bluuebunny/crossref_metadata_2025 huggingface dataset:
Methadone Maintenance Treatment, Sex Hormones and Low Bone Density in a Population of Injection Drug Users
Authors: Wehbeh Leen , Diaz Jenny Pena , Moseley Kendall Ford , Piggott Damani , Dobs Adrian Sandra , Brown Todd Tarquin
Published: May 2021

Background: Methadone maintenance treatment (MMT) is associated with low bone mineral density (BMD) in those treated for opioid addiction. However, it is unclear whether observed adverse effects on the skeleton are related to a direct effect of opioids on bone metabolism or mediated by other mechanisms including MMT-induced gonadal dysfunction. We hypothesized that MMT is associated with low BMD in persons with a history of injection drug use (PWID) and that this effect is explained by differences in sex hormones.

Methods: We recruited 280 participants from the AIDS Linked to the Intravenous Experience (ALIVE) study, a long-standing cohort of PWID. All participants had been exposed to hepatitis C virus (HCV antibody positive). In addition to a morning assessment of free testosterone (FT) and estradiol (E2), all participants underwent dual-energy x-ray absorptiometry (DXA) of the lumbar spine (LS) and hip (total hip (TH) and femoral neck (FN)). Multivariable linear regression was used to assess the relationship between MMT and T-score with and without inclusion of E2/FT concentrations. Models were stratified by sex and adjusted for age, BMI, HCV infection, HIV, current alcohol use, current smoking, vitamin D3 level, and current heroin use.

Results: All participants were African American and 37% female. The median (Q1, Q3) age was 57 years (51, 61), median (Q1, Q3) BMI was 26 kg/m2 (22, 30) and 107 (38%) were receiving MMT. FT and E2 were significantly lower in men receiving MMT vs not (p < 0.01 for both). In women, there were no differences in sex hormones based on MMT use. The prevalence of low BMD (defined as LS, TH, or FN T-score ≤ -1) was 25% (23% in men and 29% in women; p = 0.3); 12 (4.3%, 2 men and 8 women; p = 0.09) had osteoporosis (T-score ≤ -2.5). In men, MMT was associated with -0.7 lower LS-T score (95% CI [-1.3, -0.1], p=0.046) in adjusted models compared to those not receiving MMT. The magnitude of this association was reduced after adjusting for E2 and FT (-0.2, 95% CI [-0.8, 0.5], p=0.665)). In women, MMT was not associated with LS-T score (MD -0.3, 95% CI [-1.3, 0.4], p=0.631). There were no associations between MMT and TH or FN BMD in either men or women.

Conclusion: In this study, MMT was associated with lower lumbar spine BMD in men with a history of IDU, which was potentially mediated by the effect of MMT on sex hormones. More rigorous screening for co-morbidities including hypogonadism and low BMD in men receiving MMT may be warranted.
Appropriate Cutoff for 25OHD Levels in the Diagnosis of Normocalcemic Primary Hyperparathyroidism (NPHPT): A Systematic Review
Authors: Yedla Niharika , Wang Xiangbing David
Published: May 2021

