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Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study.
Huang, J, Lin, Z, Lin, J, Xie, S, Xia, S, Chen, G, Zheng, Z, Xu, Z, Liu, F, Wu, H, et al
Thorax. 2024;(2):135-143
Abstract
BACKGROUND Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. METHODS Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. FINDINGS Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). INTERPRETATION Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.
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Effect of polygenic risk for schizophrenia on cardiac structure and function: a UK Biobank observational study.
Pillinger, T, Osimo, EF, de Marvao, A, Shah, M, Francis, C, Huang, J, D'Ambrosio, E, Firth, J, Nour, MM, McCutcheon, RA, et al
The lancet. Psychiatry. 2023;(2):98-107
Abstract
BACKGROUND Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations. METHODS For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression. FINDINGS Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51·5%) were female and 15 654 (48·5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes). A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5·09; p=0·00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk scores for schizophrenia and principal component 1 were negatively associated (β=-0·01 [SE 0·003]; p=0·017). Similar to the principal component analysis results, for individual cardiac phenotypes, we observed negative associations between polygenic risk scores for schizophrenia and indexed right ventricular end-systolic volume (β=-0·14 [0·04]; p=0·0013, pFDR=0·015), indexed right ventricular end-diastolic volume (β=-0·17 [0·08]); p=0·025; pFDR=0·082), and absolute longitudinal peak diastolic strain rates (β=-0·01 [0·003]; p=0·0024, pFDR=0·015), and a positive association between polygenic risk scores for schizophrenia and right ventricular ejection fraction (β=0·09 [0·03]; p=0·0041, pFDR=0·015). Models examining the transforming growth factor-β (TGF-β)-specific and acute inflammation-specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2·62, p=0·022; F=2·54, p=0·026). Using linkage disequilibrium score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume and right ventricular ejection fraction (p=0·0090, p=0·0077). INTERPRETATION High polygenic risk scores for schizophrenia are associated with decreased cardiac volumes, increased ejection fractions, and decreased absolute peak diastolic strain rates. TGF-β and inflammatory pathways might be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Reduced absolute peak diastolic strain rates indicate increased myocardial stiffness and diastolic dysfunction, which increases risk of cardiac disease. Thus, genetic risk for schizophrenia is associated with cardiac structural changes that can worsen cardiac outcomes. Further work is required to determine whether these associations are specific to schizophrenia or are also seen in other psychiatric conditions. FUNDING National Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council, Academy of Medical Sciences, Edmond J Safra Foundation, British Heart Foundation.
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Prospective, open-label, and observational study of cetuximab for metastatic colorectal carcinoma: The OPTIM1SE study.
Yang, TS, Chen, HH, Bo-Wen, L, Kim, TW, Kim, JG, Ahn, JB, Lee, MA, Lin, J, Ho, GF, Anh, LT, et al
Asia-Pacific journal of clinical oncology. 2023;(6):672-680
Abstract
AIM: The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice. METHODS OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). RESULTS From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab. CONCLUSION Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only.
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A 12-week personalised physical activity and dietary protein intervention for older adults undergoing peritoneal dialysis: A feasibility study.
Tao, X, Zhang, H, Lai, L, Cheng, J, Zhao, S, Cao, P, Xue, R, Zheng, Q, Huang, J, He, Y
Geriatric nursing (New York, N.Y.). 2022;:247-253
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Abstract
This single-arm observational study explored the feasibility and efficacy of a 12-week personalised physical activity and dietary protein intervention programme for older adults undergoing peritoneal dialysis. Older adults undergoing peritoneal dialysis received eight individualised nutrition and physical activity advice sessions provided by trained nurses. Protein intake and physical activity were regarded as primary outcomes. All data were collected at baseline and at week 12. The enrolment rate was 78.4%. Twenty-nine patients participated in the study. Of these, 86.2% (25/29) completed the intervention. There was a significant increase in protein intake (t = -4.453, P< 0.001) and physical activity levels (Z = -2.929, P = 0.004). Of the participants, 56.0% achieved the targeted protein goal, and 41.4% met the physical activity goal. The timed up-and-go performance (t = 4.135, P = 0.001) increased after intervention. Trained nurses can successfully implement personalised diet and physical activity advice, and achieve promising patient outcomes.
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The value of clinical-ultrasonographic feature model to predict the severity of secondary hyperparathyroidism.
