bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Microarchitectural Changes in Hyperthyroid Women Compared to a Normal Canadian Cohort
Authors: Arnason Terra G , Cooper David , Behdani Reza , Kontulainen Saija 
Published: May 2021

Abstract
Thyroid hormones play a critical role in bone physiology during childhood, but also impacts adult bone metabolism. Hyperthyroidism promotes accelerated bone turnover and bone remodelling which is associated with net loss of bone mineral density over time (BMD) and these changes have been quantitated using the gold standard of measuring BMD, Dual Energy X-ray Absorptiometry (DEXA). Ordinarily, biochemical thyroid hormone normalization restores BMD towards normal, yet an increased risk of fractures remains lifelong. DEXA, therefore, cannot explain the underlying etiology for fracture risk which may be due to undetected changes in bone microarchitecture. Our primary objective was to utilize an investigational 3-dimensional bone imaging technology, High Resolution peripheral Quantitative Tomography (HR-pQCT), to study bone microarchitecture in actively hyperthyroid women to determine if there are changes in cortical and trabecular bone microarchitecture from that of age-matched controls. A subset of women were rescanned using HR-pCT after thyroid hormones had been normalized for at least 6 months to determine if there were cortical/trabecular architectural changes that reversed towards normal in these individual cases.
We enrolled 20 hyperthyroid women (age 20–76) for this pilot study who had persistent TSH suppression for &gt;3 months (TSH&lt; 0.5, normal range: 0.5–4.49 mU/L) without secondary causes for bone loss. Their etiology was divided amongst TSH suppression for thyroid carcinoma, Grave’s disease and iatrogenic hyperthyroidism. HR-pQCT scans of the radius were compared to age-matched scans of normal females, available from the robust Canadian Multicentre Osteoporosis Study (CaMOS) control cohort. Four participants were re-scanned after 6 months of TSH normalization to assess reversibility. The observed data showed statistically significant differences in key parameters of bone microarchitecture in hyperthyroidism, independent of etiology. We observed decreased cortical thickness and increased failure load as statistically different from age-matched controls. Increases in cortical bone porosity and decreases in volumetric bone density (cortical, trabecular and total) were notable but did not reach significance in this small study. Repeat scans following normalization of thyroid hormone levels revealed consistent (partial, nonsignificant) normalization of multiple bone microarchitecture elements including increased trabecular number/thickness, and decreased cortical porosity. These findings suggest that there are changes in both cortical and trabecular bone during active hyperthyroidism that may contribute to increased lifelong fracture risk.
Clinical Behaviors of Atypical Parathyroid Adenomas
Authors: Pearlstein Sarah S , Eric Kim , Kate Chomsky-Higgins , Khanafshar Elham , Duh Quan-Yang 
Published: May 2021

Abstract
Background: Atypical parathyroid adenoma is a rare entity that share some pathology features of parathyroid carcinoma such as fibrosis. Little is known about the clinical behavior of atypical parathyroid adenomas. Pathologically, it is defined as a hypercellular parathyroid lesion with intratumoral banding fibrosis, mitotic figures, trabecular growth and presence of tumor in the surrounding capsule but lacks unequivocal evidence of invasion, such as invasion to peritumoral vessels, perineural invasion and surrounding structures.
Methods: A retrospective study of 15 consecutive patients with atypical parathyroid adenoma treated at a single center between 2010 and 2020 was performed. Patient demographics, clinical characteristics, biochemical profile, indications for surgery, preoperative localization studies, intraoperative findings, histopathological characteristics, disease recurrence or persistence and survival were collected.
Results: 7 of 15 were female with a median age of 62 (IQR: 52–67). Five of the 15 patients (33%) were re-operative. No patients presented with palpable neck mass. Presentations were consistent with usual primary hyperparathyroidism. Average calcium on presentation was 11.2, and average PTH was 199. One patient had known MEN1 syndrome and one patient had family history of hyperparathyroidism but had negative genetic testing. Most patients 12/15 had correctly localizing imaging pre-operatively with the other 3 having equivocal or non-localizing studies. Two patients did not have biochemical resolution of hyperparathyroidism, both were re-operative. Of the patients with biochemical cure, 6 did not have follow up beyond 6 months, and 7 patients had long term follow up with persistent biochemical resolution and no recurrence of disease for a median of 4 years (IQR: 3.75–9.25). On review of pathology, no patients had invasive features and all patients had presence of thick fibrous bands or capsule.
