Changes In Pressure Research Articles

Analysis and monitoring of the behavior of a rock fill dam ten years after construction: a case study of the Iran-Madani Dam

AbstractIn this study we compared dam monitoring results with those of numerical analysis to propose a plan for the first reservoir impounding of the Iran-Madani Rock fill dam, ten years after the completion of its construction. The stability of the dam body has been assessed using numerical analysis and data obtained from sensors installed in the dam. The correctness and accuracy of the geotechnical parameters of the dam body materials were confirmed by comparing the results of numerical analysis and monitoring through back analysis. The linear correlation coefficients between the experimental data and the numerical results for settlement, pore water pressure, and total stress are 84%, 67%, and 99%, respectively. In addition, the agreement between the design assumptions with both the numerical analysis results and instrumentation data was examined. The arching ratio values obtained from instrumentation and numerical analysis in the core of the dam are 0.47 and 0.35, respectively, indicating the safety of the dam. Finally, a numerical sensitivity analysis was conducted to present a special impounding program for the dam, with a focus on controlling simultaneous changes in pore water pressure and effective stress in the clay core, ten years after the completion of the dam body construction.

Radiation Monitoring for Volatilized Zinc Contamination Using Gamma-Ray Imaging and Spectroscopy

Abstract Gamma-ray imaging is a tool that has grown in importance in the applications of non-destructive assay (NDA) for radioactive survey and analysis of nuclear facilities. Imaging techniques have shown great promise in providing valuable information involving radioactive waste management and contamination prevention. For the application studied in this work, 65Zn has been identified as a radioactive contaminant during tritium extraction. Due to the volatile nature of 65Zn under the pressure and temperature changes during extraction operations, 65Zn can easily travel through components of the extraction system as vapor, making it difficult to trap. Previous research involving the development of a filtration system showed that the 65Zn can be trapped, mitigating product contamination. However, during the extraction process, direct analysis of the equipment to confirm that zinc contamination is trapped in the filter and has not spread to other components is impractical. In this situation, the need to assay the location of the contamination with little-to-no interference with operations is vital. In this work, we demonstrate the use of a commercialized 3D position-sensitive CdZnTe (CZT) gamma-ray imaging spectrometer to provide analysis of the 65Zn contamination. Onsite measurements during an extraction process are studied to assess the location and migration of the 65Zn. The results obtained from real-time glovebox monitoring demonstrate the feasibility of gamma-ray imaging for localizing the contamination and providing a preliminary qualitative assessment that is intended to be used in future work quantifying the contamination build-up and activity over time.

New prefilled syringe aflibercept design. A cause of symptomatic IOP spike after aflibercept PFS?

To describe ocular hypertension cases after using a new aflibercept prefilled syringe and to assess the main characteristics of these eyes and their possible association with intraocular pressure (IOP) changes. Case series. We reported all the cases of ocular hypertension following aflibercept prefilled syringes (PFS) treatment in our department between April 2021 and December 2023. A total of 4183 eyes were treated with aflibercept PSF. Thirteen transitory IOP elevations were observed immediately after injection (0.3%). Two eyes had an IOP between 30-35 mmHg, five eyes had an IOP between 36-55 mmHg and three eyes had an IOP > 56 mmHg. The mean IOP was 45.5 mmHg±11.33. Only six eyes needed anterior chamber paracentesis (37.5%). The other patients were treated conservatively (ocular massage and/or IOP-lowering drops). The mean IOP after treatment was 15.71 mmHg±7.20. Visual acuity improved after treatment in all the patients. Compared with other injectors, reports have indicated a higher incidence of moderate and severe IOP spikes with aflibercept PSF. The European Medicine Agency (EMA) has associated this significant increase with incorrect syringe handling, leading to higher injection volumes. Although plunger misalignment seems to play a role in the IOP spikes, some other characteristics of this new injector could play a role. Factors such as syringe diameter, plunger alignment, and injection force may contribute to this issue. The reason some authors found no significant differences in IOP elevation after IVI, with aflibercept PFS, could be due to variations in patient characteristics, which may also play an important role in post-IVI pressure changes. Intraocular pressure spikes after aflibercept PFS can be explained by injector characteristics. The PFS of aflibercept has a domed plunger. Incorrect alignment between the base of the plunger and the black dosing line could cause an increase in the injected volume. Furthermore, the wider syringe diameter of aflibercept PFS could imply a larger injection force, increasing the risk of IOP elevation. Patient characteristics, such as previous VPP, axial length, or glaucoma history, may also play a role. Further studies are required to develop an ideal intravitreal syringe.

