Reference Subjects Research Articles

Integrated multi-omics analysis of the microbial profile characteristics associated with pulmonary arterial hypertension in congenital heart disease.

Dysregulation of immune and inflammatory cells around blood vessels and metabolic dysfunction are key mechanisms in the development of pulmonary arterial hypertension (PAH). The homeostasis of the human microbiome plays a crucial role in regulating immune responses and the progression of diseases. For pulmonary arterial hypertension associated with congenital heart disease involving body-lung shunt (PAH-CHD), the potential impact of the microbiome on the "gut-lung axis" remains underexplored. This study recruited 15 healthy individuals and 15 patients with pulmonary arterial hypertension due to congenital heart disease from Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, and Kunming Children's Hospital. We performed differential analyses of metabolites and microbiota from both the gut and lower respiratory tract for these two groups. The goal was to investigate the "gut-lung axis" microbiome and metabolome profiles in children with PAH-CHD and to analyze the interrelationships between these profiles. Ultimately, we aim to propose the potential value of these profiles in aiding diagnosis. The results indicated that the gut and pulmonary microbiota of children with PAH-CHD are characterized by an increased abundance of beneficial symbionts, which are closely linked to changes in the metabolome. Metabolite functional enrichment analysis revealed energy metabolism reprogramming in the PAH-CHD group, with active metabolic pathways associated with bile acid secretion and carnitine homeostasis. Moreover, the differential expression of metabolites was correlated with right heart function and growth development.IMPORTANCEPrevious studies have primarily focused on the relationship between the gut microbiome and PAH. However, the impact of microbial homeostasis on the progression of PAH-CHD from the perspective of the gut-lung axis has not been adequately elucidated. Our study utilizes an integrated multi-omics approach to report on the differential characteristics of gut and lung microbiota between children with PAH-CHD and reference subjects. We found that microbiota influence the pathological changes and disease manifestations of PAH-CHD through their metabolic activity. Additionally, alterations in metabolites impact the microbial ecological structure. Our findings suggest that modulating the microbiome composition may have positive implications for maintaining and regulating the immune environment and pathological progression of PAH-CHD.

6427 Impact of Adrenalectomy On Frailty And Muscle Function In Patients With Mild Autonomous Cortisol Secretion: A Prospective Longitudinal Study

Abstract Disclosure: J. Saini: None. V. Fell: None. B. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have a higher prevalence of frailty and reduced muscle strength as compared to patients with nonfunctioning adrenal adenomas or subjects without adrenal disorders. Objective: To determine the impact of adrenalectomy on frailty and parameters of functional strength in patients with MACS. Methods: We conducted a single-center prospective longitudinal study of adults with MACS scheduled for adrenalectomy and referent subjects evaluated between 2018 and 2023. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Patients and referent subjects had a baseline and a follow-up evaluation at least 10 months later. Differences were assessed using paired t-tests for (1) Frailty Index (FI)--calculated using a questionnaire containing 47 variables on comorbidities, symptoms, and daily living activities (frailty defined as FI>0.25) (2) physical function assessed using handgrip strength (Jamar Plus digital hand dynamometer), timed up-and-go test (time taken to rise from a chair, walk to and from 3 m, and sit down), gait speed, 6-minute walk test, and (3) Advanced Glycation End (AGE) Product (using AGE reader). Results: We evaluated 41 patients before and after adrenalectomy, and 31 referent subjects at baseline and follow-up visit, at a similar interval (median 1.6, IQR 1.2-2.0 vs 1.5 years, IQR 1.0-2.2, P=0.759). While sex distributions were no different between the 2 groups (women, 66% vs 84%, P=0.086), patients with MACS were older than the referent group (median age 57.3, IQR 48.8-66.9 vs 49.0, IQR 41.7-57.9 years, P=0.005). Post-adrenalectomy, FI decreased by a mean of 0.057 (SD 0.08), P<0.001 in patients, and remained unchanged in the referent group. AGE decreased in patients by 0.148 (SD 0.45), P=0.04 but not in referent subjects (-0.047, SD 0.242, P=0.5). Patients demonstrated no improvement in parameters of muscle strength: gait speed (mean change 0.305 m/s, P=0.453), 6-minute walk test (mean change 16.4 meters, P=0.201), dominant (mean Z score change -0.055, P=0.72) and nondominant (mean Z score change -0.199, P=0.192) hand grip muscle strength. At follow-up, both patients (mean change 1.897 seconds, P<0.001) and referent subjects (mean change=1.475 seconds, P<0.001) demonstrated a deterioration on the timed up-and-go test. Conclusions: While no improvement was seen in the parameters of muscle strength, adrenalectomy improved the frailty index in patients with MACS. In addition, AGE, a biomarker associated with cardiovascular morbidity, decreased after adrenalectomy, suggesting a beneficial cardiovascular impact of MACS reversal. Presentation: 6/1/2024

