Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Association Between Microvascular Disease and Cardiorespiratory Fitness Among Adults With Type 2 Diabetes.

OBJECTIVE: Little is known about the extent to which microvascular disease is associated with cardiorespiratory fitness (CRF) among individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 4,766 participants with type 2 diabetes underwent maximal exercise testing in the Look AHEAD (Action for Health in Diabetes) study at baseline. Low CRF was defined based on the Aerobics Center Longitudinal Study reference standards. Microvascular disease was defined as having one or more of diabetes-related kidney disease (DKD), retinopathy, and neuropathy. The burden of microvascular disease was defined as the number of microvascular beds affected. RESULTS: Of the 4,766 participants (mean age 58.9 ± 6.7 years, 58.5% women, 66.1% White individuals), 1,761 (37%) had microvascular disease. Participants with microvascular complications in three vascular territories had a lower CFR than those without any microvascular disease (mean adjusted metabolic equivalent of task [MET] 6.58 vs. 7.26, P = 0.001). Participants with any microvascular disease had higher odds of low CRF than those without microvascular disease (adjusted odds ratio [OR] 1.45, 95% CI 1.24-1.71). An increasing burden of microvascular disease was associated with higher odds of low CRF (for microvascular disease in three vascular territories, adjusted OR 2.82, 95% CI 1.36-5.85). Adjusted ORs for low CRF were 1.24 (95% CI 0.99-1.55), 1.34 (95% CI 1.02-1.76), and 1.44 (95% CI 1.20-1.73) for neuropathy, retinopathy, and DKD associations, respectively. CONCLUSIONS: In a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with lower CRF.

Association of Cardiovascular Fibrosis, Remodeling, and Dysfunction With Frailty, Prefrailty, and Functional Performance: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Cardiovascular disease is associated with higher incidence of frailty. However, the nature of the mechanisms underlying this association remains unclear. The purpose of this study is to identify cardiovascular phenotypes most associated with physical frailty and functional performance in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: As part of the MESA study, 3 045 participants underwent cardiovascular magnetic resonance and computed tomography between 2010 and 2012. Of these, 1 743 completed a Six-Minute Walk test (6MWT) and questionnaires (follow-up exam: 2016-2018) which were used to generate a binary combined frail/prefrail versus robust score according to a modified FRAIL Scale (self-report questionnaire). Multivariable logistic (binary frail outcome) or linear (6MWT) regression assessed the association between frailty and cardiovascular structure and function, aortic stiffness, coronary artery calcium, and myocardial fibrosis (ECV, extracellular volume fraction). RESULTS: Participants were 66 ±â€…8 years, 52% female at the time of imaging, and 29.4% were classified as frail or prefrail. Older age and female gender were associated with greater odds of being in the frail/prefrail group. Concentric left ventricular remodeling (odds ratio [OR] 1.89, p = .008; Coef. -52.9, p < .001), increased ECV (OR 1.10, p = .002; Coef. -4.0, p = .001), and worsening left atrial strain rate at early diastole (OR 1.56, p ≤ .001; Coef. -22.75, p = .027) were found to be associated with a greater likelihood of being in a frail state and lower 6MWT distance (m). All associations with 6MWT performance were attenuated with adjustments for risk factors whereas ECV and LA strain rate remained independently associated with frailty. CONCLUSIONS: These findings suggest a significant overlap in pathways associated with subclinical cardiac dysfunction, cardiovascular fibrosis, and physical frailty.

Normative Values of Echocardiographic Chamber Size and Function in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Echocardiographic (2-dimensional echocardiography) thresholds indicating disease or impaired functional status compared with normal physiological aging in individuals aged ≥65 years are not clearly defined. In the present study, we sought to establish standard values for 2-dimensional echocardiography parameters related to chamber size and function in older adults without cardiopulmonary or cardiometabolic conditions. METHODS: In this cross-sectional study of 3032 individuals who underwent 2-dimensional echocardiography at exam 6 in the MESA (Multi-Ethnic Study of Atherosclerosis), 608 participants fulfilled our inclusion criteria of healthy aging, with normative values defined as the mean ± 1.96 standard deviation and compared across sex and race and ethnicity. Functional status measures included NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Prognostic performance using MESA cutoffs was compared with established guideline cutoffs using time-to-event analysis. RESULTS: The normative aging cohort (69.5±7.0 years, 46.2% male, 47.5% White) had lower NT-proBNP, higher 6-minute walk distance, and higher (better) Kansas City Cardiomyopathy Questionnaire summary values. Women had significantly smaller chamber sizes and better biventricular systolic function. White participants had the largest chamber dimensions, whereas Chinese participants had the smallest, even after adjustment for body size. Current guidelines identified 81.6% of healthy older adults in MESA as having cardiac abnormalities. CONCLUSIONS: Among a large, diverse group of healthy older adults, we found significant differences in cardiac structure and function by sex and race/ethnicity, which may signal sex-specific cardiac remodeling with advancing age. It is crucial for existing guidelines to consider the observed and clinically significant differences in cardiac structure and function associated with healthy aging. Our study highlights that existing guidelines, which grade abnormalities in echocardiographic cardiac chamber size and function based on younger individuals, may not adequately address the anticipated changes associated with normal aging.

