal. It is usually from homozygous or heterozygous germline-inactivating CASR variant(s). NSHPT shows a puzzling range of serum calcium and parathyroid hormone (PTH) levels. Optimal therapy is unclear.

Evidence Acquisition: We categorized genotype/phenotype pairings related to CASRs. For the 2 pairings in NSHPT, each of 57 cases of neonatal severe hyperparathyroidism required calcium, PTH, upper normal PTH, and dosage of a germline pathogenic CASR variant.

Evidence Synthesis: Homozygous and heterozygous NSHPT are 2 among a spectrum of 9 genotype/phenotype pairings relating to CASRs and NSHPT. For the 2 NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of maternofetal calcium fluxes. Homozygous dosage of CASR variants was generally more aggressive than heterozygous. Among heterozygotes, high-grade CASR variants in vitro were more pathogenic in vivo than low-grade variants. Fetal calcium insufficiency as from maternal hypoparathyroidism caused fetal secondary hyperparathyroidism, which persisted and was reversible in neonates. Among NSHPT pairings, calcium and PTH were higher in CASR homozygotes than in heterozygotes. Extreme hypercalcemia (above 4.5 mM; normal 2.2-2.6 mM) is a robust biomarker, occurring only in homozygotes (83% of that pairing). It could occur during the first week.

Conclusions: In NSHPT pairings, the homozygotes for pathogenic CASR variants show higher calcium and PTH levels than heterozygotes. Calcium levels above 4.5 mM among NSHPT are frequent and unique only to most homozygotes. This cutoff supports early and robust diagnosis of CASR dosage. Thereby, it promotes definitive total parathyroidectomy in most homozygotes.
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http://dx.doi.org/10.1210/clinem/dgz233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111126PMC
April 2020

Remission of hypertension after surgical cure of Cushing's syndrome.

Clin Endocrinol (Oxf) 2020 02 9;92(2):124-130. Epub 2019 Dec 9.

Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Context: Hypertension associated with Cushing's syndrome (CS) increases cardiovascular risk. The time-course of improvement after cure is unclear.

Objective: To describe the time-course and predictors of blood pressure (BP) normalization during one year after surgical cure of CS.

Design: Retrospective chart review of 75 hypertensive adults cured of CS (72 with ACTH-dependent CS; 3 with adrenal adenoma). Hypertension was defined as current use of antihypertensives, a systolic BP >130 mm Hg, or diastolic BP >80 mm Hg.

Main Outcome Measure(s): Remission of hypertension: BP ≤130/80 mm Hg and no antihypertensive medications. Improvement in hypertension: BP >130/80 mm Hg and decreased number or dose of medications, or blood pressure ≤130/80 with continued use of medications at constant dose.

Results: At postoperative discharge, 17 (23%, P < .001), 51 (68%, P < .001) and 7 (9%) patients had remission, improvement in hypertension or no change. Twenty-nine had no follow-up. Others achieved remission at 3 (n = 5), 6 (n = 6), or 12-months (n = 5). At the last evaluation, 33/75 (44%) had remission, 36/75 (48%) had improved hypertension and 6 were unchanged. Patients with improvement discontinued a median of one medication (P < .001). At 12-months, 27/42 (64%) patients had normal BP (P < .002). Longer estimated duration of CS (P = .0106), younger age (P = .0022), and lower baseline body mass index (P = .0413) predicted hypertension remission.

Conclusions: About 80% of CS patients experienced BP normalization or improvement within 10 days of cure, but about half failed to normalize BP by one year. BP should be monitored after cure, and antihypertensive medications adjusted to avoid unwanted cardiovascular effects.
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http://dx.doi.org/10.1111/cen.14129DOI Listing
February 2020

Gender Differences in Psycho-Social-Spiritual Healing.

J Womens Health (Larchmt) 2019 11 6;28(11):1513-1521. Epub 2019 Sep 6.

Clinical Center, National Institutes of Health, Bethesda, Maryland.

