Prenatal MRI assessment of mediastinal shift angle as a feasible and effective risk stratification tool in isolated right-sided congenital diaphragmatic hernia.

OBJECTIVES: To develop a mediastinal shift angle (MSA) measurement method applicable to right-sided congenital diaphragmatic hernia (RCDH) in fetal MRI and to validate the predictive value of MSA in RCDH. METHODS: Twenty-seven fetuses with isolated RCDH and 53 controls were included in our study. MSA was measured on MRI axial image at the level of four-chamber view of the fetal heart. The angle between the sagittal midline landmark line and the left boundary landmark line touching tangentially the lateral wall of the left ventricle was used to quantify MSA for RCDH. Appropriate statistical analyses were performed to determine whether MSA can be regarded as a valid predictive tool for postnatal outcomes. Furthermore, predictive performance of MSA was compared with that of lung area to head circumference ratio (LHR), observed/expected LHR (O/E LHR), total fetal lung volume (TFLV), and observed/expected TFLV (O/E TFLV). RESULTS: MSA was significantly higher in the RCDH group than in the control group. MSA, LHR, O/E LHR, TFLV, and O/E TFLV were all correlated with postnatal survival, pulmonary hypertension (PH), and extracorporeal membrane oxygenation (ECMO) therapy (p < 0.05). Value of the AUC demonstrated good predictive performance of MSA for postnatal survival (0.901, 95%CI: (0.781-1.000)), PH (0.828, 95%CI: (0.661-0.994)), and ECMO therapy (0.813, 95%CI: (0.645-0.980)), which was similar to O/E TFLV but slightly better than TFLV, O/E LHR, and LHR. CONCLUSIONS: We developed a measurement method of MSA for RCDH for the first time and demonstrated that MSA could be used to predict postnatal survival, PH, and ECMO therapy in RCDH. CLINICAL RELEVANCE STATEMENT: Newly developed MRI assessment method of fetal MSA in RCDH offers a simple and effective risk stratification tool for patients with RCDH. KEY POINTS: • We developed a measurement method of mediastinal shift angle for right-sided congenital diaphragmatic hernia for the first time and demonstrated its feasibility and reproducibility. • Mediastinal shift angle can predict more prognostic information other than survival in right-sided congenital diaphragmatic hernia with good performance. • Mediastinal shift angle can be used as a simple and effective risk stratification tool in right-sided congenital diaphragmatic hernia to improve planning of postnatal management.

Patient Welfare Implications of Indication-Specific Value-Based Pricing of Multi-Indication Drugs.

OBJECTIVES: Indication-specific value-based pricing (ISVBP) is a mechanism that allows the prices of multi-indication drugs to vary across indications by aligning the drug prices with value. However, the overall impact of ISVBP on patients across indications is uncertain. This study examines the theoretical welfare effects of ISVBP for multi-indication drugs and compares consumer surplus under ISVBP and single pricing, the latter of which is based on the weighted average value. METHODS: We considered a healthcare system with government-negotiated drug prices based on the value of drugs. We assumed a drug with 2 indications and 1 relevant comparator for each indication. The value of the drug was uniformly distributed among the patients of each indication in the base case. We also considered alternative scenarios with exponentially and Pareto distributed drug values. Numerical simulations were conducted to explore potential settings where ISVBP was welfare-improving for patients compared with single pricing. RESULTS: The theoretical analysis showed that the consumer surplus change was strictly non-positive from single pricing to ISVBP. Therefore, it was not welfare-improving for patients in the settings of interest. Numerical simulations confirmed this result across various scenarios of value distributions. CONCLUSIONS: This study provides insights into the patient welfare implications of ISVBP for multi-indication drugs. We did not identify conditions under which ISVBP can enhance overall patient well-being, suggesting that it should be implemented cautiously. Future research should examine dynamic welfare implications related to innovation incentives because they may significantly affect population health in the future.

