Elucidating the association of obstructive sleep apnea with brain structure and cognitive performance.

BACKGROUND: Obstructive sleep apnea (OSA) is a pervasive, chronic sleep-related respiratory condition that causes brain structural alterations and cognitive impairments. However, the causal association of OSA with brain morphology and cognitive performance has not been determined. METHODS: We conducted a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal relationship between OSA and a range of neurocognitive characteristics, including brain cortical structure, brain subcortical structure, brain structural change across the lifespan, and cognitive performance. Summary-level GWAS data for OSA from the FinnGen consortium was used to identify genetically predicted OSA. Data regarding neurocognitive characteristics were obtained from published meta-analysis studies. Linkage disequilibrium score regression analysis was employed to reveal genetic correlations between OSA and related traits. RESULTS: Our MR study provided evidence that OSA was found to significantly increase the volume of the hippocampus (IVW ß (95% CI) = 158.997 (76.768 to 241.227), P = 1.51e-04), with no heterogeneity and pleiotropy detected. Nominally causal effects of OSA on brain structures, such as the thickness of the temporal pole with or without global weighted, amygdala structure change, and cerebellum white matter change covering lifespan, were observed. Bidirectional causal links were also detected between brain cortical structure, brain subcortical, cognitive performance, and OSA risk. LDSC regression analysis showed no significant correlation between OSA and hippocampus volume. CONCLUSIONS: Overall, we observed a positive association between genetically predicted OSA and hippocampus volume. These findings may provide new insights into the bidirectional links between OSA and neurocognitive features, including brain morphology and cognitive performance.

Association of cardiometabolic multimorbidity with all-cause and cardiovascular disease mortality among Chinese hypertensive patients.

BACKGROUND: Hypertension usually clusters with multiple comorbidities. However, the association between cardiometabolic multimorbidity (CMM) and mortality in hypertensive patients is unclear. This study aimed to investigate the association between CMM and all-cause and cardiovascular disease (CVD) mortality in Chinese patients with hypertension. METHODS: The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors (CONSIDER), which comprised 5006 participants aged 19-91 years. CMM was defined as the presence of one or more of the following morbidities: diabetes mellitus, dyslipidemia, chronic kidney disease, coronary heart disease, and stroke. Cox proportional hazard models were used to calculate the hazard ratios (HR) with 95% CI to determine the association between the number of CMMs and both all-cause and CVD mortality. RESULTS: Among 5006 participants [mean age: 58.6 ± 10.4 years, 50% women (2509 participants)], 76.4% of participants had at least one comorbidity. The mortality rate was 4.57, 4.76, 8.48, and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one, two, and three or more morbidities, respectively. In the fully adjusted model, hypertensive participants with two cardiometabolic diseases (HR = 1.52, 95% CI: 1.09-2.13) and those with three or more cardiometabolic diseases (HR = 2.44, 95% CI: 1.71-3.48) had a significantly elevated risk of all-cause mortality. The findings were similar for CVD mortality but with a greater increase in risk magnitude. CONCLUSIONS: In this study, three-fourths of hypertensive patients had CMM. Clustering with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients, suggesting more intensive treatment and control in this high-risk patient group.

Evaluation and validation of neutrophil to albumin ratio as a promising prognostic marker for all-cause mortality in patients with cancer: a multicenter cohort study.

