Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

Cost-effectiveness analysis of bevacizumab for cerebral radiation necrosis treatment based on real-world utility value in China.

BACKGROUND: Bevacizumab shows superior efficacy in cerebral radiation necrosis (CRN) therapy, but its economic burden remains heavy due to the high drug price. This study aims to evaluate the cost-effectiveness of bevacizumab for CRN treatment from the Chinese payers' perspective. METHODS: A decision tree model was developed to compare the costs and health outcomes of bevacizumab and corticosteroids for CRN therapy. Efficacy and safety data were derived from the NCT01621880 trial, which compared the effectiveness and safety of bevacizumab monotherapy with corticosteroids for CRN in nasopharyngeal cancer patients, and demonstrated that bevacizumab invoked a significantly higher response than corticosteroids (65.5% vs. 31.5%, P < 0.001) with no significant differences in adverse events between two groups. The utility value of the "non-recurrence" status was derived from real-world data. Costs and other utility values were collected from an authoritative Chinese network database and published literature. The primary outcomes were total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was evaluated via one-way and probabilistic sensitivity analyses. RESULTS: Bevacizumab treatment added 0.12 (0.48 vs. 0.36) QALYs compared to corticosteroid therapy, along with incremental costs of $ 2010 ($ 4260 vs. $ 2160). The resultant ICER was $ 16,866/QALY, which was lower than the willingness-to-pay threshold of $ 38,223/QALY in China. The price of bevacizumab, body weight, and the utility value of recurrence status were the key influential parameters for ICER. Probabilistic sensitivity analysis revealed that the probability of bevacizumab being cost-effectiveness was 84.9%. CONCLUSION: Compared with corticosteroids, bevacizumab is an economical option for CRN treatment in China.

Risk factor analysis and optimal cutoff value selection of PSAD for diagnosing clinically significant prostate cancer in patients with negative mpMRI: results from a high-volume center in Southeast China.

BACKGROUND: Multi-parametric magnetic resonance imaging (mpMRI) is a diagnostic tool used for screening, localizing, and staging prostate cancer. Patients with Prostate Imaging Reporting and Data System (PI-RADS) score of 1 and 2 are considered negative mpMRI, with a lower likelihood of detecting clinically significant prostate cancer (csPCa). However, relying solely on mpMRI is insufficient to completely exclude csPCa, necessitating further stratification of csPCa patients using biomarkers. METHODS: A retrospective study was conducted on mpMRI-negative patients who underwent prostate biopsy at the First Affiliated Hospital of Zhejiang University from January 2022 to June 2023. A total of 607 patients were included based on inclusion and exclusion criteria. Univariate and multivariate logistic regression analysis were performed to identify risk factors for diagnosing csPCa in patients with negative mpMRI. Receiver Operating Characteristic (ROC) curves were plotted to compare the discriminatory ability of different Prostate-Specific Antigen Density (PSAD) cutoff values for csPCa. RESULTS: Among the 607 patients with negative mpMRI, 73 patients were diagnosed with csPCa. In univariate logistic regression analysis, age, PSA, f/tPSA, prostate volume, and PSAD were all associated with diagnosing csPCa in patients with negative mpMRI (P < 0.05), with PSAD being the most accurate predictor. In multivariate logistic regression analysis, f/tPSA, age, and PSAD were independent predictors of csPCa (P < 0.05). PSAD cutoff value of 0.20 ng/ml/ml has better discriminatory ability for predicting csPCa and is a significant risk factor for csPCa in multivariate analysis. CONCLUSION: Age, f/tPSA, and PSAD are independent predictors of diagnosing csPCa in patients with negative mpMRI. It is suggested that patients with negative mpMRI and PSAD less than 0.20 ng/ml/ml could avoid prostate biopsy, as a PSAD cutoff value of 0.20 ng/ml/ml has better diagnostic performance than the traditional cutoff value of 0.15 ng/ml/ml.

Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

Acute Effect in Mechanical Efficiency by Pressure-Volume Loop Analysis after Transcatheter Aortic Valve Implantation.

