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  • 1
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 6, No. Supplement_1 ( 2022-11-01), p. A511-A511
    Abstract: Medical treatment of acromegaly is based on either suppressing pituitary GH secretion or inhibiting GH action by preventing interaction with its receptor in order to suppress the elevated levels of IGF1. AZP-3813 is a 16-amino acid, bicyclic peptide antagonist of the GH receptor (GHR) with a KD of 1.9nM for the human GHR, and 18.5nM for the rat GHR. The circulating half-life of AZP-3813 in the rat is 11.2 hours. In previous studies, AZP-3813 was demonstrated to suppress IGF1 secretion in juvenile rats in a dose-related manner, and to maintain IGF1 suppression when given over 4 days. To examine the ability of chronic AZP-3813 treatment to maintain suppression of IGF1 levels, we injected normal, 5-week old (∼150g), male Sprague Dawley rats subcutaneously either with vehicle or with AZP-3813 at doses of either 10 or 30mg/kg QD for 19 days (n=7/group). Blood samples were collected immediately prior to either vehicle or AZP-3813 injection on days 1, 2, 3, 7, 10, 15 and 19, and 24h after the last injection (day 20). Samples were assayed for total IGF1 content by radioimmunoassay, and samples collected on days 2, 10 and 19 were also analyzed for AZP-3813 content by LC-MS/MS. At the initiation of treatment, the average body weight of the rats was 150.3 + 3.0g, and over the 20 days of the study animals treated with vehicle gained an average of 158.4 + 4.9g. In contrast, rats treated QD with 10 or 30mg/kg AZP-3813 gained 23.6 + 2.1 and 27.9 + 2.2% less weight than the vehicle-treated controls, respectively. Accumulation of AZP-3813 levels in the blood was observed with repeated daily injections of both 10 and 30mg/kg, increasing from day 2 levels by 107.1 + 12.5 and 125.2 + 36.3%, respectively, by day 19. In the vehicle-treated control rats, IGF1 levels increased from an initial 395.1 +16.3ng/ml to 674.4 + 19.8ng/ml by day 20. Twenty-four hours after the first injections of 10 and 30mg/kg AZP-3813, IGF1 levels were suppressed by 27.6 + 3.4 and 29.2 + 3.3%, respectively, versus vehicle-treated control levels, and, with continued treatment, a similar magnitude of IGF1 suppression was maintained through day 20 despite the progressively increasing levels of IGF1 observed in the vehicle-treated rats. At study termination on day 20, animals treated with 10 and 30mg/kg AZP-3813 were observed to have 4.1 and 4.6% shorter femur length, 1.1 and 3.6% shorter body length, and 7.7 and 13.3% less liver weight, respectively, as compared with vehicle-treated control rats. These results demonstrate that with continued treatment, the potent GHR antagonist activity exhibited by AZP-3813 translates to sustained in vivo suppression of IGF1 levels and associated parameters, and support its development as a potential therapy for acromegaly. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2022
    detail.hit.zdb_id: 2881023-5
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  • 2
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 5, No. Supplement_1 ( 2021-05-03), p. A259-A260
    Abstract: Objectives: Significant knowledge gaps exist regarding the clinical burden and practice patterns associated with chronic hypoparathyroidism (cHP). This study assessed the clinical burden and practice patterns in patients with cHP identified using surgery-based criteria. Methods: This retrospective cohort study was conducted using a large (130 million individuals) US claims database, the HealthVerity Closed Payer Claim Medical and Pharmacy database (Private Source 20) from Oct 2014 to Dec 2019. The patient eligibility criteria for the surgery-based method included the presence of a procedure claim of either parathyroidectomy, complete or partial thyroidectomy, or neck dissection, followed by a HP diagnosis claim (6–15 months apart) with a subsequent second HP diagnosis claim at any time point, and with continuous enrollment for 15 months before the index date (the date of the first qualifying HP diagnosis claim) and ≥6 months after. Patients were followed one year before the surgery and up to two years after the index date. Patient characteristics, comorbidities, laboratory testing and treatment patterns were descriptively analyzed. Results: A total of 1,406 patients met the eligibility criteria, among which 1,184 patients had complete data for 1-year follow-up. The mean age was 52.1 + 16.4 (SD) years, and 83.2% were females. The mean time between surgery and qualifying HP diagnosis claim was 8.7 + 2.3 (SD) months, and 115 patients (8.2%) had a HP diagnosis prior to surgery. During the 1-year follow-up, the most common comorbidities were cancer (54.2%, of which 49% were thyroid cancers), hypertension (49.7%), hypocalcemia (47.1%), chronic pulmonary disease (21.9%), diabetes (21.7%), cardiac