OBJECTIVES: The practicality and effectiveness of using the prognostic value of the neutrophil-to-albumin ratio (NAR) in evaluating patients with cancer remain unclear, and research is needed to fully understand its potential application in the cancer population. METHODS: The Kaplan-Meier method was used for survival analysis, and the log-rank test was employed for comparison. Univariate and multivariate Cox proportional hazards models were used to determine the prognostic biomarkers, and Logistic regression analysis was conducted to investigate the relationship between NAR and 90-day outcomes and cachexia. RESULTS: The study included 14 682 patients with cancer, divided into discovery (6592 patients), internal validation (2820 patients), and external validation groups (5270 patients). Patients with high NAR had higher all-cause mortality than those with low NAR in the discovery (50.15% versus 69.29%, P < 0.001), internal validation (54.18% versus 70.91%, P < 0.001), and external validation cohorts (40.60% versus 66.68%, P < 0.001). In the discovery cohort, high NAR was observed to be independently associated with all-cause mortality in patients (HR 1.16, 95% CI 1.12-1.19; P < 0.001). Moreover, we validated the promising prognostic value of NAR as a predictor of survival in patients with cancer through internal validation (HR 1.21, 95% CI 1.16-1.27, P < 0.001) and external validation cohorts (HR 1.27, 95% CI 1.21-1.34, P < 0.001). Additionally, in the subgroup analysis by tumor type, high NAR was identified as a risk factor for most cancers, except for breast cancer. CONCLUSIONS: This study showed that NAR is a feasible and promising biomarker for predicting prognosis and cancer cachexia in cancer patients.

Short-term association of fine particulate matter and its constituents with oxidative stress, symptoms and quality of life in patients with allergic rhinitis: A panel study.

BACKGROUND: Short-term exposure to fine particulate matter (PM2.5) and its specific constituents might exacerbate allergic rhinitis (AR) conditions. However, the evidence is still inconclusive. METHOD: We conducted a panel study of 49 patients diagnosed with AR > 1 year prior to the study in Taiyuan, China, to investigate associations of individual exposure to PM2.5 and its constituents with oxidative parameters, symptoms, and quality of life among AR patients. All participants underwent repeated assessments of health and PM exposure at 4 time points in both the heating and nonheating seasons from June 2017 to January 2018. AR patients' oxidative parameters were assessed using nasal lavage, and their subjective symptoms and quality of life were determined through in-person interviews using a structured questionnaire. Short-term personal exposure to PM2.5 and its constituents was estimated using the time-microenvironment-activity pattern and data from the nearest air sampler, respectively. We applied mixed-effects regression models to estimate the short-term effects of PM2.5 and its constituents. RESULTS: The results showed that exposure to PM2.5 and its constituents, including BaP, PAHs, SO42-, NH4+, V, Cr, Cu, As, Se, Cd, and Pb, was significantly associated with increased oxidative stress, as indicated by an increase in the malondialdehyde (MDA) index. Exposure to PM2.5 and its components (V, Mn, Fe, Zn, As, and Se) was associated with decreased antioxidant activity, as indicated by a decrease in the superoxide dismutase (SOD) index. Additionally, increased visual analog scale (VAS) and rhinoconjunctivitis quality of life questionnaire (RQLQ) scores indicated that exposure to PM2.5 and its constituents exacerbated inflammatory symptoms and affected quality of life in AR patients. CONCLUSION: Exposure to PM2.5 and specific constituents, could exacerbate AR patients' inflammatory symptoms and adversely affect their quality of life in the heavily industrialized city of Taiyuan, China. These findings may have potential biological and policy implications.

Nutritional status and its correlation to prognosis of nasopharyngeal carcinoma patients in different ages in China: a multicenter cohort study.