Background: This study aimed to evaluate the immediate effect of transcatheter aortic valve implantation (TAVI) on mechanical efficiency. Methods: A total of 46 patients (25 females) with an average age of 83 ± 6.4 years underwent TAVI using the CoreValve system. During the same hospitalization, we conducted a comprehensive comparison of the patients before and after TAVI without inotropic support using echocardiography. The parameters encompassed left ventricular (LV) geometry, valvular load, global LV afterload and ventricular hemodynamics. The analysis using pressure-volume loops enabled the determination of load-independent contractility (Ees) and afterload, in addition to assessing potential energy, stroke work, and mechanical efficiency. Results: The immediate effect was an augmented aortic valve area accompanied by a reduction in the transvalvular pressure gradient. We observed reductions in left ventricular end-systolic volume and end-diastolic volume, and also reductions in global afterload and end-systolic meridional wall stress. The Ea index decreased, while the Ees index remained relatively stable. We noted increases in stroke volume and systemic arterial compliance, indicating more efficient blood transfer from the ventricle to aorta. These changes contributed to the normalization of ventricular-arterial coupling. In terms of mechanical work of the chamber, we observed significant decreases in potential energy, stroke work, and pressure-volume area. There was an increase in the mechanical efficiency of the chamber. Conclusions: The TAVI procedure immediately reduced global afterload and improved diastolic compliance of the chamber, resulting in enhanced ventricular function and mechanical efficiency.

Wnt/ß-catenin signalling pathway in breast cancer cells and its effect on reversing tumour drug resistance by alkaloids extracted from traditional Chinese medicine.

Breast cancer is a high-risk disease with a high mortality rate among women. Chemotherapy plays an important role in the treatment of breast cancer. However, chemotherapy eventually results in tumours that are resistant to drugs. In recent years, many studies have revealed that the activation of Wnt/ß-catenin signalling is crucial for the emergence and growth of breast tumours as well as the development of drug resistance. Additionally, drugs that target this pathway can reverse drug resistance in breast cancer therapy. Traditional Chinese medicine has the properties of multi-target and tenderness. Therefore, integrating traditional Chinese medicine and modern medicine into chemotherapy provides a new strategy for reversing the drug resistance of breast tumours. This paper mainly reviews the possible mechanism of Wnt/ß-catenin in promoting the process of breast tumour drug resistance, and the progress of alkaloids extracted from traditional Chinese medicine in the targeting of this pathway in order to reverse the drug resistance of breast cancer.

Cost-effectiveness analysis of ovarian function preservation with GnRH agonist during chemotherapy in premenopausal women with early breast cancer.

