A Combined Method of Seismic Monitoring and Transient Electromagnetic Detection for the Evaluation of Hydraulic Fracturing Effect in Coal Burst Prevention.

In order to mitigate the risk of roof-dominated coal burst in underground coal mining, horizontal long borehole staged hydraulic fracturing technology has been prevailingly employed to facilitate the weakening treatment of the hard roof in advance. Such weakening effect, however, can hardly be evaluated, which leads to a lack of a basis in which to design the schemes and parameters of hydraulic fracturing. In this study, a combined underground-ground integrated microseismic monitoring and transient electromagnetic detection method was utilized to carry out simultaneous evaluations of the seismic responses to each staged fracturing and the apparent resistivity changes before and after all finished fracturing. On this basis, the comparable and applicable fracturing effects on coal burst prevention were evaluated and validated by the distribution of microseismic events and their energy magnitude during the mining process. Results show that the observed mining-induced seismic events are consistent with the evaluation results obtained from the combined seismic-electromagnetic detection method. However, there is a limited reduction effect on resistivity near the fractured section that induces far-field seismic events. Mining-induced seismic events are concentrated primarily within specific areas, while microseismic events in the fractured area exhibit high frequency but low energy overall. This study validates the rationality of combined seismic-electromagnetic detection results and provides valuable insights for optimizing fracturing construction schemes as well as comprehensively evaluating outcomes associated with underground directional long borehole staged hydraulic fracturing.

SLC3A2 promotes tumor-associated macrophage polarization through metabolic reprogramming in lung cancer.

Tumor-associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidence indicates that altered metabolic properties in cancer cells support the tumorigenic functions of TAMs. However, the mechanisms and mediators the underly the cross-talk between cancer cells and TAMs remain largely unknown. In the present study, we revealed that high solute carrier family 3 member 2 (SLC3A2) expression in lung cancer patients was associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in a coculture system. Using metabolome analysis, we identified that SLC3A2 knockdown altered the metabolism of lung cancer cells and changed multiple metabolites, including arachidonic acid, in the tumor microenvironment. More importantly, we showed that arachidonic acid was responsible for SLC3A2-mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAM polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming through arachidonic acid.

A nomogram model for predicting malnutrition among older hospitalized patients with type 2 diabetes: a cross-sectional study in China.

BACKGROUND: Malnutrition remains a pervasive issue among older adults, a prevalence that is markedly higher among those diagnosed with diabetes. The primary objective of this study was to develop and validate a risk prediction model that can accurately identify instances of malnutrition among elderly hospitalized patients with type 2 diabetes mellitus (T2DM) within a Chinese demographic. METHODS: This cross-sectional study was conducted between August 2021 and August 2022, we enrolled T2DM patients aged 65 years and above from endocrinology wards. The creation of a nomogram for predicting malnutrition was based on risk factors identified through univariate and multivariate logistic regression analyses. The predictive accuracy of the model was evaluated by the receiver operating characteristic curve (ROC),the area under the ROC (AUC), the concordance index (C-index), and calibration curves. RESULTS: The study included a total of 248 older T2DM patients, with a recorded malnutrition prevalence of 26.21%. The identified critical risk factors for malnutrition in this cohort were body mass index, albumin, impairment in activities of daily living, dietary habits, and glycosylated hemoglobin. The AUC of the nomogram model reached 0.914 (95% CI: 0.877-0.951), with an optimal cutoff value of 0.392. The model demonstrated a sensitivity of 80.0% and a specificity of 88.5%. Bootstrap-based internal verification results revealed a C-index of 0.891, while the calibration curves indicated a strong correlation between the actual and predicted malnutrition risks. CONCLUSIONS: This study underscores the critical need for early detection of malnutrition in older T2DM patients. The constructed nomogram represents a practical and reliable tool for the rapid identification of malnutrition among this vulnerable population.

Evaluation of Anti-Burst Performance in Mining Roadway Support System.