Nasopharyngeal carcinoma (NPC) patients usually presented malnutrition under chemoradiotherapy (CRT)/radiotherapy (RT). Few studies stratified by age to investigate the association of nutritional status with overall survival (OS) in NPC patients. This study aimed to explore the nutritional parameters related prognosis of NPC patients in different age. The total 1365 NPC patients were classified into young (18~45), middle-aged (46~60), and old groups (> 60). PG-SGA scores, NRS-2002 scores, Karnofsky performance status scores, anthropometric, and blood indicators (albumin, prealbumin, transferrin, C-reactive protein, hemoglobin, and total lymphocyte) were assessed. Cox regression analysis was performed to evaluate the association between risk factors of nutritional status and the overall survival in different age group of NPC patients. Kaplan-Meier (KM) survival analysis was used to estimate the effect of nutritional indexes on prognosis. The abnormal rate of albumin, prealbumin, hemoglobin, hand grip strength, and calf circumference increased with age. The malnutrition occurred in all age group and low calf circumference (HR, 4.427, 1.167-16.791) was an independent death risk in young adults. Distant metastasis (HR, 4.754, 2.737-8.260), low albumin (HR, 3.530, 1.708-7.296), hand grip strength (HR, 1.901, 1.160-3.115), and the nutritional intervention requirement (NRS-2002 ≥ 3) (HR, 2.802, 1.211-6.483) was significantly correlated with poor OS in NPC patients with middled age adults. Distant metastasis (HR, 2.546, 1.497-4.330), low albumin (HR, 1.824, 0.949-3.507), low hemoglobin (HR, 1.757, 1.015-3.044), low hand grip strength (HR, 1.771, 1.112-2.818), and low calf circumference (HR, 1.951, 1.074-3.545) were associated with increased risk of death in the elderly. KM analysis indicated that over 60 years, distant metastasis, low albumin, low hand grip strength, low calf circumference, and malnutritional risk (NRS-2002 ≥ 3) were correlated to prognosis of NPC patients. Low calf circumference could be a prognosis not only in elderly but also in young adults of NPC patients, whereas low albumin and distant metastasis were the prognostic factors in middle-aged and elderly patients. Patients aged over 60 years exhibited poorer OS compared with young and middle-aged adults.

New-Onset Age of Nonalcoholic Fatty Liver Disease and Cancer Risk.

Importance: The onset age of nonalcoholic fatty liver disease (NAFLD) is decreasing, and whether earlier ages of NAFLD onset are associated with increased cancer risk is currently unclear. Objective: To explore the association between NAFLD new-onset age and cancer risk. Design, Setting, and Participants: This cohort study was conducted among 179 328 participants included in the Kailuan Cohort Study between 2006 and 2021. In total, 46 100 incident NAFLD cases were identified. For each case, a participant matched by age (older or younger by 1 year) and sex was randomly selected to create a new matched study cohort. Data were analyzed from December 2022 through April 2023. Exposure: Onset of NAFLD. Main Outcomes and Measures: The association between the onset age of NAFLD and the risk of different cancer types was evaluated using weighted Cox regression models. Population-attributable fractions (PAFs) were used to quantify the association of NAFLD with cancer risk at different ages. Results: Among 63 696 participants (mean [SD] age, 51.37 [12.43] years; ‭10 932 females [17.2%] and ‭52 764 males [82.8%]), 31 848 individuals had NAFLD and 31 848 individuals were in the control group. During a median (IQR) follow-up of 10.16 (7.89-11.67) years, 2415 patients were diagnosed with cancer. Compared with the matched group, patients aged less than 45 years at NAFLD onset exhibited a higher risk of cancer (average hazard ratio [AHR], 1.52; 95% CI, 1.09-2.12), and as the onset age of NAFLD increased, the cancer risk decreased (ages 45-54 years: AHR, 1.50; 95% CI, 1.15-1.97; ages 55-64 years: AHR, 1.13; 95% CI, 0.97-1.33; ages >65 years: AHR, 0.75; 95% CI, 0.45-1.27; P for interaction < .001). Among patients aged less than 45 years at NAFLD onset, cancers were mainly digestive system and lung cancers, with AHR values of 2.00 (95% CI, 1.08-3.47) and 2.14 (95% CI, 1.05-4.36), respectively. PAFs also showed that in patients aged less than 45 years at NAFLD onset, 17.83% (95% CI, 4.92%-29.86%) of cancer risk was attributable to NAFLD.‬‬‬‬. Conclusions and Relevance: This study found that NAFLD was associated with increased cancer risk and there was an interaction with onset age, such that the younger the onset age of NAFLD, the greater the cancer risk.