Association of disproportionate liver fat with markers of heart failure: The multi-ethnic study of atherosclerosis.

BACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) has been linked to heart failure with preserved ejection fraction (HFpEF). We sought to understand association between individuals with amounts of liver adiposity greater than would be predicted by their body mass index (BMI) in order to understand whether this disproportionate liver fat (DLF) represents a proxy of metabolic risk shared between liver and heart disease. METHODS: We studied 2,932 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who received computed tomography (CT) measurements of hepatic attenuation. Quartiles of DLF were compared and multivariable linear regression was performed to evaluate the association of DLF with clinical, echocardiographic, and quality of life metrics. RESULTS: Compared to the lowest quartile of DLF, individuals in the highest quartile of DLF were more likely to be male (52.0% vs 47.1%, P < .001), less likely to be Black or African American (14.8 % vs 38.1% P < .001), have higher rates of dysglycemia (31.9% vs 16.6%, P < .001) and triglycerides (140 [98.0, 199.0] vs 99.0 [72.0, 144.0] mg/dL, P > .001). These individuals had lower global longitudinal strain (-0.13 [-0.25, -0.02], P = .02), stroke volumes (-1.05 [-1.76, -0.33], P < .01), lateral e' velocity (-0.10 [-0.18, -0.02], P = .02), and 6-minute walk distances (-4.25 [-7.62 to -0.88], P = .01). CONCLUSION: DLF is associated with abnormal metabolic profiles and ventricular functional changes known to be associated with HFpEF and may serve as an early metric to assess for those that may progress to clinical HFpEF.

From pole to pole, life-long research of sleep in extreme environments.

In November 1965, Michel Jouvet accepted me into his laboratory in Lyon as a medical student at a time when sleep research was an adventure. After 4 years of investigations in cats, I obtained my medical doctorate. Being a military physician, I was posted to Antarctica for wintering over and was initiated by Jean Rivolier into the psychology of small isolated human groups. I recorded 180 polysomnographic (PSG) nights in eight of my companions. This was my first contribution to research on human sleep under extreme environments and conditions. I then entered René Hénane's military thermophysiology laboratory, where I analyzed thermal exchanges during human sleep in the heat. Back to the cold, I spent 2 years in Canada and analyzed sleep during the Arctic winter under the direction of Manny W. Radomski, who headed the Defense and Civil Institute of Environmental Medicine and judged my PhD dissertation along with my first two mentors. Throughout my career, I worked in collaboration with Manny Radomski under the auspices of the Franco-Canadian Accord for Defence Research. We studied sleep and exercise, sleep deprivation, and recovery with and without chemical help. He also gave me support during several investigations in Africa. There, I studied normal sleep under various tropical climates (warm and dry in Niger, warm and humid in Côte d'Ivoire and Congo, temperate mid-mountain in Angola). I determined that human African trypanosomiasis, the ravaging sleeping sickness or tsetse disease, is not a hypersomnia, but a disorder of circadian rhythms, notably in the sleep-wake cycle.

Pegylated liposomal doxorubicin combined with trabectedin as a treatment option in uterine sarcomas: a single-institution retrospective analysis.