Impact of CYP2A6 Gene Polymorphism on the Efficacy and Safety of S-1 Therapy in Patients with Gastric Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: The relationship of CYP2A6 polymorphisms with S-1 therapy outcomes in gastric cancer is unclear. This review aimed to assess the association between CYP2A6 gene polymorphisms (CYP2A6*4, *7, *9, *10) and S-1 therapy outcomes in gastric cancer, aiming to identify predictive markers for S-1 efficacy and adverse reactions. METHODS: We searched seven databases, using random or fixed-effect models to calculate hazard ratio (HR) and 95% confidence interval (CI) based on study heterogeneity. RESULTS: A total of 1,143 articles were retrieved from multiple online databases as of March 28, 2023. After screening, seven articles containing seven investigations were included in the meta-analysis. Our results revealed a significant association between the CYP2A6 polymorphism site and the overall survival (OS) of variant/variant group (V/V) patients compared to wild-type/wild-type (W/W) or wild-type/variant (W/V) patients (HR = 2.73, 95% CI: 1.45-5.14, p = 0.002). S-1 was more beneficial for W/W or W/V patients than V/V patients in terms of progression-free survival (PFS) (HR = 3.15, 95% CI: 1.47-6.75, p = 0.003). There was no association between CYP2A6 polymorphism and hematological adverse reactions (OR = 0.52, 95% CI: 0.23-1.15, p = 0.104). CONCLUSION: CYP2A6 polymorphisms correlate with S-1 efficacy (OS and PFS) in gastric cancer, suggesting their potential as predictive markers. However, the generalizability of findings is limited by the small number of studies from Eastern countries and variations in chemotherapy regimens and detection methods. Further, large-scale studies are needed to confirm these associations.

Cerebral circulation time on DSA after thrombectomy associated with hemorrhagic transformation in acute ischemic stroke.

BACKGROUND: To investigate the association between cerebral circulation time (CCT) on digital subtraction angiography immediately after thrombectomy and hemorrhagic transformation (HT) in acute ischemic stroke (AIS). METHODS: Retrospectively enrolled consecutive AIS patients presented with large vessel occlusion who received thrombectomy and achieved successful recanalization between January 2019 and June 2021. The time interval from the beginning of the siphon segment of internal carotid artery visualization until the end of the arterial phase during cerebral angiography was calculated as CCT. The independent association of CCT with HT was evaluated using logistic regression analyses. The receiver operating characteristic curve was analyzed to evaluate the association between CCT and HT. RESULTS: Two hundred and twenty-four patients were included, of whom 86 (38.4%) suffered HT. Compared with patients without HT, patients with HT were of advanced age, less commonly male, had more diabetes mellitus, had higher baseline National Institutes of Health Stroke Scale score, lower Alberta Stroke Program Early Computed Tomographic Score, and shorter CCT (P < 0.05). Multivariable logistic regression suggested that CCT was independently associated with HT (adjusted odds ratio, 0.170; 95% confidence interval, 0.004-0.450; P < 0.001). According to the receiver operating characteristic curve, the optimal cut-off value for the strong correlation between CCT and HT was 1.72 s, which had 76.6% sensitivity, 81.6% specificity, and the area under the curve was 0.846. CONCLUSION: Shorter post-thrombectomy CCT was independently associated with HT.

Manganese promotes α-synuclein amyloid aggregation through the induction of protein phase transition.

α-Synuclein (α-Syn) is the major protein component of Lewy bodies, a key pathological feature of Parkinson's disease (PD). The manganese ion Mn2+ has been identified as an environmental risk factor of PD. However, it remains unclear how Mn2+ regulates α-Syn aggregation. Here, we discovered that Mn2+accelerates α-Syn amyloid aggregation through the regulation of protein phase separation. We found that Mn2+ not only promotes α-Syn liquid-to-solid phase transition but also directly induces soluble α-Syn monomers to form solid-like condensates. Interestingly, the lipid membrane is integrated into condensates during Mn2+-induced α-Syn phase transition; however, the preformed Mn2+/α-syn condensates can only recruit lipids to the surface of condensates. In addition, this phase transition can largely facilitate α-Syn amyloid aggregation. Although the Mn2+-induced condensates do not fuse, our results demonstrated that they could recruit soluble α-Syn monomers into the existing condensates. Furthermore, we observed that a manganese chelator reverses Mn2+-induced α-Syn aggregation during the phase transition stage. However, after maturation, α-Syn aggregation becomes irreversible. These findings demonstrate that Mn2+ facilitates α-Syn phase transition to accelerate the formation of α-Syn aggregates and provide new insights for targeting α-Syn phase separation in PD treatment.