STUDY QUESTION: Is it economically worthwhile to use GnRH agonist (GnRHa) to prevent menopausal symptoms (MS) and protect fertility in premenopausal women with breast cancer (BC) during chemotherapy from the US perspective? SUMMARY ANSWER: It is cost-effective to administer GnRHa during chemotherapy in order to forefend MS in premenopausal patients with BC when the willingness-to-pay (WTP) threshold is $50 000.00 per quality-adjusted life-year (QALY), and to preserve fertility in young patients with BC who undergo oocyte cryopreservation (OC), or no OC, when the WTP thresholds per live birth are $71 333.33 and $61 920.00, respectively. WHAT IS KNOWN ALREADY: Chemotherapy often results in premature ovarian insufficiency (POI) in premenopausal survivors of BC, causing MS and infertility. Administering GnRHa during chemotherapy has been recommended for ovarian function preservation by international guidelines. STUDY DESIGN, SIZE, DURATION: Two decision-analytic models were developed, respectively, for preventing MS and protecting fertility over a 5-year period, which compared the cost-effectiveness of two strategies: adding GnRHa during chemotherapy (GnRHa plus Chemo) or chemotherapy alone (Chemo). PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were early premenopausal women with BC aged 18-49 years who were undergoing chemotherapy. Two decision tree models were constructed: one for MS prevention and one for fertility protection from the US perspective. All data were obtained from published literature and official websites. The models' primary outcomes included QALYs and incremental cost-effectiveness ratios (ICERs). The robustness of the models was tested by sensitivity analyses. MAIN RESULTS AND THE ROLE OF CHANCE: In the MS model, GnRHa plus Chemo resulted in an ICER of $17 900.85 per QALY compared with Chemo, which was greater than the WTP threshold of $50 000.00 per QALY; therefore, GnRHa plus Chemo was a cost-effective strategy for premenopausal women with BC in the USA. Probabilistic sensitivity analysis (PSA) results showed an 81.76% probability of cost-effectiveness in the strategy. In the fertility model, adding GnRHa for patients undergoing OC and those who were unable to undergo OC resulted in ICERs of $67 933.50 and $60 209.00 per live birth in the USA, respectively. PSA indicated that GnRHa plus Chemo was more likely to be cost-effective over Chemo when the WTP for an additional live birth exceed $71 333.33 in Context I (adding GnRHa to preserve fertility in young patients with BC after OC) and $61 920.00 in Context II (adding GnRHa to preserve fertility in young patients with BC who cannot accept OC). LIMITATIONS, REASONS FOR CAUTION: The indirect costs, such as disease-related mental impairment and non-medical costs (e.g. transportation cost) were not included. All data were derived from previously published literature and databases, which might yield some differences from the real world. In addition, the POI-induced MS with a lower prevalence and the specific strategy of chemotherapy were not considered in the MS model, and the 5-year time horizon for having a child might not be suitable for all patients in the fertility model. WIDER IMPLICATIONS OF THE FINDINGS: When considering the economic burden of cancer survivors, the results of this study provide an evidence-based reference for clinical decision-making, showing that it is worthwhile to employ GnRHa during chemotherapy to prevent MS and preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Natural Science Foundation of Fujian Province [2021J02038]; and the Startup Fund for Scientific Research, Fujian Medical University [2021QH1059]. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Long-term trend of future Cancer onset: A model-based prediction of Cancer incidence and onset age by region and gender.

OBJECTIVES: This study provided estimates of cancer incidence rate and onset age by Socio-demographic Index (SDI) regions and gender from 2020 to 2040, aiming to clarify the long-term patterns of future cancer onset. METHOD: Based on the incidence data from the Global Burden of Diseases (GBD) 2019 study, we constructed the Bayesian age-period-cohort model to calculate the age-standardized incidence rates (ASIR) of cancers from 2020 to 2040. Using the average annual percentage change (AAPC) to quantify the trends of ASIR and the onset age. In addition, the incidences in 2019 were fixed to distinguish the age onset changes caused by demographic and incidence from 2020 to 2040. RESULTS: Globally, two-thirds of cancers have escalating trends of incidence rate, and the proportion of cancer weighted average onset age above 60 years old will grow from 62% to 76% between 2020 and 2040. In five SDI regions, the proportion of weighted average onset age above 60 years old will rise above 10% in the next 20 years and increase sequentially with the rise of the SDI level. Preclude sex-specific cancers, the onset age is younger in men than in women in 2040. Rule out the influence of changing demographics, half of cancer's morbidity has a youth-oriented tendency globally, which is concentrated in hormone-related and digestive tract cancer. CONCLUSION: From 2020 to 2040, the incidence and onset age changes demonstrate marked geographic and gender variations in the cancer spectrum. Cancer incidence and onset age are predicted to continuously increase worldwide in the future.

The role of HIF in angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers.

Typically associated with solid tumors, hypoxia contributes to tumor angiogenesis and lymphangiogenesis through various molecular mechanisms. Accumulating studies indicate that hypoxia-inducible factor is the key transcription factor coordinating endothelial cells to respond to hypoxia in urological cancers, mainly renal cell carcinoma, prostate cancer, and bladder cancer. Moreover, it has been suggested that tumor hypoxia in tumor microenvironment simultaneously recruits stromal cells to suppress immune activities. This review summarizes the mechanisms by which HIF regulates tumorigenesis and elaborates on the associations between HIF and angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers.