Conclusion: Patients with atypical adenoma have good response to surgery and low recurrence rates. Reoperation with associated scarring and fibrous bands can confound pathological findings. Our experience shows that patients found to have atypical parathyroid adenoma at their primary operation with resulting biochemical cure can be followed long-term with seemingly indolent and nonaggressive behavior.
Hip Geometry Variation in Homozygous Ectonucleotide Pyrophosphatase/ Phosphodiesterase 1 (ENPP1) Deficient Patients
Authors: Theng Elizabeth H , Gafni Rachel Ilana , Ferreira Carlos R 
Published: May 2021

Abstract
ENPP1 is an important regulator of skeletal and soft tissue mineralization. Mouse models have demonstrated a link between defective ENPP1 and altered bone mineralization, including osteopenia and mild osteomalacia. In humans, rare homozygous loss of ENPP1 leads to generalized arterial calcification of infancy (GACI), characterized by vascular, joint, and organ calcification, hypophosphatemic rickets/osteomalacia, and skin and retinal findings. Heterozygous ENPP1 deficiency has been described in early-onset osteoporosis and an ENPP1 polymorphism was found to be strongly associated with variation in hip geometry, as measured by DXA hip structural analysis (HSA). However, the overall skeletal phenotype of ENPP1-deficiency is not well characterized in affected individuals. In addition to bone density, DXA provides surrogate information about mechanical strength, resistance to compression, tension, and buckling, offering a non-invasive and clinically accessible tool to assess hip geometry. Parameters include cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), subperiosteal width (SPW), endocortical width (ECW), cortical thickness (CT), section modulus (Z), and buckling ratio (BR)—each measured in the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS) regions. SPW and ECW increase with age and are correlated with bone fragility. In mice, CSA and CSMI are inversely correlated with bone fragility when assessed by biomechanical tests. However, the opposite correlation has been observed in patients with fractures. HSA by DXA was assessed in 7 homozygous ENPP1-deficient patients (age range 5–56 years) and in 73 sex- and age-matched controls. All ENPP1-deficient patients were hypophosphatemic, of which, 2 were receiving treatment. Given the small sample size, standardized test statistics (t-scores) were derived for 21 hip geometry parameters; comparisons between groups were performed using the Mann-Whitney test. The Benjamini-Hochberg test was used to correct for multiple comparisons with a false discovery rate (FDR) q-value threshold set at 0.15. Compared with controls, ENPP1-deficient patients had significant changes in structural and derived measures of strength. Increases were seen in NN SPW, NN ECW, and FS SPW, which are correlated with bone fragility. In contrast, the increases seen in FS CSA, FS Z, FS CSMI, and NN CSMI are associated with improved bone strength. Although a q-value threshold of 0.15 indicates that 15% (~1/7) of all significant discoveries will represent a false positive, most findings represented true discoveries. These findings suggest that ENPP1 influences bone structure and strength, supporting findings from the aforementioned ENPP1 polymorphism study describing increased SPW in the NN and FS regions. This work contributes to the nascent body of literature studying the impact of ENPP1 on skeletal homeostasis.