Mediastinal shift angle (MSA) measurement with MRI: a simple and effective tool for prenatal risk stratification in fetuses with congenital diaphragmatic hernia.

OBJECTIVES: To investigate the predictive value of mediastinal shift angle (MSA) in congenital diaphragmatic hernia (CDH). METHODS: A retrospective analysis was performed on 87 fetuses with prenatally diagnosed left-sided CDH (LCDH) and 88 controls. MSA was measured on magnetic resonance imaging (MRI). Lung area to head circumference ratio (LHR), ratio of the observed/expected LHR (O/E LHR), total fetal lung volume (TFLV), and observed/expected total fetal lung volume (O/E TFLV) were also measured. Correlation of MSA with pulmonary hypertension (PH), extracorporeal membrane oxygenation (ECMO) use, duration of hospitalization and survival in neonates with CDH was analyzed. Performance of MSA in prediction of postnatal outcomes was compared with LHR, O/E LHR, TFLV, and O/E TFLV. RESULTS: There were significant differences in MSA values not only between the CDH group and the control group but also in CDH patients with different survival outcomes. MSA was inversely correlated with O/E LHR, O/E TFLV, and TFLV. MSA, LHR, O/E LHR, TFLV, and O/E TFLV could all be used to predict survival of CDH patients. In addition, the receiver operating characteristic (ROC) curve showed that the test performance of MSA was similar to that of TFLV, O/E TFLV, and O/E LHR, but superior to that of LHR. MSA was also correlated with PH, need for ECMO support, and duration of hospitalization. CONCLUSION: MRI measurement of MSA can provide various prognostic information for prenatally diagnosed LCDH, in addition to postnatal survival. The test performance of MSA is similar to TFLV, O/E TFLV, and O/E LHR. KEY POINTS: • Mediastinal shift angle (MSA) can be measured quickly and reproducibly on MRI images. • MSA could provide more prognostic information other than postnatal survival for LCDH with good test performance. • MSA should be incorporated into prenatal risk stratification for LCDH to improve planning of postnatal management.

Pick's disease presenting with corticobasal syndrome: A case report and clinicopathological review.

Pick's disease (PiD) is a rare form of frontal temporal lobar degeneration. The pathognomonic feature is atrophy of the frontotemporal lobes and intraneuronal deposits of 3R-τ inclusions, the Pick body. Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome with a heterogeneous spectrum of underlying pathologies. We report a case of clinically diagnosed CBS with a post-mortem diagnosis of PiD and conduct a clinicopathological review of the literature on this unusual presentation.

Population impact of fine particulate matter on tuberculosis risk in China: a causal inference.

BACKGROUND: Previous studies have suggested the potential association between air pollution and tuberculosis incidence, but this association remains inconclusive and evidence to assess causality is particularly lacking. We aimed to draw causal inference between fine particulate matter less than 2.5 µm in diameter (PM2.5) and tuberculosis in China. METHODS: Granger causality (GC) inference was performed within vector autoregressive models at levels and/or first-differences using annual national aggregated data during 1982-2019, annual provincial aggregated data during 1982-2019 and monthly provincial aggregated data during 2004-2018. Convergent cross-mapping (CCM) approach was used to determine the backbone nonlinear causal association based on the monthly provincial aggregated data during 2004-2018. Moreover, distributed lag nonlinear model (DLNM) was applied to quantify the causal effects. RESULTS: GC tests identified PM2.5 driving tuberculosis dynamics at national and provincial levels in Granger sense. Empirical dynamic modeling provided the CCM causal intensity of PM2.5 effect on tuberculosis at provincial level and demonstrated that PM2.5 had a positive effect on tuberculosis incidence. Then, DLNM estimation demonstrated that the PM2.5 exposure driven tuberculosis risk was concentration- and time-dependent in a nonlinear manner. This result still held in the multi-pollutant model. CONCLUSIONS: Causal inference showed that PM2.5 exposure driving tuberculosis, which showing a concentration gradient change. Air pollutant control may have potential public health benefit of decreasing tuberculosis burden.