Zhang, X, Xu, W, Huang, T, Huang, J, Zhang, C, Zhang, Y, Xie, X, Xu, M
Renal failure. 2022;(1):146-154
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Abstract
OBJECTIVES To analyze conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) features in patients with secondary hyperparathyroidism (SHPT) and to evaluate the clinical-ultrasonographic feature based model for predicting the severity of SHPT. METHODS From February 2016 to March 2021, a total of 59 patients (age 51.3 ± 11.7 years, seCr 797.8 ± 431.7 μmol/L, iPTH 1535.1 ± 1063.9 ng/L) with SHPT (including 181 parathyroid glands (PTGs)) without the history of intact parathyroid hormone (iPTH)-reducing drugs using were enrolled. The patients were divided into the mild SHPT group (mSHPT, iPTH <800 ng/L) and the severe SHPT group (sSHPT, iPTH ≥ 800 ng/L) according to the serum iPTH level. The clinical test data of patients were collected and CUS and CEUS examinations were performed for every patient. Multivariable logistic regression model according to clinical-ultrasonographic features was adopted to establish a nomogram. We performed K-fold cross-validation on this nomogram model and nomogram performance was determined by its discrimination, calibration, and clinical usefulness. RESULTS There were 19 patients in the mSHPT group and 40 patients in the sSHPT group. Multivariable logistic regression indicated serum calcium, serum phosphorus and total volume of PTGs were independent predictors related with serum iPTH level. Even though CEUS score of wash-in and wash-out were showed related to severity of SHPT in univariate logistic regression analysis, they were not predictors of SHPT severity (p = 0.539, 0.474 respectively). The nomogram developed by clinical and ultrasonographic features showed good calibration and discrimination. The accuracy and the area under the curve (AUC), positive predictive value (PPV), negative predictive value (NPV) and accuracy of this model were 0.888, 92.5%, 63.2% and 83.1%, respectively. When applied to internal validation, the score revealed good discrimination with stratified fivefold cross-validation in the cohort (mean AUC = 0.833). CONCLUSIONS The clinical-ultrasonographic features model has good performance for predicting the severity of SHPT.
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Efficacy and Safety of a Simplified Lamivudine Plus Dolutegravir Dual Therapy in HIV-1-Infected Patients: A Multicenter Cohort Study in China.
Zhong, M, Chen, C, Hu, Y, Zou, M, Yan, L, Huang, J, Lv, R, Su, Y, Qi, M, Ye, Z, et al
Journal of acquired immune deficiency syndromes (1999). 2022;(S1):S42-S50
Abstract
BACKGROUND Results from both clinical trials and real-world observational studies suggest that lamivudine plus dolutegravir (3TC + DTG) dual therapy has excellent virological efficacy and safety in HIV-1-infected patients. However, there is still no relevant study related to this dual therapy reported in China. METHODS In this multicenter, retrospective, observational study that included HIV-1-infected patients in China, baseline and follow-up data were collected to analyze the virological suppression rate, immune restoration, and adverse events during follow-up in HIV-1-infected patients who switched to the 3TC + DTG dual therapy. RESULTS This study recruited 112 HIV-1-infected patients, including 101 men (90.2%), with a median age of 44.0 years (IQR: 33.00-57.75) and median CD4+ T-cell count of 432.13 cells/μL (IQR: 237.75-578.50). The overall virological suppression rate was 94.5% at the 24-week follow-up. However, the virological suppression rates of men who have sex with men patients and patients with CD4+ T-cell count of <350 cells/μL were higher than the baseline value (P < 0.05) at week 24. The results of Cox regression analysis showed that the baseline CD4+ T-cell count was an independent determinant of immune restoration in patients, and patients with baseline CD4+ T-cell count of 350-500 cells/μL outperformed patients with baseline CD4+ T-cell count of <350 cells/μL in immune restoration (hazard ratio: 4.469, 95% confidence interval: 1.801 to 11.091, P = 0.001). Adverse events were reported in 5 patients (incidence rate of 4.5%); among them, 3 patients developed neuropsychiatric symptoms. Results from the laboratory data analysis showed that patients with grade 1 and 2 adverse events had elevated levels of low-density lipoprotein cholesterol and total bilirubin. Furthermore, grade 3 and 4 adverse events were associated with the elevation of blood glucose level in 4 patients. CONCLUSIONS Thus, the 3TC + DTG dual therapy displayed an excellent virological efficacy against HIV-1 infections and had an acceptable safety profile, with predominantly mild adverse events in HIV-1-infected patients in China.
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Correlation between air temperature, air pollutants, and the incidence of coronary heart disease in Liaoning Province, China: a retrospective, observational analysis.
Huang, J, Yang, Z
Annals of palliative medicine. 2021;(12):12412-12419
Abstract
BACKGROUND The concentration of air pollutants is affected by changes in climatic conditions. Air temperature is a main factor affecting the concentration of air pollutants. This study sought to examine the relationship between air temperature, air pollutants, and their interactions in elderly patients with coronary heart disease (CHD) in Liaoning Province, China. METHODS The population data primarily comprised data on daily hospitalizations due to CHD between January 1, 2015 and December 31, 2019 at the Shengjing Hospital of China Medical University. A total of 25,461 patients, who were permanent residents of Liaoning Province, were included in the study. The meteorological data included data on the average daily temperature and air pollutant data of the average daily concentrations of sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) over the hospitalization period. A multiple linear regression model was constructed to analyze the relationship between meteorological factors and CHD. RESULTS The interaction between air temperature and SO2, NO2, and O3 concentrations was related to the number of daily CHD-related hospitalizations in elderly patients aged ≥65 years (P=0.0023); however, this correlation was lower than that of the interaction between SO2 and NO2 concentrations (P=0.0026). Additionally, age exerted a greater effect than air temperature and air pollutants. CONCLUSIONS The incidence of CHD in elderly patients aged ≥65 years was found to be related to the interaction of SO2 and NO2 concentrations, and the interaction of air temperature and the concentrations of SO2, NO2, and O3.