Leisure sedentary behaviour increases the risk of venous thromboembolism: a Mendelian randomisation study.

BACKGROUND: Venous thromboembolism (VTE) is a substantial contributor to the global burden of disease. Observational studies have suggested that leisure sedentary behaviours (LSB) are related to the risk of VTE; however, the causal role of LSB in VTE remains unclear. METHODS: Using data obtained from genome-wide association studies in the UK Biobank (N = 422,218), we identified 84, 21, and 4 single nucleotide polymorphisms (SNPs) related to sedentary television (TV) watching, computer use, and driving, respectively. These SNPs were employed as instrumental variables. Summary statistics for SNP-VTE associations was obtained from the FinnGen study (5,403 cases and 130,235 controls). Two-sample Mendelian randomisation (MR) analyses were performed using inverse-variance weighted (IVW), MR-Egger,weighted median, and weighted mode approaches. Sensitivity analyses were conducted to ensure robustness of the results. RESULTS: The main IVW approach demonstrated a positive association between the genetically predicted sedentary TV watching and the risk of VTE [odds ratio (OR):1.35, 95% confidence interval (CI):1.02-1.80, P = 0.039]. However, no significant association was observed for genetically predicted sedentary computer use or driving and VTE risk. The results from our series of sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and MR-Pleiotropy RESidual Sum and Outlier method, further supported these findings. CONCLUSION: This study provides evidence of an association between genetically predicted sedentary TV watching and the risk of VTE. Further studies are required to elucidate the underlying causal mechanisms.

Adjuvant zoledronic acid therapy for postmenopausal women with early breast cancer in China: a cost-effectiveness analysis.

Combination therapy of zoledronic acid (ZOL) plus aromatase inhibitor (AI) was found to reduce bone metastasis risk and improve overall survival for treatment-naïve postmenopausal women (PMW) with hormone receptor-positive (HR+) early breast cancer (EBC), when compared with AI alone. The objective of this study was to evaluate the cost-effectiveness of adding ZOL to AI in treating PMW with HR+ EBC in China. A 5-state Markov model was constructed to evaluate the cost-effectiveness of adding ZOL to AI for PMW-EBC (HR+) over a lifetime horizon from the perspective of Chinese healthcare provider. Data used were obtained from previous reports and public data. The primary outcomes of this study were direct medical cost, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed to examine the robustness of the presented model. Over a lifetime horizon, adding ZOL to AI was projected to yield a gain of 1.286 LYs and 1.099 QALYs compared with AI monotherapy, which yielded ICER $11 140.75 per QALY with an incremental cost of $12 247.36. The one-way sensitivity analysis indicated that the cost of ZOL was the most influential factor in our study. The probability that adding ZOL to AI was cost-effective at a threshold of $30 425 per QALY in China was 91.1%. ZOL is likely to be cost-effective in reducing bone metastasis risk and improving overall survival for PMW-EBC (HR+) in China.

Functional Disability Among Middle-Aged and Older Adults in China: The Intersecting Roles of Ethnicity, Social Class, and Urban/Rural Residency.

This study explores how ethnicity, family income, and education level differentiate patterns of functional limitations among urban and rural Chinese (aged 45 ≥ years). Based on the 2018 China Family Panel Studies (CFPS) (n = 16,589), this nationwide study employed binary/multinomial logistic regression analyses, stratified by urban/rural residency, to estimate the likelihood of instrumental activities of daily living (IADLs) disability (0/1-2/≥3 limitations) by social determinants of health (SDoH). The estimated overall prevalence of IADLs disability was 14.3%. The multivariable analyses did not find significant ethnic disparity in IADLs disability in urban China, while in rural China, ethnic minorities were 44% more likely to have IADLs disability than Han Chinese. Among rural residents, Mongolians, Tibetans, and Yi minority more than tripled the odds of having ≥3 limitations than Han Chinese; and the intersections of ethnicity and social class were associated with functional limitations. Long-term care and anti-poverty programs should target minority aging populations in rural China.