Individual differences in contextual threat generalisation and uncertainty: The role of intolerance of uncertainty.

Threat generalisation is an adaptive process that is essential for individual survival. In contrast, over-generalisation is a pathological process that underlies the development of anxiety disorders. Intolerance of uncertainty (IU) is an individual characteristic known to influence threat generalisation by altering the responses to threat in uncertain situations. However, how it affects contextual threat generalisation remains unclear. Here, we used a novel paradigm to investigate whether contextual threat generalisation varied between individuals depending on their IU level (high or low) and the predictability of a situation (predictable or unpredictable). We analysed shock expectancy in 82 participants (age: 18-27 years) during threat acquisition and generalisation. Results showed that compared with the low IU group, the high IU group exhibited increased contextual threat generalisation to threat-related cues in unpredictable situation. These findings suggest that IU could be a marker for anxiety disorder susceptibility, as well as a target for anxiety treatment.

An examination of machine learning to map non-preference based patient reported outcome measures to health state utility values.

Non-preference-based patient-reported outcome measures (PROMs) are popular in health outcomes research. These measures, however, cannot be used to estimate health state utilities, limiting their usefulness for economic evaluations. Mapping PROMs to a multi-attribute utility instrument is one solution. While mapping is commonly conducted using econometric techniques, failing to specify the complex interactions between variables may lead to inaccurate prediction of utilities, resulting in inaccurate estimates of cost-effectiveness and suboptimal funding decisions. These issues can be addressed using machine learning. This paper evaluates the use of machine learning as a mapping tool. We adopt a comprehensive approach to compare six machine learning techniques with eight econometric techniques to map the Patient-Reported Outcomes Measurement Information System Global Health 10 (PROMIS-GH10) to the EuroQol five dimensions (EQ-5D-5L). Using data collected from 2015 Australians, we find the least absolute shrinkage and selection operator (LASSO) model out-performed all machine learning techniques and the adjusted limited dependent variable mixture model (ALDVMM) out-performed all econometric techniques, with the LASSO performing better than ALDVMM. The variable selection feature of LASSO was then used to enhance the performance of the ALDVMM in a hybrid model. Our analysis identifies the potential benefits and challenges of using machine learning techniques for mapping and offers important insights for future research.

Global-local multi-stage temporal convolutional network for cataract surgery phase recognition.

BACKGROUND: Surgical video phase recognition is an essential technique in computer-assisted surgical systems for monitoring surgical procedures, which can assist surgeons in standardizing procedures and enhancing postsurgical assessment and indexing. However, the high similarity between the phases and temporal variations of cataract videos still poses the greatest challenge for video phase recognition. METHODS: In this paper, we introduce a global-local multi-stage temporal convolutional network (GL-MSTCN) to explore the subtle differences between high similarity surgical phases and mitigate the temporal variations of surgical videos. The presented work consists of a triple-stream network (i.e., pupil stream, instrument stream, and video frame stream) and a multi-stage temporal convolutional network. The triple-stream network first detects the pupil and surgical instruments regions in the frame separately and then obtains the fine-grained semantic features of the video frames. The proposed multi-stage temporal convolutional network improves the surgical phase recognition performance by capturing longer time series features through dilated convolutional layers with varying receptive fields. RESULTS: Our method is thoroughly validated on the CSVideo dataset with 32 cataract surgery videos and the public Cataract101 dataset with 101 cataract surgery videos, outperforming state-of-the-art approaches with 95.8% and 96.5% accuracy, respectively. CONCLUSIONS: The experimental results show that the use of global and local feature information can effectively enhance the model to explore fine-grained features and mitigate temporal and spatial variations, thus improving the surgical phase recognition performance of the proposed GL-MSTCN.