OBJECTIVE: The use of conventional doxorubicin in combination with trabectedin leads to a considerable prolongation of progression-free survival in the treatment of uterine sarcomas but is associated with dose-limiting toxicities. Significant progression-free survival improvement was recently obtained through treatment prolongation with trabectedin single agent. We hypothesize that the therapeutic index of pegylated liposomal doxorubicin combined with trabectedin could be superior to the combination with conventional doxorubicin due to a more favorable toxicity profile. METHODS: In this retrospective cohort study, the clinical outcome was analyzed in patients with advanced or recurrent uterine sarcomas with measurable disease treated with pegylated liposomal doxorubicin 30 mg/m2 plus trabectedin 1.5 mg/m2 given every 3 weeks between January 2011 and April 2023 at the University Hospital in Innsbruck. Response evaluation was done every three cycles. Toxicity was evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria on 107 administered cycles. RESULTS: A total of 21 patients were included in the study. In 67% (n=14) of patients, pegylated liposomal doxorubicin plus trabectedin was given as first-line treatment. One patient (5%) achieved a complete response and four (19%) a partial response, resulting in an objective response rate of 24%. Four other patients (19%) had stable disease. The median duration of the response was 14 months (range 3-74). Progression was recorded in 12 patients (57%). Median progression-free survival was 6 months (95% CI 1 to 11 months), while median overall survival was 26 months (95% CI 9 to 43 months). A median of 6 (range 1-11) cycles per patient were administered. Regarding grade ≥3 toxicity, neutropenia was recorded in 29%, thrombocytopenia in 14%, and febrile neutropenia in 19% of patients. Hematologic toxicity was the most frequent reason for dose delays (n=16) and dose reductions (n=5). CONCLUSION: Our study found an overall clinical benefit for the combination of pegylated liposomal doxorubicin plus trabectedin in metastatic uterine sarcomas of 43% and appears to exhibit a favorable toxicity profile which allows prolonged administration of this regimen.

Understanding uptake of COVID-19 testing, vaccination, and boosters among Spanish-speaking Latines in the United States: Qualitative insights from Spanish speakers and key informants.

BACKGROUND: Latine communities in the United States have been disproportionately affected by COVID-19. It is critical to gain a better understanding of the sociocultural determinants that challenge and facilitate COVID-19 testing, vaccination, and booster uptake within these vulnerable communities to inform culturally congruent strategies and interventions. METHODS: In summer 2022, our community-based participatory research partnership conducted 30 key informant interviews and 7 focus groups with 64 Spanish-speaking Latine participants in North Carolina. Interviewees consisted of representatives from health and service organizations, most of whom were engaged with direct service to Spanish speakers. Interviews were conducted in either English or Spanish, depending on the preference of the participant; all focus groups were conducted in Spanish. Interviews and focus groups were conducted in person or by videoconference. RESULTS: Twenty themes emerged that we organize into four domains: general perceptions about COVID-19; barriers to COVID-19 testing, vaccination, and booster uptake; facilitators to COVID-19 testing, vaccination, and booster uptake; and recommendations to promote testing, vaccination, and booster uptake. DISCUSSION: Results underscore important sociocultural determinants of ongoing COVID-19 testing, vaccination, and booster uptake to consider in developing interventions for Spanish-speaking Latines in the United States. Based on this formative work, our partnership developed Nuestra Comunidad Saludable (Our Healthy Community). We are implementing the intervention to test whether trained peer navigators can increase COVID-19 testing, vaccination, and booster uptake among Spanish-speaking Latines through blending in-person interactions and mHealth (mobile health) strategies using social media.

Multi-Ethnic Study of Atherosclerosis Early Heart Failure Study: Rationale, Design, and Baseline Characteristics.

BACKGROUND: Current prevalence estimates of heart failure (HF) are primarily based on self-report or HF hospitalizations. There is an unmet need to define the prevalence and pathogenesis of early symptomatic HF, which may be undiagnosed and precedes HF hospitalization. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) Early HF study was conducted during MESA exam 6 to determine the prevalence of early HF and investigate the transition from risk factors to early HF in a diverse population-based cohort of older adults. Between 2016 and 2018, 3285 MESA participants from 6 field centers underwent comprehensive speckle-tracking echocardiography with passive leg raise maneuver, Kansas City Cardiomyopathy Questionnaire, 6-minute walk test, arterial stiffness assessment, and proteomics (including NT-proBNP [N-terminal pro-B-type natriuretic peptide]). RESULTS: Median age was 73 (25th-75th percentile 67-81) years, 53.2% were female, 25.6% were Black, 12.8% were Chinese, and 40.0% were White. The prevalence of HF risk factors was high: hypertension, 61.9%; former or current smoking, 53.7%; obesity 34.8%; diabetes; 24.7%; and chronic kidney disease; 22%. Overt cardiovascular disease, which ranged from 2.1% (HF) to 13.6% (atrial fibrillation), was less common. Of the 3285 participants, 96% underwent proteomics, 94% Kansas City Cardiomyopathy Questionnaire, 93% speckle-tracking echocardiography with passive leg raise, 82% arterial stiffness exam, and 77% 6-minute walk test. Feasibility of resting speckle-tracking echocardiography (87%-99% across cardiac chambers) and passive leg raise Doppler/speckle-tracking echocardiography (>84%) measurements was high. A total of 120 unique echocardiographic indices were measured. CONCLUSIONS: The MESA Early HF study is a key resource for cardiovascular researchers who are interested in improving the epidemiological and phenotypic characterization of early HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005487.

