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Frontiers in Immunology 2024Immune checkpoint inhibitors (ICPis) induce autoimmune diseases, including autoimmune polyendocrine syndrome type 2 (APS-2), which is defined as a combination of at... (Review)
Review
BACKGROUND
Immune checkpoint inhibitors (ICPis) induce autoimmune diseases, including autoimmune polyendocrine syndrome type 2 (APS-2), which is defined as a combination of at least two of the following endocrinopathies: autoimmune thyroid disease, type 1 diabetes, and Addison's disease. Cases with the full triad are rare. We present a case of an elderly woman who developed APS-2 with the complete triad shortly after starting anti-programmed cell death 1 (anti-PD1) treatment and review the related literature.
CASE
A 60-year-old woman, without any personal or family history of autoimmune and endocrine diseases, started the immunotherapy of anti-PD1 (camrelizumab) for squamous cell carcinoma of the urethral meatus. She developed primary hypothyroidism with elevated antibodies to thyroid peroxidase and thyroglobulin after 25 weeks of treatment, and developed primary adrenal insufficiency with adrenal crisis and fulminant type 1 diabetes with ketoacidosis after 45 weeks. Therefore, this patient met the diagnosis of APS-2 and was given multiple hormone replacement including glucocorticoid, levothyroxine and insulin therapy. Continuous improvement was achieved through regular monitoring and titration of the dosage.
CONCLUSIONS
Different components of APS-2 may appear at different time points after anti-PD1 administration, and can be acute and life-threatening. A good prognosis can be obtained by appropriate replacement with multiple hormones.
INSIGHTS
With the clinical application of ICPis to APS-2, the complexity of its treatment should be paid enough attention.
Topics: Humans; Female; Polyendocrinopathies, Autoimmune; Middle Aged; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Diabetes Mellitus, Type 1
PubMed: 38707904
DOI: 10.3389/fimmu.2024.1366335 -
Cureus Apr 2024We report a case of a 17-year-old girl who developed toxic epidermal necrolysis (TEN) secondary to preoperative iodine administration before thyroidectomy for Graves'...
We report a case of a 17-year-old girl who developed toxic epidermal necrolysis (TEN) secondary to preoperative iodine administration before thyroidectomy for Graves' disease. Past medical history was significant for COVID-19 and multisystem inflammatory syndrome in Children (MISC-C), with subsequent diagnoses of type 1 diabetes mellitus (T1DM), Addison disease, and Graves' disease. Her Graves disease was initially managed with methimazole. While there are reported cases of Stevens-Johnson syndrome (SJS) and TEN due to methimazole, the patient had discontinued methimazole over one month prior. Therefore, she likely represents the first case of TEN reported secondary to potassium iodide solution in a pediatric patient. Given the rarity of TEN in pediatric patients, our case highlights the challenges in managing complex autoimmune conditions and underscores the importance of careful medication choices in such cases.
PubMed: 38707124
DOI: 10.7759/cureus.57618 -
Obesity Pillars Jun 2024This joint expert review by the Obesity Medicine Association (OMA) and National Lipid Association (NLA) provides clinicians an overview of the pathophysiologic and...
BACKGROUND
This joint expert review by the Obesity Medicine Association (OMA) and National Lipid Association (NLA) provides clinicians an overview of the pathophysiologic and clinical considerations regarding obesity, dyslipidemia, and cardiovascular disease (CVD) risk.
METHODS
This joint expert review is based upon scientific evidence, clinical perspectives of the authors, and peer review by the OMA and NLA leadership.
RESULTS
Among individuals with obesity, adipose tissue may store over 50% of the total body free cholesterol. Triglycerides may represent up to 99% of lipid species in adipose tissue. The potential for adipose tissue expansion accounts for the greatest weight variance among most individuals, with percent body fat ranging from less than 5% to over 60%. While population studies suggest a modest increase in blood low-density lipoprotein cholesterol (LDL-C) levels with excess adiposity, the adiposopathic dyslipidemia pattern most often described with an increase in adiposity includes elevated triglycerides, reduced high density lipoprotein cholesterol (HDL-C), increased non-HDL-C, elevated apolipoprotein B, increased LDL particle concentration, and increased small, dense LDL particles.