An Economic Evaluation of Australia's Newborn Hearing Screening Program: A Within-Study Cost-Effectiveness Analysis.

OBJECTIVES: Hearing loss is one of the most prevalent congenital disorders among children. Many countries have implemented universal newborn hearing screening (UNHS) for the early diagnosis and treatment of hearing loss. Despite widespread implementation, the value for money of UNHS is unclear due to lack of cost and outcomes data from rigorous study designs. The objective of this research is to conduct a within-study cost-effectiveness analysis of UNHS compared with targeted screening (targeting children with risk factors of hearing loss) from the Australian healthcare system perspective. This evaluation is the first economic evaluation to assess the cost-effectiveness of UNHS compared to targeted screening using real-world data from a natural experiment. DESIGN: The evaluation assumed the Australian healthcare system perspective and considered a time horizon of 5 years. Utilities were estimated using responses to the Health Utilities Index Mark III. Screening costs were estimated based on the Victorian Infant Hearing Screening Program. Ongoing costs were estimated based on administrative data, while external data sources were used to estimate costs related to hearing services. Missing data were handled using the multiple imputation method. Outcome measures included quality-adjusted life years (QALYs) and four language and communication-related outcomes: Peabody Picture Vocabulary Test, Wechsler Nonverbal Scale of Ability, Progressive Achievement Test, and comprehensive, expressive, and total language scores based on the Preschool Language Scale. RESULTS: On average, the UNHS cost an extra Australian dollar (A$)22,000 per diagnosed child and was associated with 0.45 more QALYs per diagnosed child compared with targeted screening to 5 years, resulting in an incremental cost-effectiveness ratio (ICER) of A$48,000 per QALY gained. The ICERs for language outcomes lay between A$3,900 (for expressive language score) and A$83,500 per one-point improvement in language score (for Wechsler Nonverbal Scale of Ability). UNHS had a 69% probability of being more cost-effective compared to targeted screening at a willingness to pay threshold of A$60,000 per QALY gained. ICERs were most sensitive to the screening costs. CONCLUSIONS: The evaluation demonstrated the usefulness of a within-study economic evaluation to understand the value for money of the UNHS program in the Australian context. Findings from this evaluation suggested that screening costs were the key driver of cost-effectiveness results. Most outcomes were not significantly different between UNHS and targeted screening groups. The ICER may be overestimated due to the short follow-up period. Further research is warranted to include long-term resource use and outcome data, late diagnosis, transition and remission between severity levels, and timing of diagnosis and treatment.

Tackling brain drain at Chinese CDCs: understanding job preferences of public health doctoral students using a discrete choice experiment survey.

