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Bilateral Adrenal Nodules Presenting With Mild Autonomous Cortisol Secretion
No full textOBJECTIVE: Benign adrenocortical adenomas are frequently diagnosed on cross-sectional imaging performed for unrelated reasons. Up to 15% to 20% of adrenal nodules are bilateral, representing bilateral adenomas or primary bilateral macronodular adrenal hyperplasia.
METHODS: Mild autonomous cortisol secretion (MACS), diagnosed based on an abnormal dexamethasone suppression test, is seen in 19% to 44% of patients with adrenal adenomas. Distinguishing unilateral from bilateral MACS in patients with bilateral nodules is important to guide appropriate therapy and relies on imaging phenotype, and, in some cases, on adrenal vein sampling.
RESULTS: MACS is associated with cardiovascular morbidity, poor quality of life, frailty, and increased mortality. Reversal of MACS improves these outcomes; however, management of patients with bilateral MACS is challenging. Unilateral adrenalectomy in patients with bilateral nodules and MACS may lead to permanent remission (if MACS is unilateral), temporary remission, or improvement of the degree of MACS (if MACS is bilateral). No medical therapy is currently approved for MACS.
CONCLUSION: Here, we review the presentation, diagnosis, and management of patients with bilateral adrenal nodules and MACS
Effect of recombinant human parathyroid hormone and zoledronic acid on osteoblast gene expression using multifaceted approach: An in vitro study
No full textBACKGROUND: Bone is an endocrine organ that despite being inert in appearance constantly undergoes remodeling, in which wear and tear of bone cells occur. With more than two decades of clinical experience, the molecular mechanisms of anti-fracture drugs are not completely understood because they inhibit osteoclastic activity and differentiate the osteoblast cells. Recent studies suggest fundamentally different mechanisms of action for key anti-fracture drugs, bisphosphonates, and recombinant human parathyroid hormone (rhPTH) at the tissue level; however, their molecular basis of action has not been explored completely. Here, we showed the effect of varying concentrations of zoledronic acid (ZOL) and rhPTH on human osteogenic sarcoma cells (U2OS cells).
MATERIALS AND METHODS: Cellular viability, mineralization, and osteogenic gene expressions were assessed to elucidate the effects of these two prototypic drugs with diametrically different mechanisms of action.
RESULTS: Cellular viability was not affected either by ZOL or rhPTH alone or in tandem treatments. Osteoblastic activity increased significantly with rhPTH followed by ZOL. Further, alkaline phosphatase activity increased significantly with tandem treatment of rhPTH followed by ZOL both at the mRNA and protein levels. Moreover, osteoblastic genes (COL1A1 and osteocalcin) were significantly modulated by sequential treatment with rhPTH followed by ZOL.
CONCLUSIONS: We conclude that rhPTH (5 μg) treatment followed by ZOL (1 μM) showed the best anabolic or bone-forming effect. Our results warrant further research in assessing similar combinations of anti-fracture drugs, which augment osteogenesis to maximize their anabolic effects in preventing osteoporosis in susceptible individuals
Comparative performance and age dependence of tuberculin and defined antigen bovine tuberculosis skin tests assessed with Bayesian latent class analysis
No full textTuberculin skin tests (TST), the primary diagnostic tool for bovine tuberculosis (bTB), cross-react with BCG vaccine. Recently developed defined antigen skin tests (DSTs) aim to differentiate infected amongst vaccinated animals. We evaluated the field performance of different interpretations of the TST and DSTs relative to IGRA and IDEXX M. bovis antibody tests. This panel of tests was assessed in 446 unvaccinated cattle across 22 Ethiopian dairy herds using Bayesian latent class models. We extended the standard Walter-Hui model to include age-related effects to explore evidence of the presence of diagnostic anergy. The latent class models estimate sensitivity and specificity of the DSTs to be between 84-88% and 79-85% respectively. The DSTs perform intermediately between the comparative intradermal test (CIT, sensitivity 77%, specificity 100%) and single intradermal test (SIT, sensitivity 99%, specificity 76%). We observed significant age-related declines in test sensitivity, most notably for CIT (declining from 75 to 52% over 9 years) and DST10 (83% to 68%), while other tests showed more stable sensitivity across age groups. This variable pattern across tests suggests mechanisms beyond simple age-related anergy. Together, these findings demonstrate that DSTs\u27 superior sensitivity to CIT and comparable or better specificity than SIT, combined with their ability to distinguish vaccinated animals, creates a viable pathway for implementing BCG vaccination programs. Given the absence of any gold standard definition of infection with bTB, latent class analyses are essential to assess the relative performance of different diagnostic tests. While our results provide encouraging news for the sensitivity of the new DST tests, the high prevalence of bTB within our study population makes our design underpowered to assess the specificity of the DSTs. Future research, including assessment of the specificity of DSTs in disease-free populations and optimization of test formulation and validation through large-scale field trials is essential to fully establish the case for use in vaccination and surveillance programs