The hazardous effect of a mine earthquake on a roadway is not only related to its energy scale but also to its distance from the roadway. In this study, a signal attenuation model and a disaster-causing model were established to evaluate the mine earthquake effects based on peak particle velocity (PPV) data recorded for 37221-1 upper roadway of the Dongxia Coal Mine, China. The characteristic of dynamic loads due to mine earthquake propagation to roadway surfaces was researched, and critical PPV values were identified using FLAC3D numerical simulation, which can be used to evaluate the roadway anti-burst performance under the existing support system. The results show that the support system is able to resist a mine earthquake with energy below 2.33 × 103 J; however, considering the energy accumulation volume of surrounding rocks and the range of source fracture, the maximum resistible mine earthquake energy can be up to 7.09 × 106 J when the roadway is 50 m away from the source. The validity and applicability of the disaster-causing models was verified by two rockburst cases that occurred during the excavation of the working face.

The rapid start-up of CANON process through adding partial nitration sludge to ANAMMOX system.

This study aimed to start up the completely autotrophic nitrogen removal over nitrite (CANON) process after adding partial nitration (PN) sludge to the ANAMMOX reactor, so as to help the rapid start-up and stable operation of the CANON process in practical engineering applications. There were three steps in the research: cultivating the PN sludge, building a reliable ANAMMMOX system, and finally starting and running the CANON process. The PN sludge was successfully cultivated in less than 45 days with around 90% nitrite accumulation rate. The ANAMMOX reactor enriched a significant quantity of red granular sludge within 70 days, achieving the maximum nitrogen removal rate of 1.74 kg/(m3·d). Eventually, the CANON reactor was started up successfully, which achieved 95.08% of average ammonium removal efficiency and 84.51% of average total nitrogen removal efficiency in 60 days. The residual recalcitrant nitrite-oxidizing bacteria in the CANON process was successfully inhibited by intermittent aeration and 12 mg/L free ammonia in UASB reactor. Besides, Candidatus Kuenenia, Candidatus Brocadia and Nitrosomonas were the main functional microorganisms involved in the CANON process.

Decomposition Mechanism of Isoprenoid Hydrocarbon p-Menthane in the Presence of Pt@FGS Nanoparticles: A ReaxFF-MD Study.

Pt@FGS nanoparticles have shown effective enhancement in the decomposition of hydrocarbon fuels. To further explore the potential enhancing mechanisms of Pt@FGS nanoparticles, the catalytic decomposition of p-menthane, a bioderived isoprenoid "drop-in" fuel with great promise, is investigated here using the reactive force-field molecular dynamics (ReaxFF-MD) simulations. The results show that the Pt@FGS nanoparticles exhibit good catalytic reactivity with a reduction of the activation energy by nearly 62%. Possible initial reactions of enhanced p-menthane (PMT) decomposition are discussed, which suggests that the supported Pt-cluster plays a key role in the dehydrogenation of PMT, as does the oxygen-containing functional group of the functionalized graphene sheets (FGS). It is also interesting to note that the presence of Pt@FGS causes the initial reactions, which are dominated by H-abstraction, favorable in both kinetics and thermodynamics.

Evolution Characteristics of Seismic Detection Probability in Underground Mines and Its Application for Assessing Seismic Risks-A Case Study.

Seismic hazards are typical mining hazards causing dynamic failure of coal and rock mass, which greatly threatens the safety of personnel and equipment. At present, various seismic analysis methods are used to assess seismic risks but their accuracy is significantly limited by the incompleteness of seismic data. The probability of detecting earthquakes (PDE) method has been proven as a powerful means for retrieving missed seismic events and enhancing the seismic data integrity in mines. However, to date, the reliability of the results of the PDE method has not been assessed and the highly integrated seismic data have not been linked with the actual hazard potential. To fill these gaps, this paper investigated the impacts of the seismic data volume used for calculation and the modification of the layout of sensors on the reliability and robustness of the PDE method. The event counts and seismic energy were compensated using the PDE method, correlated with strong seismic events. The results indicated that the compensated seismic data presented higher accuracy in locating future hazardous events than before. This research provides references on enhancing the performance of seismic analysing methods for seismic risk assessments.

Template Guiding for the Encapsulation of Uniformly Subnanometric Platinum Clusters in Beta-Zeolites Enabling High Catalytic Activity and Stability.

