Comprehensive characterization of costimulatory molecule gene for diagnosis, prognosis and recognition of immune microenvironment features in sepsis.

The present study, which involved 10 GEO datasets and 3 ArrayExpress datasets, comprehensively characterized the potential effects of CMGs in sepsis. Based on machine learning algorithms (Lasso, SVM and ANN), the CMG classifier was constructed by integrating 6 hub CMGs (CD28, CD40, LTB, TMIGD2, TNFRSF13C and TNFSF4). The CMG classifier exhibit excellent diagnostic values across multiple datasets and time points, and was able to distinguish sepsis from other critical diseases. The CMG classifier performed better in predicting mortality than other clinical characteristics or endotypes. More importantly, from clinical specimens, the CMG classifier showed more superior diagnostic values than PCT and CRP. Alternatively, the CMG classifier/hub CMGs is significantly correlated with immune cells infiltration (B cells, T cells, Tregs, and MDSC), pivotal immune and molecular pathways (inflammation-promoting, complement and coagulation cascades), and several cytokines. Collectively, CMG classifier was a robust tool for diagnosis, prognosis and recognition of immune microenvironment features in sepsis.

Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy.

BACKGROUND AND AIM: Controlled attenuation parameter (CAP) is a novel ultrasound-based elastography method for detection of steatosis severity. This meta-analysis aimed to assess the performance of CAP. METHODS: PubMed, the Cochrane Library, and the Web of Knowledge were searched to find studies, published in English, relating to accuracy evaluations of CAP for detecting stage 1 (S1), stage 2 (S2), or stage 3 (S3) hepatic steatosis which was diagnosed by liver biopsy. Sensitivities, specificities, and hierarchical summary receiver operating characteristic (HSROC) curves were used to examine CAP performance. The clinical utility of CAP was also evaluated. RESULTS: Nine studies, with 11 cohorts were analyzed. The summary sensitivities and specificities values were 0.78 (95% confidence interval [CI], 0.69-0.84) and 0.79 (95% CI, 0.68-0.86) for ≥ S1, 0.85 (95% CI, 0.74-0.92) and 0.79 (95% CI, 0.71-0.85) for ≥ S2, and 0.83 (95% CI, 0.76-0.89) and 0.79 (95% CI, 0.68-0.87) for ≥ S3. The HSROCs were 0.85 (95% CI, 0.81-88) for ≥ S1, 0.88 (95% CI, 0.85-0.91) for ≥ S2, and 0.87 (95% CI, 0.84-0.90) for ≥ S3. Following a "positive" measurement (over the threshold value) for ≥ S1, ≥ S2, and ≥ S3, the corresponding post-test probabilities for the presence of steatosis (pretest probability was 50%) were 78%, 80% and 80%, respectively; if the values were below these thresholds ("negative" results), the post-test probabilities were 22%, 16%, and 17%, respectively. CONCLUSIONS: CAP has good sensitivity and specificity for detecting hepatic steatosis; however, based on a meta-analysis, CAP was limited in their accuracy of steatosis, which precluded widespread use in clinical practice.

Sufentanil-induced Nrf2 protein ameliorates cerebral ischemia-reperfusion injury through suppressing neural ferroptosis.