Hypophosphatemia Gene Panel Sponsored Program: A High Yield of Molecular Diagnoses from Clinically Confirmed XLH and Suspected Genetic Hypophosphatemia
Authors: Dahir Kathryn , Rush Eric , Beltran Daniel , Eisenbeis Scott , Johnson Britt , Ramesan Prameela , Sarafrazi Soodabeh , Truty Rebecca , Miller Nicole 
Published: May 2021

Abstract
X-linked hypophosphatemia (XLH), a dominant disorder caused by a disease-associated variant in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. XLH is one of multiple etiologies of hypophosphatemia; depending on genetic cause, management may differ. Acquired hypophosphatemia (e.g. tumor induced osteomalacia) is non-hereditary in nature. This program provides a no-charge genetic test to confirm a clinical XLH diagnosis or to aid suspected genetic hypophosphatemia diagnosis. Patients aged &gt;/= 6 months with either a clinical XLH diagnosis or suspicion of genetic hypophosphatemia, as evidenced by 2 or more clinical signs/ symptoms, were eligible for testing. The next generation sequencing panel includes 13 genes: ALPL, CLCN5, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, PHEX, SLC34A3 and VDR. Copy number variant detection was performed. 831 unrelated individuals were tested as of June 30, 2020. 569 (68.5%) of these subjects had a PHEX variant: 519 (91.2%) were either pathogenic or likely pathogenic (P/LP) and 50 (8.8%) were variants of uncertain significance (VUS). Of the 312 (37.5%) cases where no PHEX molecular diagnosis was found, 38 (12.2%) had molecular diagnoses associated with other genes/disorders: 4 had a variant (P/LP) in FGF23 (autosomal dominant [AD] hypophosphatemic rickets), 2 had two variants (P/LP) in CYP27B1 (autosomal recessive [AR] vitamin D dependent rickets), 1 had P/LP variants in ENPP1 (AR hypophosphatemic rickets Type 2). There were 27 cases with single P or LP variants in ALPL (AD hypophosphatasia, HPP); 4 cases carried two variants (P/LP) in ALPL (AR form). Of 237 unique P/LP PHEX variants detected: 59 were deletions, duplications or insertions; 37 were copy number variants; 52 were splice-site variants; 89 were single nucleotide variants. Additional family member testing/clinical information resulted in 48 cases having VUS reclassified to P/LP, highlighting the value of cascade family testing/clinical info to resolve VUS. RNA analyses to resolve VUS may further improve molecular diagnostic yield. Program results demonstrate a high diagnostic yield for XLH/ genetic hypophosphatemia and new insight into XLH-associated PHEX variants.
Improving the Accuracy and Reliability of Parathyroid Hormone Levels Through the Mass-Spectrometric Measurement of Full-length PTH and C-Terminal PTH Fragments
Authors: Ulmer Candice Z , Smith Bianca , Thonkulpitak Janet , Vesper Hubert W 
Published: May 2021

Abstract
Parathyroid hormone (PTH) is a key biomarker for hypo/hyperparathyrioidism as well as chronic kidney disease, one of the leading health conditions in the USA. As a result, the most recent update of the Kidney Disease Improving Global Outcomes (KDIGO) guideline for CKD-MBD management emphasized the role of PTH as one of the key biomarkers of this disorder. The earlier stages of CKD generate few symptoms and only until the kidney is significantly impaired do patients begin experiencing signs of renal failure. Therefore, the measurement of parathyroid hormone (PTH) in serum and/or plasma is critical not only for the correct detection, diagnosis, and prevention of renal failure, but also calcium, phosphate, and vitamin D disorders. Current laboratory methods for PTH show high variability and inaccuracy, thus creating the need for a reference measurement procedure that can help laboratories and assay manufacturers improve their measurement accuracy and reliability to avoid the misclassification of patients. Due to the short half-life of PTH, this 84 amino-acid polypeptide hormone is produced at low circulating levels in normal conditions ranging from 10 - 65 pg/mL. In addition, N-terminal and C-terminal peptides, which have shown to interfere with clinical analyzer platforms, account for over 80% of all circulating PTH levels. Therefore, a highly specific and sensitive method is needed for the accurate detection of full-length PTH and these PTH fragments. There is clinical relevancy in the ability to measure C-terminal PTH fragments as the ratio of these PTH fragments to full-length PTH has been diagnostic for severe or end-stage renal disease, non-dynamic bone disease, and hyperparathyroid-associated bone loss. Bottom-up proteomics approaches that incorporate enzymatic digestion steps during sample preparation will result in the loss of information for the fragments. Therefore, a new, innovative, top-down proteomics method was developed to measure full-length PTH and its breakdown products (fragments) by mass spectrometry (UHPLC-HRMS). This method enabled, for the first time, the detection of full-length PTH at very low concentrations typically observed in patients with hypoparathyroidism as well as C-terminal fragments that may interfere with regular immunoassays typically used in patient care. The highly specific and sensitive method for PTH and related peptides in CKD patient sera demonstrated no interference from the internal standards and other PTH fragments. Therefore, the optimized method was applied for the screening of normal and CKD serum at various stages of disease progression. Preliminary results demonstrated that certain PTH fragments are correlated with eGFR and different stages of chronic kidney diseases (CKD). This method along with the respective findings from this study will help to improve the diagnosis, treatment, and prevention of CKD-MBD.