arrhythmias (18.4%), CKD stage 3–5 (11.3%), osteoporosis (9.8%), and neuropsychiatric disorders, including anxiety (23.9%), depressive disorders (21.8%), and sleep-wake disorders (20.9%). Most cHP patients were monitored for lab values. These included serum calcium (93.2%), eGFR/creatinine (86.2%), 25-Hydroxy Vitamin D (66.5%), intact PTH (63.0%), serum magnesium (40.9%), serum phosphorous (38.4%), bone mineral density (9.8%), and 24h-urine calcium (8.4%) during the 1-year follow up. Also within the 1-year follow-up, 66.9% of patients had a prescription claim for thyroid replacement therapy, 51.6% for calcitriol, 13.3% for ergocalciferol, and 5.5 % for PTH. Conclusion: This cHP population, identified using surgery-based criteria, largely consists of patients with a recent diagnosis, and had a substantial comorbidity burden that aligned with the monitoring patterns. Already at this early stage of cHP, kidney function appears to be a key concern and may be important when considering therapeutic intervention. These data are consistent with our findings from a larger cHP population identified in the same database using a diagnosis-based approach.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
    detail.hit.zdb_id: 2881023-5
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  • 3
    In: Journal of Medical Internet Research, JMIR Publications Inc., Vol. 22, No. 12 ( 2020-12-3), p. e24286-
    Abstract: The emergence of SARS-CoV-2, the virus that causes COVID-19, has led to a global pandemic. The United States has been severely affected, accounting for the most COVID-19 cases and deaths worldwide. Without a coordinated national public health plan informed by surveillance with actionable metrics, the United States has been ineffective at preventing and mitigating the escalating COVID-19 pandemic. Existing surveillance has incomplete ascertainment and is limited by the use of standard surveillance metrics. Although many COVID-19 data sources track infection rates, informing prevention requires capturing the relevant dynamics of the pandemic. Objective The aim of this study is to develop dynamic metrics for public health surveillance that can inform worldwide COVID-19 prevention efforts. Advanced surveillance techniques are essential to inform public health decision making and to identify where and when corrective action is required to prevent outbreaks. Methods Using a longitudinal trend analysis study design, we extracted COVID-19 data from global public health registries. We used an empirical difference equation to measure daily case numbers for our use case in 50 US states and the District of Colombia as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. Results Examination of the United States and state data demonstrated that most US states are experiencing outbreaks as measured by these new metrics of speed, acceleration, jerk, and persistence. Larger US states have high COVID-19 caseloads as a function of population size, density, and deficits in adherence to public health guidelines early in the epidemic, and other states have alarming rates of speed, acceleration, jerk, and 7-day persistence in novel infections. North and South Dakota have had the highest rates of COVID-19 transmission combined with positive acceleration, jerk, and 7-day persistence. Wisconsin and Illinois also have alarming indicators and already lead the nation in daily new COVID-19 infections. As the United States enters its third wave of COVID-19, all 50 states and the District of Colombia have positive rates of speed between 7.58 (Hawaii) and 175.01 (North Dakota), and persistence, ranging from 4.44 (Vermont) to 195.35 (North Dakota) new infections per 100,000 people. Conclusions Standard surveillance techniques such as daily and cumulative infections and deaths are helpful but only provide a static view of what has already occurred in the pandemic and are less helpful in prevention. Public health policy that is informed by dynamic surveillance can shift the country from reacting to COVID-19 transmissions to being proactive and taking corrective action when indicators of speed, acceleration, jerk, and persistence remain positive week over week. Implicit within our dynamic surveillance is an early warning system that indicates when there is problematic growth in COVID-19 transmissions as well as signals when growth will become explosive without action. A public health approach that focuses on prevention can prevent major outbreaks in addition to endorsing effective public health policies. Moreover, subnational analyses on the dynamics of the pandemic allow us to zero in on where transmissions are increasing, meaning corrective action can be applied with precision in problematic areas. Dynamic public health surveillance can inform specific geographies where quarantines are necessary while preserving the economy in other US areas.