Use of probiotics, prebiotics, and synbiotics in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with non-alcoholic fatty liver disease (NAFLD) exhibit compositional changes in their gut microbiome, which represents a potential therapeutic target. Probiotics, prebiotics, and synbiotics are microbiome-targeted therapies that have been proposed as treatment for NAFLD. We aim to systematically review the effects of these therapies in liver-related outcomes of NAFLD patients. METHODS: We conducted a systematic search in Embase (Ovid), Medline (Ovid), Scopus, Cochrane, and EBSCOhost from inception to August 19, 2022. We included randomized controlled trials (RCTs) that treated NAFLD patients with prebiotics and/or probiotics. We meta-analyzed the outcomes using standardized mean difference (SMD) and assessed study heterogeneity using Cochran's Q test and I2 statistics. Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. RESULTS: A total of 41 (18 probiotics, 17 synbiotics, and 6 prebiotics) RCTs were included. Pooled data demonstrated that the intervention had significantly improved liver steatosis (measured by ultrasound grading) (SMD: 4.87; 95% confidence interval [CI]: 3.27, 7.25), fibrosis (SMD: -0.61 kPa; 95% CI: -1.12, -0.09 kPa), and liver enzymes including alanine transaminase (SMD: -0.86 U/L; 95% CI: -1.16, -0.56 U/L), aspartate transaminase (SMD: -0.87 U/L; 95% CI: -1.22, -0.52 U/L), and gamma-glutamyl transferase (SMD: -0.77 U/L; 95% CI: -1.26, -0.29 U/L). CONCLUSIONS: Microbiome-targeted therapies were associated with significant improvements in liver-related outcomes in NAFLD patients. Nevertheless, limitations in existing literature like heterogeneity in probiotic strains, dosage, and formulation undermine our findings. This study was registered with PROSPERO (CRD42022354562) and supported by the Nanyang Technological University Start-up Grant and Wang Lee Wah Memorial Fund.

[Effect of multi-glycosides of Tripterygium wilfordii on renal injury in diabetic kidney disease rats through NLRP3/caspase-1/GSDMD pyroptosis pathway].

This study investigated the effect of multi-glycosides of Tripterygium wilfordii(GTW) on renal injury in diabetic kidney disease(DKD) rats through Nod-like receptor protein 3(NLRP3)/cysteine-aspartic acid protease-1(caspase-1)/gsdermin D(GSDMD) pyroptosis pathway and the mechanism. To be specific, a total of 40 male SD rats were randomized into the normal group(n=8) and modeling group(n=34). In the modeling group, a high-sugar and high-fat diet and one-time intraperitoneal injection of streptozotocin(STZ) were used to induce DKD in rats. After successful modeling, they were randomly classified into model group, valsartan(Diovan) group, and GTW group. Normal group and model group were given normal saline, and the valsartan group and GTW group received(ig) valsartan and GTW, respectively, for 6 weeks. Blood urea nitrogen(BUN), serum creatinine(Scr), alanine ami-notransferase(ALT), albumin(ALB), and 24 hours urinary total protein(24 h-UTP) were determined by biochemical tests. The pathological changes of renal tissue were observed based on hematoxylin and eosin(HE) staining. Serum levels of interleukin-1ß(IL-1ß) and interleukin-18(IL-18) were detected by enzyme-linked immunosorbent assay(ELISA). Western blot was used to detect the expression of pyroptosis pathway-related proteins in renal tissue, and RT-PCR to determine the expression of pyroptosis pathway-related genes in renal tissue. Compared with the normal group, the model group showed high levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1ß and IL-18(P<0.01), low level of ALB(P<0.01), severe pathological damage to kidney, and high protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01). Compared with the model group, valsartan group and GTW group had low levels of BUN, Scr, ALT, and 24 h-UTP and serum levels of IL-1ß and IL-18(P<0.01), high level of ALB(P<0.01), alleviation of the pathological damage to the kidney, and low protein and mRNA levels of NLRP3, caspase-1, and GSDMD in renal tissue(P<0.01 or P<0.05). GTW may inhibit pyroptosis by decreasing the expression of NLRP3/caspase-1/GSDMD in renal tissue, thereby relieving the inflammatory response of DKD rats and the pathological injury of kidney.