BACKGROUND: Given the demands for public health and infectious disease management skills during COVID-19, a shortage of the public health workforce, particularly with skills and competencies in epidemiology and biostatistics, has emerged at the Centers for Disease Controls (CDCs) in China. This study aims to investigate the employment preferences of doctoral students majoring in epidemiology and biostatistics, to inform policy-makers and future employers to address recruitment and retention requirements at CDCs across China. METHODS: A convenience sampling approach for recruitment, and an online discrete choice experiment (DCE) survey instrument to elicit future employee profiles, and self-report of their employment and aspirational preferences during October 20 and November 12, 2020. Attributes included monthly income, employment location, housing benefits, children's education opportunities, working environment, career promotion speed and bianzhi (formally established post). RESULTS: A total of 106 doctoral epidemiology and biostatistics students from 28 universities completed the online survey. Monthly income, employment location and bianzhi was of highest concern in the seven attributes measured, though all attributes were statistically significant and presented in the expected direction, demonstrating preference heterogeneity. Work environment was of least concern. For the subgroup analysis, employment located in a first-tier city was more likely to lead to a higher utility value for PhD students who were women, married, from an urban area and had a high annual family income. Unsurprisingly, when compared to single students, married students were willing to forgo more for good educational opportunities for their children. The simulation results suggest that, given our base case, increasing only monthly income from 10,000 ($ 1449.1) to 25,000 CNY ($ 3622.7) the probability of choosing the job in the third-tier city would increase from 18.1 to 53.8% (i.e., the location choice is changed). CONCLUSION: Monthly income and employment location were the preferred attributes across the cohort, with other attributes then clearly ranked and delineated. A wider use of DCEs could inform both recruitment and retention of a public health workforce, especially for CDCs in third-tier cities where resource constraints preclude all the strategies discussed here.

Diagnostic performance of an immunoassay based on urine exfoliated cell enrichment nanotechnology for upper tract urothelial carcinoma: a retrospective, monocentric study.

BACKGROUND: Noninvasively urine-based diagnostic modalities for upper urinary tract urothelial carcinoma (UTUC) were still lacking. We evaluated the diagnostic value of our previously developed urine-based assay (UTC assay) in UTUC. METHODS: We retrospectively analyzed 90 patients with suspected UTUC and 40 donors without UTUC. Voided urine specimens were analyzed by UTC assay and fluorescence in situ hybridization (FISH). The performance of UTC assay and FISH was compared among the 60 histologically proven UTUC patients and the 40 donors with benign disease. RESULTS: Of the 60 UTUCs, there were 8 low-grade and 52 high-grade cases. Overall sensitivity for UTC assay and FISH were 85% and 73.3%, respectively (P = 0.116). Specificities for UTC assay and FISH were 92.5% and 95%, respectively (P = ns.). By grade, sensitivities of UTC assay and FISH were 87.5% vs. 37.5% for low-grade (P = 0.119), and 84.6% vs. 78.8% for high- grade UTUC (P = 0.446), respectively. By stage, UTC assay showed significantly higher sensitivity than FISH for detecting non-muscle-invasive UTUC, which were 88.5% vs. 61.5%, respectively (P = 0.025). CONCLUSION: UTC assay has good performance for the non-invasive diagnosis of UTUC. UTC assay may improve the diagnosis and surveillance of low-grade or superficial UTUC.

Characterization of hepatitis B virus DNA integration patterns in intrahepatic cholangiocarcinoma.

AIM: Hepatitis B virus (HBV) integration is one of the mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in intrahepatic cholangiocarcinoma (ICC) is poorly understood. This study aims to characterize the viral integration in HBV-related ICC. METHODS: The presence of HBV S and C gene in ICCs and the paratumor tissue was determined by polymerase chain reaction direct sequencing. Hepatitis B virus integration was detected by a high-throughput capture sequencing method. The expression analysis of the genes targeted by HBV in ICC was undertaken in The Cancer Genome Atlas dataset. RESULTS: Hepatitis B virus S and/or C gene fragments were detected in 71.43% (10/14) ICCs and 57.14% (8/14) paratumor tissues. Using the high-throughput capture sequencing approach, 139 and 183 HBV integration breakpoints were identified from seven ICC and seven paired paratumor tissues, respectively. Seven genes (TERT, CEACAM20, SPATA18, TRERF1, ZNF23, LINC01449, and LINC00486) were recurrently targeted by HBV-DNA in different ICC tissues or different cell populations of the same tissue. TERT, which is the most preferential HBV target gene in HCC, was found to be repeatedly interrupted by HBV-DNA in three different ICC tissues. Based on The Cancer Genome Atlas dataset, TERT, as well as three other HBV recurrently targeted genes (SPATA18, TRERF1, and ZNF23), showed differential expression levels between ICC and para-ICC tissues. CONCLUSIONS: Taken together, HBV integration is a common event in HBV-related ICC. The HBV recurrent integration genes identified from this study, such as TERT, provide new clues for further research on the causative link between HBV infection and ICC.