Many individuals exhibit significant distress in response to serious and/or life-limiting illness. However, there are others who make life-transforming changes, which involve healing experiences in the psychological, social, and spiritual domains of life regardless of illness outcome. The aim of the present study is to determine if there are any differences in psycho-social-spiritual healing between genders. The NIH Healing Experiences in All Life Stressors (NIH-HEALS), a 35-item measure of psycho-social-spiritual healing, is composed of three factors: Connection, Reflection & Introspection, and Trust & Acceptance. NIH-HEALS and a demographic questionnaire were administered to 193 patients with serious and/or life-limiting illness at the National Institutes of Health Clinical Center. In response to NIH-HEALS, men and women significantly differed on the Reflection & Introspection factor. Women reported increased enjoyment of mind-body practices ( < 0.001), compassion ( = 0.005), gratitude ( = 0.014), and a desire to be more positive ( = 0.044) compared to men. Men rated their pain levels ( = 0.035) and severity of illness ( = 0.016) higher and their overall level of health ( = 0.010) poorer compared to women. Women's responses to items regarding compassion ( = 0.37,  < 0.001) and gratitude ( = 0.24,  = 0.015) correlated positively with better overall health ratings. Men and women show some differences in their self-reported psycho-social-spiritual healing, which may have implications when designing interventions aimed at promoting a healing experience in the context of serious and life-limiting illness.
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http://dx.doi.org/10.1089/jwh.2019.7837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862956PMC
November 2019

Botulinum toxin for chronic pelvic pain in women with endometriosis: a cohort study of a pain-focused treatment.

Reg Anesth Pain Med 2019 Jul 8. Epub 2019 Jul 8.

Office of the Clinical Director, Intramural Research Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Background And Objectives: Many women with endometriosis continue to have pelvic pain despite optimal surgical and hormonal treatment; some also have palpable pelvic floor muscle spasm. We describe changes in pain, spasm, and disability after pelvic muscle onabotulinumtoxinA injection in women with endometriosis-associated pelvic pain, a specific population not addressed in prior pelvic pain studies on botulinum toxin.

Methods: We present an open-label proof-of-concept case series of women with surgically diagnosed endometriosis. Under conscious sedation and with topical anesthetic, 100 units of onabotulinumtoxinA was injected transvaginally into pelvic floor muscle spasm areas under electromyography guidance. Changes in pain intensity, muscle spasm, disability, and pain medication use were assessed at periodic visits for up to 1 year after injection.

Results: Thirteen women underwent botulinum toxin injection and were followed for at least 4 months. Before injection, 11 of the 13 women had spasm in >4/6 assessed pelvic muscles and reported moderate pain (median visual analog scale (VAS): 5/10; range: 2-7). By 4-8 weeks after injection, spasm was absent/less widespread (≤3 muscles) in all (p=0.0005). Eleven rated their postinjection pain as absent/mild (median VAS: 2; range: 0-5; p<0.0001); 7/13 reduced pain medication. Disability decreased in 6/8 women with at least moderate preinjection disability (p=0.0033). Relief lasted 5-11 months in 7 of the 11 patients followed for up to 1 year. Adverse events were mild and transient.

Conclusions: These findings suggest pelvic floor spasm may be a major contributor to endometriosis-associated pelvic pain. Botulinum toxin injection may provide meaningful relief of pain and associated disability.

Trial Registration Number: NCT01553201.
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http://dx.doi.org/10.1136/rapm-2019-100529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946887PMC
July 2019

Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks.

Pediatr Res 2019 09 21;86(3):375-381. Epub 2019 May 21.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, USA.

Background: Cardiovascular (CV) complications are the most significant cause of mortality in adults with Cushing disease (CD); little is known about CV risk factors in children with CD. Measurement of lipoprotein particles by nuclear magnetic resonance (NMR) spectroscopy is a novel technology to assess CV risk. The objective of the current study is to analyze the NMR lipid profile in pediatric CD patients before and 1 year after remission.