8740 Visceral Adipose Tissue Assessment in Patients With Mild Autonomous Cortisol Secretion Using Dual-Energy X-Ray Absorptiometry: A Cross-Sectional Study

Abstract Disclosure: J. Saini: None. C.D. Zhang: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Several studies employing computed tomography (CT) scans for body composition measurements have reported lower muscle mass and a higher proportion of visceral fat in patients with mild autonomous cortisol secretion (MACS) compared to referent subjects. While a CT scan assesses visceral adipose tissue (VAT) at a single slice level (L3), no studies have evaluated the overall VAT in patients with MACS using Dual-Energy X-ray absorptiometry (DXA). Objective: To determine the impact of MACS on VAT using DXA scan as compared to referent subjects. Methods: We conducted a single-center cross-sectional study of adults with 75 MACS and 75 referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. All the participants underwent a full body DXA scan between 04/2019 and 07/2022. We applied the CoreScan software to estimate the (1) total lean and fat mass (2) visceral fat mass and volume (3) lean android, fat android, and android mass, and compared measurements of patients and referent subjects using linear regression models adjusted for sex and BMI. Results: A total of 75 patients with MACS (median age 57.0 years, IQR 47.8-65.6, 67% women) and 75 referent subjects (median age 57.6 years, IQR 49.1-65.8, 67% women) were included. Patients had a higher BMI compared to referent subjects (median 31.7 kg/m2, IQR 27.4-37.9 vs 28.7, IQR, 25.4-33.8, P=0.004). The median post-DST cortisol in patients was 3.1 mcg/dL (IQR, 2.2-5.2). When compared to referent subjects, and after adjustment for sex and BMI, patients had a similar total body fat (estimate=846, p-value=0.28) and lean mass (estimate=-201, p-value=0.83), similar android fat mass (estimate=59, p-value=0.64) but lower gynoid fat mass (estimate=400, 0.007). Notably, sex and BMI-adjusted analysis also showed that patients had a higher VAT fat mass (estimate= -225, p-value=0.084) and a higher VAT fat mass/total mass ratio (estimate= -0.007, p-value=0.026). Conclusions: When adjusted for BMI and sex, patients with MACS do not demonstrate differences in overall fat and lean mass. However, we showed that MACS is associated with increased visceral adiposity, a known cardiovascular risk factor. Body composition assessment by DXA could be a safer and less expensive alternative in the evaluation and follow-up of patients with MACS. Presentation: 6/2/2024

6425 Impact Of Adrenalectomy On Mood, Sleep, And Quality Of Life In Patients With Mild Autonomous Cortisol Secretion: A Prospective Longitudinal Study

Abstract Disclosure: J. Saini: None. V. Fell: None. B. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have an impaired quality of life and a higher prevalence of sleep and mood disturbances as compared to patients with nonfunctioning adrenal adenomas. The impact of adrenalectomy on quality of life, mood, and sleep is unclear. Objective: To determine the impact of adrenalectomy on quality of life, sleep, and mood in patients with MACS Methods: We conducted a single-center prospective longitudinal study of adults with MACS scheduled for adrenalectomy and referent subjects evaluated between 2018 and 2023. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Patients and referent subjects had a baseline and a follow-up evaluation at least 10 months later. Differences were assessed using paired t-tests for (1) Quality of life using Short Form-36 (SF 36) survey (Physical and Mental component summary score), sex and age-adjusted (2) Mood using Beck’s Depression Inventory (BDI) (3) Sleep using Pittsburgh Sleep Quality Index (PSQI). Results: We evaluated 41 patients before and after adrenalectomy, and 31 referent subjects at baseline and follow-up visit, at a similar interval (median 1.6, IQR 1.2-2.0 vs 1.5 years, IQR 1.0-2.2, P=0.759). While sex distribution was similar between the groups (66% vs 84% women, P=0.086), patients with MACS were older than the referent group (median age 57.3, IQR 48.8-66.9 vs 49.0, IQR 41.7-57.9 years, P=0.005). After adrenalectomy, patients improved their mood with a mean decrease of -4.71 (SD: 9.11), P=0.002 on the BDI questionnaire. Patients also demonstrated improvement in the SF-36 mental component score by a mean of 6.48 (SD: 10.97), P<0.001. While the overall SF36 physical component score did not improve after adrenalectomy (1.953 (SD: 11.02), P=0.269), one of the PCS components, role-physical limitation, increased by a mean of 6.25 (SD: 13.03). Patients reported better sleep with PSQI score decreasing by a mean of -2.59 (SD: 3.64), P<0.001. No differences in BDI, SF36, and PSQI were observed between baseline and follow-up in referent subjects. Conclusions: After adrenalectomy, patients with MACS showed an improvement in sleep, mood, and mental component of quality of life. Presentation: 6/3/2024