As an oxidative stress and inflammation-related disease, cerebral ischemia-reperfusion injury (CIRI) is a prevalent pathogenic factor of ischemic stroke (IS) and seriously degrades the life quality of human beings. As an opioid analgesic for anesthesia, Sufentanil (SUF) can activate the Nrf2 protein-induced anti-oxidant effects, which indicate that SUF may be used as alternative drug for CIRI therapy, but little is known regarding to its molecular mechanisms. Thus, this research aimed to examine whether SUF pre-treatment alleviated CIRI through the modulation of Nrf2 protein-mediated antioxidant activity. Our research revealed that middle cerebral artery occlusion/reperfusion (MCAO/R)-treated rats exhibited apparent CIRI-related symptoms and induced damages in rats' brain, which were all notably mitigated in the MCAO/R rats. The subsequent in vitro cellular experiments verified that oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cytotoxicity were apparently reversed by SUF co-treatment in HT22 and BV2 cells, and it was also validated that SUF was capable of suppressing inflammation and ferroptosis in CIRI models by inhibiting oxidative stress-related damages. Mechanistically, the Akt/GSK-3ß pathway was excessively activated by SUF to promote Nrf2 protein expressions and enhance Nrf2-meidated anti-oxidant effects, and it was found that SUF-induced protective effects during CIRI progression were all abrogated by co-treating cells with MK2206 (Akt inhibitor), NP-12 (GSK-3ß inhibitor), or ML385 (Nrf2 inhibitor). In conclusion, SUF activated the Akt/GSK-3ß pathway to initiate Nrf2 protein-mediated antioxidant effects, which further suppressed oxidative stress-related inflammation and ferroptosis to ameliorate CIRI progression, and SUF could potentially be used as novel therapeutic agent for CIRI treatment in clinic.

Subtyping treatment response of tirofiban in acute ischemic stroke based on neuroimaging features.

In a previously published clinical trial, we demonstrated that tirofiban was effective and safe in acute ischemic stroke (AIS) patients who did not undergo early recanalization treatments. We aimed to evaluate neuroimaging characteristics and their clinical significance to guide tirofiban treatment. In this post hoc analysis, location of infarcts (anterior circulation stroke [ACS] vs. posterior circulation stroke [PCS]), degree of cerebral artery stenosis (≤69% vs. ≥70% or occlusion), total infarct volume, and ASPECTS were used to predict the treatment effects of tirofiban, defined as the proportions of excellent and favorable functional outcome (modified Rankin Scale [mRS] score of 0-1, 0-2) at 90 days. ACS patients were more likely to achieve excellent (OR 2.08; 95% CI 1.25-3.45; p = 0.004) and favorable functional outcome (OR 2.28; 95% CI 1.24-4.22; p = 0.008) when treated with tirofiban. However, there was no significant difference in PCS patients between tirofiban and the control group. For patients with severe stenosis (≥70% or occlusion), tirofiban treatment improved the proportion of good outcomes (OR 2.84; 95% CI 1.44-5.60; p = 0.002 for mRS 0-1; OR 2.42; 95% CI 1.22-4.77; p = 0.011 for mRS 0-2). Meanwhile, we found that tirofiban improved outcome in patients with ASPECTS 8-10 and was independent of total infarct volume. These findings support the hypothesis that patients with ACS and severe stenosis may be recommended for tirofiban treatment, which can be predicted independent of total infarct volume.

Discovery of novel acetohydroxyacid synthase inhibitors as active agents against Mycobacterium tuberculosis by virtual screening and bioassay.

Acetohydroxyacid synthase (AHAS) has been regarded as a promising drug target against Mycobacterium tuberculosis (MTB) as it catalyzes the biosynthesis of branched-chain amino acids. In this study, 23 novel AHAS inhibitors were identified through molecular docking followed by similarity search. The determined IC(50) values range from 0.385 ± 0.026 µM to >200 µM against bacterium AHAS. Five of the identified compounds show significant in vitro activity against H37Rv strains (MICs in the range of 2.5-80 mg/L) and clinical MTB strains, including MDR and XDR isolates. More impressively, compounds 5 and 7 can enhance the killing ability against macrophages infected pathogen remarkably. This study suggests our discovered inhibitors can be further developed as novel anti-MTB therapeutics targeting AHAS.

Bidirectional flow in the vertebral artery is not always indicative of the subclavian steal phenomenon.

