Adrenalectomy Improves Body Weight, Glucose, and Blood Pressure Control in Patients With Mild Autonomous Cortisol Secretion: Results of an Randomized Controlled Trial by the Co-work of Adrenal Research (COAR) Study.

OBJECTIVE: To assess the metabolic effects of adrenalectomy in patients with mild autonomous cortisol secretion (MACS). BACKGROUND: Despite retrospective studies showing the association of adrenalectomy for MACS with beneficial metabolic effects, there have been only 2 randomized prospective studies with some limitations to date. METHODS: A prospective, multicenter study randomized 132 patients with adrenal incidentaloma without any features of Cushing syndrome but with serum cortisol >50 nmol/L after a 1 mg overnight dexamethasone suppression test into an adrenalectomy group (n = 66) or control group (n = 66). The primary outcomes were changes in body weight, glucose, and blood pressure (BP). RESULTS: Among the 118 participants who completed the study with a median follow-up duration of 48 months (range: 3-66), the adrenalectomy group (n = 46) exhibited a significantly higher frequency of improved weight control, glucose control, and BP control (32.6%, 45.7%, and 45.7%, respectively) compared with the control group (n = 46; 6.5%, P = 0.002; 15.2%, P = 0.002; and 23.9%, P = 0.029, respectively) after matching for age and sex. Adrenalectomy [odds ratio (OR) = 10.38, 95% CI = 2.09-51.52, P = 0.004], body mass index (OR = 1.39, 95% CI = 1.08-1.79, P = 0.010), and cortisol after a 1 mg overnight dexamethasone suppression test levels (OR = 92.21, 95% CI = 5.30-1604.07, P = 0.002) were identified as independent factors associated with improved weight control. Adrenalectomy (OR = 5.30, 95% CI = 1.63-17.25, P = 0.006) and diabetes (OR = 8.05, 95% CI = 2.34-27.65, P = 0.001) were independently associated with improved glucose control. Adrenalectomy (OR = 2.27, 95% CI = 0.87-5.94, P = 0.095) and hypertension (OR = 10.77, 95% CI = 3.65-31.81, P < 0.001) demonstrated associations with improved BP control. CONCLUSIONS: adrenalectomy improved weight, glucose, and BP control in patients with MACS.

Kinase inhibitor pulldown assay (KiP) for clinical proteomics.

Protein kinases are frequently dysregulated and/or mutated in cancer and represent essential targets for therapy. Accurate quantification is essential. For breast cancer treatment, the identification and quantification of the protein kinase ERBB2 is critical for therapeutic decisions. While immunohistochemistry (IHC) is the current clinical diagnostic approach, it is only semiquantitative. Mass spectrometry-based proteomics offers quantitative assays that, unlike IHC, can be used to accurately evaluate hundreds of kinases simultaneously. The enrichment of less abundant kinase targets for quantification, along with depletion of interfering proteins, improves sensitivity and thus promotes more effective downstream analyses. Multiple kinase inhibitors were therefore deployed as a capture matrix for kinase inhibitor pulldown (KiP) assays designed to profile the human protein kinome as broadly as possible. Optimized assays were initially evaluated in 16 patient derived xenograft models (PDX) where KiP identified multiple differentially expressed and biologically relevant kinases. From these analyses, an optimized single-shot parallel reaction monitoring (PRM) method was developed to improve quantitative fidelity. The PRM KiP approach was then reapplied to low quantities of proteins typical of yields from core needle biopsies of human cancers. The initial prototype targeting 100 kinases recapitulated intrinsic subtyping of PDX models obtained from comprehensive proteomic and transcriptomic profiling. Luminal and HER2 enriched OCT-frozen patient biopsies subsequently analyzed through KiP-PRM also clustered by subtype. Finally, stable isotope labeled peptide standards were developed to define a prototype clinical method. Data are available via ProteomeXchange with identifiers PXD044655 and PXD046169.

Stability of twisted states in power-law-coupled Kuramoto oscillators on a circle with and without time delay.

Other than the fully synchronized state, a twisted state can also be an equilibrium solution in the Kuramoto model and its variations. In the present work, we explore the stability of the twisted state in Kuramoto oscillators put on a rim of a planar circle in the two-dimensional space in the presence of power-law decaying interaction strength (∼r^{-α} with the distance r) and time delays due to a finite speed of information transfer. For example, our model can phenomenologically mimic a large sports stadium where many people try to sing or clap their hands in unison; the sound intensity decays with the distance and there can exist a time delay proportional to the distance due to the finiteness of sound speed. We first consider the case without the time delay effect and numerically find that stable twisted states emerge when the exponent α exceeds a critical value of α_{c}≈2. In other words, for α<α_{c}, the fully synchronized state, not the twisted state, is the only stable fixed point of the dynamics. In our analytic approach, we also derive an equation for α_{c} and discuss its solutions. In the presence of time delay, we find that it is possible that the synchronized state becomes unstable while twisted states are stable.