Interrelationships Between Serum Levels of Procalcitonin and Inflammatory Markers
Authors: Oka Kosuke , Araki Jo , Yamamoto Koichiro , Hanayama Yoshihisa , Tokumasu Kazuki , Hagiya Hideharu , Obika Mikako , Ogawa Hiroko , Otsuka Fumio 
Published: May 2021

Abstract
Various laboratory markers are utilized in general practice to detect inflammation, and procalcitonin (PCT) has also been routinely measured in many patients as a marker of bacterial infection and sepsis. An increase in PCT starts before an increase in C-reactive protein (CRP), and PCT level is useful not only for the diagnosis of bacterial infection, sepsis, as an indicator of the severity and prognosis of systemic inflammatory diseases, and is also useful for determination of the response to individual treatment. PCT is a precursor of calcitonin and PCT is not produced in a healthy state but is produced by various tissues in septic conditions. Since there are many patients with elevated levels of PCT due to nonbacterial causes, the levels of serum PCT have been apt to be used for a marker for the early detection of not only bacterial infection but also many inflammatory and/or febrile disorders including fever of unknown origin (FUO) in the clinical setting of general medicine. Here we attempted to clarify the differences and similarities of inflammatory markers for a clinical setting. We retrospectively reviewed 359 patients in whom serum PCT had been measured. According to our earlier study, the patients were categorized into 7 groups: bacterial, non-bacterial infection, non-specific inflammation, neoplasm, connective tissue disease (CTD), drug-induced diseases, and unidentified causes. Data for 332 PCT-positive cases including cases of bacterial infection (20.5%), non-specific inflammation (20.8%), neoplasm (9.9%), CTD (8.4%), and non-bacterial infection (7.2%) were used for analysis. Serum PCT level was highest in the bacterial infection group (1.94 ng/ml) followed by the non-specific inflammatory group (0.58 ng/ml) and neoplastic diseases group (0.34 ng/ml). Of note, serum PCT level was positively correlated with serum levels of C-reactive protein (R2=0.39), soluble interleukin-2 receptor (sIL-2R; R2=0.48), and ferritin, plasma level of D-dimer level and white blood cell count, whereas it was negatively correlated with serum albumin level (R2=0.27), hemoglobin concentration and platelet count. The result of the strongly positive correlation with serum level of sIL-2R suggested that an increased serum PCT level may indicate not only an inflammatory state but also a neoplastic state such as malignant lymphomas in the diagnostic process of various inflammatory disorders in a clinical setting of general practice for diagnosing febrile conditions.