In silico development and in vitro validation of a novel five-gene signature for prognostic prediction in colon cancer.

Colon cancer is one of the most common cancers in digestive system, and its prognosis remains unsatisfactory. Therefore, this study aimed to identify gene signatures that could effectively predict the prognosis of colon cancer patients by examining the data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. LASSO-Cox regression analysis generated a five-gene signature (DCBLD2, RAB11FIP1, CTLA4, HOXC6 and KRT6A) that was associated with patient survival in the TCGA cohort. The prognostic value of this gene signature was further validated in two independent GEO datasets. GO enrichment revealed that the function of this gene signature was mainly associated with extracellular matrix organization, collagen-containing extracellular matrix, and extracellular matrix structural constituent. Moreover, a nomogram was established to facilitate the clinical application of this signature. The relationships among the gene signature, mutational landscape and immune infiltration cells were also investigated. Importantly, this gene signature also reliably predicted the overall survival in IMvigor210 anti-PD-L1 cohort. In addition to the bioinformatics study, we also conducted a series of in vitro experiments to demonstrate the effect of the signature genes on the proliferation, migration, and invasion of colon cancer cells. Collectively, our data demonstrated that this five-gene signature might serve as a promising prognostic biomarker and shed light on the development of personalized treatment in colon cancer patients.

Triceps skinfold-albumin index significantly predicts the prognosis of cancer cachexia: A multicentre cohort study.

BACKGROUND: The fat mass and nutritional status play important roles in the onset and progression of cancer cachexia. The present study evaluated the joint prognostic value of the fat mass, as indicated by the triceps skinfold thickness (TSF), and the serum albumin level, for mortality in patients with cancer cachexia. METHODS: We performed a multicentre cohort study including 5134 patients with cancer cachexia from January 2013 to April 2019. The sum of the TSF (mm) and serum albumin (g/L) was defined as the triceps skinfold-albumin index (TA). Harrell's C index, a time-dependent receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) were used to evaluate the prognostic performance of the TA and other indices. Optimal stratification was used to identify the thresholds to define a low TA, and the association of the TA with all-cause mortality was evaluated using Kaplan-Meier analysis and Cox proportional hazard regression models. RESULTS: The study enrolled 2408 women and 2726 men with a median age of 58.6 years and a median follow-up of 44 months. A total of 607 women (TA < 49.9) and 817 men (TA < 45.6) were classified as having a low TA. The TA showed better discrimination performance (C index = 0.621, 95% confidence interval [CI] = 0.607-0.636) to predict mortality in patients with cancer cachexia than the handgrip strength, the nutritional risk index, the prognostic nutritional index, the controlling nutritional status index, the systemic immune-inflammation index, the modified Glasgow prognostic score, and the TSF or albumin alone in the study population (all P < 0.05). The 1-, 3- and 5-year time-dependent ROC analyses (AUC = 0.647, 0.625 and 0.630, respectively) showed that the TA had the highest prognostic value among all indices investigated (all P < 0.05). Univariate analysis showed that a lower TA was associated with an increased death hazard (hazard ratio [HR] = 1.859, 95% CI = 1.677-2.062), regardless of the sex and cancer type. Multivariable survival analysis showed that a lower TA was independently associated with an increased death hazard (HR = 1.381, 95% CI = 1.223-1.560). This association was significantly strengthened in patients who did not receive curative chemotherapy (HR = 1.491, 95% CI = 1.298-1.713), those who had higher serum total protein levels (HR = 1.469, 95% CI = 1.284-1.681) and those with better physical performance (HR = 1.453, 95% CI = 1.271-1.662). CONCLUSIONS: This study defined and evaluated a new prognostic index, the TA, which may improve the selection of intervention strategies to optimize the survival of patients with cancer cachexia.

Applications of artificial intelligence in dementia research.