Retinal vessel caliber and cognitive performance: the multi-ethnic study of atherosclerosis (MESA).

Retinal vessel calibers share anatomic and physiologic characteristics with the cerebral vasculature and can be visualized noninvasively. In light of the known microvascular contributions to brain health and cognitive function, we aimed to determine if, in a community based-study, retinal vessel calibers and change in caliber over 8 years are associated with cognitive function or trajectory. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who completed cognitive testing at Exam 5 (2010-2012) and had retinal vascular caliber measurements (Central Retinal Artery and Vein Equivalents; CRAE and CRVE) at Exam 2 (2002-2004) and Exam 5 were included. Using multivariable linear regression, we evaluated the association of CRAE and CRVE from Exam 2 and Exam 5 and their change between the two exams with scores on tests of global cognitive function (Cognitive Abilities Screening Instrument; CASI), processing speed (Digit Symbol Coding; DSC) and working memory (Digit Span; DS) at Exam 5 and with subsequent change in cognitive scores between Exam 5 and Exam 6 (2016-2018).The main effects are reported as the difference in cognitive test score per SD increment in retinal vascular caliber with 95% confidence intervals (CI). A total of 4334 participants (aged 61.6 ± 9.2 years; 53% female; 41% White) completed cognitive testing and at least one retinal assessment. On multivariable analysis, a 1 SD larger CRAE at exam 5 was associated with a lower concomitant CASI score (- 0.24, 95% CI - 0.46, - 0.02). A 1 SD larger CRVE at exam 2 was associated with a lower subsequent CASI score (- 0.23, 95%CI - 0.45, - 0.01). A 1 SD larger CRVE at exam 2 or 5 was associated with a lower DSC score [(- 0.56, 95% CI - 1.02, - 0.09) and - 0.55 (95% CI - 1.03, - 0.07) respectively]. The magnitude of the associations was relatively small (2.8-3.1% of SD). No significant associations were found between retinal vessel calibers at Exam 2 and 5 with the subsequent score trajectory of cognitive tests performance over an average of 6 years. Wider retinal venular caliber was associated with concomitant and future measures of slower processing speed but not with later cognitive trajectory. Future studies should evaluate the utility of these measures in risk stratification models from a clinical perspective as well as for screening on a population level.

Concurrent Clade I and Clade II Monkeypox Virus Circulation, Cameroon, 1979-2022.

During 1979-2022, Cameroon recorded 32 laboratory-confirmed mpox cases among 137 suspected mpox cases identified by the national surveillance network. The highest positivity rate occurred in 2022, indicating potential mpox re-emergence in Cameroon. Both clade I (n = 12) and clade II (n = 18) monkeypox virus (MPXV) were reported, a unique feature of mpox in Cameroon. The overall case-fatality ratio of 2.2% was associated with clade II. We found mpox occurred only in the forested southern part of the country, and MPXV phylogeographic structure revealed a clear geographic separation among concurrent circulating clades. Clade I originated from eastern regions close to neighboring mpox-endemic countries in Central Africa; clade II was prevalent in western regions close to West Africa. Our findings suggest that MPXV re-emerged after a 30-year lapse and might arise from different viral reservoirs unique to ecosystems in eastern and western rainforests of Cameroon.