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Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples.
Semaan, A, Bernard, V, Lee, JJ, Wong, JW, Huang, J, Swartzlander, DB, Stephens, BM, Monberg, ME, Weston, BR, Bhutani, MS, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(4):1082-1093
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PURPOSE Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials. EXPERIMENTAL DESIGN Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC. RESULTS Potentially actionable mutations were identified in >20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort. CONCLUSIONS Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
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Trefoil factor-2, an early predictor for acute gastrointestinal injury in patients with acute pancreatitis.
Xie, RL, Chen, WW, Qi, MZ, Tan, D, Zhao, B, Huang, J, Li, L, Wang, JL, Zhong, M, Yuan, J, et al
Medicine. 2021;(28):e26624
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Acute gastrointestinal injury (AGI) is commonly present in patients with acute pancreatitis (AP). It is often difficult to predict gastrointestinal function in the early stage due to lack of reliable markers. We aimed to assess whether early plasma trefoil factor 2 (TFF-2) is a potential predictor for AGI.Fifty one patients were included for the onset of AP (from developing abdominal pain) within 72 hours in this prospective observational single-center study from January 2013 to July 2015. Among them 23 patients were classified as mild, 17 as moderately severe, and 11 as severe according to 2012 Atlanta classification. Plasma samples were collected only once at admission to the ICU. Twenty samples of healthy adults were also collected as control. The TFF-2 levels were determined by using a human TFF-2 enzyme-linked immunoassay. AGI grades from 1st to 7th day after admission were observed.The plasma TFF-2 levels among AP patients in early stage were significantly higher than healthy controls (766.41 ng/mL vs 94.37 ng/mL, P < .0001). The correlations between TFF-2 levels and AGI grades from 1st to 4th day after admission were positive (r = 0.47, 0.43, 0.42, 0.40 respectively, P < .05). As a predictor of acute gastrointestinal failure, plasma TFF-2 was superior to others: Acute Physiology and Chronic Health Evaluation II, sequential organ failure assessment, procalcitonin, C-reactive protein, serum calcium. In addition, TFF-2 increased along with the severity of AP (r = 0.554, P < .0001) and associated with Acute Physiology and Chronic Health Evaluation II, sequential organ failure assessment, C-reactive protein, serum calcium.The plasma TFF-2 levels were increased in patients in early stage of AP and correlated with AGI grades and disease severity in our study. TFF-2 might be a potential predictor for acute gastrointestinal failure in patients with AP.
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Cardiovascular and renal disease manifestation and healthcare resource utilization in patients on first-line oral therapy for type 2 diabetes: A claims-based observational cohort study.
Olufade, T, Jiang, L, Israni, R, Huang, J, Gosmanov, AR
Diabetes, obesity & metabolism. 2021;(12):2741-2751
Abstract
AIM: To examine incident cardiovascular disease (CVD) and chronic kidney disease (CKD) diagnosis and associated healthcare resource utilization (HCRU) in a real-world population of patients with type 2 diabetes (T2D) initiating first-line oral antidiabetes drug (OAD) therapy. MATERIALS AND METHODS Adults with T2D without CVD/CKD initiating first-line OAD therapy from 2008 to 2018 IBM MarketScan claims data were included. Incident CVD/CKD diagnoses following OAD initiation and first diagnosis type were assessed. Risk of incident diagnosis of heart failure (HF) among patients with CKD and of CKD among patients with HF was evaluated. HCRU and costs were compared for the 12 months before and after the first CVD/CKD diagnosis. RESULTS Of 12 286 016 patients, 1 286 287 met all the inclusion criteria. During follow-up (mean 752 days), 205 865 (16.0%) patients had CVD/CKD diagnoses; the most common first diagnosis was the composite cardiorenal outcome of HF and/or CKD (64.6%). Most first diagnoses were within 2 years of OAD initiation. For HF and CKD, diagnosis of one was associated with increased risk of subsequent diagnosis of the other (both P < .001). Average annualized visits per patient increased by 31% after the first CVD/CKD diagnosis and annualized payer and patient costs increased by 75% and 26%, respectively, compared with the 12 months prediagnosis. Costs increased for all diagnosis types. CONCLUSIONS Most first CVD/CKD diagnoses occurred within 2 years after OAD initiation and were associated with increased HCRU and costs. Reducing CVD/CKD risk with T2D treatments that improve both cardiovascular and renal outcomes may attenuate the burden of illness.