Reproducibility of in-home CFRD screening using continuous glucose monitoring and mixed meal tolerance test.

Background: Cystic fibrosis related diabetes (CFRD) is associated with insulin-remediable pulmonary decline, so early detection is critical. Continuous glucose monitors (CGM) have shown promise in screening but are not recommended by clinical practice guidelines. Little is known about the reproducibility of CGM results for a given patient. Methods: Twenty non-insulin treated adults and adolescents with CF placed an in-home CGM and wore it for two 14-day periods. Participants underwent a mixed meal tolerance test (MMTT) on day 5 of each 14-day period. Glycemic data from CGM 1 and CGM 2 were compared regarding published thresholds to define abnormality: percent time >140 mg/dL of ≥4.5%, percent time >140 mg/dL of >17.5%, and percent time >180 mg/dL of >3.4%. Results of the repeat MMTT were compared for peak glucose and 2-hour glucose thresholds: >140 mg/dL, >180 mg/dL, and >200 mg/dL. Results: For percent time >140 mg/dL of ≥ 4.5%, five of 20 subjects had conflicting results between CGM 1 and CGM 2. For percent time >140 mg/dL of >17.5% and >180 mg/dL of >3.4%, only one of 20 subjects had conflicting results between CGM 1 and CGM 2. On the MMTT, few participants had a 2-hour glucose >140 mg/dL. Peak glucose >140 mg/dL, 180 mg/dL, and 200 mg/dL were more common, with 10-37% of participants demonstrating disagreement between CGM 1 and CGM 2. Conclusions: Repeated in-home CGM acquisitions show reasonable reproducibility regarding the more stringent thresholds for time >140 mg/dL and >180 mg/dL. More data is needed to determine thresholds for abnormal mixed meal tolerance tests in CFRD screening.

Endocrine complications after solid-organ transplant in cystic fibrosis.

In individuals with cystic fibrosis (CF), severe pulmonary or liver disease is frequently addressed with lung or liver transplant, respectively. Specific endocrine co-morbidities including diabetes mellitus, osteoporosis, and adrenal insufficiency accompany solid organ transplant and may be particularly problematic in individuals with CF, who are already at increased risk of diabetes and compromised bone health. Diabetes and osteoporosis screening and initiation of appropriate preventive measures are recommended prior to transplant. We review the existing data to provide practitioners with guidance regarding management of these endocrine conditions post-transplant. Further studies are needed to establish appropriate screening strategies and treatment regimens for endocrine complications of solid organ transplant in patients with CF.

Cystic fibrosis related diabetes: Nutrition and growth considerations.

Nutritional considerations are crucial to the optimal management of cystic fibrosis related diabetes (CFRD). The development of abnormal glucose tolerance and CFRD can have negative effects on CF nutritional status. Treatment of CFRD with insulin replacement is essential; however, medical nutrition therapy is important to maintain nutritional status while normalizing blood glucose levels. CF Foundation Nutritional Guidelines are recommended for the nutritional management of CFRD; specifically, the diet should be high in calories, protein, fat, and salt. Carbohydrate intake is not limited, but carbohydrate counting can be used to guide insulin dosing and maintain consistent blood glucose levels. CFTR modulator therapy shows early promise for the improvement of growth and nutritional parameters in CF.

Puberty in cystic fibrosis.

Historically, delayed puberty was considered a common clinical feature of cystic fibrosis (CF). More recent reports have documented normal pubertal progression in the majority of individuals with CF. However, youth with more severe disease are still at risk for delayed puberty. Careful evaluation of pubertal development in children and adolescents with CF is important as pubertal timing impacts linear growth, bone mineral accrual, body image and psychosocial wellbeing, all of which can also be impacted directly by CF. This article reviews the physiology of puberty, timing of puberty in CF, evaluation of pubertal development, and the differential diagnosis, evaluation, and management of delayed and precocious puberty in people with CF.

Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients.