OBJECTIVE: To evaluate the causes of bidirectional flow in the vertebral artery detected by Doppler sonography and its differential diagnosis. METHODS: Twenty-nine patients with bidirectional flow in the vertebral artery were retrospectively studied. The vertebral artery parameters, including peak antegrade velocity (PAV), peak reversed velocity (PRV), maximum peak velocity (MPV), peak systolic velocity, resistive index (RI), and diameter, were measured. The MPV was defined as the MPV of bidirectional flow regardless of the velocity of antegrade or retrograde flow. To better predict the cause of bidirectional flow, receiver operating characteristic curves were constructed for these parameters, and the best cutoff values were obtained. The cause of bidirectional flow was determined by angiography. RESULTS: The causes of bidirectional flow were classified as the subclavian steal phenomenon (n = 21) and factors unrelated to the steal phenomenon (n = 8, including a hypoplastic vertebral artery [n = 4] and proximal vertebral artery stenosis and occlusion [n = 4]). Significant differences were observed between the steal phenomenon and non-steal phenomenon groups (P< .05) for MPV, PRV, PAV, target vertebral artery diameter, and contralateral RI. To determine the cause of bidirectional flow, areas under the receiver operating characteristic curves for the different parameters were obtained: 0.929 for MPV, 0.881 for PRV, 0.824 for PAV, 0.753 for target vertebral artery diameter, and 0.845 for contralateral RI. The cutoff value for MPV was 26.1 cm/s, and the accuracy was 93% (27 of 29). CONCLUSIONS: Bidirectional flow in the vertebral artery is not always indicative of the subclavian steal phenomenon. Measurement of hemodynamic parameters in the vertebral artery, such as MPV, can facilitate determination of the cause of bidirectional flow.

The impact of aerobic exercise on health-related quality of life among patients undergoing maintenance hemodialysis.

To investigate the effect of exercise on cardiopulmonary function and the life quality of maintenance hemodialysis patients. Eighty-four patients who underwent maintenance hemodialysis treatment for more than 3 months were randomly divided into experimental group and control group. The general data and nutritional indexes, including hemoglobin and plasma albumin, before and after the experiment. The differences in lung function, cardiac ultrasound, cardiopulmonary function, exercise endurance between the 2 groups before and after intervention were compared. The short form 36-item health survey (SF-36) and self-rating depression scale (SDS) were assessed. In our study, the experimental group had better Force vital capacity (FVC) and peak expiratory flow (PEF) after the intervention compared to the control group (P < .05). Anaerobic threshold and 6-minute walk test (6MWT) improved significantly in the experimental group (P < .05), and SF-36 showed better physical functioning, social functioning, general health, and vitality scores in the experimental group compared to the control group (P < .05). In addition, following 24 weeks of exercise, the Depression score of the exercise group showed a statistically significant improvement when compared to the control group (P < .05). After the intervention, hemoglobin improved significantly in the experimental group (P < .05). Intradialytic exercise can improve hemoglobin, Alb, pulmonary function, aerobic capacity, and exercise endurance in maintenance hemodialysis patients, so as to improve the quality of life, which is worthy of further promotion.

Early diagnosis of caesarean scar pregnancy by ultrasound - a novel, simple and rapid clinical classification scoring system.

AIM: In the recent years, with the increase in the caesarean section rate, the incidence of caesarean scar pregnancy (CSP) has shown a significant upwards trend. We propose a novel, simple and rapid clinical and ultrasound (US) classification scoring system to assist in the early diagnosis of CSP. MATERIAL AND METHODS: A total of 385 patients with CSP were included in the study. All patients were given a comprehensive score, iincluding clinical data (whether HCG is consistent with gestational age and vaginal bleeding) and US findings (linea a and b, gestational sac morphology, the presence of primitive cardiac tube beat, and color Doppler aspect). The scores were analysed by ROC curve analysis, and sensitivity and specificity were calculated. RESULTS: A score of 4 has a specificity of 91.7% and a sensitivity of 95.6% in diagnose CSP. The area under the ROC curve was 0.973. CONCLUSION: This scoring system may be a reliable tool for the early diagnosis of CSP and has the characteristics of being simple and rapid. For patients with a total score of ≥4 points, CSP is suggested, and early clinical treatment can be carried out, while patients with a score of less than 4 points can temporarily retain pregnancy and be closely followed up.