Tropospheric amplification of stratosphere–troposphere coupling

AbstractDuring northern winter the stratospheric polar vortex is highly variable — even breaking down completely during sudden stratospheric warmings. The strength of the stratospheric polar vortex is observed to be coupled to surface weather, primarily through swings in the phase of the Northern Annular Mode — which is nearly uuivalent to polar‐cap sea‐level pressure. Pressure changes (as a function of height) are largest at the surface, which is difficult to reconcile with the remote effects of stratospheric variability. This conundrum requires some mechanism(s) to amplify the polar sea‐level pressure anomalies. A simple, intuitive explanation has remained elusive. We use Japanese 55‐year Reanalysis (JRA‐55) reanalyses to investigate the reason that stratospheric variability causes large polar sea‐level pressure changes. The main result of this paper is that vertical movement of the polar tropopause is essential in understanding how surface pressure changes are generated. The strength of the polar vortex is strongly coupled to the height of the polar tropopause, resulting in stretching/compression of the polar tropospheric air column. This causes pressure changes that are largest at the surface. For example, the lowering of the polar tropopause during a sudden stratospheric warming leads to a compression and spin down of the tropospheric column and is therefore associated with higher polar sea‐level pressure. This mechanism can be compared to the textbook example of conservation of potential vorticity as an air column moves over a mountain range — except in this case the column depth changes because the stratosphere is changing the height of the tropopause. The observed vertical profile of pressure changes matches closely what would be expected from the stretching/compression mechanism. The higher polar sea‐level pressure associated with a sudden stratospheric warming is due mainly to mass moving into the polar cap within the troposphere, rather than rearranged mass in the stratosphere.

Low Intraocular Pressure Induces Fibrotic Changes in the Trabecular Meshwork and Schlemm's Canal of Sprague Dawley Rats.

Continuous artificial aqueous humor drainage in the eyes of patients with glaucoma undergoing trabeculectomy likely exerts abnormal shear stress. However, it remains unknown how changes in intraocular pressure (IOP) can affect aqueous humor outflow (AHO). Here, we induced and maintained low intraocular pressure (L-IOP) in healthy Sprague Dawley (SD) rats by puncturing their eyes using a tube (200-µm diameter) for 2 weeks. After the rats were euthanized, their eyes were removed, fixed, embedded, stained, and scanned to analyze the physiological and pathological changes in the trabecular meshwork (TM) and Schlemm's canal (SC). We measured SC parameters using ImageJ software and assessed the expression of various markers related to flow shear stress (KLF4), fibrosis (TGF-β1, TGF-β2, α-SMA, pSmad1/5, pSmad2/3, and fibronectin), cytoskeleton (integrin β1 and F-actin), diastolic function (nitric oxide synthase and endothelial nitric oxide synthase [eNOS]), apoptosis (cleaved caspase-3), and proliferation (Ki-67) using immunofluorescence or immunohistochemistry. L-IOP eyes showed a larger SC area, higher eNOS expression, and lower KLF4 and F-actin expression in the TM and SC (both P < 0.05) than control eyes. The aqueous humor of L-IOP eyes had a higher abundance of fibrotic proteins and apoptotic cells than that of control eyes, with significantly higher TGF-β1, α-SMA, fibronectin, and cleaved caspase-3 expression (all P < 0.05). In conclusion, a persistence of L-IOP for 2 weeks may contribute to fibrosis in the TM and SC and might be detrimental to conventional AHO in SD rat eyes. Clinicians should consider that aberrant shear force induced by aqueous humor fluctuation may damage AHO outflow channel when treating patients.

Typical Heterotrophic and Autotrophic Nitrogen Removal Process Coupled with Membrane Bioreactor: Comparison of Fouling Behavior and Characterization.

There is limited research on the relationship between membrane fouling and microbial metabolites in the nitrogen removal process coupled with membrane bioreactors (MBRs). In this study, we compared anoxic-oxic (AO) and partial nitritation-anammox (PNA), which were selected as representative heterotrophic and autotrophic biological nitrogen removal-coupled MBR processes for their fouling behavior. At the same nitrogen loading rate of 100 mg/L and mixed liquor suspended solids (MLSS) concentration of 4000 mg/L, PNA-MBR exhibited more severe membrane fouling compared to AO-MBR, as evidenced by monitoring changes in transmembrane pressure (TMP). In the autotrophic nitrogen removal process, without added organic carbon, the supernatant of PNA-MBR had higher concentrations of protein, polysaccharides, and low-molecular-weight humic substances, leading to a rapid flux decline. Extracellular polymeric substances (EPS) extracted from suspended sludge and cake sludge in PNA-MBR also contributed to more severe membrane fouling than in AO-MBR. The EPS subfractions of PNA-MBR exhibited looser secondary structures in protein and stronger surface hydrophobicity, particularly in the cake sludge, which contained higher contents of humic substances with lower molecular weights. The higher abundances of Candidatus Brocadia and Chloroflexi in PNA-MBR could lead to the production of more hydrophobic organics and humic substances. Hydrophobic metabolism products as well as anammox bacteria were deposited on the hydrophobic membrane surface and formed serious fouling. Therefore, hydrophilic membrane modification is more urgently needed to mitigate membrane fouling when running PNA-MBR than AO-MBR.