Assessing physical function in transplantation and CAR-T recipients: expert recommendations from the survivorship, aging and biobehavioral special interest groups of ASTCT
No full textThe past few decades have witnessed significant advancements in stem cell transplantation and cell therapy (TCT). This has allowed their expanded use in older patients and those with comorbidities with favorable outcomes. However, these procedures carry significant risks, such as graft-versus-host disease, infection, cytokine release syndrome, and immune effector cell-associated neurotoxicity. Therefore, physical function assessment is crucial to assess patient fitness and potential optimization before and after TCT. The existence of diverse assessment tools makes implementation, comparison, and sharing knowledge among centers difficult. This paper proposes a tiered approach aiming to harmonize physical assessment in the TCT. This allows healthcare facilities to prioritize recommended assessments based on their current capabilities and resources. TCT patients should receive comprehensive physical assessments pre- and post-TCT using a combination of both patient-reported and objective measures. For patient-reported measures, the Patient-Reported Outcomes Measurement Information System should be considered. For objective measures, we recommend considering a physical performance assessment (eg, gait speed) or muscle strength assessment (eg, hand grip), if feasible. Albumin and C reactive protein are also informative in predicting the risk of nonrelapse mortality. Other composite tools, questionnaire libraries, biomarkers, imaging, and wearables can be added according to research and clinical needs. A care workflow needs to be in place in case any impairment is found during the evaluation with goals of increasing physiologic reserve and mitigating stressors. This tiered approach will increase awareness and adoption of these tools and hence improve patient care, facilitate data sharing, and enhance collaboration in this field
Endothelial CHOP as a central mechanism in renovascular hypertension-induced vascular endothelial dysfunction and cardiac fibrosis
No full textOBJECTIVE: In this study, we sought to determine the significant impact of the vascular endothelial endoplasmic reticulum (ER) stress C/EBP homologous protein (CHOP) in renovascular hypertension-induced vascular endothelial dysfunction and cardiac fibrosis.
APPROACH AND RESULTS: Eight-week-old male and female CHOP(flox/flox) and EC(CHOP-/-) mice were randomly divided into eight groups with and without 2-Kidney-1-Clip (2K1C) surgery for four weeks. Body weight, systolic blood pressure, running performance, cardiac hypertrophy and fibrosis, lung edema, inflammation, vascular endothelial function, and signaling were assessed. For the mechanism, we utilized human coronary endothelial cells, both with and without CHOP down-regulation, and then stimulated them with and without angiotensin II ± ATP to determine eNOS phosphorylation level and the presence of inflammatory factors. Male and female CHOP(flox/flox) mice subjected to 2K1C for four weeks exhibited hypertension, cardiac hypertrophy and fibrosis, lung edema, impaired running performance, endothelium-dependent vascular relaxation dysfunction, reduction in eNOS phosphorylation, and inflammation induction. In contrast, male and female EC(CHOP-/-) mice subjected to 2K1C for four weeks were protected against the pathogenesis of renovascular hypertension. In vitro, data showed that deletion of CHOP in endothelial cells protected eNOS phosphorylation level and blunted the induction of inflammation in response to angiotensin II ± ATP.
CONCLUSION: Our research findings determined that CHOP is a central mechanism driving vascular endothelial dysfunction and cardiac fibrosis in renovascular hypertension. Therefore, targeting CHOP in endothelial cells could be a potential therapeutic approach to protect against the pathogenesis of renovascular hypertension
Outcomes of Oral Anticoagulation with Concomitant NSAID Use: A Registry Based Cohort Study
No full textBACKGROUND: Concomitant use of oral anticoagulants (OACs) and nonsteroidal anti-inflammatory drugs (NSAIDs) is common despite concerns about increased bleeding risk. We sought to assess the frequency of co-administering NSAIDs for patients on OAC and the impact on clinical outcomes.
METHODS: We conducted a multicenter registry-based cohort study, utilizing 4:1 propensity score matching to compare patients on OAC monotherapy to those on OAC+NSAIDs therapy between 2011 and 2023 at six anticoagulation clinics of the Michigan Anticoagulation Quality Improvement Initiative. Adults on OAC for venous thromboembolism and/or atrial fibrillation were included. Patients with a history of heart valve replacement, under 3 months of follow-up, or using two or more antiplatelet drugs were excluded. The primary outcome was any bleeding. Secondary outcomes included bleeding subtypes, thrombosis/thromboembolism, healthcare utilization, and mortality.