A Synthetic Review of Cognitive Load in Distance Interpreting: Toward an Explanatory Model.

Distance Interpreting (DI) is a form of technology-mediated interpreting which has gained traction due to the high demand for multilingual conferences, live-streaming programs, and public service sectors. The current study synthesized the DI literature to build a framework that represents the construct and measurement of cognitive load in DI. Two major areas of research were identified, i.e., causal factors and methods of measuring cognitive load. A number of causal factors that can induce change in cognitive load in DI were identified and reviewed. These included factors derived from tasks (e.g., mode of presentation), environment (e.g., booth type), and interpreters (e.g., technology awareness). In addition, four methods for measuring cognitive load in DI were identified and surveyed: subjective methods, performance methods, analytical methods, and psycho-physiological methods. Together, the causal factors and measurement methods provide a multifarious approach to delineating and quantifying cognitive load in DI. This multidimensional framework can be applied as a tool for pedagogical design in interpreting programs at both the undergraduate and graduate levels. It can also provide implications for other fields of educational psychology and language learning and assessment.

Risk factors of delirium in paediatric intensive care units: A meta-analysis.

BACKGROUND: Delirium is a brain dysfunction syndrome, which children have a higher incidence. At present, there have been more and more studies and reports on delirium in paediatric intensive care unit, but there are some differences in the risk factor results among different studies. To better manage delirium, this study was performed. OBJECTIVE: To integrate and clarify the risk factors for delirium in paediatric intensive care unit. METHODS: CNKI, CBMdisc, Wanfang Data Knowledge Service Platform, VIP, PubMed, Embase, Cochrane Library, JBI and PsycInfo were searched for relevant literature. The study subjects were patients in PICU and literature was included according to the PICOS principle. Literature screening and risk of bias assessment were mainly completed by two researchers, and RevMan 5.3 software and Stata software were used for data analysis. The GRADE systerm was used to assess the quality of evidence. RESULTS: A total of 10 studies were included, all in English, involving 4343 children. Within the GRADE system, 4 indicators were scored A, 1 indicators were scored B, and 3 indicators were scored C regarding evidence levels. Three studies analysed the influence of developmental delay on the occurrence of delirium in PICU, total sample size of which was 1823, and the results showed that the combined effect was statistically significant [OR = 3.34, 95%CI(2.46-4.53), Z = 7.75, P<0.001]; Five studies analysed the effects of mechanical ventilation on the occurrence of delirium in PICU, sample size of which was 1562, and the results showed that the combined effect was statistically significant [OR = 4.11, 95%CI(3.13-5.40), Z = 10.16, P<0.001]; Two studies analysed the effects of benzodiazepines on children developing delirium, sample size of which was 1635, and the results showed that the combined effect was statistically significant [OR = 5.05, 95%CI(3.65-6.97), Z = 9.83, P<0.001]; Two studies analysed the effects of anticholinergic drug use on children developing delirium in PICU, sample size of which was 1703, and the results suggested the combined effect was statistically significant [OR = 5.04, 95%CI (3.62-7.00), Z = 9.63, P<0.001]; Two studies compared the same age period, sample size of which was 1724 and the results showed that children 2-5 years old has a 48% incidence rate of delirium relative to children younger than 2 years old, and the combined effect was statistically significant [OR = 0.48, 95%CI(0.25-0.92), Z = 2.22, P = 0.030], children 5-13 years old has a 39% incidence rate of delirium relative to children younger than 2 years old, and the combined effect was statistically significant [OR = 0.39, 95%CI(0.26-0.59), Z = 4.43, P<0.001]. Two studies analysed the effects of PICU LOS on children developing delirium and the combined effect of PICU LOS on the occurrence of delirium in children in PICU was statistically significant [OR = 1.10, 95%CI(1.05-1.15), Z = 4.07, P<0.001]. CONCLUSION: Developmental delay, mechanical ventilation, benzodiazepine use, anticholinergic use, age and PICU length of stay are independent risk factors for delirium in children in PICU. However, only a few articles were included in this study, which may lead to a certain bias and affect the analysing results. More large-sample, multicentre studies should be conducted to further explore and clarify the independent influencing factors of delirium in children in PICU and to provide guidance for clinical practice.