CFD modeling of DME synthesis based on methanol dehydration process by an adiabatic reactor: Characterization

Today, Dimethyl ether (DME) can be used as a fuel in various applications, including as a substitute for diesel fuel. Despite its advantages, there are some challenges associated with DME as a fuel. One of the main challenges is the limited availability of DME refueling stations and the need for dedicated storage facilities due to their different properties compared to traditional fuels. DME shows promise as a clean-burning alternative fuel with the potential to reduce emissions and dependence on fossil fuels, especially in the transportation and power generation sectors. Ongoing research and development efforts are focused on improving production methods, expanding infrastructure, and exploring new applications for DME as a fuel. DME is a colorless gas that can be used as a fuel or as a precursor for the production of other chemicals. The most common method for DME synthesis involves the dehydration of methanol. Methanol is first converted to dimethyl ether by removing a molecule of water. This reaction is typically catalyzed by acidic materials such as alumina or zeolites. In this work, to study the physical properties of the methanol dehydration reaction, CFD modeling of the adiabatic reactor has been accomplished. The researchers showed that the use of an alumina catalyst, which has selective mechanical properties and unique surface properties, is a suitable choice as a catalyst for DME synthesis. The results of this study indicate that laboratory data such as pressure, energy, and velocity in the adiabatic reactor satisfy the reaction conditions well. Also, temperature profile diagrams with changes in temperature, pressure, and velocity show that the reaction of methanol dehydration is strongly dependent on environmental factors and presents different results under the influence of other conditions.

Blood Pressure Reduction and Changes in Antihypertensive Medication Use Among Patients With Hypertension Who Initiated Sodium-Glucose Cotransporter-2 Inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated a blood pressure (BP) reduction benefit despite other indications for use. We evaluated BP changes and antihypertensive medication use pre- and post-SGLT2i initiation among 12 960 patients with treated hypertension and among subgroups with apparent treatment-resistant hypertension (aTRH) and/or proteinuria. Post-SGLT2i initiation, the mean (SD) systolic blood pressure (SBP) was reduced from 133.9 (16.4) to 128.6 (15.5) mmHg and the mean diastolic blood pressure (DBP) was reduced from 70.8 (11.8) to 68.3 (11.3) mmHg among all patients. The mean SBP/DBP reduction was 5.3/2.5, 6.2/2.8, and 6.1/2.9mmHg among all patients, patients with aTRH, and patients with proteinuria, respectively. Achieved BP < 130/80mmHg increased by 12.5%, 16.9%, and 11.1% for all patients, patients with aTRH, and patients with proteinuria, respectively. Discontinuation of ≥ 1 antihypertensive medication within 12 months of SGLT2i initiation occurred in 33.4% overall, 47.6% of patients with aTRH, and 38.7% of patients with proteinuria.

Mathematical Modelling and Deep Learning Techniques for Predicting Cardiovascular Disease

Putting together mathematical models and deep learning has become a strong way to identify cardiovascular disease (CVD) in recent years. This paper looks at how dynamical systems, control theory, and machine learning methods can work together to make CVD forecast more accurate and reliable. To improve the ability of diagnostic tools to predict the future by using mathematical models like differential equations to describe how the heart works and deep learning architectures like Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) for feature extraction. This method considers both the time patterns of how the heart works and the non-linear complexity of risk factors like high blood pressure, high cholesterol, and family tendencies. The most important part of our method is creating a multi-stage prediction model. This model starts with differential equations that show how heart rate and blood pressure change over time. Next, it uses deep learning models that have been trained on large CVD datasets. Normalization and feature engineering methods are used to prepare the information. Key measures like age, BMI, and cholesterol levels are used as inputs. Metrics like precision, sensitivity, specificity, and F1-score are used to judge how well the model works. Early findings indicate that combining mathematical models with deep learning makes predictions a lot more accurate than using only standard machine learning models. In particular, adding time dynamics to the model lets it find hidden trends in physiological data that simple models often miss. Deep learning also lets the system learn on its own how different risk factors are related to each other, making it a strong tool for finding CVD early and predicting how bad it will be. The research shows that a mix of approaches could make personalized medicine better by giving doctors accurate and easy to understand prediction tools. In the future, researchers will focus on making these models work better so it can be used in real time in hospital settings. This could help lower the number of people who get cardiovascular disease around the world.