Introduction: The Fourth International Workshop in 2014 delineated guidelines for the diagnosis of NPHPT which include ruling out secondary causes of hyperparathyroidism, and recommended cutoffs for 25 vitamin D (25OHD) to be ≥20ng/mL. Keeping in mind that the exact levels to optimize 25OHD in hyperparathyroid states are unknown, we aim to review possible variation in the prevalence of NPHPT if 25OHD cutoffs were to be raised to rule out vitamin D deficiency with more specificity. Methods: A PubMed search was conducted with key words “normocalcemic primary hyperparathyroidism” to review studies about NPHPT and 25OHD status. 533 articles were found, and 127 articles were identified by title/abstract screening with year of publication between 2014 to 2020. Ten studies were identified for the systematic review based on full text review for relevance. Results: Studies have been conducted in various countries across all continents to characterize NPHPT further. 5/10 studies used 25OHD cutoff of ≥20ng/mL and 4 studies had a cutoff of ≥30ng/mL and 1 study looked into the difference in prevalence with both cutoffs. All 3 studies from Italy used the higher cutoff. Rosario et al from Brazil reported a decrease in prevalence of NPHPT from 6.8% (25OHD≥20ng/mL) to 0.74% by supplementing those subjects to 25OHD ≥30ng/mL without any increase in serum calcium or parathyroid hormone (PTH) levels.1 Wang et al found that when total 25OHD levels were kept between 30–40 ng/mL, free 25OHD levels were actually lower compared to normal subjects.2 Conclusion: The levels of 25OHD that would define deficiency in NPHPT remain undetermined and both >20 ng/mL and >30ng/mL have been studied as cutoffs. It is well known that vitamin D insufficiency (25D 20-30ng/mL) drives up PTH and supplementation to 30-40ng/mL is required to reduce such effects. Wang et al suggest that free 25OHD levels correlate better with PTH as compared to total 25OHD and maybe a more reliable marker of 25OHD status. We suggest that a diagnostic criterion of ≥30ng/mL would be more appropriate in ruling out 25OHD deficiency in this special population. The role of free 25OHD levels in PHPT needs further evaluation. References: 1. Rosário PW, Calsolari MR. Normocalcemic Primary Hyperparathyroidism in Adults Without a History of Nephrolithiasis or Fractures: A Prospective Study. Horm Metab Res. 2019 Apr;51(4):243–247. doi: 10.1055/a-0859-1020. Epub 2019 Mar 6. PMID: 30840998. 2. Wang X, Meng L, Su C, Shapses SA. LOW FREE (BUT NOT TOTAL) 25-HYDROXYVITAMIN D LEVELS IN SUBJECTS WITH NORMOCALCEMIC HYPERPARATHYROIDISM. Endocr Pract. 2020 Feb;26(2):174–178. doi: 10.4158/EP-2019-0325. Epub 2019 Sep 26. PMID: 31557077
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

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 >3 months (TSH< 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.
Cardiovascular Events in Adult Patients With Chronic Hypoparathyroidism Treated With rhPTH(1–84) Compared With a Historical Control Cohort
Authors: Kaul Sanjiv , Ayodele Olulade , Sherry Nicole , Swallow Elyse , Mu Fan , Berman Richard , Gosmanova Elvira , Rejnmark Lars
Published: May 2021

Chronic hypoparathyroidism is associated with an increased risk of cardiovascular (CV) complications. This study investigated CV events over a period of up to 5 years in adult patients with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1–84), rhPTH(1–84), compared with a historical control cohort of patients who did not receive rhPTH(1–84). The rhPTH(1–84)-treated patient cohort was derived from the NCT00732615 (REPLACE), NCT01268098 (RELAY), and NCT01297309 (RACE) clinical trials. A control cohort of adult patients who did not receive rhPTH(1–84) or rhPTH(1–34) was selected from the US Explorys electronic medical record database (Jan 2007−Aug 2019) using selection criteria similar to the enrollment criteria used in the trials. Index date was the day after initiation of treatment for the rhPTH(1–84) cohort and the day after the first calcitriol prescription for the control cohort. The primary outcome was the risk of a composite CV event (defined as any event of cerebrovascular disease, coronary artery disease, heart failure, or peripheral vascular disease) in the rhPTH(1–84) cohort compared with the control cohort through 5 years post-index. Patients with a CV event at baseline were excluded from the analysis. Risk of a CV event was assessed in a Kaplan-Meier analysis and a Cox proportional hazards model adjusted for demographic characteristics, baseline clinical conditions, and baseline serum calcium levels. The analysis included 113 patients in the rhPTH(1–84) cohort and 618 patients in the control cohort. Patients in the rhPTH(1–84) cohort, compared with the control cohort, were younger (mean ± SD age, 47.8±12.0 vs 51.0±16.8 years; P<0.05), a higher proportion were White (94.7% vs 81.9%; P<0.01), and fewer had acute manifestations of hypoparathyroidism before the index date (22.1% vs 69.6%; P<0.001). In a Kaplan-Meier analysis, rhPTH(1–84)-treated patients had a significantly reduced risk of developing a CV event compared with patients in the control cohort (P<0.01); 3.5% of rhPTH(1–84)-treated patients and 16.3% of control cohort patients developed a CV event over the 5-year follow-up period. The adjusted hazard ratio for developing a CV event associated with rhPTH(1–84) treatment vs no rhPTH(1–84) treatment was 0.23 (95% CI, 0.07−0.74; P<0.05). This analysis is limited by differences in patient management under predefined clinical trial protocols for the rhPTH(1–84) cohort vs real-world clinical practice for the control cohort. Over 5 years, patients with chronic hypoparathyroidism treated with rhPTH(1–84) in clinical trials had a significantly reduced risk of CV events compared with a control cohort of patients who did not receive rhPTH(1–84). Further research is needed to better understand the mechanism underlying the association between chronic hypoparathyroidism and risk of developing a CV event.
Clinical Behaviors of Atypical Parathyroid Adenomas
Authors: Pearlstein Sarah S , Eric Kim , Kate Chomsky-Higgins , Khanafshar Elham , Duh Quan-Yang
Published: May 2021