    Type of Medium: Online Resource
    ISSN: 1438-8871
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2020
    detail.hit.zdb_id: 2028830-X
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  • 4
    Online Resource
    Online Resource
    The Endocrine Society ; 2010
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 5 ( 2010-05-01), p. 2516-2516
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 5 ( 2010-05-01), p. 2516-2516
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
    detail.hit.zdb_id: 2026217-6
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  • 5
    In: Endocrinology, The Endocrine Society, Vol. 151, No. 6 ( 2010-06-01), p. 2474-2482
    Abstract: Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains α-aminoisobutyric acid substitutions replacing Ala8 and Gly35 of hGLP-1(7-36)NH2. The binding affinity [radioligand binding assay using [125I] hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably overexpressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36)NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 ± 0.2 nm) to the natural ligand (affinity constant 1.5 ± 0.3 nm) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC50 Taspo 0.06 nm and EC50 hGLP-1(7-36)NH2 0.08 nm). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36)NH2. Stimulation of insulin secretion is co ncentration dependent and evident in the presence of high-glucose concentrations (16.7 mm) with a taspoglutide concentration as low as 0.001 nm. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36)NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
    detail.hit.zdb_id: 2011695-0
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  • 6
    In: Endocrinology, The Endocrine Society, Vol. 148, No. 6 ( 2007-06-01), p. 3004-3012
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2007
    detail.hit.zdb_id: 2011695-0
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  • 7
    In: JMIR Public Health and Surveillance, JMIR Publications Inc., Vol. 7, No. 6 ( 2021-6-17), p. e24251-
    Abstract: COVID-19 transmission rates in South Asia initially were under control when governments implemented health policies aimed at controlling the pandemic such as quarantines, travel bans, and border, business, and school closures. Governments have since relaxed public health restrictions, which resulted in significant outbreaks, shifting the global epicenter of COVID-19 to India. Ongoing systematic public health surveillance of the COVID-19 pandemic is needed to inform disease prevention policy to re-establish control over the pandemic within South Asia. Objective This study aimed to inform public health leaders about the state of the COVID-19 pandemic, how South Asia displays differences within and among countries and other global regions, and where immediate action is needed to control the outbreaks. Methods We extracted COVID-19 data spanning 62 days from public health registries and calculated traditional and enhanced surveillance metrics. We use an empirical difference equation to measure the daily number of cases in South Asia as a function of the prior number of cases, the level of testing, and weekly shifts in variables with a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano–Bond estimator in R. Results Traditional surveillance metrics indicate that South Asian countries have an alarming outbreak, with India leading the region with 310,310 new daily cases in accordance with the 7-day moving average. Enhanced surveillance indicates that while Pakistan and Bangladesh still have a high daily number of new COVID-19 cases (n=4819 and n=3878, respectively), their speed of new infections declined from April 12-25, 2021, from 2.28 to 2.18 and 3.15 to 2.35 daily new infections per 100,000 population, respectively, which suggests that their outbreaks are decreasing and that these countries are headed in the right direction. In contrast, India’s speed of new infections per 100,000 population increased by 52% during the same period from 14.79 to 22.49 new cases per day per 100,000 population, which constitutes an increased outbreak. Conclusions Relaxation of public health restrictions and the spread of novel variants fueled the second wave of the COVID-19 pandemic in South Asia. Public health surveillance indicates that shifts in policy and the spread of new variants correlate with a drastic expansion in the pandemic, requiring immediate action to mitigate the spread of COVID-19. Surveillance is needed to inform leaders whether policies help control the pandemic.