9360 Evaluating The More Accurate Indicator Of Kidney Function In Mild Autonomous Cortisol Secretion: EGFR Creatinine Versus EGFR Cystatin

Abstract Disclosure: L. Rahimi: None. J. Saini: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) have higher prevalence of cardiovascular comorbidities including chronic kidney disease. However, considering that patients with MACS may have relative skeletal muscle atrophy, it is unclear whether the creatine-based assessment of kidney function is accurate in this population. Objective: To characterize the differences in assessing estimated glomerular filtration rate using cystatin (eGFRcys) versus creatinine (eGFRcre) in patients with MACS versus referent subjects. Methods: Cross-sectional single-center study, 2019-2022. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST). For each patient, eGFRcre, eGFRcys and eGFRcre/eGFRcys ratio were measured and compared between the two groups. Body composition was measured by DXA scan. The Kruskal-Wallis test was used to compare measurements between groups. Result: A total of 37 patients with MACS (median age 59 years (interquartile range, IQR 47-67), 25 (68%) women) and 45 referent subjects (median age 57 years (IQR 51-66), 30 (67%) women) were included. The distribution of BMI, total body fat mass and total body lean mass were similar between the two groups. In the MACS cohort, the median cortisol following 1-mg DST was 3.0 ug/dL (IQR, 2.2-4.0). While assessment of kidney function with eGFRcre showed no differences between patients with MACS and referent subjects (median 85.1 vs 87.0 ml/min/1.73m2, P=0.431), kidney function using eGFRcys was lower in MACS (median 78.0 vs 89.3 ml/min/1.73m2 in referents, P<0.014), resulting also in a higher eGFRcre/eGFRcys ratio (median 1.07 vs 0.97 in MACS vs referents, P=0.053). After adjusting for age, sex, and BMI, a higher 1 mg DST cortisol level in the MACS cohort was associated with a higher eGFRcre/eGFRcys ratio (Spearman correlation coefficient of 0.35, P = 0.042). Lower eGFRcys was associated with higher fat mass (Spearman correlation of -0.26, P = 0.023), and a higher eGFRcre/eGFRcys ratio showed a trend towards lower lean mass (Spearman correlation of -0.20, P = 0.081). Conclusion: Creatinine-based eGFR assessment in patients with MACS underestimates the degree of kidney dysfunction, likely due to underlying skeletal muscle atrophy. eGFRcys is a more accurate indicator of kidney function in patients with hypercortisolism. Presentation: 6/1/2024