The Influence of Helium Addition on the Combustion Process in a Hydrogen-Fueled Turbulent Jet Ignition Engine

There are considerably fewer requirements for the quality of hydrogen combusted in an engine than its quality for fuel cells. Therefore, the analysis was carried out on the combustion of hydrogen–helium mixtures in an engine with a two-stage combustion system (TJI—Turbulent Jet Ignition). A single-cylinder research engine with a passive and active prechamber was used. A hydrogen–helium mixture was supplied to the main chamber in proportions of 100:0, 90:10, 80:20, 30:70, and 60:40 volume fractions. The prechamber was fueled only with pure hydrogen. Combustion was carried out in the lean charge range (λ = 1.5–3) and at a constant value of the Center of Combustion (CoC = 8–10 deg aTDC). It was found that the helium concentration in the mixture affected the changes in combustion pressure, heat release rate and the amount of heat release. It was observed that increasing the proportion of helium in the mixture by 10% also reduces the IMEP by approximately 10% and reduces the rate of heat release by approximately 20%. In addition, helium influences knock combustion. Limits of MAPO = 1 bar mean assumed that knock combustion occurs in the main chamber at values of λ &lt; 1.9. Increasing the excess air ratio results in a gradual reduction in the temperature of the exhaust gas, which has a very rapid effect on changes in the concentration of nitrogen oxides. Studies carried out on the helium addition in hydrogen fuel indicate that it is possible to use such blends with a partial deterioration of the thermodynamic properties of the two-stage combustion process.

Identification of the Characteristics of Thermal Engineering Materials Under Conditions of Nonstationary Heating With Changes in Pressure by Solving Inverse Heat Exchange Problems. 1. Development of Computing Algorithms

Identification of the Characteristics of Thermal Engineering Materials Under Conditions of Nonstationary Heating With Changes in Pressure by Solving Inverse Heat Exchange Problems. 1. Development of Computing Algorithms

6602 Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort

Abstract Disclosure: M.D. Ettleson: None. G.C. Penna: Consulting Fee; Self; Ipsen, Bayer, Inc.. W. Wan: None. I.M. Bensenor: None. N. Laiteerapong: None. A.C. Bianco: Consulting Fee; Self; Abbvie. Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort Introduction: Hypothyroidism is a common endocrine disorder for which levothyroxine (LT4) serves as the primary treatment. Periods during which thyroid stimulating hormone (TSH) levels are outside the normal range have been associated with adverse cardiovascular outcomes, including mortality. In practice, serial TSH levels are measured over time to ensure therapeutic LT4 treatment is maintained. However, there is no measure of the quality of treatment maintenance over time. TSH trajectory classification represents a novel approach to define the adequacy of LT4 treatment for hypothyroidism over time utilizing multiple observation points. Methods: With longitudinal clinical data, including thyroid function from a large prospective study, we aimed to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over a 9 year study period with three observation points. Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to measure within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. Results: From the 621 LT4-treated study participants, the best-fit GMM approach identified four TSH trajectory classes, as defined by their relationship to the normal TSH range: 1) High-high normal TSH, 2) Normal TSH, 3) Normal-to-low TSH, and 4) Low-to-normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 mcg, p &amp;lt;0.001). There were no significant differences in CV health markers between the classes at baseline. At least one significant difference in CV markers occurred in all classes, highlighted by the low-to-normal class, in which total and HDL cholesterol, triglycerides, and A1c all increased significantly (p = 0.049, p &amp;lt;0.001, p &amp;lt;0.001, and p = 0.001, respectively). Medication utilization increased in all classes over the study period. Conclusion: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. In the future, more comprehensive datasets will allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes. Defining the adequacy of LT4 treatment using a longitudinal scope could allow clinicians to more accurately communicate treatment progress and identify patients at risk for adverse CV outcomes. Presentation: 6/3/2024

7038 Continuous Subcutaneous Hydrocortisone Infusion Is Practical And Effective In Select Patients With Adrenal Insufficiency