    Type of Medium: Online Resource
    ISSN: 2369-2960
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2021
    detail.hit.zdb_id: 2874192-4
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  • 8
    In: Cerebral Cortex Communications, Oxford University Press (OUP), Vol. 2, No. 2 ( 2021-04-01)
    Abstract: The factors that control the occurrence of interictal epileptiform discharges (IEDs) are not well understood. We suspected that this phenomenon reflects an attention-dependent suppression of interictal epileptiform activity. We hypothesized that IEDs would occur less frequently when a subject viewed a task-relevant stimulus compared with viewing a blank screen. Furthermore, IEDs have been shown to impair memory when they occur in certain regions during the encoding or recall phases of a memory task. Although these discharges have a short duration, their impact on memory suggests that they have longer lasting electrophysiological effects. We found that IEDs were associated with an increase in low-frequency power and a change in the balance between low- and high-frequency oscillations for several seconds. We found that the occurrence of IEDs is modified by whether a subject is attending to a word displayed on screen or is observing a blank screen. In addition, we found that discharges in brain regions in every lobe impair memory. These findings elucidate the relationship between IEDs and memory impairment and reveal the task dependence of the occurrence of IEDs.
    Type of Medium: Online Resource
    ISSN: 2632-7376
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3040464-2
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  • 9
    In: JMIR Public Health and Surveillance, JMIR Publications Inc., Vol. 7, No. 4 ( 2021-4-28), p. e25695-
    Abstract: The COVID-19 pandemic has severely impacted Europe, resulting in a high caseload and deaths that varied by country. The second wave of the COVID-19 pandemic has breached the borders of Europe. Public health surveillance is necessary to inform policy and guide leaders. Objective This study aimed to provide advanced surveillance metrics for COVID-19 transmission that account for weekly shifts in the pandemic, speed, acceleration, jerk, and persistence, to better understand countries at risk for explosive growth and those that are managing the pandemic effectively. Methods We performed a longitudinal trend analysis and extracted 62 days of COVID-19 data from public health registries. We used an empirical difference equation to measure the daily number of cases in Europe as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. Results New COVID-19 cases slightly decreased from 158,741 (week 1, January 4-10, 2021) to 152,064 (week 2, January 11-17, 2021), and cumulative cases increased from 22,507,271 (week 1) to 23,890,761 (week 2), with a weekly increase of 1,383,490 between January 10 and January 17. France, Germany, Italy, Spain, and the United Kingdom had the largest 7-day moving averages for new cases during week 1. During week 2, the 7-day moving average for France and Spain increased. From week 1 to week 2, the speed decreased (37.72 to 33.02 per 100,000), acceleration decreased (0.39 to –0.16 per 100,000), and jerk increased (–1.30 to 1.37 per 100,000). Conclusions The United Kingdom, Spain, and Portugal, in particular, are at risk for a rapid expansion in COVID-19 transmission. An examination of the European region suggests that there was a decrease in the COVID-19 caseload between January 4 and January 17, 2021. Unfortunately, the rates of jerk, which were negative for Europe at the beginning of the month, reversed course and became positive, despite decreases in speed and acceleration. Finally, the 7-day persistence rate was higher during week 2 than during week 1. These measures indicate that the second wave of the pandemic may be subsiding, but some countries remain at risk for new outbreaks and increased transmission in the absence of rapid policy responses.
    Type of Medium: Online Resource
    ISSN: 2369-2960
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2021
    detail.hit.zdb_id: 2874192-4
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  • 10
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 1998
    In:  Medical Care Vol. 36, No. 6 ( 1998-06), p. 804-817
    In: Medical Care, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 6 ( 1998-06), p. 804-817
    Type of Medium: Online Resource
    ISSN: 0025-7079
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1998
    detail.hit.zdb_id: 2045939-7
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