[Epidemiological Characteristics and Drug Resistance of Microbial Pathogens of Patients With Silicosis Combined With Pulmonary Infection].

Objective: To investigate the epidemiological characteristics of patients with silicosis combined with pulmonary infection in recent years, to study the distribution and the drug susceptibility of fungal and bacterial pathogens in their sputum samples, and to provide references for the prevention and treatment of silicosis and the appropriate drug use. Methods: The clinical data and drug sensitivity test results of patients with silicosis combined with pulmonary infection diagnosed at the Department of Occupational Diseases, West China Fourth Hospital, Sichuan University were retrospectively analyzed. Results: A total of 318 patients with silicosis combined with pulmonary infection who received treatment between January 2017 and December 2020 were enrolled. All the patients had positive microorganism test results. All participants were male. Their median age at the time of onset was 51.00 years and the median time of exposure to silica dust at work was 12.40 years. They worked mostly in construction, non-ferrous metal mining, and coal mining. The main types of work they did were pneumatic drilling, coal digging, and mining. The positive detection rates for the first, second and third phases of silicosis were 27.54%, 28.32%, and 32.97%, respectively. A total of 341 strains of fungal and bacterial pathogens were isolated, of which, 54.1% were fungi, including 114 strains (35.8%) of Candida albicans, and 53.1% were bacteria, including 168 strains (52.8%) of gram-negative bacteria, most of which being Klebsiella pneumoniae (30.2%). There was only 1 strain (0.3%) of gram-positive bacteria, namely Staphylococcus hemolyticus. Gram-negative bacilli were most resistant to ampicillin and highly sensitive to penicillin G and ofloxacin. Conclusion: Among patients with silicosis combined with pulmonary infection, the incidence of pulmonary infection increases along with the progress of silicosis. Microorganism analysis reveals high detection rates for fungi and the bacteria detected are predominantly gram-negative bacteria. The overall prospect for drug resistance rate was not optimistic.

Diagnostic value of an enhanced MRI combined with serum CEA, CA19-9, CA125 and CA72-4 in the liver metastasis of colorectal cancer.

OBJECTIVE: This paper aims to explore the diagnostic value of enhanced magnetic resonance imaging (MRI) combined with a carcinoembryonic antigen (CEA) and carbohydrate antigen in terms of the liver metastasis of colorectal cancer. METHODS: A total of 167 colorectal cancer patients with liver metastasis and 167 colorectal cancer patients without liver metastasis were selected as the subjects. An automatic electrochemiluminescence analyser was then used to detect the tumour markers CEA, CA19-9, CA125 and CA72-4. The consistency between the MRI examination and clinical pathological examination was also analysed, and the sensitivity, specificity and positive and negative predictive values of various combined detection methods were compared. RESULTS: The abnormal rates of CEA, CA19-9, CA125 and CA72-4 in the two groups were statistically significant (P < 0.05), while the results of the enhanced MRI and clinicopathological examination for liver metastasis in patients with colon cancer were largely consistent (Kappa coefficient = 0.788, P < 0.000). However, the two methods were inconsistent. The false positive rate of the enhanced MRI examination was 15.3%, while the false negative rate was 6.0%. The specificity (94.61%), positive predictive value (92.68%) and positive likelihood ratio (12.67%) were the highest for the MRI combined with serial CEA, while the sensitivity (98.80%) and negative predictive value (97.22%) were the highest with the MRI combined with parallel CEA, and this combination returned the lowest negative likelihood ratio (0.03). CONCLUSION: The combination of MRI and CEA excludes non-metastatic patients and identifies colorectal liver metastasis cancer patients. Overall, it has a higher diagnostic value.

First-Line Durvalumab in Addition to Etoposide and Platinum for Extensive-Stage Small Cell Lung Cancer: A U.S.-Based Cost-Effectiveness Analysis.