CONCLUSIONS
Obesity increases CVD risk, at least partially due to promotion of an adiposopathic, atherogenic lipid profile. Obesity also worsens other cardiometabolic risk factors. Among patients with obesity, interventions that reduce body weight and improve CVD outcomes are generally associated with improved lipid levels. Given the modest improvement in blood LDL-C with weight reduction in patients with overweight or obesity, early interventions to treat both excess adiposity and elevated atherogenic cholesterol (LDL-C and/or non-HDL-C) levels represent priorities in reducing the risk of CVD.
PubMed: 38706496
DOI: 10.1016/j.obpill.2024.100108 -
Physiological Reports May 2024Myosteatosis, or the infiltration of fatty deposits into skeletal muscle, occurs with advancing age and contributes to the health and functional decline of older adults.... (Review)
Review
Myosteatosis, or the infiltration of fatty deposits into skeletal muscle, occurs with advancing age and contributes to the health and functional decline of older adults. Myosteatosis and its inflammatory milieu play a larger role in adipose tissue dysfunction, muscle tissue dysfunction, and increased passive muscle stiffness. Combined with the age-related decline of sex hormones and development of anabolic resistance, myosteatosis also contributes to insulin resistance, impaired muscle mechanics, loss of force production from the muscle, and increased risk of chronic disease. Due to its highly inflammatory secretome and the downstream negative effects on muscle metabolism and mechanics, myosteatosis has become an area of interest for aging researchers and clinicians. Thus far, myosteatosis treatments have had limited success, as many lack the potency to completely rescue the metabolic and physical consequences of myosteatosis. Future research is encouraged for the development of reliable assessment methods for myosteatosis, as well as the continued exploration of pharmacological, nutritional, and exercise-related interventions that may lead to the success in attenuating myosteatosis and its clinical consequences within the aging population.
Topics: Humans; Muscle, Skeletal; Aging; Aged; Adipose Tissue
PubMed: 38705872
DOI: 10.14814/phy2.16042 -
American Heart Journal Aug 2024Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein... (Randomized Controlled Trial)
Randomized Controlled Trial
Obicetrapib on top of maximally tolerated lipid-modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN.
BACKGROUND
Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events.
METHODS AND RESULTS
BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024.
CONCLUSION
These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.
Topics: Humans; Atherosclerosis; Anticholesteremic Agents; Double-Blind Method; Cholesterol, LDL; Male; Female; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Hyperlipoproteinemia Type II; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoprotein(a); Middle Aged
PubMed: 38705341
DOI: 10.1016/j.ahj.2024.05.002 -
ACS Omega Apr 2024In the development of proteins, aptamers, and molecular imprints for diagnostic purposes, a major goal is to obtain a molecule with both a high binding affinity and...
In the development of proteins, aptamers, and molecular imprints for diagnostic purposes, a major goal is to obtain a molecule with both a high binding affinity and specificity for the target ligand. Cushing syndrome or Addison's disease can be diagnosed by cortisol level tests. We have previously characterized and solved the crystal structure of an anti-cortisol (17) Fab fragment having a high affinity to cortisol but also significant cross-reactivity to other glucocorticoids, especially the glucocorticoid drug prednisolone. We used native mass spectrometry (MS) to determine the binding affinities of nine steroid hormones to anti-cortisol (17) Fab, including steroidogenic precursors of cortisol. Based on the results, the number of hydroxyl groups in the structure of a steroid ligand plays a key role in the antigen recognition by the Fab fragment as the ligands with three hydroxyl groups, cortisol and prednisolone, had the highest affinities. The antibody affinity toward steroid hormones often decreases with a decrease in the number of hydroxyl groups in the structure. The presence of the hydroxyl group at position C11 increased the affinity more than did the other hydroxyl groups at positions C17 or C21. The binding affinities obtained by native MS were compared to the values determined by surface plasmon resonance (SPR), and the affinities were found to correlate well between these two techniques. Our study demonstrates that native MS with a large dynamic range and high sensitivity is a versatile tool for ligand binding studies of proteins.
PubMed: 38645339
DOI: 10.1021/acsomega.3c09027 -
Critical Care (London, England) Apr 2024Vitamin D deficiency in critically ill patients is associated with poor outcomes, and vitamin D supplementation is recommended for patients with chronic kidney disease.... (Observational Study)
Observational Study
BACKGROUND
Vitamin D deficiency in critically ill patients is associated with poor outcomes, and vitamin D supplementation is recommended for patients with chronic kidney disease. Whether acute kidney injury (AKI) is associated with altered Vitamin D metabolism is unknown. We aimed to compare the longitudinal profiles of serum 25(OH)D and 1,25(OH)D concentrations in critically ill patients with and without moderate to severe AKI and explore the impact of renal recovery and parathyroid hormone (PTH).