Efficacy of Morphine Combined with Mechanical Ventilation in the Treatment of Heart Failure with Cardiac Magnetic Resonance Imaging under Artificial Intelligence Algorithms.

This study was aimed at exploring the efficacy of morphine combined with mechanical ventilation in the treatment of heart failure with artificial intelligence algorithms. The cardiac magnetic resonance imaging (MRI) under the watershed segmentation algorithm was proposed, and the local grayscale clustering watershed (LGCW) model was designed in this study. A total of 136 patients with acute left heart failure were taken as the research objects and randomly divided into the control group (conventional treatment) and the experimental group (morphine combined with mechanical ventilation), with 68 cases in each group. The left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), N-terminal pro-brain natriuretic peptide (NT-proBNP), arterial partial pressure of oxygen (PaO2), and arterial partial pressure of carbon dioxide (PaCO2) were observed. The results showed that the mean absolute deviation (MAD) and maximum mean absolute deviation (max-MAD) of the LGCW model were lower than those of the fuzzy k-nearest neighbor (FKNN) algorithm and local gray-scale clustering model (LGSCm). The Dice metric was also significantly higher than that of other algorithms with statistically significant differences (P < 0.05). After treatment, LVEDD, LVESD, and NT-proBNP of patients in the experimental group were significantly lower than those in the control group, and LVEF in the experimental group was higher than that in the control group (P < 0.05). PaO2 of patients in the experimental group was also significantly higher than that in the control group (P < 0.05). It suggested that the LGCW model had a better segmentation effect, and morphine combined with mechanical ventilation gave a better clinical efficacy in the treatment of acute left heart failure, improving the patients' cardiac function and arterial blood gas effectively.

Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation.

Fbxo45, a conserved F-box protein, comprises of an atypical SKP1, CUL1, F-box protein (SCF) ubiquitin ligase complex that promotes tumorigenesis and development. However, the biological function and molecular mechanisms of Fbxo45 involved in pancreatic carcinogenesis are ambiguous. We conducted several approaches, including transfection, coIP, real-time polymerase chain reaction (RT-PCR), Western blotting, ubiquitin assays, and animal studies, to explore the role of Fbxo45 in pancreatic cancer. Here, we report that USP49 stability is governed by Fbxo45-mediated ubiquitination and is enhanced by the absence of Fbxo45. Moreover, Fbxo45 binds to a short consensus sequence of USP49 through its SPRY domain. Furthermore, Fbxo45-mediated USP49 ubiquitination and degradation are enhanced by NEK6 kinase. Functionally, Fbxo45 increases cell viability and motility capacity by targeting USP49 in pancreatic cancer cells. Xenograft mouse experiments demonstrated that ectopic expression of Fbxo45 enhanced tumor growth in mice and that USP49 overexpression inhibited tumor growth in vivo. Notably, Fbxo45 expression was negatively associated with USP49 expression in pancreatic cancer tissues. Fbxo45 serves as an oncoprotein to facilitate pancreatic oncogenesis by regulating the stability of the tumor suppressor USP49 in pancreatic cancer.

Classification of 5-HT(1A) receptor agonists and antagonists using GA-SVM method.