A link between systemic low-grade inflammation and frailty in older adults: clinical evidence from a nationwide population-based study.

Background/Aims: Despite the possible role of systemic low-grade inflammation on frailty, the majority of previous studies have focused solely on the phenotypic frailty with limited participant numbers, thereby weakening the evidence supporting the notion that circulating C-reactive protein (CRP) could be a potential frailty biomarker. Methods: This study is a nationally representative, population-based, cross-sectional analysis from the Korea National Health and Nutrition Examination Survey, involving 5,359 participants aged 65 and older. We generated a deficit accumulation frailty index (FI) based on 38 items, encompassing physical, cognitive, psychological, and social status. Frailty was classified as non-frail (FI ≤ 0.15), pre-frail (0.15 < FI ≤ 0.25), or frail (FI > 0.25). Serum high-sensitivity CRP (hsCRP) levels were measured by immunoturbidometric method. Results: After adjusting for confounders including age, sex, income, education, smoking, hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases, and body mass index, serum hsCRP levels were 29.4% higher in frail participants compared to their non-frail counterparts (p = 0.001). Additionally, circulating hsCRP concentrations positively correlated with the FI (p = 0.003), and the odds ratio for frailty per standard deviation increase in serum hsCRP was 1.18 (p = 0.001). Moreover, older adults in the highest hsCRP quartile exhibited a significant higher FI with a 1.59-fold increased odds ratio for frailty than those in the lowest quartile (p = 0.002 and 0.001, respectively). Conclusions: These findings validate the impact of age-related systemic low-grade inflammation on frailty and support the utility of serum hsCRP as a potential biomarker for detecting frailty in older adults.

Impact of COVID-19 on the Incidence of Fragility Fracture in South Korea.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and the consequent social distancing period are thought to have influenced the incidence of osteoporotic fracture in various ways, but the exact changes have not yet been well elucidated. The purpose of this study was to investigate the impact of the COVID-19 pandemic on the incidence of osteoporotic fracture using a nationwide cohort. METHODS: The monthly incidence rates of vertebral; hip; and non-vertebral, non-hip fractures were collected from a nationwide database of the Korean National Health Insurance Review and Assessment from July 2016 to June 2021. Segmented regression models were used to assess the change in levels and trends in the monthly incidence of osteoporotic fractures. RESULTS: There was a step decrease in the incidence of vertebral fractures for both males (6.181 per 100,000, P=0.002) and females (19.299 per 100,000, P=0.006). However, there was a negative trend in the incidence of hip fracture among both males (-0.023 per 100,000 per month, P=0.023) and females (-0.032 per 100,000 per month, P=0.019). No impact of COVID-19-related social distancing was noted. CONCLUSIONS: In conclusion, during the early days of the COVID-19 pandemic, vertebral fracture incidence considerably decreased with the implementation of social distancing measures.

Quintic refractive index profile-based funnel-shaped silicon antireflective structures for enhanced photodetector performance.

Antireflection, vital in optoelectronics devices such as solar cells and photodetectors, reduces light reflection and increases absorption. Antireflective structures (ARS), a primary method by which to realize this effect, control the refractive index (RI) profile based on their shape. The antireflection efficiency depends on the refractive index profile, with the quintic RI profile being recognized as ideal for superior antireflection. However, fabricating nano-sized structures with a desired shape, particularly in silicon with a quintic RI profile, has been a challenge. In this study, we introduce a funnel-shaped silicon (Si) ARS with a quintic RI profile. Its antireflective properties are demonstrated through reflectance measurements and by an application to a photodetector surface. Compared to the film Si and cone-shaped ARS types, which are common structures to achieve antireflection, the funnel-shaped ARS showed reflectance of 4.24% at 760 nm, whereas those of the film Si and cone-shaped ARS were 32.8% and 10.6%, respectively. Photodetectors with the funnel-shaped ARS showed responsivity of 0.077 A/W at 950 nm, which is 19.54 times higher than that with the film Si and 2.45 times higher than that with the cone-shaped ARS.

Higher serum uric acid as a risk factor for frailty in older adults: A nationwide population-based study.