Methods: NMR lipid profile was obtained via the Vantera NMR analyzer, using frozen serum samples from 33 CD patients (mean age 13.8 ± 4.0 years) evaluated between 1997 and 2017 at the National Institutes of Health (NIH) Clinical Center (CC).

Results: GlycA (glycosylated acute-phase proteins), triglyceride-rich particles (TRLP medium and very small sizes), low-density lipoprotein (LDL) particles (LDLP total and large size), high-density lipoprotein (HDL) particles (HDLP total, medium and small sizes), total cholesterol, LDL-cholesterol, HDL-cholesterol, GlycA inflammatory biomarker, and apolipoprotein B and apolipoprotein A1 (ApoA1) concentrations showed statistically significant changes after remission of CD (p < 0.05).

Conclusion: In our study population, most of the lipid variables improved post-CD remission, with the exception of HDL and ApoA1, indicating that NMR lipoprotein profile may be a helpful tool in assessing the CV risk in pediatric patients with CD.
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http://dx.doi.org/10.1038/s41390-019-0438-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702083PMC
September 2019

Patient-perceived Burden of Disease in Pediatric Relapsing Polychondritis.

J Rheumatol 2019 12 1;46(12):1627-1633. Epub 2019 May 1.

From the US National Institute of Arthritis and Musculoskeletal and Skin Disorders (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland; University of North Carolina at Chapel Hill School of Medicine, Medical Scientist Training Program, Chapel Hill, North Carolina; NIH Clinical Center, Biostatistics and Clinical Epidemiology Service, NIH, Bethesda, Maryland, USA.

Objective: To assess patient-reported burden of disease in pediatric patients with relapsing polychondritis (RP) and to compare those findings to adult patients.

Methods: A survey based on known clinical symptoms of RP was developed and administered to patients with a pediatric diagnosis of RP. Adult patients completed a similar survey.

Results: Twenty-one pediatric patients, or their parents, completed surveys. Median age at symptom onset was 6 years (interquartile range 1.8-12). Prior to diagnosis, most pediatric patients went to the emergency room (ER; 61.9%), saw > 3 physicians (57.1%), and took > 1 year to be diagnosed (61.9%). Pediatric patients were often diagnosed with asthma (42.9%), ear infections (42.9%), or sinusitis (33.3%) prior to diagnosis of RP. Symptoms prior to diagnosis included ear pain/redness (85.7%), joint pain/swelling (61.9%), and airway symptoms (38.1%). Four pediatric patients (19%) reported tracheomalacia requiring tracheostomy. Pediatric patients frequently missed school because of their disease (71.4%). Surveys from 290 adult patients were compared to pediatric patients. Pediatric patients were significantly more likely to undergo biopsy (42.9% vs 17.4%; p < 0.01) and be treated with biologics (42.9% vs 19%; p = 0.02). Adults were significantly more likely to be female (87.8% vs 28.6%; p < 0.01) and to report airway symptoms (77.9% vs 47.6%; p = 0.01). Prevalence of disease complications was not significantly different between adult and pediatric patients.

Conclusions: The burden of disease in pediatric patients with RP includes missed school, diagnostic delay, ER visits, and multisystem disease, with resultant damage to cartilaginous structures. Differences in airway involvement and treatment approaches may exist between pediatric and adult patients.
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http://dx.doi.org/10.3899/jrheum.181456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824962PMC
December 2019

Aortic pulse wave velocity in children with Cushing syndrome: A window into a marker of early cardiovascular disease.

Endocrinol Diabetes Metab 2019 Apr 15;2(2):e00054. Epub 2019 Jan 15.

Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health Bethesda Maryland.

Objective: To investigate early signs of cardiovascular arterial remodelling in paediatric patients with Cushing syndrome (CS) in comparison with normative values from healthy children.