6612 Both Overt And Mild Hypercortisolism Accelerate Biological Aging

Abstract Disclosure: K. Yu: None. J. Saini: None. J.N. Farr: None. F. Vanessa: None. S. Khosla: None. I. Bancos: Advisory Board Member; Self; AstraZeneca, Adrenas, Neurocrine, Spruce, Recordati, Xeris, Novo Nordisk, HRA Pharmaceuticals, Sparrow, Diurnal, Corcept. Research Investigator; Self; HRA Pharmaceuticals, Recordati. Importance: Patients with both mild autonomous cortisol secretion (MACS) and overt Cushing syndrome (CS) demonstrated high prevalence of aging-related morbidity and an increased mortality. Objective: To determine whether p16INK4a in T cell, a cell cycle enzyme that associated with chronological aging and cell senescence, is associated with hypercortisolism and hypercortisolism-related comorbidities. Design, Setting, and Participants: In this single-center cross-sectional study, we prospectively recruited consecutive patients with hypercortisolism between July 1, 2020 and August 24 2022. Patients were included if they were diagnosed with Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS). Age- (± 2 years) and sex-matched referent subjects without known adrenal disorders were included if abdominal imaging was available. Participants on exogenous glucocorticoids within 3 months prior were excluded. Exposure: Presence of hypercortisolism (MACS and CS). Main Outcomes and Measures: Primary outcomes included p16INK4a, advanced glycation end products (AGE) reader result, Frailty Index score, frailty (defined as frailty index>0.31), and physical performances in patients and matched referents at index date. Secondary outcomes included correlation between biological age markers, hormonal workup and the risk of comorbidities. p16INK4a expression analysis was adjusted for age, sex, smoking, and alcohol use for all analyses except for associations with CVD and frailty. Results: Of 85 patients (87% women, mean age 53 years), 51 (60%) had MACS (34 had matched referents), 34 (40%) had overt CS (16 had matched referents). Patients with CS demonstrated a median 1.9-fold higher p16INK4a expression (P<.001), and patients with MACS showed a median of 1.70-fold p16INK4a expression (P=.013), when compared to referent subjects. Age- and sex-adjusted p16INK4a expression was associated with frailty index score (r=0.23, P=.035), time-up-and-go test (r=0.28, P=.048), gait speed (r=-0.36, P=.035), but not with AGE reader result, 6-minute walk test, or hand grip measurement. The p16INK4a expression was associated with history of cardiovascular disease (age-adjusted odds ratio (aOR)=3.70, 95% confidence interval (CI), 1.20-11.43) and frailty (aOR=2.27, 95%CI, 1.04-4.98). Conclusion and relevance: We demonstrated evidence of cell senescence in both patients with CS and patients with MACS. Further studies need to determine the impact of surgical, cortisol-lowering, and senolytic medical therapies in MACS on cell senescence and associated aging-related comorbidities. Presentation: 6/1/2024

12426 Performance Of Dehydroepiandrosterone-Sulphate In Diagnosing Mild Autonomous Cortisol Secretion: A Systematic Review And Meta-Analysis

Abstract Disclosure: J. Saini: None. B. Salama: None. S.R. Chacko: None. K. Yu: None. I. Bancos: None. Objective: Measurement of baseline dehydroepiandrosterone sulfate (DHEAS) is suggested by the guidelines in support of diagnosing mild autonomous cortisol secretion (MACS). However, evidence on the diagnostic accuracy of DHEAS in MACS is difficult to interpret due to differences in the diagnostic cutoffs, small sample size, and heterogeneous reference standards. We aimed to conduct a systematic review and meta-analysis of published literature to assess the performance of DHEAS in diagnosing MACS, as defined in the 2023 guidelines. Methods: A comprehensive search was conducted using several databases from each database’s inception to January 8th, 2024. Databases include Ovid MEDLINE (R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Databases of Systematic Reviews, and Scopus. Only original studies of at least 20 participants were included. MACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. QUADAS-2 was used to assess the risk of bias. Bivariate and random effects meta-analysis was used to generate pooled diagnostic accuracy estimates. Results: The initial search yielded 285 articles, and only 7 studies met the inclusion criteria. In 7 studies (1 from North America, 3 from Asia, and 3 from Europe), a total of 574 patients with MACS and 830 referent subjects (patients with adrenal tumors without MACS) were included. The mean age was specified only in 5 studies and was similar in patients with MACS (55.5 years) and referent group (53.3 years). Patients with MACS had a higher number of women (323/472, 68.4%) as compared to the referent group (352/658, 53.4%). DHEAS cutoffs studied included: lower cutoff of age-and sex-specific ranges (3 studies), 40 mcg/dL (3 studies), 60 mcg/dL (1 study), and 67.5 mcg/dL (1 study). With increasing DHEAS cutoff, sensitivity for MACS diagnosis increased, and specificity decreased. Most studies (4 studies) used the chemiluminescent immunoassay to measure DHEAS. A meta-analysis of studies using DHEAS cut-off between 40-70 mcg/dL was performed, with a pooled sensitivity of 68% (95% CI: 51-81) and a pooled specificity of 85% (78-89). The positive likelihood ratio was 4 (95% CI: 3-6; I2=36.94, P=0.175) and the negative likelihood ratio was 0.4 (0.3-0.6; I2=49.97, P=0.092). Most studies were at a high risk of bias for selection of patients, index, or reference standard. Conclusion: Based on limited heterogeneous evidence, measurement of DHEAS provides additional value in diagnosing MACS. Further larger diagnostic accuracy studies should explore various DHEAS cutoffs and consider assay variability. Presentation: 6/3/2024