Abstract Disclosure: J.E. Lee: None. O. Hamidi: None. S. Mirfakhraee: None. Continuous subcutaneous hydrocortisone infusion (CSHI) via insulin pump is an alternative therapy for treating patients with adrenal insufficiency (AI) and allows for adjustable hydrocortisone delivery to provide more physiologic glucocorticoid replacement. Retrospective case series of 9 patients on CSHI showed a reduction in total daily dose of glucocorticoid by 34% and a decrease in hospitalization admissions due to adrenal crisis by 50%. In a double-blind placebo-controlled study, CSHI in patients with primary AI did not demonstrate benefit in subjective health status metrics compared to oral hydrocortisone; however, patients had good baseline subjective health scores. Due to a scarcity of data, CSHI is likely underutilized in patients who may benefit from this individualized therapy. Our research objectives were to analyze the change in total daily glucocorticoid dose, number of adrenal crises events and hospitalization days, glucocorticoid-related comorbidities, and quality of life of patients transitioned to CSHI. We performed a single-center, retrospective longitudinal follow-up study in 23 consecutive patients (87% women, median age 40 years at time of CSHI initiation) treated with CSHI between 2015 and 2023. Types of adrenal insufficiency were 48% secondary AI, 35% glucocorticoid induced AI, and 17% primary AI. CSHI delivery settings were generated by a formula that we derived using each patient’s daily oral glucocorticoid dose and preferred waking time. Median time from AI diagnosis to CSHI implementation was 41 months, and median duration of CSHI was 25 months. Total daily dose of glucocorticoid (in hydrocortisone equivalent) before CSHI vs during CSHI decreased from 30.0mg (15.0mg to 80.0mg) to 26.6mg (14.4mg to 200.5mg) (p= 0.45). Median number of adrenal crisis events decreased from 1 (0 to 13) to 0 (0 to 38) (p=0.25), and hospitalization days due to adrenal crisis decreased from 2 (0 to 46) to 0 (0 to 58) (p=0.53). No significant differences were noted for change in weight, blood pressure, diabetes, cardiovascular and cerebrovascular events, total cholesterol, LDL, and triglyceride levels. Median HDL decreased from 59 to 51 (p=0.01). In terms of subjective health status, 10 patients completed SF-36 survey while on CSHI. Significant impairments were noted in physical health, vitality, and general health with median score less than 40. At the conclusion of the study, 20 patients (87%) preferred CSHI therapy. Only 3 patients stopped CSHI for reasons of inconvenience, skin irritation at pump site, and better symptom control on oral therapy. No significant CSHI-related safety concerns were noted. In conclusion, CSHI is a safe and effective way to deliver individualized therapy to patients with difficult to control AI. CSHI led to reduction in glucocorticoid exposure and fewer adrenal crisis events and hospitalization days due to adrenal crisis. Presentation: 6/1/2024

8424 Complex Management Of Adrenal Insufficiency In Pregnancy: A Challenging Case

Abstract Disclosure: T. Avanessian: None. H. Alsamarraie: None. Background: Physiologic changes, including changes in the HPA axis and RAAS, during pregnancy pose challenges in the management of adrenal insufficiency in pregnant women. This case report discusses the management of adrenal insufficiency in a young primigravida female with Addison’s disease. Clinical Case: At 19.5 weeks of gestation, a 26-year-old primigravida, previously diagnosed with Addison’s disease 5 years ago, presented to an acute care center for syncopal episodes. The pregnancy had been complicated by persistent nausea and vomiting, labeled as hyperemesis gravidarum, and recurrent syncopal episodes, resulting in 6 ED visits and 3 hospitalizations, with symptoms improving each time after IV hydration and then returning within a few days. At presentation, the patient reported lightheadedness, sweating, palpitations, dyspnea, fatigue, nausea, vomiting, and a 10 lb weight loss since the beginning of pregnancy. The pre-pregnancy regimen was hydrocortisone 10 mg in the morning and 5 mg in the afternoon, with fludrocortisone 0.1mg daily. At 8 weeks of gestation, due to increased fatigue and hypotension, the hydrocortisone dose was doubled, while fludrocortisone was continued the same. During admission, blood pressure ranged from 67/37 to 90/56 mmHg, and heart rate ranged between 93-103 bpm. On labs, electrolytes were normal, and the serum renin level was elevated at 5.803 ng/ml/hr (0.167-5.380). Treatment included IV hydration and hydrocortisone 40 mg in the morning and 20 mg in the afternoon. Despite symptom improvement, blood pressure remained low. Thus, fludrocortisone was increased to 0.1 mg twice daily. Within 3 days, all symptoms improved, allowing for the down-titration of the hydrocortisone dose. The patient was discharged with hydrocortisone 30 mg at 8 AM, 10 mg at 3 PM, 5 mg at 7 PM, and fludrocortisone at 0.1 mg twice daily. Conclusion: Managing symptoms of adrenal insufficiency during pregnancy is challenging due to the overlap of symptoms and signs with physiologic manifestations of pregnancy. The use of biochemical testing is limited, given the physiological activation of RAAS and progressive increases in renin, CRH, ACTH (from both pituitary and placental sources), and cortisol during pregnancy. Monitoring mineralocorticoid requirements is further complicated by physiological changes in blood pressure and interstitial fluid status. While some literature suggests that adjusting fludrocortisone may not be necessary, as an increase in glucocorticoid dose can compensate, determining the correct dose of glucocorticoid and mineralocorticoid replacement should be tailored to each patient and their specific symptoms.