Study Design: The metrics used to assess cardiac health were from thoracic aorta and carotid MRI. Scans were performed on 18 children with CS (mean: 12.5 ± 3.1 years, range: 6.0-16.8 years, 10 female). Pulse wave velocity (PWV), aortic distensibility (AD) and carotid intima-media thickness (cIMT), well-validated measurements of cardiac compromise, were measured from the images and compared to normative age-matched values where available.

Results: Patients with CS had significantly higher PWV compared to age-adjusted normal median control values (4.0 ± 0.7 m/s vs. 3.4 ± 0.2 m/s, respectively,  = 0.0115). PWV was positively correlated with midnight plasma cortisol ( = 0.56,  = 0.02). Internal and common cIMT were negatively correlated with ascending AD ( = -0.75,  = 0.0022,  = -0.69,  = 0.0068, respectively).

Conclusion: Pulse wave velocity data indicate that paediatric patients with CS have early evidence of cardiovascular remodelling. The results suggest the opportunity for monitoring as these changes begin in childhood.
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http://dx.doi.org/10.1002/edm2.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458483PMC
April 2019

A retrospective cohort study of antibiotic exposure and vancomycin-resistant Enterococcus recolonization.

Infect Control Hosp Epidemiol 2019 04 7;40(4):414-419. Epub 2019 Feb 7.

National Institutes of Health,Bethesda,Maryland.

Objective: In the National Institutes of Health (NIH) Clinical Center, patients colonized or infected with vancomycin-resistant Enterococcus (VRE) are placed in contact isolation until they are deemed "decolonized," defined as having 3 consecutive perirectal swabs negative for VRE. Some decolonized patients later develop recurrent growth of VRE from surveillance or clinical cultures (ie, "recolonized"), although that finding may represent recrudescence or new acquisition of VRE. We describe the dynamics of VRE colonization and infection and their relationship to receipt of antibiotics.

Methods: In this retrospective cohort study of patients at the National Institutes of Health Clinical Center, baseline characteristics were collected via chart review. Antibiotic exposure and hospital days were calculated as proportions of VRE decolonized days. Using survival analysis, we assessed the relationship between antibiotic exposure and time to VRE recolonization in a subcohort analysis of 72 decolonized patients.

Results: In total, 350 patients were either colonized or infected with VRE. Among polymerase chain reaction (PCR)-positive, culture (Cx)-negative (PCR+/Cx-) patients, PCR had a 39% positive predictive value for colonization. Colonization with VRE was significantly associated with VRE infection. Among 72 patients who met decolonization criteria, 21 (29%) subsequently became recolonized. VRE recolonization was 4.3 (P = .001) and 2.0 (P = .22) times higher in patients with proportions of antibiotic days and antianaerobic antibiotic days above the median, respectively.

Conclusion: Colonization is associated with clinical VRE infection and increased mortality. Despite negative perirectal cultures, re-exposure to antibiotics increases the risk of VRE recolonization.
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http://dx.doi.org/10.1017/ice.2019.15DOI Listing
April 2019

The National Institutes of Health measure of Healing Experience of All Life Stressors (NIH-HEALS): Factor analysis and validation.

PLoS One 2018 12;13(12):e0207820. Epub 2018 Dec 12.

Clinical Center, National Institutes of Health, Bethesda, Maryland, United States of America.

Two hundred patients with severe and/or life-threatening disease were recruited form the NIH Clinical Center and participated in the validation of the NIH-HEALS, which included exploratory factor analysis, principal component analysis, reliability, convergent validity, and divergent validity analyses. Item-reducing principal components analysis and internal consistency and split-half reliability demonstrated excellent internal consistency and split-half reliability (Cronbach's alpha = 0.89, split-half reliability = 0.95). Exploratory factor analysis revealed a three-factor structure, namely Connection (including religious, spiritual, and interpersonal), Reflection & Introspection, and Trust & Acceptance. Seven items were not retained. Convergent and divergent validity of 35-item NIH-HEALS against other validated measures of healing and spirituality provided strong evidence for its validity. As predicted, the Healed factor of the Self-Integration Scale (SIS), and Meaning, Peace, and Faith factors of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being-12 Scale (FACIT-SP12) were all positively and significantly correlated with the NIH-HEALS and its three factors. Divergent validity was also confirmed by the significant negative correlation between the NIH-HEALS and the Codependent factor on the SIS. Confirmatory Factor Analyses revealed good model fit by GFI (0.96), adjusted GFI (0.95), SRMR (0.077), and RMSEA (0.065), supporting the use of the NIH-HEALS with 35 items.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291293PMC
May 2019

Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia.