Increased Plasma Branched Short-Chain Fatty Acids and Improved Glucose Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Short-chain fatty acids (SCFAs) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched SCFAs (BSCFAs; isobutyrate, isovalerate, and methylbutyrate) is largely unknown. In a cohort of 219 non-Hispanic White participants and 126 African American participants, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, and lipid traits, and other SCFAs. We observed a bimodal distribution of BSCFAs, with 25 individuals having high levels (H-BSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared with the L-BSCFA group (16% vs. 49%; P = 0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFAs. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose levels were lower and the disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial C-peptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of P<1.6×10-4, we identified 3 genes (ATP1B1, ARVCF, and LIPG) associated with CAC and 2 genes (ABCG8 and EIF2B2) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

Relationship of Race With Functional and Clinical Outcomes With the REHAB-HF Multidomain Physical Rehabilitation Intervention for Older Patients With Acute Heart Failure.

Background The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) randomized trial demonstrated that a 3-month transitional, tailored, progressive, multidomain physical rehabilitation intervention improves physical function, frailty, depression, and health-related quality of life among older adults with acute decompensated heart failure. Whether there is differential intervention efficacy by race is unknown. Methods and Results In this prespecified analysis, differential intervention effects by race were explored at 3 months for physical function (Short Physical Performance Battery [primary outcome], 6-Minute Walk Distance), cognition, depression, frailty, health-related quality of life (Kansas City Cardiomyopathy Questionnaire, EuroQoL 5-Dimension-5-Level Questionnaire) and at 6 months for hospitalizations and death. Significance level for interactions was P≤0.1. Participants (N=337, 97% of trial population) self-identified in near equal proportions as either Black (48%) or White (52%). The Short Physical Performance Battery intervention effect size was large, with values of 1.3 (95% CI, 0.4-2.1; P=0.003]) and 1.6 (95% CI, 0.8-2.4; P<0.001) in Black and White participants, respectively, and without significant interaction by race (P=0.56). Beneficial effects were also demonstrated in 6-Minute Walk Distance, gait speed, and health-related quality of life scores without significant interactions by race. There was an association between intervention and reduced all-cause rehospitalizations in White participants (rate ratio, 0.73 [95% CI, 0.55-0.98]; P=0.034) that appears attenuated in Black participants (rate ratio, 1.06 [95% CI, 0.81-1.41]; P=0.66; interaction P=0.067). Conclusions The intervention produced similarly large improvements in physical function and health-related quality of life in both older Black and White patients with acute decompensated heart failure. A future study powered to determine how the intervention impacts clinical events is required. REGISTRATION URL: https://www.clinicaltrials.gov. Identifier: NCT02196038.

Regulatory T cell frequency in peripheral blood of women with advanced cervical Cancer including women living with HIV.

BACKGROUND: Persistent high-risk Human papillomavirus (HR-HPV) infections are the main cause of cervical cancer. Cumulative evidence implicates regulatory T cells (Tregs) as a critical factor in the failure to eliminate HPV-induced cancers leading to their persistence and progression to cancer. Also, the WHO recognised cervical cancer as 100% attributable to persistent HR-HPV infection. The province of KwaZulu-Natal (KZN) in South Africa has a high prevalence of cervical cancer and HIV infection. MATERIALS AND METHODS: We evaluated Treg frequency in dual infection of HR HPV and HIV coinfection using phenotypic markers, CD4, CD25 and intracellular Foxp3, in the peripheral blood of 51 cervical cancer and 46 non-cervical cancer participants and evaluated the effect of HIV on regulatory T cell proportion. Peripheral blood mononuclear cells were surface stained with a cocktail fluorescent labelled CD4 and CD25 and subsequently with APC anti-human FoxP3 (eBioscience). Flow cytometry was performed with FACS analysis. Statistical analysis of results was done using Instat 3 program (GraphpadR). Tregs results were expressed as median ± interquartile range (IQR). Associations of cervical cancer with demographic, clinical and laboratory variables were evaluated by univariate and multivariate logistic regression analysis using SPSS version 27 (IBM). RESULTS: Tregs frequency was significantly higher in individuals with cervical cancer (11.00 ± 19.79%) compared to controls (1.71 ± 8.91%) (p < 0.0001). HIV infection was associated with an increase in Tregs frequency. In controls a significant difference in Tregs frequency was noted between women living with HIV (6.00 ± 10.57%, n = 9) and those without HIV (1.30 ± 6.10%, n = 37), p = 0.0023. In multivariate logistic regression, Tregs frequency was significantly associated with cervical cancer after controlling for age, smoking, weight loss, presence of STI, HIV and HPV genotype. DISCUSSION/CONCLUSION: Higher Tregs frequency was significantly associated with cervical cancer highlighting the immunosuppressive role of Tregs in cervical cancer. Treg frequency was more strongly associated with cervical cancer than HIV infection. We provide baseline data for monitoring Treg frequencies in response to new preventive and therapeutic strategies in the management of cervical cancer.