RESULTS: Among the 12,083 patients receiving OAC, 449 (3.7%) were concurrently prescribed NSAIDs. The 1,796 patients on OAC monotherapy were compared to 449 patients on OAC+NSAID therapy after propensity matching. The matched groups were well balanced and followed for an average of 30 months. No significant differences were observed in bleeding event rates per 100 patient-years between the two groups, including overall (25.1 vs. 24.3, p= 0.56), major, and non-major bleeding. Rates of thrombosis, emergency room visits, hospitalizations, transfusion, and mortality were also similar.
CONCLUSION: Clinical outcomes were similar between OAC monotherapy and OAC with concomitant NSAIDs use in this real-world observational study. As there are limited treatment options for pain, further prospective research should be conducted to replicate these findings
The Impact of a Novel Transfer Process on Patient Bed Days and Length of Stay: A Five-Year Comparative Study at the Mayo Clinic in Rochester and Mankato Quaternary and Tertiary Care Centers
No full textIntroduction: This study evaluated the impact of parallel-level patient transfers on bed utilization efficiency within the Mayo Clinic Health System in Southern Minnesota, focusing on optimizing resources across tertiary and critical access hospitals.
Methods: A retrospective analysis of 179,066 Emergency Department visits (2018-2022) was conducted, with ~2% involving parallel-level transfers for observation or admission. Machine learning was utilized to identify patients suitable for parallel transfers based on demographics, comorbidities, and clinical factors. A Random Forest model with an AUROC of 0.87 guided transfer decisions. Saved patient days were calculated as the difference between the actual LOS and the benchmark LOS based on Diagnosis-Related Groups (DRGs). Generalized estimating equations analyzed length of stay (LOS) differences, adjusted for confounders, with 95% confidence intervals (CI). Statistical analyses were conducted using SPSS (v.26).
Results: The mean patient age was 56 years (SD = 17.2), with 51.4% being female. Saved patient days increased from ~600 to 5200 days over the study period. Transferred patients had a 5.7% longer unadjusted LOS compared to non-transferred patients (95% CI: 2.9-8.6%, p \u3c 0.001). After adjustment for demographics and comorbidities, the LOS difference was not significant (adjusted mean difference: 0.4%, 95% CI: -1.7-2.5%, p = 0.51).
Conclusions: Parallel-level transfers increased saved patient days, reflecting enhanced resource utilization. However, the adjusted LOS differences were not significant, highlighting the need for robust transfer protocols and controlled studies to confirm these findings
The use of onabotulinum toxin type A and other neurotoxins for the treatment of chronic migraine: An American Headache Society survey study
No full textPURPOSE: OnabotA is the only US Food and Drug Administration-approved neurotoxin for chronic migraine prevention; however, non-onabotA toxins may be equally effective. Few studies have explored clinician practices and patient outcomes with non-onabotA neurotoxins. Our study aimed to generate a statistical snapshot of clinician perspectives and treatment practices regarding onabotulinum toxin A (onabotA) and other neurotoxins for chronic migraine and comorbid conditions.
METHODS: A 15-question survey was distributed online to clinician members of the American Headache Society (AHS) assessing clinical practices using onabotA and non-onabotA toxins for chronic migraine and comorbid conditions, and descriptive analysis was performed.
RESULTS: 168 respondents (162 from the United States and 6 from Canada) completed the survey (response rate 10.1 % [168/1665]). Of 48 respondents (28 % of total) using non-onabotA toxins for chronic migraine, 27 (16 %) used incobotulinum toxin A; 23 (14 %) used abobotulinum toxin A; and 12 (7 %) used rimabotulinum toxin B. Non-onabotA toxins were predominantly used due to administration/payor imposed issues (19/48; 40 %) and cost (18/48 [38 %]). Most clinicians using non-onabotA toxins reported similar efficacy to onabotA (32/48; 67 %), while fewer reported better efficacy (9/48 [19 %]) or worse efficacy (7/48 [15 %]) than onabotA. Many respondents (114/168 [68 %]) had used neurotoxins for chronic migraine in addition to other comorbid conditions, including temporomandibular joint disorders (95/114 [83 %]) and cervical dystonia (64/114 [56 %]).
CONCLUSION: While non-onabotA toxins are used less frequently for chronic migraine, they may have similar efficacy as onabotA and are used off-label in clinical practice due to administrative/payor issues or cost
A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss
No full textThe emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200-800 mg) in healthy lean volunteers; (B) multiple ascending doses (200-400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment. Overall, SANA appears to be a first-in-class activator of creatine-dependent energy expenditure and thermogenesis, highlighting its potential as a therapeutic candidate for \u27diabesity\u27. Australian New Zealand Clinical Trials Registry registration: ACTRN12622001519741