Clin Endocrinol (Oxf) 2018 10 8;89(4):399-407. Epub 2018 Aug 8.

National Institutes of Health Clinical Center, Bethesda, Maryland.

Background: In a phase 2 short-term (6 months) study of patients with congenital adrenal hyperplasia (CAH), continuous subcutaneous hydrocortisone infusion (CSHI) was found to be a safe, effective and well-tolerated method of replacing cortisol with improved disease and patient-related outcomes.

Objective: To evaluate the safety and efficacy of long-term CSHI.

Design: Single-centre, open-label, phase 2 extension study.

Patients: Five adults with classic CAH.

Measurements: Biomarkers of disease control, metabolic indices and health-related quality-of-life (HRQoL) estimates.

Results: Six of eight patients chose to continue on long-term CSHI therapy. Compared to baseline, eighteen months of CSHI resulted in decreased (P = 0.043) 0700-hour ACTH, 17-hydroxyprogesterone, androstenedione and progesterone; increased whole-body lean mass (P = 0.024); and improved HRQoL, especially symptoms of adrenal insufficiency (P = 0.003). Findings at six and eighteen months did not differ, and improvements achieved in androgen control, lean body mass and HRQoL after 6 months of CSHI were maintained at eighteen months. The hydrocortisone dose appeared to decrease with time [6 vs 18 months: 38.3 ± 8.8 vs 33.6 ± 12.2 mg/day (P = 0.062)], especially in women receiving oral contraceptives. Reduction of testicular adrenal rest and adrenal size observed at 6 months remained stable. In one patient, an adrenal adenoma continually decreased over time. Subjective improvement in hirsutism was reported.

Conclusions: Long-term use of CSHI is a safe and well-tolerated treatment option in a select set of adults with classic CAH. Improvements observed short term in disease control and subjective health status continued long term.
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http://dx.doi.org/10.1111/cen.13813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166869PMC
October 2018

Risk Factors for Viridans Group Streptococcal Bacteremia in Neutropenic and Non-neutropenic Patients: A Single Center Case-Case-Control Study.

Open Forum Infect Dis 2018 Jan 2;5(1):ofx260. Epub 2017 Dec 2.

National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.

Background: Viridans group streptococcal (VGS) bacteremia is common among neutropenic patients. Although VGS bacteremia occurs in non-neutropenic patients, risk factors are not well established. We conducted a case-case-control study to identify risk factors for VGS among neutropenic and non-neutropenic patients.

Methods: Patients with VGS bacteremia between January 2009 and December 2014 in our 200-bed clinical research hospital were identified using microbiology records. Neutropenic and non-neutropenic patients at the time of positive culture were matched 1:1 to controls on the basis of neutrophil count (ANC), ward, and length of stay. We extracted demographic, laboratory, medication, and other clinical data from chart reviews. Data were analyzed using McNemar's test, Wilcoxon signed-rank test, and conditional logistic regression modeling.

Results: Among 101 patients, 63 were neutropenic and 38 non-neutropenic at the time of VGS bacteremia. In multivariable analysis of neutropenic patients, only lower ANC predicted VGS bacteremia (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.05-0.59; = 0.006). Recent use of vancomycin was protective (OR, 0.23; 95% CI, 0.07-0.73; = 0.013). No clinical factors were associated with VGS in the non-neutropenic cases.