BACKGROUND: Uric acid (UA), the terminal breakdown product of purine metabolism, possesses contradictory roles, functioning both as an inflammatory mediator and as an antioxidant. Its clinical relevance, particularly in geriatric populations, remains a topic of ongoing debate. Aiming to elucidate whether circulating UA is detrimental or beneficial to human health, we investigate the association between serum UA concentrations and the frailty index-a comprehensive measure of biological aging in a nationally representative cohort of community-dwelling older adults. METHODS: We conducted a population-based, cross-sectional study utilizing data from the Korea National Health and Nutrition Examination Survey. The sample included 4268 participants aged 65 years and above. A deficit accumulation frailty index (FI) was constructed using 38 items that assess physical, cognitive, psychological, and social domains. Based on the FI, participants were categorized into non-frail (FI ≤ 0.15), pre-frail (0.15 < FI ≤ 0.25), or frail (FI > 0.25). Serum UA levels were quantified through a colorimetric enzymatic assay. RESULTS: After controlling for confounders such as age, sex, socioeconomic status (including income and education level), lifestyle factors (smoking status), and medical history (hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases), and body mass index, serum UA levels were observed to be significantly higher in frail participants compared with their non-frail counterparts (P < 0.001). Furthermore, serum UA concentrations demonstrated a positive correlation with the FI (P < 0.001), and the odds ratio for frailty per 1 mg/dL increase in serum UA was 1.22 (P < 0.001). Additionally, older adults in the highest quartile of UA levels exhibited a significantly higher FI and 1.66-fold increased odds of frailty compared with those in the lowest quartile (P = 0.011 and P = 0.005, respectively). CONCLUSIONS: These findings suggest that elevated circulating UA levels may act as a pro-aging factor rather than an anti-aging one in older adults, highlighting its potential role in accelerating biological aging. The data further support the utility of serum UA as a potential blood-based biomarker for frailty in this demographic, contributing to the expanding evidence on its significance in geriatric health assessments.

Fast-Response and Low-Power Self-Heating Gas Sensor Using Metal/Metal Oxide/Metal (MMOM) Structured Nanowires.

With the escalating global awareness of air quality management, the need for continuous and reliable monitoring of toxic gases by using low-power operating systems has become increasingly important. One of which, semiconductor metal oxide gas sensors have received great attention due to their high/fast response and simple working mechanism. More specifically, self-heating metal oxide gas sensors, wherein direct thermal activation in the sensing material, have been sought for their low power-consuming characteristics. However, previous works have neglected to address the temperature distribution within the sensing material, resulting in inefficient gas response and prolonged response/recovery times, particularly due to the low-temperature regions. Here, we present a unique metal/metal oxide/metal (MMOM) nanowire architecture that conductively confines heat to the sensing material, achieving high uniformity in the temperature distribution. The proposed structure enables uniform thermal activation within the sensing material, allowing the sensor to efficiently react with the toxic gas. As a result, the proposed MMOM gas sensor showed significantly enhanced gas response (from 6.7 to 20.1% at 30 ppm), response time (from 195 to 17 s at 30 ppm), and limit of detection (∼1 ppm) when compared to those of conventional single-material structures upon exposure to carbon monoxide. Furthermore, the proposed work demonstrated low power consumption (2.36 mW) and high thermal durability (1500 on/off cycles), demonstrating its potential for practical applications in reliable and low-power operating gas sensor systems. These results propose a new paradigm for power-efficient and robust self-heating metal oxide gas sensors with potential implications for other fields requiring thermal engineering.

A Prospective Comparative Study of 18 F-FDOPA PET/CT Versus 123 I-MIBG Scintigraphy With SPECT/CT for the Diagnosis of Pheochromocytoma and Paraganglioma.

PURPOSE: This study aimed to compare the diagnostic performances of 18 F-FDOPA PET/CT and 123 I-MIBG scintigraphy with SPECT/CT for detection of pheochromocytoma and paraganglioma (PPGL). PATIENTS AND METHODS: We conducted a prospective, single-institution comparative study. Patients suspected of having PPGL or those showing recurrence and/or distant metastasis of PPGL were enrolled. The primary objective was to affirm the noninferiority of 18 F-FDOPA PET/CT for diagnostic sensitivity. Both 123 I-MIBG scintigraphy with SPECT/CT (at 4 and 24 hours) and 18 F-FDOPA PET/CT (at 5 and 60 minutes after radiotracer administration) were performed. The final diagnosis was established either pathologically or via clinical follow-up. Nuclear physicians, unaware of the clinical data, undertook image analysis. RESULTS: Thirty-two patients were evaluated: 14 of 21 with an initial diagnosis and 9 of 11 with recurrence/metastasis had PPGLs in their final diagnoses. In patient-based analyses, 18 F-FDOPA PET/CT (95.7%) exhibited noninferior sensitivity compared with 123 I-MIBG SPECT/CT (91.3%), within the predetermined noninferiority margin of -12% by a 95% confidence interval lower limit of -10%. Both modalities showed no significant difference in specificity (88.9% vs 88.9%). In the region-based analysis for the recurrence/metastasis group, 18 F-FDOPA PET/CT demonstrated significantly higher sensitivity compared with 123 I-MIBG SPECT/CT (86.2% vs 65.5%, P = 0.031) and superior interobserver agreement (κ = 0.94 vs 0.85). The inclusion of an early phase in dual-phase 18 F-FDOPA PET/CT slightly improved diagnostic performance, albeit not to a statistically significant degree. CONCLUSIONS: 18 F-FDOPA PET/CT demonstrated noninferior sensitivity and comparable specificity to 123 I-MIBG SPECT/CT in the diagnosing PPGL. Notably, in the assessment of PPGL recurrence and metastasis, 18 F-FDOPA PET/CT outperformed 123 I-MIBG SPECT/CT in terms of both sensitivity and interobserver agreement.

PKMYT1 is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer.

Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.