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

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

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 >/= 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

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

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

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<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<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 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<0.01). Serum 25OHDTotal and m-25OHDFree levels reflected age, puberty, season, body mass index (BMI), daylight hours, and vitamin D intake (all p<0.05). The con-25OHDFree level better reflected puberty and daylight hours than did the spe-25OHDFree level (both p<0.01). The association between the 25OHDTotal level and bone parameters varied according to the BMI (interaction p<0.05). In 109 normal-weight children, the con-25OHDFree level correlated with BMC and BMD (both p<0.05), but the 25OHDTotal and 24,25-dihydroxyvitamin D3 levels were associated with BMC (both p<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.
Association Between Population Vitamin D Status and SARS-CoV-2 Related Serious-Critical Illness and Deaths
Authors: Papadimitriou Dimitrios T , Vassaras Alexandros K , Holick Michael F
Published: May 2021

Background: Vitamin-D population status may have possible unappreciated consequences to the COVID-19 pandemic. Α significant association between vitamin-D sufficiency and reduction in clinical severity and inpatient mortality from COVID-19 disease was recently shown while a recent study has claimed lower COVID-19 cases in European countries with a better vitamin D status. Aims: To further elucidate the possible role of vitamin D population status in the COVID-19 pandemic, we examined the associations between published representative and standardized population vitamin D data on European population vitamin D status and the Worldometer COVID-19 data. Methods: Data from the Worldometer on 26 European countries populated >4 million (M) were analyzed. Results: On 19-June-2020, linear regression found no correlation between published representative-standardized population vitamin-D concentrations and the total cases-recovered/M, but negative correlations predicting a reduction of 47-64-80% in serious-critical illnesses/M and of 61-82-102.4% in deaths/M, further enhanced when adapting for life expectancy by 133-177-221% if 25(OH)D concentrations reach 100-125-150 nmol/L. On 15-August-2020 these correlations were sustained indicating a truthful association, yet not proving causality. Weighted ANOVA was performed to evaluate serious-critical/M (R2=0.22) by the vitamin-D population status (deficient-D <50, insufficient-IN 50–62.5, mildly insufficient-MIN >62.5–75 and sufficient-S >75 nmol/L) and ANCOVA the deaths/M (R2=0.629) after controlling for life expectancy (R2=0.47). Serious-critical showed a decreasing trend (p<0.001) from population status D (p<0.001) to IN: 9.2%, p<0.001, MIN: 47.6%, p<0.044 and S: 100% (reference). For deaths/M the respective decreasing trend (p<0.001) was 62.9% from D (p<0.001) to IN (p<0.001), 65.15% to MIN (p<0.001) and 78.8% to S (p=0.041). Conclusions: Following the Endocrine Society’s expert committee recommendations, without previous testing being necessary, reaching and maintaining a serum 25(OH)D of 100–150 nmol/L (40–60 ng/ml) could be achieved by an initial supplementation with the upper tolerable daily intake doses (IU/day) for up to two months: <1yr 2000, 1-18yrs 4000 and all adults 10,000 (obese x 2–3 times more) and then with the maintenance proposed doses that do not require medical supervision, practically identical with the IOM’s upper tolerable limits: 1000 <6m, 1500 6m-1yr, 2500 1-3yrs, 3000 4-8yrs, and 4000 >8yrs, with adults and adolescents requiring 4000–5000 (obese x 2). Vitamin D may not prevent SARS-CoV-2 from spreading but may protect, without any risk of toxicity, from serious-critical illness and death from COVID-19 disease. While awaiting well-designed prospective studies, following the proposed approach, the gain for global public health and not only against SARS-CoV-2 may just prove invaluable.
Increasing Pediatric Hospitalizations With Severe Vitamin D Deficiency: A Concerning Trend
Authors: Carlton Jared , Lahoti Amit
Published: May 2021