Conclusions: Only lower ANC nadir increased the risk for VGS bacteremia in the neutropenic group, and vancomycin was protective. Other previously described factors (chemotherapy, radiation, oral conditions) related to neutropenia were not independently associated with VGS bacteremia. No tested clinical factors predicted infection in the non-neutropenic group. Our results suggest that VGS bacteremia should be anticipated when making antimicrobial choices in profoundly neutropenic patients, and merit further exploration in non-neutropenic patients.
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http://dx.doi.org/10.1093/ofid/ofx260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757639PMC
January 2018

Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2018 06;103(6):2336-2345

National Institutes of Health Clinical Center, Bethesda, Maryland.

Context: Patients with congenital adrenal hyperplasia (CAH) are at risk for life-threatening adrenal crises. Management of illness episodes aims to prevent adrenal crises.

Objective: We evaluated rates of illnesses and associated factors in patients with CAH followed prospectively and receiving repeated glucocorticoid stress dosing education.

Methods: Longitudinal analysis of 156 patients with CAH followed at the National Institutes of Health Clinical Center over 23 years was performed. The rates of illnesses and stress-dose days, emergency room (ER) visits, hospitalizations, and adrenal crises were analyzed in relation to phenotype, age, sex, treatment, and hormonal evaluations.

Results: A total of 2298 visits were evaluated. Patients were followed for 9.3 ± 6.0 years. During childhood, there were more illness episodes and stress dosing than adulthood (P < 0.001); however, more ER visits and hospitalizations occurred during adulthood (P ≤ 0.03). The most robust predictors of stress dosing were young age, low hydrocortisone and high fludrocortisone dose during childhood, and female sex during adulthood. Gastrointestinal and upper respiratory tract infections (URIs) were the two most common precipitating events for adrenal crises and hospitalizations across all ages. Adrenal crisis with probable hypoglycemia occurred in 11 pediatric patients (ages 1.1 to 11.3 years). Undetectable epinephrine was associated with ER visits during childhood (P = 0.03) and illness episodes during adulthood (P = 0.03).

Conclusions: Repeated stress-related glucocorticoid dosing teaching is essential, but revised age-appropriate guidelines for the management of infectious illnesses are needed for patients with adrenal insufficiency that aim to reduce adrenal crises and prevent hypoglycemia, particularly in children.
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http://dx.doi.org/10.1210/jc.2018-00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276663PMC
June 2018

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2018 07 1;24(7):1415-1423. Epub 2018 Mar 1.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.
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http://dx.doi.org/10.1016/j.bbmt.2018.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045967PMC
July 2018

Postoperative Diabetes Insipidus and Hyponatremia in Children after Transsphenoidal Surgery for Adrenocorticotropin Hormone and Growth Hormone Secreting Adenomas.

J Pediatr 2018 04 1;195:169-174.e1. Epub 2018 Feb 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD. Electronic address:

Objectives: To define the incidence and risk factors of postoperative sodium alterations in pediatric patients undergoing transsphenoidal surgery (TSS) for adrenocorticotropic hormone and growth hormone secreting pituitary adenomas.

Study Design: We retrospectively reviewed 160 patients ≤18 years of age who had TSS for pituitary adenomas at our institution from 1999 to 2017. Variables included daily serum sodium through postoperative day 10, urine specific gravity, and medications administered. We examined associations between sex, repeat surgery, manipulation of the posterior pituitary (PP), tumor invasion into the PP, tumor type and size, cerebrospinal fluid (CSF) leak, lumbar drain insertion, body mass index, puberty, and development of diabetes insipidus (DI) or syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Results: Mean age was 12.9 ± 3.4 years (female = 81). Patients had adrenocorticotropic hormone (150/160) and growth hormone (10/160) producing adenomas. Forty-two (26%) patients developed DI. Among the 37 of 160 who required desmopressin acutely, 13 of 37 required it long term. Risk of long-term need for desmopressin was significantly higher in patients who had CSF leak 9 of 48 (P = .003), lumbar drain 6 of 30 (P = .019), manipulation 11 of 50 (P < .001), or invasion 4 of 15 (P = .022) of the PP. Sixty patients developed hyponatremia, 19 because of SIADH, 39 to hypotonic fluids and 2 to cerebral salt wasting syndrome. Patients with SIADH were placed on fluid restriction; 1 received salt tablets.