Subnanometric metal clusters have attracted extensive attention because of their unique properties as heterogeneous catalysts. However, it is challenging to obtain uniformly distributed metal clusters under synthesis and reaction conditions. Herein, we report a template-guidance protocol to synthesize subnanometric metal clusters uniformly encapsulated in beta-zeolite, with the metal ions anchored to the internal channels of the zeolite template via electrostatic interactions. Pt metal clusters with a narrow size range of 0.89 to 1.22 nm have been obtained on the intersectional sites of beta-zeolite (Pt@beta) with a broad range of Si/Al molar ratios (15-200). The uniformly distributed Pt clusters in Pt@H-beta are subject to strong electron withdrawal by the zeolite, which promotes transfer of active hydrogen, providing excellent activity and stability in hydrodeoxygenation reactions. A general strategy is thus proposed for the encapsulation of subnanometric metal clusters in zeolites with high thermal stability.

The remission phase in type 1 diabetes: Changing epidemiology, definitions, and emerging immuno-metabolic mechanisms.

Type 1 diabetes mellitus (T1DM) is characterized by irreversible islet ß cell destruction. During the progression of this disease, some patients with T1DM experience a phase of remission known as honeymoon or partial remission (PR) that is mainly characterized by satisfactory glycemic control and the transient recovery of islet ß cell function. This special phase is a good model for studying the mechanism of ß cell protection, might serve as a proper intervention period for immunotherapy, and may be related to disease prognosis. This special stage is highly valuable for studies aiming to identify possible targets that may be used to cure T1DM. An in-depth understanding of the diagnosis, epidemiology, and possible mechanisms of the PR phase is highly needed. In general, patients enter the PR phase approximately 3 months after starting insulin therapy, and this phase could be sustained for 6 to 9 months. Current research increasingly focuses on the metabolic and immunological aspects to constantly update our understanding of this phase. This review concentrates on the PR phase of T1DM to provide a comprehensive outlook of its epidemiology, diagnostic criteria, and underlying immune metabolic mechanisms.

Complicated curve association of body weight at diagnosis with C-peptide in children and adults with new-onset type 1 diabetes.

AIM: To investigate the association of body mass index (BMI) or BMI z-score (BMIz) at diagnosis with ß-cell function in new-onset type 1 diabetes (T1D) patients in children and adults. METHODS: This was a retrospective cohort study; 256 children (<18 years) and 245 adults (≥18 years) with less than 1-year duration were recruited and followed for 4 years with an interval of 12 months. Smooth curve fitting, a two-piecewise linear model, and Cox proportional hazards models were utilized to investigate the influence of BMI/BMIz on C-peptide levels. RESULTS: Heavier patients (BMIz ≥ -1 in children and BMI in adults ≥20.2 kg/m2 ) had greater C-peptide with a complicated J curve in all age groups after adjustment for age of onset, sex, and disease duration. Moreover, after 4 years of follow-up, patients with higher BMI/BMIz had a lower risk of ß-cell failure (HR = 0.7; 95% CI, 0.6-1.0; P = .026). However, no association was found between baseline BMI/BMIz at diagnosis and C-peptide rate of decline during 1 year follow-up. CONCLUSION: Association between BMI/BMIz and C-peptide in T1D followed a complicated J curve pattern, and heavier patients had greater C-peptide at diagnosis and a lower risk of ß-cell failure at 4 years, suggesting that baseline BMI is a useful predictor for ß-cell function in patients with T1D.

Angiotensin II Type 1 Receptor Autoantibodies in Primary Aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1R-Abs) have been described in transplantation medicine and women with pre-eclampsia and more recently in patients with PA. Any functional role of AT1R-Abs in either of the two main subtypes of PA (aldosterone-producing adenoma or bilateral adrenal hyperplasia) requires clarification. In this review, we discuss the studies performed to date on AT1R-Abs in PA.

The Prevalence and Associated Factors of Post-COVID-19 Fatigue: A Systematic Review and Meta-Analysis.