BACKGROUND: The latest published CASPIAN trial demonstrated that adding durvalumab to etoposide and platinum (EP) improved survival dramatically for patients with extensive-stage small cell lung cancer (ES-SCLC). Considering the high cost of durvalumab, this study evaluated the cost-effectiveness of durvalumab plus EP (DEP) in the first-line setting for treatment-naïve patients with ES-SCLC from the U.S. payer perspective. MATERIALS AND METHODS: We developed a three-state Markov model to simulate the disease course and source consumption of ES-SCLC over a lifetime horizon. Pseudo-individual patient-level data were generated from digitized Kaplan-Meier curves. Direct medical costs, including drug and administration costs, disease management and adverse events treatment fees, best supportive care and terminal care costs were obtained from sources including the Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, and relevant literature. Health state utility values were derived from published literature. Main outcomes considered were total costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). All costs were adjusted for inflation to reflect 2019 U.S. dollars. The willingness-to-pay threshold was set as $150,000/QALY. One-way and probabilistic sensitivity analyses were used to explore the uncertainty of model assumptions. RESULTS: Compared with EP, DEP was projected to increase life expectancy by 0.86 LYs (1.73 vs. 0.87) and 0.44 QALYs (0.93 vs. 0.49). The incremental treatment cost was $95,907, and the corresponding ICER was $216,953/QALY. The result was most sensitive to the variation of durvalumab acquisition cost. Probabilistic sensitivity analysis revealed that the probability of DEP over EP regimen to be cost-effective was 9.4% at a willingness-to-pay threshold of $150,000/QALY. In the case of reducing the price of durvalumab by 30.7%, DEP was more cost-effective than EP. CONCLUSION: From the perspective of the U.S. payer, adding durvalumab to EP is estimated to be not cost-effective compared with EP alone for patients with untreated ES-SCLC. IMPLICATIONS FOR PRACTICE: The information provided by this analysis serves as a reference for decision makers. Lowering the price of durvalumab would be a potential measure to improve the economics of durvalumab plus etoposide and platinum (DEP), and the inclusion of durvalumab in the Medicare pharmacopeia could make DEP more economically available. These results may also guide physicians and patients to choose the most economically feasible treatment.

Post-traumatic stress disorder (PTSD) in mid-age and older adults differs by immigrant status and ethnicity, nutrition, and other determinants of health in the Canadian Longitudinal Study on Aging (CLSA).

PURPOSE: This study aimed to address knowledge gaps about post-traumatic stress disorder (PTSD) in mid-age and older adults, with particular attention to the relationship of PTSD with nutrition and with ethnicity and immigrant status. METHODS: Binary logistic regression analysis of weighted comprehensive cohort data from the baseline Canadian Longitudinal Study on Aging (CLSA; n = 27,211) was conducted using the four-item Primary Care-PTSD tool (outcome) and immigrant status by ethnicity (Canadian-born white, Canadian-born minority, immigrant white, immigrant minority). Covariates included various social, economic, nutrition and health-related variables. RESULTS: After controlling for socioeconomic and health variables, immigrants from minority groups had significantly higher odds of PTSD compared to their Canadian-born counterparts, whereas white immigrants had lower odds of PTSD. These relationships were significantly robust across seven cluster-based regression models. After adjusting for ethnicity/immigrant status, the odds of PTSD were higher among those earning lower household incomes, widowed, divorced, or separated respondents, ever smokers, and those who had multi-morbidities, chronic pain, high nutritional risk, or who reported daily consumptions of pastries, pulses and nuts, or chocolate. Conversely, those 55 years and over, who had high waist-to-height ratio, or who consumed 2-3 fiber sources daily had significantly lower odds of PTSD. CONCLUSION: Interventions aimed at managing PTSD in mid-age and older adults should consider ethnicity, immigrant status, as well as socioeconomic, health, and nutrition status.

Feasibility of using deep learning to detect coronary artery disease based on facial photo.