A noninvasive measurement technique for the initial stiffness of the radial artery

Arterial stiffness carries significant implications for cardiovascular disease. Monitoring changes in arterial stiffness is integral to proactive health management, however, current noninvasive methods of quantifying stiffness in vivo rely primarily on linear tangent stiffness, making the measurements vulnerable to the variability of blood pressure and thereby affecting the accuracy in portraying the health status of the arteries. This study proposed a novel methodology for evaluating arterial stiffness that is unaffected by changes in blood pressure. Ultrasound detection techniques are applied to accurately chronicle changes in radial artery diameters across varied blood pressures. Incorporating blood pressure measurements, the initial diameter at cuff blockade, and vessel diameters at systolic and diastolic pressures enables inverse determination of the unstressed initial radial artery stiffness. This method accurately mirrors the results of in vitro experiments employing porcine blood vessels at physiological pressures. The results underscore the technique's ability to quantify arterial mechanical properties precisely. This study offers a groundbreaking strategy for fostering the early detection of atherosclerosis, and aiding artery health regulation.

6907 Continued Improvements in Hypertension and Diabetes During Long-Term Osilodrostat Therapy in Patients with Cushing’s Disease: A Pooled Analysis from the Phase III LINC 3 and LINC 4 Studies

Abstract Disclosure: M. Fleseriu: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H Lundbeck A/S. Grant Recipient; Self; Recordati AG, Corcept Therapeutics, Xeris Pharmaceuticals (Strongbridge), Neurocrine Biosciences. J. Newell-Price: Consulting Fee; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. Grant Recipient; Self; Crinetics, Diurnal, HRA Pharmaceuticals, Recordati Rare Diseases. M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Ipsen, Pfizer, Inc., Crinetics Pharmaceuticals, Novo Nordisk. R.J. Auchus: Consulting Fee; Self; Xeris Pharmaceuticals (Strongbridge), Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, Janssen Pharmaceuticals, Quest Diagnostics, H Lundbeck A/S, Novo Nordisk, Besins Pharmaceuticals. Grant Recipient; Self; Xeris Pharmaceuticals (Strongbridge), Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, Recordati Rare Diseases. R. Feelders: Consulting Fee; Self; Recordati. A. Lacroix: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Pfizer, Inc.. Grant Recipient; Self; Novartis Pharmaceuticals, Recordati, Pfizer, Inc. A. Shimatsu: Advisory Board Member; Self; Recordati. Consulting Fee; Self; Recordati. Speaker; Self; Recordati. P. Witek: Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. Other; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. M. Bex: Consulting Fee; Self; Recordati. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati, Camurus. B.M. Biller: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; H Lundbeck A/S, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Introduction: Alleviating the burden of comorbidities such as hypertension (HTN) and diabetes mellitus (DM), through control of hypercortisolism, is an important treatment goal in the management of Cushing’s syndrome. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid, sustained cortisol normalization in Cushing’s disease (CD) patients (pts) in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734), with improvements in clinical manifestations of hypercortisolism. Here, we report on the long-term changes in blood pressure (BP) and markers of glucose homeostasis in a large, pooled pt population from both trials at weeks (W) 48 and 72. Methods: LINC 3 comprised a 48W core phase, including an 8W randomized withdrawal phase for eligible pts. LINC 4 included an upfront 12W, double-blind, randomized, placebo-controlled period and 36W of open-label osilodrostat. Both studies had an optional extension. Baseline (BL) HTN was defined as prior diagnosis, taking antihypertensive medication, and/or systolic/diastolic BP (SBP/DBP) &amp;gt;130/&amp;gt;90 mmHg. BL DM was defined as prior diagnosis, taking antidiabetic medication, HbA1c ≥6.5%, and/or fasting plasma glucose (FPG) ≥126 mg/dL. Data from LINC 3 and LINC 4 were pooled in a secondary exploratory analysis for all pts with data at BL and the given visit, excluding periods where pts were randomized to placebo. No formal statistical hypothesis testing was performed; all analyses are descriptive. Results: In pts with BL HTN (n=174/210; 82.9%), mean (95% CI) change in SBP/DBP was -13.9 (-18.5, -9.4)/-9.1 (-12.4, -5.8) mmHg at W48 and -14.7 (-20.1, -9.4)/-9.4 (-13.0, -5.7) mmHg at W72 for those not receiving antihypertensive medication during the study, and -8.4 (-11.9, -4.9)/-5.3 (-7.5, -3.1) mmHg at W48 and -10.1 (-14.3, -5.8)/-5.7 (-8.1, -3.2) mmHg at W72 for those who received antihypertensives. Of pts with BL SBP &amp;gt;130 mmHg (n=110), 50.0% had SBP ≤130 mmHg at W48 and 49.1% at W72. Of pts with BL DBP &amp;gt;90 mmHg (n=65), 64.6% had DBP ≤90 mmHg at W48 and 58.5% at W72. The proportion of pts taking antihypertensive medication declined from 54.3% at BL to 47.3% at W72. Mean (95% CI) change in potassium levels was -0.1 (-0.1, 0.0) mmol/L at W48 and 0.0 (-0.1, 0.1) mmol/L at W72 in pts with BL HTN, and -0.1 (-0.3, 0.1) mmol/L at both W48 and W72 in pts without BL HTN. 40.0% (n=84/210) of pts had BL DM. Of pts with BL FPG ≥100 mg/dL (n=60), 43.3% and 33.3% had FPG &amp;lt;100 mg/dL at W48 and W72, respectively. The proportion of pts taking antidiabetic medication declined from 21.9% at BL to 17.1% at W72. Conclusions: Many pts with CD and HTN or DM showed improvements during osilodrostat therapy, which were maintained or further improved with long-term therapy. Cortisol normalization is associated with improvements in hypercortisolism-associated comorbidities in pts with CD. Presentation: 6/2/2024