Verification of the prognostic precision of the new 2023 FIGO staging system in endometrial cancer patients - An international pooled analysis of three ESGO accredited centres.

BACKGROUND: Recently, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer (EC) critically integrating new pathological and molecular features was published. The present study evaluated the clinical impact of the new 2023 FIGO staging system by comparing it to the previous 2009 system. METHODS: This is an international, pooled retrospective study of 519 EC patients who underwent primary treatment (and molecular characterisation) at three European Society of Gynaecological Oncology (ESGO) accredited centres in Austria/Italy. Patients were categorised according to the 2009 and the 2023 FIGO staging systems. Stage shifts were analysed and (sub)stage specific 5-year progression-free (PFS) and overall survival (OS) rates were calculated and compared. Different statistical tests were applied to evaluate the prognostic precision of the two FIGO staging systems and to compare them to each other. RESULTS: (Sub)stage shifts occurred in 143/519 (27.6%) patients: 123 upshifts (23.7%) and 20 (3.9%) downshifts. 2023 FIGO staging system identified a stage I cohort with a notably higher 5-year PFS rate compared to 2009 (93.0% versus 87.4%, respectively). For stage II disease, the 5-year PFS rate was similar in the 2023 and the 2009 FIGO staging systems (70.2% versus 71.2%, respectively). The two new molecularly defined 2023 FIGO substages IAmPOLEmut and IICmp53abn displayed distinct, particularly favourable and adverse oncologic outcomes within early stage disease, respectively. A remarkably lower 5-year PFS rate for stage III patients was revealed in the 2023 FIGO staging system compared to 2009 (44.4% versus 54.1%, respectively). All applied statistical tests confirmed a more accurate prediction of PFS and OS by the 2023 FIGO staging system compared to 2009. CONCLUSION: The new 2023 FIGO stating system led to a substantial stage shift in about one quarter of patients leading to a higher prognostic precision. In early stage disease, the new substages added further prognostic granularity and identified treatment relevant subgroups.

Sepsis Prediction Model for Determining Sepsis vs SIRS, qSOFA, and SOFA.

Importance: The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not undergone validation against existing sepsis prediction tools, such as Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick Sepsis-Related Organ Failure Asessement (qSOFA). Objective: To assess the validity and timeliness of the SPM compared with SIRS, qSOFA, and SOFA. Design, Setting, and Participants: This retrospective cohort study included all adults admitted to 5 acute care hospitals in a single US health system between June 5, 2019, and December 31, 2020. Data analysis was conducted from March 2021 to February 2023. Main Outcomes and Measures: A sepsis event was defined as receipt of 4 or more days of antimicrobials, blood cultures collected within ±48 hours of initial antimicrobial, and at least 1 organ dysfunction as defined by the organ dysfunction criteria optimized for the electronic health record (eSOFA). Time zero was defined as 15 minutes prior to qualifying antimicrobial or blood culture order. Results: Of 60 507 total admissions, 1663 (2.7%) met sepsis criteria, with 1324 electronic health record-confirmed sepsis (699 [52.8%] male patients; 298 [22.5%] Black patients; 46 [3.5%] Hispanic/Latinx patients; 945 [71.4%] White patients), 339 COVID-19 sepsis (183 [54.0%] male patients; 98 [28.9%] Black patients; 36 [10.6%] Hispanic/Latinx patients; and 189 [55.8%] White patients), and 58 844 (97.3%; 26 632 [45.2%] male patients; 12 698 [21.6%] Black patients; 3367 [5.7%] Hispanic/Latinx patients; 40 491 White patients) did not meet sepsis criteria. The median (IQR) age was 63 (51 to 73) years for electronic health record-confirmed sepsis, 69 (60 to 77) years for COVID-19 sepsis, and 60 (42 to 72) years for nonsepsis admissions. Within the vendor recommended threshold PSS range of 5 to 8, PSS of 8 or greater had the highest balanced accuracy for classifying a sepsis admission at 0.79 (95% CI, 0.78 to 0.80). Change in SOFA score of 2 or more had the highest sensitivity, at 0.97 (95% CI, 0.97 to 0.98). At a PSS of 8 or greater, median (IQR) time to score positivity from time zero was 68.00 (6.75 to 605.75) minutes. For SIRS, qSOFA, and SOFA, median (IQR) time to score positivity was 7.00 (-105.00 to 08.00) minutes, 74.00 (-22.25 to 599.25) minutes, and 28.00 (-108.50 to 134.00) minutes, respectively. Conclusions and Relevance: In this cohort study of hospital admissions, balanced accuracy of the SPM outperformed other models at higher threshold PSS; however, application of the SPM in a clinical setting was limited by poor timeliness as a sepsis screening tool as compared to SIRS and SOFA.