More than 50 million older people worldwide are suffering from dementia, and this number is estimated to increase to 150 million by 2050. Greater caregiver burdens and financial impacts on the healthcare system are expected as we wait for an effective treatment for dementia. Researchers are constantly exploring new therapies and screening approaches for the early detection of dementia. Artificial intelligence (AI) is widely applied in dementia research, including machine learning and deep learning methods for dementia diagnosis and progression detection. Computerized apps are also convenient tools for patients and caregivers to monitor cognitive function changes. Furthermore, social robots can potentially provide daily life support or guidance for the elderly who live alone. This review aims to provide an overview of AI applications in dementia research. We divided the applications into three categories according to different stages of cognitive impairment: (1) cognitive screening and training, (2) diagnosis and prognosis for dementia, and (3) dementia care and interventions. There are numerous studies on AI applications for dementia research. However, one challenge that remains is comparing the effectiveness of different AI methods in real clinical settings.

Association between serum arginine levels and cancer risk: A community-based nested case-control study.

Objective: The effect of arginine on tumors appears to be bidirectional. The association of serum arginine with the risk of incident cancer remains uncovered at present. We aimed to investigate the prospective relationship of baseline serum arginine concentrations with the risk of incident cancer in hypertensive participants. Materials and methods: A nested, case-control study with 1,389 incident cancer cases and 1,389 matched controls was conducted using data from the China H-Type Hypertension Registry Study (CHHRS). Conditional logistic regression analyses were performed to evaluate the association between serum arginine and the risk of the overall, digestive system, non-digestive system, and site-specific cancer. Results: Compared with matched controls, cancer patients had higher levels of arginine (21.41 µg/mL vs. 20.88 µg/mL, p < 0.05). When serum arginine concentrations were assessed as quartiles, compared with participants in the lowest arginine quartile, participants in the highest arginine quartile had a 32% (OR = 1.32, 95% CI: 1.03 to 1.71), and 68% (OR = 1.68, 95% CI: 1.09 to 2.59) increased risk of overall and digestive system cancer, respectively, in the adjusted models. In the site-specific analysis, each standard deviation (SD) increment of serum arginine was independently and positively associated with the risk of colorectal cancer (OR = 1.35, 95% CI: 1.01 to 1.82) in the adjusted analysis. Conclusion: We found that hypertensive individuals with higher serum arginine levels exhibited a higher risk of overall, digestive system, and colorectal cancer.

Identifying cancer cachexia in patients without weight loss information: machine learning approaches to address a real-world challenge.

BACKGROUND: Diagnosing cancer cachexia relies extensively on patient-reported historic weight, and failure to accurately recall this information can lead to severe underestimation of cancer cachexia. OBJECTIVES: The present study aimed to develop inexpensive tools to facilitate the identification of cancer cachexia in patients without weight loss information. METHODS: This multicenter cohort study included 12,774 patients with cancer. Cachexia was retrospectively diagnosed using Fearon et al.'s framework. Baseline clinical features, excluding weight loss, were modeled to mimic a situation where the patient is unable to recall their weight history. Multiple machine learning (ML) models were trained using 75% of the study cohort to predict cancer cachexia, with the remaining 25% of the cohort used to assess model performance. RESULTS: The study enrolled 6730 males and 6044 females (median age = 57.5 y). Cachexia was diagnosed in 5261 (41.2%) patients and most diagnoses were made based on the weight loss criterion. A 15-variable logistic regression (LR) model mainly comprising cancer types, gastrointestinal symptoms, tumor stage, and serum biochemistry indexes was selected among the various ML models. The LR model showed good performance for predicting cachexia in the validation data (AUC = 0.763; 95% CI: 0.747, 0.780). The calibration curve of the model demonstrated good agreement between predictions and actual observations (accuracy = 0.714, κ = 0.396, sensitivity = 0.580, specificity = 0.808, positive predictive value = 0.679, negative predictive value = 0.733). Subgroup analyses showed that the model was feasible in patients with different cancer types. The model was deployed as an online calculator and a nomogram, and was exported as predictive model markup language to permit flexible, individualized risk calculation. CONCLUSIONS: We developed an ML model that can facilitate the identification of cancer cachexia in patients without weight loss information, which might improve decision-making and lead to the development of novel management strategies in cancer care. This trial was registered at https://www.chictr.org.cn as ChiCTR1800020329.