12437 Impact Of Wearable Brain Sensing Meditation Device On Quality Of Life In Patients Recovering From Hypercortisolism Following Surgical Intervention: A Prospective Longitudinal Cohort Study

Abstract Disclosure: J. Saini: None. B. Bahrani Fard: None. M. Suresh: None. R. Sandooja: None. Y. Hleibiehova: None. E. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with endogenous hypercortisolism experience glucocorticoid withdrawal syndrome (GWS) following curative surgery. The symptoms of GWS include fatigue, weakness, muscle aches, joint pain, mood changes, and sleep disturbance. Limited interventions have been explored to alleviate the symptoms of GWS and improve patients’ quality of life. The use of meditation as an intervention has been reported to enhance postsurgical recovery in patients with other conditions and offers a promising intervention for GWS. Objective: To determine the impact of a portable, wearable, electroencephalographic device (MUSE headband device) used for guided meditation practices on the quality of life of patients in the first 12 weeks post-surgery for endogenous hypercortisolism. Methods: We conducted a single-center prospective longitudinal study of adults with endogenous hypercortisolism undergoing curative surgery between 2018 and 2024. The patients were enrolled before the surgical intervention and were followed for 2 years. Only patients who completed at least 4 weeks of follow-up were included. The study comprised of 2 groups; (1) The interventional group included consecutive patients who were offered a MUSE headband with instructions to meditate for at least 10 minutes per day for 3 months (MUSE cohort) and (2) the comparison group included age-, sex-, clinical score, hypercortisolism type, and BMI-matched 3:1 patients (Referent cohort). Quality of life and symptoms of GWS were assessed with AddiQoL and Short Form-36 (SF-36) surveys. Results: At least 4 weeks post-surgical follow-up was completed by 27 patients in the MUSE cohort and 81 referent subjects. Age (median 51 vs 47 years), women (82% vs 84%), BMI (median 31 vs 32 kg/m2), the subtype of hypercortisolism (pituitary 48% vs 52%), clinical (median 16 vs 15) and biochemical (median 6 vs 7) severity scores were similar between the two groups (P>0.05 for all). At baseline, AddiQoL score was similar in groups (median of 66 vs 70, P=0.083), though symptoms of fatigue (92.6% vs 69.1%, P=0.015) and lightheadedness (37% vs 17.3%, P=0.033) were more frequent in MUSE cohort. After 12 weeks, 20 patients using MUSE demonstrated improvement compared to 67 no muse patients in the SF-36 physical component (mean delta 3.9 (SD 11.77) vs -2.19 (SD 9.67), P=0.010). The physical functioning SF-36 subcomponent (4.94 (8.77) vs 0.92 (9.24), P=0.048) and body pain SF-36 subcomponent (2.69 (11.89) vs -3.69 (8.32), P=0.008) domains improved in the MUSE intervention group, when compared to referent cohort. No significant improvement in SF-36 mental component scores was seen in both groups. Conclusions: The use of wearable electroencephalographic device for meditation was associated with improvement in the quality of life of patients recovering from hypercortisolism, particularly in the domains of body pain and physical functioning. Presentation: 6/3/2024

The shrinking space for civil society activism in Palestine

Counter-terrorism is increasingly being used to shrink the space for civil society. In October 2021, six Palestinian civil society organisations (CSOs) were proscribed by the Israeli Minister of Defense as ‘terrorist organisations’ based on the 2016 Counter-Terrorism Law. If fully implemented, in conjunction with the 1945 Defense (Emergency) Regulations, the CSOs’ offices would be closed and their staff arrested. However, the designation’s primary audience has reportedly been the donors of these organisations. This article explores whether the designation added another layer to the long-ongoing process of criminalising the CSOs, curtailing their capabilities to operate, and delegitimising them as partners for the donors and global civil society. The analysis draws on a combination of the shrinking space concept and securitisation theory. It broadens the latter to include the power of the referent subject, an aspect often neglected in the literature. Even though both audiences did not approve of the Israeli government’s securitising move and the CSOs were able to develop coping mechanisms, it deepened chilling effects. Continued attacks against the organisations contributed to further limiting their activism space. The case study builds upon a content analysis of legal documents, public statements, and data gathered through semi-structured interviews.