AIM: To construct a reliable computational model for the classification of agonists and antagonists of 5-HT(1A) receptor. METHODS: Support vector machine (SVM), a well-known machine learning method, was employed to build a prediction model, and genetic algorithm (GA) was used to select the most relevant descriptors and to optimize two important parameters, C and r of the SVM model. The overall dataset used in this study comprised 284 ligands of the 5-HT(1A) receptor with diverse structures reported in the literatures. RESULTS: A SVM model was successfully developed that could be used to predict the probability of a ligand being an agonist or antagonist of the 5-HT(1A) receptor. The predictive accuracy for training and test sets was 0.942 and 0.865, respectively. For compounds with probability estimate higher than 0.7, the predictive accuracy of the model for training and test sets was 0.954 and 0.927, respectively. To further validate our model, the receiver operating characteristic (ROC) curve was plotted, and the Area-Under-the-ROC- Curve (AUC) value was calculated to be 0.883 for training set and 0.906 for test set. CONCLUSION: A reliable SVM model was successfully developed that could effectively distinguish agonists and antagonists among the ligands of the 5-HT(1A) receptor. To our knowledge, this is the first effort for the classification of 5-HT(1A) receptor agonists and antagonists based on a diverse dataset. This method may be used to classify the ligands of other members of the GPCR family.

Matching-adjusted indirect treatment comparison of ozanimod versus teriflunomide for relapsing multiple sclerosis.

BACKGROUND: A growing number of immunomodulating disease-modifying therapies are available for treatment of relapsing multiple sclerosis (RMS). In the absence of randomized head-to-head trials, matching-adjusted indirect comparisons (MAICs) can be used to adjust for cross-trial differences and evaluate the comparative efficacy and safety of these agents. We used MAIC methodology to indirectly compare key outcomes with ozanimod (OZM) and teriflunomide (TERI) in the treatment of RMS. METHODS: A systematic literature review was conducted to identify clinical trials evaluating the efficacy and safety of OZM vs TERI. Given the absence of head-to-head trials of OZM vs TERI, we used a matching-adjusted indirect comparison to adjust for potential treatment effect modifiers and prognostic factors while assessing confirmed disability progression (CDP), relapse, and safety outcomes. Individual patient data for OZM (SUNBEAM and RADIANCE Part B trials) and aggregate level data for TERI (ASCLEPIOS I/II, TOWER, OPTIMUM, and TEMSO trials) were used to evaluate the following outcomes: annualized relapse rate (ARR), proportion of patients relapsed, CDP at 3 and 6 months, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. RESULTS: After matching, baseline patient characteristics were balanced between OZM and TERI. Compared with TERI, OZM demonstrated significant improvements in ARR (rate ratio: 0.73; 95% CI: 0.62-0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44-0.70), overall AEs (OR: 0.35; 95% CI: 0.29-0.43), SAEs (OR: 0.53; 95% CI: 0.37-0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09-0.21). OZM demonstrated statistically significant improvements in CDP at 3 months (hazard ratio [HR]: 0.78; 95% CI: 0.66-0.92) but nonsignificant differences at 6 months (HR: 0.78; 95% CI: 0.60-1.01) compared with TERI. CONCLUSION: In this indirect treatment comparison of patients with RMS, OZM appeared to have an improved benefit-risk profile over TERI.

Comparative Efficacy and Safety of Ozanimod and Dimethyl Fumarate for Relapsing-Remitting Multiple Sclerosis Using Matching-Adjusted Indirect Comparison.