TRIM7 promotes proliferation and migration of vascular smooth muscle cells in atherosclerosis through activating c-Jun/AP-1.

Atherosclerosis (AS), with associated risk of stroke or cerebrovascular disease, is one of the most common causes of death globally. It has been well established that tripartite motif-containing protein 7 Tripartite Motif-containing 7 (Trim7), as an E3 ubiquitin protein ligase, is involved in protein ubiquitination and thus regulating cellular proliferation. Moreover, TRIM7 is upregulated in advanced carotid AS. However, the detailed mechanism of TRIM7 on regulation of AS remains unclear. In the present study, we firstly discovered that TRIM7 expression was robustly induced in platelet-derived growth factor type BB-treated vascular smooth muscle cells (VSMCs) and human atherosclerotic plaques. Functional approaches established that knockdown of TRIM7 inhibited proliferation and migration of VSMCs, as well as arrested the cell cycle at G1-S, thus suppressing AS progression. Our results also identified that c-Jun/activator protein 1 (AP-1) signaling pathway was activated by TRIM7. Moreover, gain- and loss-of-function studies revealed that TRIM7 could promote proliferation and migration of VSMCs via activation of c-Jun/AP-1 signaling pathway. Finally, by using atherogenic apolipoprotein E-deficient (apoE-/-) C57BL/6 mice with high-fat diet AS model, we demonstrated that interference of TRIM7 could effectively mitigate in vivo AS via inactivation of c-Jun/AP-1 signaling pathway. In general, activation of c-Jun/AP-1 signaling pathway via TRIM7 could be an important mechanism in AS progression, thus shedding light on the development of novel therapeutics to the treatment of the disease.

From Uncertainty to Anxiety: How Uncertainty Fuels Anxiety in a Process Mediated by Intolerance of Uncertainty.

Uncertainty about future events may lead to worry, anxiety, even inability to function. The highly related concept-intolerance of uncertainty (IU)-emerged in the early 1990s, which is further developed into a transdiagnostic risk factor in multiple forms of anxiety disorders. Interests in uncertainty and intolerance of uncertainty have rapidly increased in recent years; little is known about the construct and phenomenology of uncertainty and IU and the association between them. In an attempt to reveal the nature of two concepts, we reviewed broad literature surrounding uncertainty and intolerance of uncertainty (IU). We followed the process in which the whole IU theory developed and extended, including two aspects: (1) from uncertainty to intolerance of uncertainty and (2) definition of uncertainty and intolerance of uncertainty, and further concluded uncertainty fuels to negative emotions, biased expectancy, and inflexible response. Secondly, this paper summarized the experimental research concerning uncertainty and IU, consisted of three parts: (1) uncertainty-based research, (2) measurements of IU, and (3) domain-specific IU. Lastly, we pointed out what remains unknown and needed to be investigated in future research. This result provides a comprehensive overview in this domain, enhancing our understanding of uncertainty and IU and contributing to further theoretical and empirical explorations.

Copy number variations and polymorphisms in HSP90AB1 and risk of systemic lupus erythematosus and efficacy of glucocorticoids.

The aim of our study was to assess the associations of HSP90AB1 copy number variations (CNVs) with systemic lupus erythematosus (SLE) risk and glucocorticoids (GCs) efficacy, as well as the relationship between HSP90AB1 single-nucleotide polymorphisms (SNPs) and GCs efficacy. HSP90AB1 CNVs and SLE risk were analysed in 519 patients and 538 controls. Patients treated with GCs were followed up for 12 weeks and were divided into sensitive and insensitive groups to investigate the effects of CNVs (419 patients) and SNPs (457 patients) on the efficacy of GCs. Health-related quality of life (HRQoL) was also measured by SF-36 at baseline and week 12 to explore the relationship between CNVs/SNPs and HRQoL improvements in Chinese SLE patients. Our results indicated a statistically significant association between HSP90AB1 CNVs and SLE (PBH  = 0.039), and this association was more pronounced in the female subgroup (PBH  = 0.039). However, we did not detect association of HSP90AB1 CNVs/SNPs with efficacy of GCs. But we found a marginal association between SNP rs13296 and improvement in Role-emotional, while this association was not strong enough to survive in the multiple testing corrections. Collectively, our findings suggest that the copy number of HSP90AB1 is associated with SLE susceptibility. But copy number and polymorphisms of HSP90AB1 may not be associated with efficacy of GCs.