The genetic architecture of blood pressure variability: A genome-wide association study of 9370 participants from UK Biobank.

Long-term blood pressure variability (BPV) is a risk factor for cardiovascular diseases, dementia, and stroke. However, its genetic architecture is not fully understood. This study aims to explore its genetic factors and provide more evidence on the mechanisms and further pathological study of BPV. The genome-wide association study (GWAS) is based on the UK Biobank cohort. There were four data collection rounds from 2006 to 2020, and 9370 participants with more than three blood pressure measurements were included. They had a median age of 55 and a male percentage of 50.1%. The phenotypes (BPV) were calculated by four methods and the genetic data contains 6 884 260 single nucleotide polymorphisms (SNPs) after imputation and quality control. A linear regression model was performed with adjustments for sex, age, genotype array, and a significant principal component. Subgroup analysis was performed on hypertension-free participants. The significant and suggestive significant P thresholds were set as 5 × 10-8 and 1 × 10-6 . Six genetic loci (BAD, CCDC88B, GPR137, PLCB3, RPS6KA4 for systolic BPV, and WWC2 for diastolic BPV) were identified by coding region SNPs at the suggestive significant P threshold (1 × 10-6 ). Among them, gene CCDC88B and RPS6KA4 reached the significant P threshold (5 × 10-8 ), with the strongest signal of SNP rs1229536170 (P = 6.36 × 10-8 , ß = -.29). The annotation results indicate that genes CCDC88B, GPR137, RPS6KA4, and BAD are associated with long-term SBPV. Their functions of inflammation, epithelial dysfunction, and apoptosis are related to artery stiffness, which was reported as potential mechanisms of BPV.

De novo Creation and Assessment of a Prognostic Fat-Age-Inflammation Index "FAIN" in Patients With Cancer: A Multicenter Cohort Study.

Background and Aims: Malnutrition is highly prevalent and is related to multiple impaired clinical outcomes in cancer patients. This study aimed to de novo create an objective, nutrition-related index specially for prognostic purposes in oncology populations. Methods: We performed a multicenter cohort study including 14,134 cancer patients. The prognostic impact for each baseline characteristic was estimated by calculating Harrell's C-index. The optimal parameters reflecting the nutritional and inflammatory impact on patients' overall survival were selected to develop the fat-age-inflammation (FAIN) index. The associations of the FAIN with the nutritional status, physical performance, quality of life, short-term outcomes and mortality of patients were comprehensively evaluated. Independent external validation was performed to further assess the prognostic value of the FAIN. Results: The study enrolled 7,468 men and 6,666 women with a median age of 57 years and a median follow-up of 42 months. The FAIN index was defined as: (triceps skinfold thickness + albumin) / [age + 5 × (neutrophil count/lymphocyte count)]. There were significant associations of the FAIN with the nutritional status, physical performance, quality of life and short-term outcomes. The FAIN also showed better discrimination performance than the Nutritional Risk Index, the Prognostic Nutritional Index and the Controlling Nutritional Status index (all P < 0.05). In multivariable-adjusted models, the FAIN was independently associated with a reduced death hazard both as a continuous variable (HR = 0.57, 95%CI = 0.47-0.68) and per one standard deviation (HR = 0.83, 95%CI = 0.78-0.88). External validation in a multicenter lung cancer cohort (n = 227) further confirmed the prognostic value of the FAIN. Conclusions: This study created and assessed the prognostic FAIN index, which might act as a feasible option to monitor the nutritional status and help develop intervention strategies to optimize the survival outcomes of cancer patients.

IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection.