A consensus-based classification workflow to determine genetically inferred ancestry from comprehensive genomic profiling of patients with solid tumors.

Disparities in cancer diagnosis, treatment, and outcomes based on self-identified race and ethnicity (SIRE) are well documented, yet these variables have historically been excluded from clinical research. Without SIRE, genetic ancestry can be inferred using single-nucleotide polymorphisms (SNPs) detected from tumor DNA using comprehensive genomic profiling (CGP). However, factors inherent to CGP of tumor DNA increase the difficulty of identifying ancestry-informative SNPs, and current workflows for inferring genetic ancestry from CGP need improvements in key areas of the ancestry inference process. This study used genomic data from 4274 diverse reference subjects and CGP data from 491 patients with solid tumors and SIRE to develop and validate a workflow to obtain accurate genetically inferred ancestry (GIA) from CGP sequencing results. We use consensus-based classification to derive confident ancestral inferences from an expanded reference dataset covering eight world populations (African, Admixed American, Central Asian/Siberian, European, East Asian, Middle Eastern, Oceania, South Asian). Our GIA calls were highly concordant with SIRE (95%) and aligned well with reference populations of inferred ancestries. Further, our workflow could expand on SIRE by (i) detecting the ancestry of patients that usually lack appropriate racial categories, (ii) determining what patients have mixed ancestry, and (iii) resolving ancestries of patients in heterogeneous racial categories and who had missing SIRE. Accurate GIA provides needed information to enable ancestry-aware biomarker research, ensure the inclusion of underrepresented groups in clinical research, and increase the diverse representation of patient populations eligible for precision medicine therapies and trials.

FastComposer: Tuning-Free Multi-subject Image Generation with Localized Attention

AbstractDiffusion models excel at text-to-image generation, especially in subject-driven generation for personalized images. However, existing methods are inefficient due to the subject-specific fine-tuning, which is computationally intensive and hampers efficient deployment. Moreover, existing methods struggle with multi-subject generation as they often blend identity among subjects. We present FastComposer which enables efficient, personalized, multi-subject text-to-image generation without fine-tuning. FastComposer uses subject embeddings extracted by an image encoder to augment the generic text conditioning in diffusion models, enabling personalized image generation based on subject images and textual instructions with only forward passes. To address the identity blending problem in the multi-subject generation, FastComposer proposes cross-attention localization supervision during training, enforcing the attention of reference subjects localized to the correct regions in the target images. Naively conditioning on subject embeddings results in subject overfitting. FastComposer proposes delayed subject conditioning in the denoising step to maintain both identity and editability in subject-driven image generation. FastComposer generates images of multiple unseen individuals with different styles, actions, and contexts. It achieves 300$$\times $$ × –2500$$\times $$ × speedup compared to fine-tuning-based methods and requires zero extra storage for new subjects. FastComposer paves the way for efficient, personalized, and high-quality multi-subject image creation. Code, model, and dataset are available here (https://github.com/mit-han-lab/fastcomposer).

Death euphemisms on tombstones: A case of the Vhavenḓa’s metaphorical conceptualisation of death

Direct reference to death has long been taboo in Tshivenḓa culture, and it is sanctioned by social, psychological and religious constraints. Like in other African societies, explicit reference to death is considered a taboo by the Vhavenḓa. This is because the Vhavenḓa view death as a transition from the land of the living to the land of the dead, which ultimately foregrounds their belief that a dead person transforms into an ancestor who has the power to care, protect, bless and even curse the living. Consequently, the subject of death and reference to it is treated as sacred among the Vhavenḓa. For this reason, the Vhavenḓa utilise euphemisms when discussing death. Against this backdrop, this qualitative study explored whether death-related conceptual metaphors on tombstones in Tshivenḓa lessen pain and the impact of death on those affected using the framework of the conceptual metaphor theory (CMT). A corpus of 160 epitaphs from the Khubvi Cemetery in Thulamela Local Municipality served as the source of the study’s data. The study’s findings showed that gravestone conceptualisations of death imply a favourable value judgment of human mortality and help those who are still alive cope with the loss and pain associated with death. The study lays the groundwork for further research into why conceptual metaphors of death emphasise the negative features of death, while language use emphasises the positive aspects.