Background: Deficiency of vitamin D can lead to multiple health issues in children. Though it can be asymptomatic in early stages, it can lead to symptomatic illnesses if severe/ prolonged including seizures and rickets. Deficiency can be prevented by adequate dietary vitamin D intake with/without supplementation in those at higher risk. However, there has been a recent reemergence and increase in the incidence of vitamin D deficiency in European nations, noted as early as 2008 and at least upto 2018. Hence, we performed a 10 year retrospective study of severe vitamin D deficiency in hospitalized patients at a Children’s Hospital in USA.

Methods: Electronic medical record was searched to identify patients with the following inclusion criteria: admitted at our hospital between 1/1/2010 and 12/31/2019 and had a 25-OH vitamin D (25-OH D) level <13 ng/mL with/without hypocalcemia or had a diagnosis of rickets. The study was approved by our institutional review board and consent was waived. Patient demographics, medical history and data on laboratory results, treatment given were extracted. We then ran a summative analysis of most of the data collected, analyzed trends for the number of admissions per year and the response time of calcium levels.

Results: Between 1/1/2010 and 12/31/2019, there were 109 hospital admissions with 25-OH D deficiency with or without hypocalcemia. Median 25-OH D level was 9.7 ng/mL. Admissions per year increased from 2010 to 2019 as follows: 2 in 2010, 5 in 2011, 4 in 2012, 6 in 2013, 6 in 2014, 7 in 2015, 12 in 2016, 13 in 2017, 23 in 2018, 25 in 2019. Median patient age was 27 months (range 0,228). Of those </=1 year (n=39), 13% were preterm, 38% were exclusively breastfed and 44% were formula fed. Ninety percent of these infants were not receiving vitamin D supplementation prior to hospitalization. Of the entire cohort of 109 patients, 63% were males and race distribution was as follows: 13% were White, 77% were Blacks and 10% were others. Seventy percent patients were on state sponsored insurance. About 33% had some diet restrictions/ peculiarities, 40% had a presenting complaint related to hypocalcemia including seizures, while 44% had hypocalcemia but it was not their primary reason for presentation. Seventy eight percent patients had hypocalcemia. Of the patients with initial calcium <7.5 mg/dL (n=64), it took a median of 72 hours (range 7,468) to improve to >/= 7.5 mg/dL.