Conclusions: Among 160 children who underwent TSS for pituitary adenomas, the incidence of DI and SIADH after TSS was 26% and 14%, respectively. Combined risk factors for DI and/or SIADH include female sex, manipulation of and/or tumor invasion into the PP, and CSF leak or lumbar drain.

Trial Registration: ClinicalTrials.gov: NCT00001595 and NCT00060541.
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http://dx.doi.org/10.1016/j.jpeds.2017.11.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869073PMC
April 2018

Patient Perception of Disease-Related Symptoms and Complications in Relapsing Polychondritis.

Arthritis Care Res (Hoboken) 2018 08 4;70(8):1124-1131. Epub 2018 Jul 4.

National Institutes of Health, Bethesda, Maryland.

Objective: To assess patient-reported symptoms and burden of disease in relapsing polychondritis (RP).

Methods: Patients with RP completed a disease-specific online survey to identify symptoms attributed to illness. Patients were divided into subgroups based upon presence or absence of ear/nose, airway, or joint involvement. Pathway to diagnosis, treatment, and disease-related complications were assessed within each subgroup.

Results: Data from 304 respondents were included in this analysis. Prior to diagnosis, most patients with RP went to the emergency room (54%), saw > 3 physicians (54%), and had symptoms for >5 years (64%). A concomitant diagnosis of fibromyalgia and absence of ear/nose or joint involvement was associated with diagnostic delay >1 year. Common diagnoses prior to RP diagnosis included asthma in patients with airway involvement (35% versus 22%; P = 0.03) and ear infection in patients with ear/nose involvement (51% versus 6%; P < 0.01). Patients with joint involvement were more likely to receive a glucocorticoid-sparing agent (85% versus 13%; P < 0.01). Most patients reported a major complication, including disability (25%), tracheomalacia (16%), or hearing loss (34%). Patients with airway involvement reported more tracheomalacia (20% versus 4%; P < 0.01). Disability (24% versus 7%; P < 0.01) and hearing loss (39% versus 11%; P < 0.01) were prevalent in the joint involvement subgroup.

Conclusion: Patient-reported data in RP highlight a significant burden of disease. Patterns of organ involvement may lead to diagnostic delay and influence treatment decisions, ultimately impacting the development of disease-related complications. Timely diagnosis, standardization of treatment approaches, and prevention of disease-related complications are major unmet needs in RP.
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http://dx.doi.org/10.1002/acr.23492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003821PMC
August 2018

Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome.

Pediatr Res 2018 02 6;83(2):431-437. Epub 2017 Dec 6.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

BackgroundHypercortisolemia results in changes of the immune system and elevated infection risk, but data on the WBC changes in pediatric Cushing syndrome (CS) are not known. We describe the changes of the WBC lineages in pediatric endogenous hypercortisolemia, their associations with the markers of disease severity, and the presence of infections.MethodsWe identified 197 children with endogenous CS. Clinical and biochemical data were recorded. Sixty-six children with similar age and gender, and normocortisolemia served as controls.ResultsThe absolute lymphocyte count of CS patients was significantly lower than that of controls, while the total WBC and the absolute neutrophil counts were significantly higher. These changes correlated with several markers of CS severity and improved after resolution of hypercortisolemia. Infections were identified in 35 patients (17.8%), and their presence correlated to elevated serum morning cortisol, midnight cortisol, and urinary free cortisol levels, as well as with the decrease in absolute lymphocyte count.ConclusionsChildren with endogenous CS have abnormal WBC counts, which correlate with the severity of CS, and normalize after cure. Infections are common in this population; clinicians should be aware of this complication of CS and have low threshold in diagnosis and treating infections in CS.
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http://dx.doi.org/10.1038/pr.2017.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866174PMC
February 2018

Motivations, enrollment decisions, and socio-demographic characteristics of healthy volunteers in phase 1 research.