Enhanced long cycling durability of Ce2Ni7-type single-phase Sm–Mg–Ni-based hydrogen storage alloys for nickel metal hydride batteries

La–Mg–Ni-based superlattice structure alloys are promising negative material candidates for nickel metal hydride (Ni-MH) batteries, but their application is challenged by cycling life. Herein, we propose Sm–Mg–Ni-based alloys beyond La–Mg–Ni-based alloys to promote long-term durability. Specifically, Ce2Ni7-type single-phase Sm0.58La0.25Mg0.17Ni3.26Al0.18 and Sm0.54La0.29Mg0.17Ni3.26Al0.18 alloys have been obtained, delivering significantly high-capacity retention rates over 70 % after 500 cycles at a 1C charge and discharge rate. Furthermore, the alloy's discharge ability has been optimized via manipulating Sm/La ratios, of which its effect on the structure and electrochemical properties is detailly studied. It is found that the discharge capacity of the Sm0.58La0.25Mg0.17Ni3.26Al0.18 alloy with a higher Sm/La ratio outperforms the Sm0.54La0.29Mg0.17Ni3.26Al0.18 alloy. However, the low Sm/La ratio Sm0.54La0.29Mg0.17Ni3.26Al0.18 alloy is favorable for discharge ability at a high-rate current rate and features lower plateau pressure and enthalpy change compared with Sm0.58La0.25Mg0.17Ni3.26Al0.18. The work is expected to offer new insights into the composition design of hydrogen storage alloys with long cycling life for Ni-MH batteries.

Baseline cystometric parameters in conscious and anesthetized sheep: experimental data and systematic review.