Association of Domains of Sedentary Behavior with Cardiovascular Disease Events in The Multi-Ethnic Study of Atherosclerosis.

Background: Sedentary behavior is associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. Little is known about this relationship in an ethnically diverse population. The objective of our study is to assess the effects of leisure time and occupational sedentary behavior on multiple cardiovascular outcomes in a multi-ethnic cohort. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) includes 2619 Caucasian, 1495 Hispanic, 1891 Black, and 804 Chinese-American adults aged 45-84 years and free of clinical CVD at enrollment, Sedentary behavior was self-reported at baseline. Participants were followed for an average of 13.6 years, and 14 types of cardiovascular outcomes were ascertained. Hazards of each cardiovascular outcome were modeled with adjustment for potential confounders, including physical activity. Results: Every one hour per day increase in leisure time sedentary behavior predicts a 6% increase in the adjusted hazards for CVD death ( P < 0.05). Every one hour increase in occupational sedentary time predicts a 21% and 20% decrease in the hazard for PVD and other revascularization, respectively ( P < 0.05). Conclusions: Leisure time sedentary behavior was associated with increased hazards for CVD death, but occupational sedentary time appears to be protective of peripheral vascular disease and other revascularization. Condensed Abstract: Sedentary behavior has been consistently associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. The Multi-Ethnic Study of Atherosclerosis (MESA) consists of a racially and ethnically diverse cohort of adults age 45-84, free from CVD at baseline. Greater levels of leisure time sedentary behavior predicted increased hazards for PVD and CVD death after an average follow up of 13.6 years whereas occupational sedentary behaviors predicted reduced PVD. These results underscore the importance of reducing time spent sitting in addition to advocating for meeting physical activity targets across ethnicities.

Cross-sectional and longitudinal analyses of variations of anthropometric measures of obesity with age in the Jackson Heart Study.

OBJECTIVE: To explore how anthropometric measures of obesity vary with age among African American (AA) adults. PARTICIPANTS AND SETTING: 3634 AA adults participated in the Jackson Heart Study (Jackson, Mississippi, USA) from 2004 to 2013. OUTCOME MEASURES: Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR). METHODS: Linear regression models were used to estimate the mean differences in anthropometric measures cross-sectionally by age group. Longitudinal changes in anthropometric measures over time (ie, the ageing effect) within each sex and age group were analysed using mixed effects models. All regression models were adjusted for education and lifestyle factors. RESULTS: In cross-sectional analysis, older age was associated with lower BMI, WC and WHtR, but higher WHR in both sexes. Compared with 25 to <44 years age group, the mean (95% CI) BMI, WC and WHtR was 0.80 (0.66 to 0.94), 0.27 (0.13 to 0.42) and 0.18 (0.03 to 0.32) standardised (SD) unit lower, while WHR was 0.48 (0.33 to 0.62) SD unit higher in the 75+ years age group. In longitudinal analysis, ageing was associated with increased BMI, WC and WHtR, among younger age groups but not in older age groups. However, WHR tended to increase with ageing across all age groups in both sexes. Among men 75+ years old, the mean change (95% CI) in BMI, WC and WHtR for every 5 years increase in age, was -0.20 (-0.29 to -0.11), -0.19 (-0.31 to -0.07), -0.15 (-0.27 to -0.02) SD unit, respectively, while it was 0.24 (0.05 to 0.44) SD unit for WHR. CONCLUSIONS: Among middle-aged AA adults, all four anthropometric measures of obesity examined increased with ageing. However, among elderly AA adults, only WHR showed continued increase with ageing. WHR may be a better anthropometric measure for monitoring obesity in older AA adults.