Total, Free and Bioavailble 25 OH D and Bone Disease in Primary Hyperparathyroidism
Authors: Santos Lívia Marcela , Ohe Monique Nakayama , Pallone Sthefanie Giovanna , Nacaguma Isabela Ohki , Silva Renata Elen Costa , Kunii Ilda Sizue , Vieira Jose Gilberto , Lazaretti-Castro Marise 
Published: May 2021

Abstract
Background: Low levels of vitamin D 25OHD are frequently described in PHP patients. The aim of this study was to evaluate bone parameters and vitamin D status in PHP patients and controls. Methods: Prior to surgery, 64 PHP patients and 63 healthy matched control subjects regarding age, gender and body mass index were enrolled in this study along 18 months. 25OHD and PTH were measured using Roche® Immunoassays. Bone mineral density (BMD) by dual X-ray absorptiometry (DXA) (Hologic QDR 4500) and TBS (InSight™) were determined in all patients and controls. Distribution of total, bioavailable and free (calculated) 25OH and its correlation with TBS and DXA in both groups was evaluated. DBP (vitamin D binding protein) SNPs genetic analysis was performed by ABI 7500 real time PCR System. None of the patients and controls were taking vitamin D supplements before the study. Results: PHP patients had lower BMD values than controls in all sites (p&lt;0.01). TBS measurements were also reduced in PHP patients compared to controls, as expected (1233 vs 1280, p=0.04). There was no statistical difference in free, total and bioavailable 25OHD measurements between the PHP and the control group, mean±SD: 3.4±1.7 vs 3.1±1.7 pg/mL (p=0.44), 22.6± 6.1 vs 20.6± ng/dL (p=0.13) 1.53±0.66 vs 1.41±0.61 ng/mL (p=0.28), respectively. Likewise, there was no statistical difference in DBP haplotypes 1s/1s, 1f/1f, 1s/1f, 2/2, 1s/2, 1f/2 analysis between groups. There was no correlation with 25OHD and DXA measurements in both groups. However, total 25OHD presented statistical significant correlation with TBS measurements in the PHP group (r=0.28; p=0.02) and total, free and bioavailable 25OHD measurements with TBS in the control group (r=0.42; r=0.42; r=0.43; p&lt;0.01). Conclusion: Vitamin D status correlates with TBS, but not with DXA, highlighting the relation of the vitamin D with the microarchitecture bone parameters in both PHP patients and controls. However, this correlation was more evident among controls than in PHP patients, spotlighting the primary hyperparathyroidism effects in bone.
A Comparison of Free and Total 25-hydroxyvitamin D Levels as Functional Indicators of Bone Health in Healthy Children
Authors: Heo You Joung , Lee Yun Jeong , Lee Kyunghoon , Kim Jae Hyun , Shin Choong Ho , Lee Young Ah , Song Junghan 
Published: May 2021

Abstract
Abstract Context: The “free hormone” hypothesis suggests that the free 25-hydroxyvitamin D (25OHDFree) level may usefully indicate bone health. Objective: To determine which vitamin D measure is optimally correlated with clinical and bone parameters in healthy children. Design and Participants: A cross-sectional study including 146 healthy children (71 boys, 9.5±1.9 years) at a tertiary medical center. Main Outcome Measures: We used a multiplex liquid chromatography-tandem mass spectrometry-based assay to simultaneously measure vitamin D metabolites. The 25OHDFree level was directly measured (m-25OHDFree) or calculated using genotype-constant or genotype-specific affinity coefficients of vitamin D-binding proteins (con-25OHDFree or spe-25OHDFree). Bone mineral content (BMC) and density (BMD) were assessed via dual-energy X-ray absorptiometry. Results: The concentrations of total 25OHD (25OHDTotal), the three forms of 25OHDFree, and 24,25-dihydroxyvitamin D3 correlated with parathyroid hormone levels (all p&lt;0.01). Serum 25OHDTotal and m-25OHDFree levels reflected age, puberty, season, body mass index (BMI), daylight hours, and vitamin D intake (all p&lt;0.05). The con-25OHDFree level better reflected puberty and daylight hours than did the spe-25OHDFree level (both p&lt;0.01). The association between the 25OHDTotal level and bone parameters varied according to the BMI (interaction p&lt;0.05). In 109 normal-weight children, the con-25OHDFree level correlated with BMC and BMD (both p&lt;0.05), but the 25OHDTotal and 24,25-dihydroxyvitamin D3 levels were associated with BMC (both p&lt;0.05). No association was found in overweight or obese children. Conclusions: In healthy children, total and free 25OHD levels comparably reflected lifestyle
factors. In normal-weight children, the con-25OHDFree level reflected BMC and BMD, whereas the 25OHDTotal level was associated with BMC.