Conclusions: Our hospital has witnessed a significant increase in severe vitamin D deficiency in admitted patients between 2010 and 2019. A large proportion of these were Blacks, on state sponsored insurances and infants not on vitamin D supplementation. Greater than 3/4th of patients had hypocalcemia and over 50% patients had hypocalcemia that required a median of 3 days to correct. This is a concerning trend of an often easily preventable morbidity and another health issue that highlights disparities in our health system.
Lack of Association Between 25-Hydroxyvitamin D Level and Outcomes in Hospitalized Indian Patients With COVID-19
Authors: Jevalikar Ganesh , Sharma Rutuja , Farooqui Khalid J , Singh Anshu , Budhiraja Sandeep , Dewan Arun , Mithal Ambrish
Published: May 2021

Vitamin D deficiency (VDD) is thought to play a role in determining the outcomes of COVID-19. India has a high prevalence of VDD. We hypothesized that VDD as measured by serum 25-hydroxyvitamin D (25OHD) <20 ng/mL is associated with severe COVID-19 infection. Outcomes were assessed by the WHO ordinal scale for clinical improvement (OSCI)1, the need for oxygen therapy, admission to an intensive care unit (ICU), and inflammatory markers. The diagnosis of COVID-19 was proven by RT-PCR on the nasopharyngeal swab for SARS-CoV2. Serum 25OHD and PTH were measured in addition to the standard protocol for COVID-19. Clinical and laboratory data were extracted from electronic medical records and analyzed using SPSS v22.0. Patients with OSCI score < 5 were classified as mild and ≥5 as severe disease. The study was approved by the Institutional Ethics Committee. A total of 410 patients (127 females, 9 pediatric, 17 asymptomatic) were included with a median age of 54 years (6–92 years) with 272(66.3%) having at least one co-morbid condition, including diabetes (190, 46.3%) and hypertension (164,40%). Patients with VDD (197,48%) were significantly younger (46.7±17.1 vs. 57.8±14.7 years) and had lesser prevalence of diabetes and hypertension (39.1% vs 52.4%, 29.4% vs 49.5%). Proportion of severe cases (26,13.2% vs. 31,14.6%), mortality (4, 2% vs. 11, 5.2%), oxygen requirement (68,34.5% vs.92,43.4), ICU admission (29, 14.7% vs. 42, 19.8%), need for inotropes (7,3.6% vs.12,5.7%) was not significantly different between patients with VDD and those with normal 25OHD level. The proportion of severe cases was similar across all 25OHD categories. There was no significant correlation between 25OHD levels and outcome OSCI, inflammatory markers (CRP, IL-6, D-dimer, ferritin, LDH). PTH levels positively correlated with D-dimer (r 0.117, p- 0.019), ferritin (r 0.132, p-0.010) and LDH (r0.124, p-0.018). Amongst VDD patients, 128(64.9%) were treated with cholecalciferol with a median dose of 60000 IU. The proportion of severe cases, oxygen, or ICU admission was not significantly different in the treated vs. untreated group. In conclusion, baseline levels of 25OHD did not determine the severe clinical outcomes of COVID-19 or levels of inflammatory markers. Treatment with cholecalciferol did not make any difference to the clinical outcomes of those with VDD. Reference:1WHO R&D Blueprint, novel Coronavirus. Retrieved from: https://www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf
The Impact of Glucose Tolerance States on Bone Mineral Density and Fracture Rate
Authors: Villacreses Maria Chang , Panjawatanan Panadeekarn , Karnchanasorn Rudruidee , Ou Horng-Yih , Feng Wei , Samoa Raynald , Chuang Lee-Ming , Chiu Ken C
Published: May 2021

It is generally acknowledged that fracture rate is higher in diabetic subjects than non-diabetic subjects. However, the impact of diabetes on bone is less clear due to contradictory results of bone mineral density (BMD) and fracture rate. To date, most of reports were based on the studies from relatively small sample sizes. To clarify the issues, we examined the fracture rates and BMD across a spectrum of glucose tolerance in a representative US population.