After the coronavirus disease 2019 (COVID-19) pandemic, numerous individuals experienced the enduring consequences of infection. One of the psychological symptoms that patients report most frequently is persistent fatigue, which is also called post-COVID-19 fatigue. This persistent fatigue can prolong recovery time for hospitalized patients and reduce exercise motivation for residents, affecting their health and working conditions. To determine the prevalence and associated factors, we conducted searches in PubMed, Embase, Web of Science, and Cochrane Library, from inception to 27 March 2023, and a total of 38 studies and 17,738 patients were included in this analysis. We analyzed data and estimated publication bias by Egger's test and funnel plot by STATA 14. We summarized the prevalence of post-COVID-19 fatigue and calculated the pooled OR to determine associated factors. This study revealed that the prevalence of fatigue in post-COVID-19 syndrome was 46.6% (95% CI: 38.5%-54.7%). Being female (OR: 0.40, 95% CI: 0.24-0.56), older age (OR: 0.04, 95% CI: 0.01-0.07), clinical severity (OR: 0.66, 95% CI: 0.24-1.09), the number of acute COVID symptoms (OR: 3.23, 95% CI: 1.83-5.69), preexisting hypertension (OR: 1.24, 95% CI: 1.08-1.42), lung disease (OR: 2.71, 95% CI: 1.07-6.89), and depression (OR: 1.55, 95% CI: 1.01-2.39) were risk factors for post-COVID-19 fatigue. By revealing the association of these factors with fatigue, it can help us to identify and treat post-COVID-19 fatigue early.

Efficacy of non-pharmacological interventions for sleep quality in Parkinson's disease: a systematic review and network meta-analysis.

Background: Sleep disorders are one of the most common non-motor symptoms in PD. It can cause a notable decrease in quality of life and functioning in PD patients, as well as place a huge burden on both patients and caregivers. Currently, there are numerous non-pharmacological interventions available to improve sleep quality in PD, with disagreement as to which intervention is most effective. This network meta-analysis was performed to compare and rank non-pharmacological interventions to explore their efficacy in improving sleep quality in PD and to select the best interventions, with a view to providing references and bases for the development of clinical treatments and care programs. Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched from inception to December 6, 2023. Two authors independently screened all studies, extracted the data, and evaluated risk of bias of included studies. STATA software version 17.0 was used to conduct the network meta-analysis. Results: Our network meta-analysis included 29 studies involving 1,477 participants and 16 non-pharmacological interventions. Although most nonpharmacological interventions showed non-significant effects, the surface under the cumulative ranking curve (SUCRA) values indicated that the best non-pharmacological intervention for sleep disorders was massage therapy (97.3%), followed by music therapy (94.2%), and Treadmill training (85.7%). Conclusion: Massage therapy can be considered as an effective therapy for improving sleep quality in patients with PD. Due to limited quantity and quality of the included studies, more high quality studies are required to verify the conclusions of this network meta-analysis. Systematic review registration: identifier CRD42023429339, PROSPERO (york.ac.uk).

Impacts of information quantity and display formats on driving behaviors in a connected vehicle environment.

The emerging connected vehicle (CV) technologies facilitate the development of integrated advanced driver assistance systems (ADASs), with which various functions are coordinated in a comprehensive framework. However, challenges arise in enabling drivers to perceive important information with minimal distractions when multiple messages are simultaneously provided by integrated ADASs. To this end, this study introduces three types of human-machine interfaces (HMIs) for an integrated ADAS: 1) three messages using a visual display only, 2) four messages using a visual display only, and 3) three messages using visual plus auditory displays. Meanwhile, the differences in driving performance across three HMI types are examined to investigate the impacts of information quantity and display formats on driving behaviors. Additionally, variations in drivers' responses to the three HMI types are examined. Driving behaviors of 51 drivers with respect to three HMI types are investigated in eight field testing scenarios. These scenarios include warnings for rear-end collision, lateral collision, forward collision, lane-change, and curve speed, as well as notifications for emergency events downstream, the specified speed limit, and car-following behaviors. Results indicate that, compared to a visual display only, presenting three messages through visual and auditory displays enhances driving performance in four typical scenarios. Compared to the presentation of three messages, a visual display offering four messages improves driving performance in rear-end collision warning scenarios but diminishes the performance in lane-change scenarios. Additionally, the relationship between information quantity and display formats shown on HMIs and driving performance can be moderated by drivers' gender, occupation, driving experience, annual driving distance, and safety attitudes. Findings are indicative to designers in automotive industries in developing HMIs for future CVs.

Preoperative supine time for adrenal venous sampling: a prospective randomized controlled trial.