BACKGROUND: Resistance to anti-tuberculosis (TB) drugs is a major issue in TB control, and demands the discovery of new drugs targeting the virulence factor ESX-1. METHODS: We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacteria and reducing bacterial virulence. We further investigated the probability of inducing drug resistance and the underlying mechanism using mycobacterial protein fragment complementation. RESULTS: A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drugs, and exhibit high potency against chronic mycobacterial infection. CONCLUSIONS: Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

A fusion decision system to identify and grade malnutrition in cancer patients: Machine learning reveals feasible workflow from representative real-world data.

BACKGROUND AND AIMS: Most nutritional assessment tools are based on pre-defined questionnaires or consensus guidelines. However, it has been postulated that population data can be used directly to develop a solution for assessing malnutrition. This study established a machine learning (ML)-based, individualized decision system to identify and grade malnutrition using large-scale data from cancer patients. METHODS: This was an observational, nationwide, multicenter cohort study that included 14134 cancer patients from five institutions in four different geographic regions of China. Multi-stage K-means clustering was performed to isolate and grade malnutrition based on 17 core nutritional features. The effectiveness of the identified clusters for reflecting clinical characteristics, nutritional status and patient outcomes was comprehensively evaluated. The study population was randomly split for model derivation and validation. Multiple ML algorithms were developed, validated and compared to screen for optimal models to implement the cluster prediction. RESULTS: A well-nourished cluster (n = 8193, 58.0%) and a malnourished cluster with three phenotype-specific severity levels (mild = 2195, 15.5%; moderate = 2491, 17.6%; severe = 1255, 8.9%) were identified. The clusters showed moderate agreement with the Patient-Generated Subjective Global Assessment and the Global Leadership Initiative on Malnutrition criteria. The severity of malnutrition was negatively associated with the nutritional status, physical status, quality of life, and short-term outcomes, and was monotonically correlated with reduced overall survival. A multinomial logistic regression was found to be the optimal ML algorithm, and models built based on this algorithm showed almost perfect performance to predict the clusters in the validation data. CONCLUSIONS: This study developed a fusion decision system that can be used to facilitate the identification and severity grading of malnutrition in patients with cancer. Moreover, the study workflow is flexible, and might provide a generalizable solution for the artificial intelligence-based assessment of malnutrition in a wider variety of scenarios.

Long-Term Blood Pressure Variability Increases Risks of Dementia and Cognitive Decline: A Meta-Analysis of Longitudinal Studies.

[Figure: see text].

Exposure to multiple metals and the risk of hypertension in adults: A prospective cohort study in a local area on the Yangtze River, China.

BACKGROUND: Exposure to multiple metals is recognized as a common and real scenario in daily life. However, limited prospective studies have assessed associations between multiple metals exposure and hypertension. METHODS: In total, 2625 adults in a local area on the Yangtze River were investigated at baseline from 2014 to 2015 and followed up in 2019. We measured baseline urine levels of 22 metals and used multivariate logistic analysis and Bayesian kernel machine regression (BKMR) to explore associations between multiple metals exposure and the risk of hypertension. RESULTS: A total of 385 individuals (29.6%) were diagnosed with hypertension. Five metals (cadmium, copper, magnesium, molybdenum and zinc) were positively associated with hypertension in single-metal models. Cadmium and zinc remained significantly positive associations after adjusting for these five metals, with the odds ratio (OR) in the highest quartiles of 1.49 (95% CI: 1.01, 2.21; p-trend = 0.05) and 1.60 (95% CI: 1.08, 2.38; p-trend = 0.02), respectively. BKMR analysis showed a significant joint effect of multiple metals on hypertension when the concentrations of five metals were at or above their 55th percentile compared with their median values. A potential interaction between cadmium and zinc in increasing the risk of hypertension was observed with the ORint of 1.41 (95%CI: 1.05, 1.89). CONCLUSIONS: We identified the joint effect of multiple metals on hypertension and observed a significant interaction between cadmium and zinc. Further cohort studies are needed to clarify the health effects of multiple metals exposure in a larger population.