BACKGROUND: Patients with multiple sclerosis (MS) experience relapses and sustained disability progression. Since 2004, the number of disease-modifying therapies (DMTs) for MS has grown substantially. As a result, patients, healthcare providers, and insurers are increasingly interested in comparative efficacy and safety evaluations to distinguish between treatment options, but head-to-head studies between DMTs are limited. OBJECTIVE: The aim of the current study was to compare efficacy and safety outcomes with the DMTs ozanimod and dimethyl fumarate (DMF) using a matching-adjusted indirect comparison (MAIC) to adjust for cross-trial differences in study design and population. METHODS: A systematic literature review was performed to identify clinical studies evaluating the efficacy and safety of ozanimod compared with DMF. Individual patient-level data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate-level patient data (APD) for DMF were obtained from CONFIRM and DEFINE. A MAIC is used to weight IPD to APD based on important baseline patient characteristics considered to be effect modifiers or prognostic factors in order to balance the covariate distribution to establish more homogenous trial populations. Once trial populations are determined to be sufficiently homogenous, outcomes of interest are estimated and used to generate treatment effects between the weighted IPD and APD. We used MAIC methodology to compare efficacy and safety outcomes of interest between ozanimod 1.0 mg once daily (OD) and DMF 240 mg twice daily (BID), including confirmed disability progression (CDP) at 3 and 6 months, annualized relapse rate (ARR), proportion of patients relapsed, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. RESULTS: After matching patient data, baseline patient characteristics were balanced between patients receiving ozanimod and those receiving DMF. Compared with DMF, ozanimod demonstrated significantly improved CDP at 3 months (hazard ratio 0.67; 95% confidence interval [CI] 0.53-0.86), ARR (rate ratio [RR] 0.80; 95% CI 0.67-0.97), proportion of patients relapsed (odds ratio [OR] 0.66; 95% CI 0.52-0.83), overall AEs (OR 0.11; 95% CI 0.08-0.16), SAEs (OR 0.27; 95% CI 0.19-0.39), and discontinuations (OR 0.11; 95% CI 0.07-0.17). CDP at 6 months did not differ significantly between the two agents (RR 0.89; 95% CI 0.62-1.26). CONCLUSIONS: After adjustment of baseline patient characteristics, the MAIC demonstrated that the efficacy and safety of ozanimod 1.0 mg OD was superior to that of DMF 240 mg BID. Although a MAIC is less likely to produce biased estimates than a naïve or a standard indirect treatment comparison via a common comparator, limitations include potential confounding due to unobserved and thus unaccounted for baseline differences.

Ozanimod and dimethyl fumarate (DMF) are disease-modifying therapies used to treat relapsing-remitting multiple sclerosis (MS). Comparative efficacy and safety evaluation is important to key patients, healthcare providers, and health insurers; however, head-to-head studies between MS therapies are limited. In this analysis, we used an indirect treatment comparison method, specifically a matching-adjusted indirect comparison (MAIC), to compare results of clinical trials of ozanimod and DMF. In this MAIC, findings suggested that ozanimod was associated with greater reductions of relapses, a lowered risk of disability progression at 3 months, and improved safety outcomes compared with DMF. Although MAICs were conducted while adjusting for important treatment-effect modifiers and/or prognostic factors, the possibility of confounding as a result of unobserved baseline differences remains. Such an issue can be resolved only by conducting a head-to-head treatment comparison in a randomized clinical trial.

The impact of high-risk and chronic opioid use among commercially insured endometriosis patients on health care resource utilization and costs in the United States.