BACKGROUND: Primary aldosteronism (P.A.) is the most common form of secondary hypertension, accounting for 5% of hypertensive patients and 17-23% of patients with resistant hypertension. Compared to primary hypertension, P.A. is more prone to cause severe organ damage and even early death. Adrenal venous sampling (AVS) is a practical confirmatory test for subtyping aldosterone-producing adenoma and bilateral adrenal hyperplasia, helping physicians to make an accurate decision between surgery or medication. According to guidelines, supine in bed before AVS is recommended for a desirable result of AVS. However, investigations about the most optimal preoperative supine time before AVS are lacking. METHODS/DESIGN: This is a multi-center prospective randomized controlled study. One hundred twenty patients diagnosed as P.A. and willing for AVS examination will be included. Participants will be randomly allocated to a 15-min supine time group or 2-h supine time group. The primary outcome is the degree of biochemical remission (serum potassium and orthostatic ARR). The secondary outcomes are degrees of clinical remission (blood pressure, type and dose of antihypertensive drugs), the technical success rate, and the adverse event of AVS (selective index ≥ 2 is considered successful surgery without corticotropin stimulation). DISCUSSION: P.A. is an intractable public health problem, and many techniques including AVS have been developed to identify this disease correctly. This study will help to understand whether the length of preoperative supine time would affect the diagnostic efficacy of AVS and thus help to formulate a more reasonable AVS procedure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05658705. Registered on 10 September 2022.

Frequency and Risk Factors of Subsyndromal Delirium in the Intensive Care Units: A Prospective Cohort Study.

Background: Subsyndromal delirium (SSD) is a common neuropsychiatric disorder among the intensive care units (ICU) patients. SSD is characterized by the presence of delirium symptoms but it does not meet the diagnostic criteria of delirium, resulting in poor patient prognosis. Objective: The aim of this study was to explore the prevalence and risk factors for SSD among adult patients admitted to the ICU of XXX hospital in Southwest China. Methods: The study participants comprised 309 patients referred to the ICU in XXX hospital between 10th August 2021 and 5th June 2022. Demographic information, medical history, and other patient information were recorded. ICDSC assessment, physical examination and laboratory tests were performed on enrolled patients. Cognitive evaluation was conducted using the MMSE method. Results: The results showed that out the 309 patients, 99 had possible SSD (prevalence of 32.0%), with 55 SSD1 cases (ICDSC score of 1, 17.8% prevalence), 29 SSD2 cases (ICDSC score of 2, 9.4% prevalence) and 15 SSD3 cases (ICDSC score of 3, 4.9% prevalence). Previous history of mental illness (OR, 3.741; 95% CI, 1.136-12.324; P <0.05), auxiliary ventilation (OR, 3.364; 95% CI, 1.448-7.813; P <0.01), hemodialysis (OR, 11.369; 95% CI, 1.245-103.840; P <0.05), MMSE score (OR, 0.845; 95% CI, 0.789-0.904; P <0.001) and a temperature ≥ 37.5 °C (OR, 3.686; 95% CI, 1.404-9.732; P <0.01) were independent risk factors for occurrence of SSD among ICU patients. Conclusion: Approximately one-third of the patients in the intensive care unit had high risk of SSD. Nursing staff should pay attention to management of the high-risk patients to prevent SSD from progressing delirium to improve patient prognosis.

Effects of collision warning characteristics on driving behaviors and safety in connected vehicle environments.

With the emerging connected vehicle (CV) technologies, a novel in-vehicle omni-direction collision warning system (OCWS) is developed. For example, vehicles approaching from different directions can be detected, and advanced collision warnings caused by vehicles approaching from different directions can be provided. Effectiveness of OCWS in reducing crash and injury related to forward, rear-end and lateral collision is recognized. However, it is rare that the effects of collision warning characteristics including collision types and warning types on micro-level driver behaviors and safety performance is assessed. In this study, variations in drivers' responses among different collision types and between visual only and visual plus auditory warnings are examined. In addition, moderating effects by driver characteristics including drivers' demographics, years of driving experience, and annual driving distance are also considered. An in-vehicle human-machine interface (HMI) that can provide both visual and auditory warnings for forward, rear-end, and lateral collisions is installed on an instrumented vehicle. 51 drivers participate in the field tests. Performance indicators including relative speed change, time taken to accelerate/decelerate, and maximum lateral displacement are adopted to reflect drivers' responses to collision warnings. Then, generalized estimation equation (GEE) approach is applied to examine the effects of drivers' characteristics, collision type, warning type and their interaction on the driving performance. Results indicate that age, year of driving experience, collision type, and warning type can affect the driving performance. Findings should be indicative to the optimal design of in-vehicle HMI and thresholds for the activation of collision warnings that can increase the drivers' awareness to collision warnings from different directions. Also, implementation of HMI can be customized with respect to individual driver characteristics.

TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas.

BACKGROUND: Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a condition of low-renin hypertension, in which aldosterone overproduction is usually driven by a somatic activating mutation in an ion pump or channel. TSPAN12 is differentially expressed in different subgroups of APAs suggesting a role in APA pathophysiology. Our objective was to determine the function of TSPAN12 (tetraspanin 12) in adrenal physiology and pathophysiology. METHODS: APA specimens, pig adrenals under dietary sodium modulation, and a human adrenocortical cell line HAC15 were used for functional characterization of TSPAN12 in vivo and in vitro. RESULTS: Gene ontology analysis of 21 APA transcriptomes dichotomized according to high versus low TSPAN12 transcript levels highlighted a function for TSPAN12 related to the renin-angiotensin system. TSPAN12 expression levels in a cohort of 30 APAs were inversely correlated with baseline plasma aldosterone concentrations (R=-0.47; P=0.009). In a pig model of renin-angiotensin system activation by dietary salt restriction, TSPAN12 mRNA levels and TSPAN12 immunostaining were markedly increased in the zona glomerulosa layer of the adrenal cortex. In vitro stimulation of human adrenocortical human adrenocortical cells with 10 nM angiotensin II for 6 hours caused a 1.6-fold±0.13 increase in TSPAN12 expression, which was ablated by 10 µM nifedipine (P=0.0097) or 30 µM W-7 (P=0.0022). Gene silencing of TSPAN12 in human adrenocortical cells demonstrated its inverse effect on aldosterone secretion under basal and angiotensin II stimulated conditions. CONCLUSIONS: Our findings show that TSPAN12 is a negative regulator of aldosterone production and could contribute to aldosterone overproduction in primary aldosteronism.

Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas.

BACKGROUND: Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). We exploited these differences to decipher the roles of transcriptome and metabolome reprogramming in tumor pathogenesis. METHODS: Consecutive adrenal cryosections (7 APAs and 7 paired adjacent adrenal cortex) were analyzed by spatial transcriptomics (10x Genomics platform) and metabolomics (in situ matrix-assisted laser desorption/ionization mass spectrometry imaging) co-integrated with CYP11B2 immunohistochemistry. RESULTS: We identified intratumoral transcriptional heterogeneity that delineated functionally distinct biological pathways. Common transcriptomic signatures were established across all APA specimens which encompassed 2 distinct transcriptional profiles in CYP11B2-immunopositive regions (CYP11B2-type 1 or 2). The CYP11B2-type 1 signature was characterized by zona glomerulosa gene markers and was detected in both APA-KCNJ5MUT and APA-KCNJ5WT. The CYP11B2-type 2 signature displayed markers of the zona fasciculata or reticularis and predominated in APA-KCNJ5MUT. Metabolites that promote oxidative stress and cell death accumulated in APA-KCNJ5WT. In contrast, antioxidant metabolites were abundant in APA-KCNJ5MUT. Finally, APA-like cell subpopulations-negative for CYP11B2 gene expression-were identified in adrenocortical tissue adjacent to APAs suggesting the existence of tumor precursor states. CONCLUSIONS: Our findings provide insight into intra- and intertumoral transcriptional heterogeneity and support a role for prooxidant versus antioxidant systems in APA pathogenesis highlighting genotype-dependent capacities for tumor expansion.

Primary aldosteronism: Pathophysiological mechanisms of cell death and proliferation.

Primary aldosteronism is the most common surgically curable form of hypertension. The sporadic forms of the disorder are usually caused by aldosterone overproduction from a unilateral adrenocortical aldosterone-producing adenoma or from bilateral adrenocortical hyperplasia. The main knowledge-advances in disease pathophysiology focus on pathogenic germline and somatic variants that drive the excess aldosterone production. Less clear are the molecular and cellular mechanisms that lead to an increased mass of the adrenal cortex. However, the combined application of transcriptomics, metabolomics, and epigenetics has achieved substantial insight into these processes and uncovered the evolving complexity of disrupted cell growth mechanisms in primary aldosteronism. In this review, we summarize and discuss recent progress in our understanding of mechanisms of cell death, and proliferation in the pathophysiology of primary aldosteronism.