Steroid Profiling and Circadian Cortisol Secretion in Patients with Mild Autonomous Cortisol Secretion: A Cross-Sectional Study.

Mild autonomous cortisol secretion (MACS) is diagnosed based on post-dexamethasone cortisol>1.8 mcg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS. To characterize 24-hour (h) urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS versus referent subjects. Cross-sectional study, 2018-2023. Referral center. Patients with MACS and age-, sex-, BMI-, and menopausal status-matched referent subjects. Urine was collected over 24h period as separate day- and night-time collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects were admitted for every 2h serum measurements of free and total cortisol. Steroids, sums, and ratios. Patients with MACS (n=72) had lower mcg/24h median androgens (2084 vs 3283, P<0.001), higher glucocorticoids (15754 vs 12936, P<0.001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P<0.001), compared to referent subjects. Patients also had lower steroid day/night ratios compared to referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour area under the curves for total and free cortisol were similar. However, evening mean total (5.3 vs 4.0 mcg/dL, P=0.056) and free (0.2 vs 0.1 mcg/dL, P=0.035) cortisol was higher in patients vs referent subjects. Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production.

La referencia lingüística y la decolonización de los nombres propios en las lenguas de señas

The subject of the proper name is the subject of reference. Proper names are paradigmatic examples because they refer to unique entities in the world (uniqueness). In sign languages, there are gestural expressions that identify people in deaf communities and are distinguished from the spelling of their name given in Latin alphabet. Studies on this topic have described the signed proper name according to hand configurations and its other articulatory characteristics, according to some general principles about the significance of having the proper name in the community and how it functions. However, almost no mention is made of the basic concepts involved in the theoretical formulation of names and uniqueness. In this paper, we argue that descriptions of this topic are deliberately simplistic and reductionist, not because there is a desire to marginalize sign languages, but because we have been historically conditioned to act this way. From a decolonial critique and an anti-representationalist perspective of language, we show the controversies that shape the issue of proper names and propose an integrated view that advances in the deconstruction of polarizations and false dichotomies in the linguistic and identity discourse.

The reaction of London newspapers to the proclamation of the Monroe doctrine

The presented article analyzes the reaction of the British press to the proclamation of the Monroe Doctrine by the American president in 1823. The reaction of leading London periodicals such as The Examiner, The Monthly Magazine, The London Magazine and The Morning Post is considered. The author describes in detail the diversity of opinions: from support for Republican ideals and their contrast with the monarchical aspects of the policy of the Holy Alliance to expressing concerns about the negative impact of the doctrine on Britain's trade and economic interests in Latin America. The author concludes that the London newspapers have a balanced, albeit emotional assessment of the influence of the Monroe Doctrine on international relations and the specific interests of Great Britain. The article focuses on the period of the 1820s and the British reaction to American foreign policy activity, neglecting to consider the British position in the context of the War of Independence of the Spanish colonies of 1808-1819. In the study of newspaper materials by domestic and foreign scientists, general philosophical (deduction and induction, systematic approach, synergetic approach, etc.), general scientific (observation, comparative method, etc.) and private scientific methods specific to a particular field of knowledge. The Monroe Doctrine provides a rare example of a 200-year-old speech that remains the subject of regular references when discussing the current international political agenda to this day. The article examines the reaction to the Monroe Doctrine, which is one of the fundamental documents of American public policy, which became one of the first steps for the formation of American strategic culture in its current state. The relevance of the article is based on the need for a comprehensive study of the reports of the leading London press to identify their impact on international relations and the specific interests of the United Kingdom. Despite the fact that the Monroe Doctrine has been around for two hundred years, it does not lose its relevance in relation to Latin American states with the United States, and, more importantly, in relation to the United States, with other actors in world politics.