To characterize cystometry in conscious and anesthetized sheep, including bladder response to sacral root electrical stimulation, thereby providing a baseline set of values. Single-fill cystometries were repeated in adult mule ewes both conscious (n = 5) and under general anesthesia (18) using a commercial system. Parameters including bladder capacity, detrusor (bladder) pressure, urethral opening pressure, bladder compliance, number of nonvoiding detrusor contractions, and bladder pressure change in response to electrical stimulation of the sacral roots under general anesthesia are reported. Pubmed, Embase, and Web of Science databases were searched for studies relating to ovine cystometry, and a systematic review was conducted. In awake sheep, mean ± SD bladder capacity was 79.6 ± 32.2 mL, urethral opening pressure was 26.0 ± 10.7 cm H2O, and compliance was 3.5 ± 1.9 mL/cm H2O. Peak detrusor pressures during micturition reached 57.7 ± 28.3 cm H2O. In anesthetized animals, mean bladder capacity (endpoint, 50 cm H2O) was 333 ± 191 mL, and mean bladder compliance was 7.7 ± 4.9 mL/cm H2O. Values for these parameters from our systematic review are presented for comparison and reference. Electrical stimulation of the second and third sacral roots caused a greater increase in detrusor pressure than stimulation of the first and fourth sacral roots. We present a comprehensive set of data for normal cystometry parameters in sheep, including the first report of detrusor response to sacral root stimulation in anesthetized sheep. This report provides a valuable set of baseline values for a potential translational model of value to neurourologic research and may be a useful reference for clinicians.

Household fuel use and the regression from prehypertension to normotension among Chinese middle-aged and older adults: a cohort study.

To examine the association of household fuel use with prehypertension regression among middle-aged and older people based on the China Health and Retirement Longitudinal Study (CHARLS), we included a total of 3501 participants with prehypertension at baseline, and they were followed up from 2011-2012 to 2015-2016 with information on blood pressure and household solid fuel use (heating and cooking fuels). Cox proportional hazards regression models were used to explore the hazard ratio (HR) and 95% confidence interval (CI) between fuel use and prehypertension regression. Additionally, we investigated the impact of switching fuels (2011-2013) on the regression to normotension during the 4-year follow-up. Linear regression was used to examine the effect of household fuel use on changes in blood pressure. Compared to solid fuel users, those who used clean fuel for heating at baseline had a positive effect on the regression of prehypertension (HR: 1.28, 95% CI: 1.08-1.53). Participants who used clean fuels for both heating and cooking had increased odds for the regression of prehypertension (HR: 1.32, 95% CI: 1.09-1.60). Compared to consistent solid fuel users, those who consistently used clean fuel for heating had a higher likelihood of transitioning from prehypertension to normotension (HR: 1.36, 95% CI: 1.06-1.73) and exhibited 2.45 mmHg lower systolic blood pressure. In conclusion, household clean fuel use for heating was positively associated with the regression of prehypertension to normotension. Furthermore, switching from solid fuel to clean fuel for heating could reduce the risk of prehypertension in Chinese middle-aged and older adults.

A pilot randomized controlled trial comparing noradrenaline and adrenaline as a first-line vasopressor for fluid-refractory septic shock in neonates.

Limited data exists on noradrenaline therapy in neonatal septic shock. We compared the efficacy of noradrenaline with adrenaline in neonatal septic shock. This single center, open label, pilot randomized controlled trial included neonates with clinical evidence of sepsis and shock. Primary outcomes were: 1) resolution of shock one hour after treatment, and 2) mortality during hospital stay. Secondary outcomes included: need for additional vasopressors; hemodynamic stability without further administration of vasopressors for ≥2 h; changes in blood pressure and heart rate after 1 h of vasopressor treatment; and morbidities during the hospital stay. Of 65 eligible neonates, 42 were randomized (21 each in adrenaline and noradrenaline treatment arms) between August 2020 and January 2022, at level III neonatal intensive care unit (NICU) of Bharati Vidyapeeth Deemed University Medical College and Hospital (BVDUMCH). The mean (SD) gestational age and mean (SD) birth weight were 36.1(4.2) weeks and 1.8 (0.2) kilograms birth weight for noradrenaline and 36.9 (4.1) weeks and 1.7 (0.7) kilograms for adrenaline. Shock resolved within 1 h of vasopressor therapy in 76.2% neonates in the noradrenaline arm and 61.9% in adrenaline arm (p value-0.53). Mortality during hospital stay was 28.6% (6/21) in noradrenaline group and 33.3% (7/21) in adrenaline group (p value- 0.58). Additional vasopressors were required in 23.8% neonates of the noradrenaline group compared to 38.1% neonates in adrenaline arm (p value-0.53). Median (SD) duration of intensive care stay was 6 (SD) days in the noradrenaline group and 10 (SD) days in the adrenaline group (p value-0.045). Among neonates with septic shock, the efficacy of noradrenaline was comparable to adrenaline in resolving septic shock after one hour of infusion and on the mortality during hospital stay. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NDI2NTc=&Enc=&userName=noradrenaline, Clinical Trials Registry - India with identifier CTRI/2020/08/027185 (17/08/2020).