The participants of the National Health and Nutrition Survey 2005–2010 were used in this study. Among adult subjects (age≥20 years old) with reported BMI, we were able to define the states of glucose tolerance in 31,073 subjects cording to the diagnostic criteria based on HbA1c, fasting glucose, and/or 2-h post-changed glucose with established diabetes and using diabetes medications, into normal glucose tolerance (NGT), abnormal glucose tolerance (AGT), and diabetes mellitus (DM). Those who received osteoporosis medications were excluded from BMD analysis. Fracture information was available in 15,547 subjects; validated hip BMD was available in 12,317 subjects; and validated lumbar spine BMD was available in 10,329 subjects. Fracture rates were compared among 3 groups of glucose tolerance states and odds ratio (OR) with 95% confidence intervals (95% CI) were calculated in reference to the NGT group with sample weighting. BMD was compared among 3 groups of glucose tolerance with consideration of covariates.

The reported osteoporosis diagnosed rate differed among 3 groups of glucose tolerances (3.99%, 5.77%, and 8.41%, P<0.001, for NGT, AGT, and DM respectively). Worsening states of glucose tolerance were associated increased fracture OR at Hip [AGT, 2.1770 (95% CI: 2.1732–2.1807) and DM, 2.7369 (95% CI: 2.7315–2.7423)], spine [AGT, 0.9924 (95% CI: 0.9912–0.9936); DM, 1.2405 (95% CI: 1.2387–1.2423)]. In contrast, a different trend was observed on the wrist fracture rate [AGT, 0.9556 (95% CI: 0.9551–0.9562); DM, 0.9053 (95% CI: 0.9045–0.9060)]. After adjustment for covariates, higher BMD was noted in AGT and DM when compared to NGT at total femur (NGT, 0.9760±0.0015 gm/cm2; AGT, 0.9853±0.0021 gm/cm2; DM 0.9847±0.0034 gm/cm2, mean±SE, P=0.001) and femoral neck (NGT, 0.8388±0.0015 gm/cm2; AGT, 0.8474±0.0020 gm/cm2; DM, 0.8496±0.0032 gm/cm2, P=0.0007) while no difference was found in lumbar spine BMD (NGT, 0.1.0441±0.0018 gm/cm2; AGT, 1.0406±0.0025 gm/cm2; DM, 1.0464±0.0041 gm/cm2, P=0.35).

Our observed significant increased fracture risk at hip (OR: 2.7369) and lumbar spine (OR: 1.2405) in DM subjects when compared to NGT subjects. DM subjects had higher BMD at total femur and femoral neck than NGT subjects while no difference was noted at lumbar spine BMD when compared to NGT subjects. Further studies are required to explore the discrepancy between the increased fracture risk with higher BMDs in diabetes.
Association Between Thyroid Hormones and Lipids Stratified by Race and Sex
Authors: Shakoor Musa , Ahmad Zahid
Published: May 2021