Clin Trials 2017 Oct 8;14(5):526-536. Epub 2017 Aug 8.

4 The Department of Medical Ethics & Health Policy, University of Pennsylvania, Philadelphia, PA, USA.

Background/aim: Phase 1 trials with healthy volunteers are an integral step in drug development. Commentators worry about the possible exploitation of healthy volunteers because they are assumed to be disadvantaged, marginalized, and inappropriately influenced by the offer of money for research for which they do not appreciate the inherent risks. Yet there are limited data to support or refute these concerns. This study aims to describe the socio-demographic characteristics, motivations, and enrollment decision-making of a large cohort of healthy volunteers.

Methods: We used a cross-sectional anonymous survey of 1194 healthy volunteers considering enrollment in phase 1 studies at Pfizer Clinical Research Units in New Haven, CT; Brussels, Belgium; and Singapore. Descriptive statistics describe motivations and socio-demographic characteristics. Comparisons between groups were examined.

Results: The majority rated consideration of risks as more important to their enrollment decision than the amount of money, despite reporting that their primary motivation was financial. Risk, time, money, the competence and friendliness of research staff, and contributing to medical research were important factors influencing enrollment decisions for most participants. The majority of healthy volunteers in this cohort were male, single, reported higher than high school education, and 70% had previous research experience. Many reported low annual incomes (50% below USD$25,000) and high rates of unemployment (33% overall). Nonetheless, risk as an important consideration, money, and other reported considerations and motivations, except for time, did not vary by income, employment, education, or previous experience. There were regional differences in both socio-demographic characteristics and factors important to participation decisions.

Conclusion: Healthy volunteers in phase 1 studies consider risks as more important to their enrollment decisions than the amount of money offered, although most are motivated to participate by the offer of money. Healthy volunteers are indeed low income, disproportionately unemployed, and have significant prior research experience. Yet these factors do not appear to affect either their motivations for participation or factors important to their research enrollment decisions.
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October 2017

Phase 1 healthy volunteer willingness to participate and enrollment preferences.

Clin Trials 2017 Oct 2;14(5):537-546. Epub 2017 Aug 2.

1 Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Background/aims: Healthy volunteers in phase 1 clinical trials contribute to the development of safe drugs and other biologics and accept risks and burdens without anticipated health benefits from participation. Although emerging data have shown that healthy volunteers are influenced by risk, some still worry that financial incentives lead them to take on unreasonable risk. Yet little is known about healthy volunteers' preferences and how they make choices about enrolling in research studies.

Methods: We surveyed 654 healthy volunteers at the end of their participation in a phase 1 Pfizer trial in the United States, Belgium, and Singapore to examine their reported willingness to enroll in studies of different types, with various procedures, and with possible side-effects.

Results: The majority of respondents were willing to join many kinds of studies, but fewer were willing to participate in first-in-human vaccine studies or studies of psychiatric drugs than in other study types. With regard to procedures, a substantial proportion were unwilling to participate in studies that involved invasive procedures, such as a lumbar puncture (45.4%) and bone marrow biopsy (42.3%), but willing to participate in studies with less invasive procedures such as a computed tomography scan of the heart (86.8%), magnetic resonance imaging (87.4%), and skin allergy testing (86.8%). Although there was some variation by gender and region, the majority were willing to participate in studies with side-effects like pain (80%) or nausea and vomiting (64%), but only a minority were willing to join if the research drug would result in their having a one in a million chance of death (34.4%), a small chance of kidney damage (16.7%), or influence how their mind works (23.2%; Figure 4).

Conclusion: Our results suggest that healthy volunteers are willing to participate in a wide range of types of phase 1 clinical trials, and express preferences for low risk and familiar studies and study procedures, preferences which are partially affected by offers of payment.
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http://dx.doi.org/10.1177/1740774517722131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010312PMC
October 2017