AIMS: Facial features were associated with increased risk of coronary artery disease (CAD). We developed and validated a deep learning algorithm for detecting CAD based on facial photos. METHODS AND RESULTS: We conducted a multicentre cross-sectional study of patients undergoing coronary angiography or computed tomography angiography at nine Chinese sites to train and validate a deep convolutional neural network for the detection of CAD (at least one ≥50% stenosis) from patient facial photos. Between July 2017 and March 2019, 5796 patients from eight sites were consecutively enrolled and randomly divided into training (90%, n = 5216) and validation (10%, n = 580) groups for algorithm development. Between April 2019 and July 2019, 1013 patients from nine sites were enrolled in test group for algorithm test. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated using radiologist diagnosis as the reference standard. Using an operating cut point with high sensitivity, the CAD detection algorithm had sensitivity of 0.80 and specificity of 0.54 in the test group; the AUC was 0.730 (95% confidence interval, 0.699-0.761). The AUC for the algorithm was higher than that for the Diamond-Forrester model (0.730 vs. 0.623, P < 0.001) and the CAD consortium clinical score (0.730 vs. 0.652, P < 0.001). CONCLUSION: Our results suggested that a deep learning algorithm based on facial photos can assist in CAD detection in this Chinese cohort. This technique may hold promise for pre-test CAD probability assessment in outpatient clinics or CAD screening in community. Further studies to develop a clinical available tool are warranted.

An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials.

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.

Red-Emitting Carbon Nanodot-Based Wide-Range Responsive Nanothermometer for Intracellular Temperature Sensing.

Precise sensing of intracellular temperature can provide plenty of information on disease-related cell states and promote the development of a diagnostic method. Fluorescence-based nanothermometers, as the "noncontact" sensors, exhibit great advantages over traditional thermometers due to the dual function of imaging and sensing at the molecular level. Herein, we report a red-emitting carbon nanodots (RCDs)-based nanothermometer for intracellular temperature sensing. Results indicate that RCDs exhibit favorable temperature-responsive fluorescence property with a good linear relationship, reversibility, and reproducibility under heating and cooling treatments in a wide range from 4 to 80 °C. Meanwhile, the RCDs possess satisfactory thermal sensitivity and temperature resolution, which are superior or comparable to the current nanothermometers. The low cytotoxicity and excellent temperature-responsive fluorescence property of RCDs have also been verified in living cell studies. Therefore, the RCDs will be a promising nanothermometer for intracellular temperature sensing in diverse areas.

A Population-Based, Nationwide Longitudinal Study of Bipolar Disorder With Incident Dementia in Taiwan.

OBJECTIVE: Affective disorders are associated with increased risk of dementia, yet most studies focus on the association of major depressive disorder or depressive episodes of bipolar disorder with increased dementia risk. The association of manic/mixed episodes of bipolar disorder with increased dementia risk is unclear. PARTICIPANTS: Between January 1, 2001 and December 31, 2009, 20,535 individuals aged 45-80 years with bipolar disorder and 82,140 age- and sex-matched comparisons were enrolled and followed up to December 2011 in Taiwan. Those who developed dementia (ICD-9-CM codes: 290.0-290.4, 294.1-294.2, and 331.0-331.2) during the follow-up period were identified. DESIGN AND METHODS: Cox proportional hazards models were used to examine the relationship between manic/mixed/depressive episodes of bipolar disorder and incident dementia. We also assessed the association between the frequency of psychiatric admissions (total, manic/mixed, and depressive episodes per year) for bipolar disorder and dementia risk. RESULTS: Bipolar disorder was associated with increased risk of incident dementia (hazard ratio [HR]: 7.52, 95% confidence interval [CI]: 6.86-8.25). Greater frequency of manic/mixed (>2/year: HR: 4.50, 3.50-5.79; 1-2/year: HR: 3.17, 2.31-4.36) and depressive episodes (>2/year: HR: 7.84, 5.93-10.36; 1-2/year: HR: 2.93, 2.05-4.19) were associated with increased risk of incident dementia. CONCLUSIONS: Not only depressive episode of bipolar disorder, but manic/mixed episodes of bipolar play a role as a risk factor of incident dementia, especially for those patients with more than two manic/mixed episodes per year. These findings remind the clinicians the importance of preventing the relapse of bipolar disorder for the potential subsequent cognitive decline and disease.