BACKGROUND: Hepatic steatosis is a common form of cystic fibrosis associated liver disease (CFLD) seen in an estimated 15%-60% of patients with cystic fibrosis (CF). The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown. In the general population, hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes. Cystic fibrosis related diabetes (CFRD) impacts 40%-50% of CF adults and is characterized by both insulin insufficiency and insulin resistance. We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes. AIM: To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF. METHODS: Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study. Only pancreatic insufficient patients with CFRD or normal glucose tolerance (NGT) were included. Patients with established CFLD, end stage lung disease, or persistently elevated liver enzymes were excluded. Mean magnetic resonance imaging (MRI) proton density fat fraction (PDFF) was obtained for all participants. Clinical characteristics [age, sex, body mass index, percent predicted forced expiratory volume at 1 s (FEV1), lumacaftor/ivacaftor use] and blood chemistries were assessed for possible association with hepatic steatosis. Hepatic steatosis was defined as a mean MRI PDFF > 5%. Patients were grouped by diabetes status (CFRD, NGT) and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use (lumacaftor/ivacaftor, no lumacaftor/ivacaftor) to determine between group differences. Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher's exact test. RESULTS: Twenty subjects were included in the final analysis. The median age was 22.3 years (11.3-39.0) and median FEV1 was 77% (33%-105%). Twelve subjects had CFRD and 8 had NGT. Nine subjects were receiving lumacaftor/ivacaftor. The median PDFF was 3.0% (0.0%-21.0%). Six subjects (30%) had hepatic steatosis defined as PDFF > 5%. Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor (median, range) (2.0%, 0.0%-6.4%) than in patients not receiving lumacaftor/ivacaftor (4.1%, 2.7-21.0%), P = 0.002. Though patients with CFRD had lower PDFF (2.2%, 0.0%-14.5%) than patients with NGT (4.9%, 2.4-21.0%) this did not reach statistical significance, P = 0.06. No other clinical characteristic was strongly associated with hepatic steatosis. CONCLUSION: Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis. No association between CFRD and hepatic steatosis was found in this cohort.

Challenges in the diagnosis and management of disorders of sex development.

Disorders of sex development (DSD) represent a spectrum of uncommon but very complex disorders with medical, psychosexual, and family implications for those affected by them. The diagnosis and management of these disorders requires a coordinated team of multiple specialists. Following an international conference in Chicago in 2005, a consensus statement was created and presented, which has resulted in a new paradigm in the nomenclature, classification, and management of DSDs. Since that time, many improvements have been forthcoming, most notably in the area of molecular genetic technologies. These developments have advanced our understanding of the specific etiologies underlying many of these conditions. In this article, we present an overview of the physiology of sex development, a few clinical vignettes highlighting specific pathologic conditions, discussions regarding the evaluation and management of these disorders, and some thoughts on future directions in this field. Birth Defects Research (Part C) 108:293-308, 2016. © 2016 Wiley Periodicals, Inc.

A Rare Case Report of Immobility-Induced Hypercalcemia in an Infant.

Immobility-induced hypercalcemia is a rare cause of hypercalcemia in children, and to our knowledge it has never been reported in an infant. Infants and children are in a state of high bone turnover. Therefore, they are prone to the imbalance of osteoblastic and osteoclastic activity that occurs with prolonged immobilization, leading to hypercalcemia. Here we present the case of an infant with hypercalcemia who presented with fatigue, irritability, and failure to thrive after prolonged immobilization. Therapeutic interventions were conservative and included hydration and increased mobility leading to complete resolution. This case highlights the importance of including this rare entity in a differential diagnosis of hypercalcemia as well as screening postsurgical patients with prolonged immobility for hypercalcemia.

Postnatal Pancraniosynostosis in a Patient With Infantile Hypophosphatasia.

Hypophosphatasia is a rare metabolic bone disorder that predisposes patients to craniosynostosis. Typically, patients born with hypophosphatasia will exhibit fused cranial sutures at birth. This is the first reported case of delayed onset of pancraniosynostosis in a patient with infantile hypophosphatasia. The severity of onset and delayed presentation in this patient are of interest and should give pause to those care providers who treat and evaluate patients with hypophosphatasia.

Quantifying wheelchair activity of children: a pilot study.

OBJECTIVE: The purpose of this study was to investigate mobility-related wheelchair activity of children in their community setting. DESIGN: Mobility-related wheelchair activity data from 18 community-dwelling children (9 manual and 9 electric powered) were collected using custom-designed data logging devices. The children were between 8 and 17 yrs of age and independently used a wheelchair as their primary means of mobility. A data logging device was installed on their wheelchair for 7 days. However, because the device was attached and removed at different times of the day, the first and last days of the study period were not analyzed. Therefore, a total of 5 days of data were used to investigate wheelchair activity. RESULTS: Overall, the children who used manual wheelchairs traveled on an average of 1602.31 m/day (SD, 976.78) at a speed of 0.67 m/sec (SD, 0.12), and the children who used electric-powered wheelchairs drove 1752.42 m/day (SD, 835.14) at a speed of 0.75 m/sec (SD, 0.35). It was also calculated that the average daily number of starts/ stops per thousand meters the manual and electric-powered wheelchair users completed were 166.77 (SD, 64.32) and 112.53 (SD, 62.27), respectively. A comparison of mobility-related wheelchair activity revealed a significant (P = 0.008) difference in the average daily distance traveled between genders, with the boys traveling further than the girls. CONCLUSIONS: The mobility data obtained from the children wheelchair users suggest that one possible factor of variability among wheelchair activity is between genders. The data collected provide us with direction for future research in this area.