METHODS
In this prospective, observational study in two centres in the UK, critically ill patients with and without AKI underwent serial measurement of serum 25(OH)D and 1,25(OH)D and plasma PTH concentrations for 5 days. Linear mixed model analysis and sensitivity analyses were performed.
RESULTS
Serial data of 137 patients were analysed. Seventy-one patients had AKI stage II/III of whom 23 recovered kidney function during the 5-day study period; 66 patients did not have AKI at enrolment of whom 14 developed new AKI. On day of enrolment, patients' serum 25(OH)D concentrations were low (median 18 nmol/L) but there was no significant difference between patients with and without AKI. Median serum 1,25(OH)D levels were significantly lower in patients with AKI II/III (41 pmol/L [IQR 26, 58]) compared to similarly unwell patients without AKI (54 pmol/L [IQR 33, 69]) during the 5-day period. Recovery of kidney function in patients with AKI was associated with a rise in 1,25(OH)D concentrations. Plasma PTH results were impacted by serum calcium and magnesium levels but not associated with 1,25(OH)D levels.
CONCLUSIONS
Critically ill patients with moderate-to-severe AKI have significantly lower serum 1,25(OH)D concentrations than similarly sick patients without AKI but there was no difference in serum 25(OH)D concentrations. Recovery of AKI was associated with a rise in serum 1,25(OH)D concentrations. More research is needed to investigate the health benefits and safety of supplementation with active vitamin D in critically ill patients with moderate-to-severe AKI. Trial registration Clinicaltrials.gov (NCT02869919), registered on 16 May 2016.
Topics: Humans; Prospective Studies; Critical Illness; Vitamin D; Vitamin D Deficiency; Parathyroid Hormone; Acute Kidney Injury
PubMed: 38566240
DOI: 10.1186/s13054-024-04869-4 -
Frontiers in Immunology 2024Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide...
Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes and , which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.
Topics: Humans; Addison Disease; DNA Copy Number Variations; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adaptor Proteins, Signal Transducing
PubMed: 38562931
DOI: 10.3389/fimmu.2024.1374499 -
The Journal of Nutrition May 2024There is an increasing body of evidence supporting a link between low intakes of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) and numerous diseases and health... (Review)
Review
There is an increasing body of evidence supporting a link between low intakes of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) and numerous diseases and health conditions. However, few people are achieving the levels of fish/seafood or eicosapentaenoic acid and docosahexaenoic acid intake recommended in national and international guidelines. Knowledge of a person's ω-3 LCPUFA status will benefit the interpretation of research results and could be expected to lead to an increased effort to increase intake. Dietary intake survey methods are often used as a surrogate for measuring ω-3 PUFA tissue status and its impact on health and functional outcomes. However, because individuals vary widely in their ability to digest and absorb ω-3 PUFA, analytical testing of biological samples is desirable to accurately evaluate ω-3 PUFA status. Adipose tissue is the reference biospecimen for measuring tissue fatty acids, but less-invasive methods, such as measurements in whole blood or its components (e.g., plasma, serum, red blood cell membranes) or breast milk are often used. Numerous commercial laboratories provide fatty acid testing of blood and breast milk samples by different methods and present their results in a variety of reports such as a full fatty acid profile, ω-3 and ω-6 fatty acid profiles, fatty acid ratios, as well as the Omega-3 Index, the Holman Omega-3 Test, OmegaScore, and OmegaCheck, among others. This narrative review provides information about the different ways to measure ω-3 LCPUFA status (including both dietary assessments and selected commercially available analytical tests of blood and breast milk samples) and discusses evidence linking increased ω-3 LCPUFA intake or status to improved health, focusing on cardiovascular, neurological, pregnancy, and eye health, in support of recommendations to increase ω-3 LCPUFA intake and testing.
Topics: Humans; Diet; Fatty Acids, Omega-3; Nutritional Status; Recommended Dietary Allowances
PubMed: 38522783
DOI: 10.1016/j.tjnut.2024.03.015 -
American Heart Journal Plus :... Feb 2024As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular...
As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.
PubMed: 38510746
DOI: 10.1016/j.ahjo.2023.100354