Isolation and Retrieval of Extracellular Vesicles for Liquid Biopsy of Malignant Ground-Glass Opacity.

Extracellular vesicles (EVs) are cell-released vesicles of submicrometer size. EVs contain a tissue-specific signature wherein a variety of proteins and nucleic acids are selectively packaged. Recent studies validate that EVs can be used for cancer diagnostics, staging, and treatment monitoring. EV-related clinical translation requires effective EV isolation as a prerequisite. However, lengthy procedures, low yield, low throughput, and high levels of contaminants disqualify the existing isolation approaches for large-scale clinical use. Hence, new approaches for rapid, efficient, and low-cost isolation of EVs in high purity for flexible analyses of the diverse contents in real-world clinical settings are highly desired yet are currently unavailable. Here, we report the effective use of heparin/polymer-coated microspheres (HPM) for EV isolation and retrieval. Approximately 81% of EVs can be isolated from plasma in 1 h with depletion of ∼99.5% plasma protein and nucleic acid contaminants, and 72% of isolated EVs can be retrieved with saline in 5 min for various cargo analyses. This approach was further validated with clinical samples derived from patients with malignant ground-glass opacity (GGO). In eight patients, the mutation concordance between EV DNA and tissue DNA is 39.8%. The prevalence and mutation count of EGFR, TP53, and NF1 are higher than those of other oncogenes and antioncogenes that are intensely associated with lung adenocarcinoma. Moreover, different mutation prevalence and patterns between smokers and nonsmokers can be observed. Our findings suggest that the combination of HPM assay and targeted sequencing of EV DNA could be translated in the differential diagnosis of malignant GGO with short turnaround time.

Mapping the Strengths and Difficulties Questionnaire onto the Child Health Utility 9D in a large study of children.

PURPOSE: Non-preference-based measures cannot be used to directly obtain utilities but can be converted to preference-based measures through mapping. The only mapping algorithm for estimating Child Health Utility-9D (CHU9D) utilities from Strengths and Difficulties Questionnaire (SDQ) responses has limitations. This study aimed to develop a more accurate algorithm. METHODS: We used a large sample of children (n = 6898), with negligible missing data, from the Longitudinal Study of Australian Children. Exploratory factor analysis (EFA) and Spearman's rank correlation coefficients were used to assess conceptual overlap between SDQ and CHU9D. Direct mapping (involving seven regression methods) and response mapping (involving one regression method) approaches were considered. The final model was selected by ranking the performance of each method by averaging the following across tenfold cross-validation iterations: mean absolute error (MAE), mean squared error (MSE), and MAE and MSE for two subsamples where predicted utility values were < 0.50 (poor health) or > 0.90 (healthy). External validation was conducted using data from the Child and Adolescent Mental Health Services study. RESULTS: SDQ and CHU9D were moderately correlated (ρ = - 0.52, p < 0.001). EFA demonstrated that all CHU9D domains were associated with four SDQ subscales. The best-performing model was the Generalized Linear Model with SDQ items and gender as predictors (full sample MAE: 0.1149; MSE: 0.0227). The new algorithm performed well in the external validation. CONCLUSIONS: The proposed mapping algorithm can produce robust estimates of CHU9D utilities from SDQ data for economic evaluations. Further research is warranted to assess the applicability of the algorithm among children with severe health problems.