Genetic control of pubertal timing.

PURPOSE OF REVIEW: Puberty is an important developmental and life stage that leads to sexual maturation and reproductive capability. Although the physiology of puberty is similar among individuals, the timing of puberty is quite variable and affected by environmental and genetic influences. Identification of the responsible genetic factors will greatly enhance the understanding of the key components and the modulation of the hypothalamic-pituitary-gonadal axis. RECENT FINDINGS: Genetic analyses are increasingly elucidating the genetic basis of pathological abnormalities in pubertal timing, including causes of idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Ongoing studies are also investigating the genetic control of puberty in the general population, although no definitive association between genetic variants and variations in pubertal timing has been discovered so far. SUMMARY: This review summarizes recent advances regarding the genetic control of pubertal timing and presents areas for future investigation.

Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation.

The cellular and molecular mechanisms underlying the blunted allo-responsiveness of umbilical cord blood (UCB) T cells have not been fully elucidated. Protein expression of NFATc2 (nuclear factor of activated T cells c2), a critical transcription factor necessary for up-regulation of multiple cytokines known to amplify T-cell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purified CD4+ UCB T cells to adult peripheral blood CD4+ T cells (AB) at baseline, 6, and 16 hours of primary stimulation. NFAT-regulated genes exhibited lower expression in UCB CD4+ T cells including the following: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor alpha (IL-2Ralpha; CD25), CD40L, and macrophage inflammatory protein 1 alpha (MIP-1alpha). Transcription factors involved in the NFAT pathway including C/EBPbeta, JunB, and Fosl1 (Fra-1), as well as Th1- and Th2-related transcription factors STAT4 (signal transducers and activators of transcription 4), T-bet, and c-maf showed reduced expression in UCB compared with AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data were confirmed using RNase protection assays, flow cytometry, and quantitative multiplexed cytokine measurements. Reduced global expression of NFAT-associated genes, as well as cytokines and chemokines, in UCB CD4+ T cells may contribute to the decreased graft-versus-host disease (GVHD) observed after UCB transplantation.

Deficient IFN-gamma expression in umbilical cord blood (UCB) T cells can be rescued by IFN-gamma-mediated increase in NFATc2 expression.

Regulation of nuclear factor of activated T cells-c2 (NFATc2) gene expression is not clearly defined. We previously reported reduced NFATc2 protein expression in cord blood T lymphocytes. Here we show that NFATc2 expression in T cells is dependent in part on the presence of IFN-gamma during primary stimulation, as blocking of IFN-gamma blunted NFATc2 protein and mRNA upregulation. Conversely, addition of exogenous IFN-gamma during stimulation resulted in increased expression of NFATc2 in cord blood T lymphocytes. This correlated with rescue of deficient IFN-gamma expression by cord blood T cells. Rescue of IFN-gamma expression in cord blood T cells was dependent on the presence of antigen-presenting cells, as addition of IFN-gamma during stimulation of purified cord blood T cells did not result in an increase of IFN-gamma expression, and depletion of monocytes ablated the rescue of IFN-gamma expression. Our results point to impaired function in the antigen-presenting cell population of cord blood, playing a role in the hyporesponsiveness of T cells.

Integrated control and related technology of assistive devices.

Assistive devices are now available that allow persons with severe physical disabilities to complete tasks independently. When the user has severe physical limitations, it may be advantageous to have an integrated control system where a single control interface (e.g., joystick, head switches, voice recognition system, keypad) is used to operate two or more assistive devices (e.g., power wheelchairs, augmentative communication devices, computers, environmental control units, and other devices that are controlled electronically). The advantages of integrated control are that persons with limited motor control can access several devices with one access site without assistance, and the user does not need to learn a different operating mechanism for each device. The purpose of this review is to convey the depth and breadth of the research that has been conducted on integrated control systems, as well as to provide some insights into future directions. We reviewed research works pertaining to communication and environmental control, computer access, and wheelchair guidance systems. Information gathered in this study will help people become fully aware of the status of contemporary integrated control technology in order to increase the quality of life of people who use electronic assistive devices.