It has been well-established that thyroid hormones play a role in cholesterol and lipoprotein metabolism. However, there is limited data assessing the variability in the association between thyroid hormones and lipids across sex and race. We hypothesized that thyroid dysfunction is associated with changes in lipids and lipoproteins with no substantial variability in this association between races and sex. The electronic medical record of a large county hospital in Dallas, TX was queried to obtain data on all patients who had lipid panels and thyroid function tests checked on the same day from 1/1/2013 to 1/1/2018. The results were stratified into hypothyroid (TSH greater than 4.5 mcIU/L and Free T4 less than 0.8 ng/dL), hyperthyroid (TSH less than 0.5 mcIU/L and Free T4 greater than 1.8 ng/dL) and normal (TSH between 0.5 and 4.5 mcIU/L, Free T4 between 0.8 and 1.8 ng/dL). Results consistent with subclinical thyroid disease were excluded from further analysis. There were 25,290 unique results for thyroid hormones and lipid panels checked on the same day. The results were further stratified by race and sex, and the relationship between thyroid function and lipids was assessed. The correlation coefficient (r) was compared between sexes within each race for the following variables: TSH vs HDL-C, TSH vs LDL-C, TSH vs Total Cholesterol, TSH vs triglycerides, FT4 vs HDL-C, FT4 vs LDL-C, FT4 vs Total Cholesterol, and FT4 vs triglycerides. Among black males with hypothyroidism, there was a notably stronger correlation when compared to black females in the relationship between TSH vs LDL-C, and TSH vs Total Cholesterol. Specifically, the correlation coefficient of TSH vs LDL-C among Black males with hypothyroidism was 0.582, compared to 0.133 among Black females with hypothyroidism (P=0.0053). Furthermore, the correlation coefficient of TSH vs Total Cholesterol among Black males was 0.567 compared to 0.184 among Black females (P=0.016). In contrast, no difference in any of the relationships between thyroid and lipids was demonstrated between sexes amongst Whites, Asians, and Hispanics. Overall, we found differences in Black patients compared to patients of other races with regards to the association between thyroid and lipids. Specifically, it was found that Black males with hypothyroidism had a stronger positive correlation in TSH vs LDL-C and TSH vs Total Cholesterol than Black females. This type of difference between sexes was not found amongst any other race. These findings suggest that thyroid dysfunction is associated with changes in lipids, and the way these changes manifest may vary depending on the race and sex. This further highlights the importance of checking lipid panels in patients with thyroid dysfunction. Further research is needed to more clearly characterize the variation that is seen in thyroid and lipid function amongst races.
Exploring Cardio-Metabolic Effects of Liraglutide in Patients With Type 2 Diabetes Through a Proteomic Approach
Authors: Ekhzaimy Aishah Ali , Masood Afshan , Benabdelkamel Hicham , Elhassan Tasnem , Alfadda Assim A
Published: May 2021

Background: Diabetes is associated with complications that increase the risk of cardiovascular events in diabetic patients by 3 folds compared to healthy population. Liraglutide is a GLP-1 receptors agonist that showed cardiovascular benefits beside its glycemic advantage and weight reduction. The cardioprotective benefit of liraglutide in diabetic patients is unclear. Objective: To explore potential cardiovascular-protective and metabolic effects of Liraglutide treatment in patients with T2DM, through evaluation of alterations in circulatory proteins using a proteomics approach. To relate the altered proteins to identify pathways using bioinformatics and network pathway analysis. Methods: Twenty adult patients with T2DM were recruited with HbA1c of 8–11 %, on oral anti-diabetic agents or insulin in whom liraglutide was indicated, after obtaining the consent. At baseline: anthropometric measurements, basal blood for HBA1c, Renal function, creatinine clearance, lipid profile and urine in the fasting state. Then Liraglutide 1.8 mg subcutaneous once daily injection was initiated as prescribed by the treating physician. AT 3 months follow up visit post-treatment, similar parameters were measured. Primary endpoint was the reduction from baseline in HbA1c for ≥ 0.5 %. Results: Alterations in the abundance of urinary proteins, analyzed by Progenesis software, revealed statistically significant differential abundance in a total of 80 spots corresponding to 71 proteins, 14 up and 57 down (≥1.5-fold change, ANOVA, p ≤ 0.05) in the post treatment group. The proteins identified in our study are known to regulate processes related to acute phase response (APR), cellular metabolism and transport. The post treatment group demonstrated an increased abundance of proteins that included alpha-1-antitrypsin, alpha-1-antichymotrypsin, serotransferrin, transthyretin, plasma protease C1 inhibitor, adenosylhomocysteinase 3 and beta-2-glycoprotein 1. The proteins with a decrease in abundance following treatment included transthyretin, serotransferrin, haptoglobin, complement C3, retinol binding protein and ceruloplasmin. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) identified dysregulation of pathways related cellular compromise, inflammatory response, and neurological disease. It also identified the involvement of the inflammatory signalling pathways, NFκb, AKT, p38 MAPK via their interactions with interleukin 12 as the central nodes.

Conclusion: The altered proteins identified in the present study showed an increase in the APR in patients with diabetes before treatment with liraglutide which was significantly reduced in the post treatment group. Increase in the APR is known to lead to a state of chronic inflammation predisposing individuals to cardiometabolic stress and disease.