Myocardial infarction in a population-based cohort of patients with biopsy-confirmed giant cell arteritis in southern Sweden

ObjectivesTo determine the incidence rate (IR) of myocardial infarction (MI), relative risk of MI, and impact of incident MI on mortality in individuals with biopsy-confirmed giant cell arteritis (GCA).MethodsMIs in...

Enhanced chronic inflammation and increased branched chain amino acids in adrenal disorders: a cross-sectional study.

Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality. We aimed to determine the impact of adrenal disorders on the inflammation marker GlycA, total branched-chain amino acids (BCAA), ketone bodies and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine. We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFA), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGL), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n=802). Referent subjects included participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) study (n=5241). GlycA, BCAA, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus and statin therapy. In age-and sex-adjusted comparison to referent subjects, increased GlycA was noted in all patient categories, increased BCAA in NFA, MACS, CS, PA and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of subjects with diabetes and cardiovascular disease. Patients with functioning and non-functioning adrenal masses demonstrated increased GlycA and BCAA, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.

Determination of Toxic Elements in Cannabinoid and Opioid Drugs and Their Impact on Addicts' Health: A Comparative Study.

Drug addiction is associated with significant health risks, including cardiovascular complications, cancer, and mental disorders. Illicit drugs, such as cannabinoids and opioids, including prescription medications, are widely consumed and have profound health consequences. Understanding the health effects of the toxic elements in these substances is critical for overdose prevention and effective recovery strategies. This study aimed to determine toxic elements, including arsenic (As), cadmium (Cd), mercury (Hg), and nickel (Ni), in cannabinoid and opioid drugs and in biological samples (whole blood, scalp hair, and serum) from 311 male drug abuse patients aged 15-60years with a history of drug abuse. The participants were categorized into three age groups. The comparative analysis involved 113 reference subjects of the same age groups. The sample preparation employed microwave-assisted acid digestion, and the toxic elements were quantified using atomic absorption spectrophotometry. Accuracy was ensured using certified reference materials for hair, whole blood, and serum samples. Drug-addicted subjects had significantly higher concentrations of toxic elements (arsenic, cadmium, mercury, and nickel) in biological samples than referent subjects (p > 0.001). Elevated levels of these toxic elements may increase susceptibility to infections, possibly due to malnutrition, drug-related effects, and additional contaminants. These findings necessitate further studies to explore the long-term health outcomes, potential treatment options, and broader socioeconomic impacts of substance abuse. This study serves as a baseline for future research in this critical public health field.

Modeling Climate Change Effects on Genetic Diversity of an Endangered Horse Breed Using Canonical Correlations.

The historical increase in the occurrence of extreme weather events in Spain during the last thirty years makes it a perfect location for the evaluation of climate change. Modeling the effects of climate change on domestic animals' genetic diversity may help to anticipate challenging situations. However, animal populations' short life cycle and patent lack of historical information during extended periods of time drastically compromise the evaluation of climate change effects. Locally adapted breeds' gene pool is the base for their improved resilience and plasticity in response to climate change's extreme climatic conditions. The preservation of these domestic resources offers selection alternatives to breeders who seek such improved adaptability. The Spanish endangered autochthonous Hispano-Arabian horse breed is perfectly adapted to the conditions of the territory where it was created, developed, and widespread worldwide. The possibility to trace genetic diversity in the Hispano-Arabian breed back around seven decades and its global ubiquity make this breed an idoneous reference subject to act as a model for other international populations. Climate change's shaping effects on the genetic diversity of the Hispano-Arabian horse breed's historical population were monitored from 1950 to 2019 and evaluated. Wind speed, gust speed, or barometric pressure have greater repercussions than extreme temperatures on genetic diversity. Extreme climate conditions, rather than average modifications of climate, may push breeders/owners to implement effective strategies in the short to medium term, but the effect will be plausible in the long term due to breed sustainability and enhanced capacity of response to extreme climate events. When extreme climatic conditions occur, breeders opt for mating highly diverse unrelated individuals, avoiding the production of a large number of offspring. People in charge of domestic population conservation act as catalyzers of the regulatory changes occurring during breeds' climate change adaptive process and may identify genes conferring their animals with greater adaptability but still maintaining enhanced performance. This model assists in determining how owners of endangered domestic populations should plan their breeding strategies, seeking the obtention of animals more resilient and adapted to climate-extreme conditions. This efficient alternative is focused on the obtention of increased profitability from this population and in turn ensuring their sustainability.

Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.