OBJECTIVES: Evaluate all-cause and endometriosis-related health care resource utilization and costs among newly diagnosed endometriosis patients with high-risk versus low-risk opioid use or patients with chronic versus non-chronic opioid use. METHODS: A retrospective analysis of IBM MarketScan® Commercial Claims data from 2009 to 2018 was performed for females aged 18 to 49 with newly diagnosed endometriosis (International Classification of Diseases, Ninth Edition code: 617.xx; International Classification of Diseases, Tenth Edition code: N80.xx). Two sub-cohorts were identified: high-risk (⩾1 day with ⩾90 morphine milligram equivalents per day or ⩾1-day concomitant benzodiazepine use) or chronic opioid utilization (⩾90-day supply prescribed or ⩾10 opioid prescriptions). High-risk or chronic utilization was evaluated during the 12-month assessment period after the index date. Index date was the first opioid prescription within 12 months following endometriosis diagnosis. All outcomes were assessed over 12-month post-assessment period while adjusting for demographic and clinical characteristics. RESULTS: Out of 61,019 patients identified, 18,239 had high-risk opioid use and 5001 chronic opioid use. Health care resource utilization drivers were outpatient visits and pharmacy fills, which were higher among high-risk versus low-risk patients (outpatient visits: 17.49 vs 15.51; pharmacy fills: 19.58 vs 16.88, p < 0.0001). Chronic opioid users had a higher number of outpatient visits (19.53 vs 15.00, p < 0.0001) and pharmacy fills (23.18 vs 16.43, p < 0.0001) compared to non-chronic opioid users. High-risk opioid users had significantly higher all-cause health care costs compared to low-risk opioid users (US$16,377 vs US$13,153; p < 0.0001). Chronic opioid users also had significantly higher all-cause health care costs compared to non-chronic opioid users (US$20,930 vs US$12,272; p < 0.0001). Similar patterns were observed among endometriosis-related HCRU, except pharmacy fills among high-risk and chronic sub-cohorts. CONCLUSION: This analysis demonstrates significantly higher all-cause and endometriosis-related health care resource utilization and total costs for high-risk opioid users compared to low-risk opioid users among newly diagnosed endometriosis patients over 1 year. Similar trends were observed for comparing chronic opioid users with non-chronic opioid users, except for endometriosis-related pharmacy fills and associated costs.

Healthcare Resource Use and Costs Associated with Opioid Initiation Among Patients with Newly Diagnosed Endometriosis with Commercial Insurance in the USA.

INTRODUCTION: To compare all-cause and endometriosis-related healthcare resource utilization (HCRU) and healthcare costs by service categories (outpatient, inpatient, emergency room [ER], pharmacy) among patients with newly diagnosed endometriosis using opioids compared to patients with endometriosis not using opioids. METHODS: A retrospective analysis of IBM® MarketScan® Commercial Claims data from 2009 to 2018 was performed for women aged 18-49 with newly diagnosed endometriosis (International Classification of Diseases (ICD)-9 code 617.xx; ICD-10 code N80.xx) over 24 months follow-up. Patients were stratified on the basis of opioid use within 12 months post first endometriosis diagnosis date. Patients with opioid use were 1:1 matched to patients without opioid use using propensity score matching. RESULTS: A total of 85,329 female patients with a new endometriosis diagnosis were identified and 48,470 patients (24,235 opioid and 24,235 non-opioid users) remained after inclusion-exclusion criteria and matching. Opioid patients had an estimated mean 30.33 outpatient visits, 29.59 pharmacy fills, 0.28 inpatient visits, 0.65 ER visits, and total length of stay (LOS) was 1.01 days. Non-opioid patients had an estimated mean 27.94 outpatient visits, 22.06 pharmacy fills, 0.23 inpatient visits, 0.42 ER visits, and total LOS was 0.82 days. On average, opioid patients had significantly greater all-cause HCRU compared to non-opioid patients (all p < 0.0001). Among endometriosis-related healthcare utilization, there were similar ER visits, but lower outpatient visits, inpatient visits, and total LOS and higher pharmacy fills among opioid and non-opioid patients. Estimated mean all-cause costs were higher among opioid ($26,755) vs. non-opioid ($19,302) users (p < 0.0001). A similar trend was observed for estimated mean endometriosis-related costs. CONCLUSION: This analysis observed significantly higher all-cause HCRU and costs for opioid users compared to non-opioid users among patients with newly diagnosed endometriosis. While observed endometriosis-related costs were significantly higher in opioid users compared to non-opioid users during a 24-month follow-up period, endometriosis-related HCRU varied by service categories for these two populations over this time period.

Complex 2D photonic crystals with analogue local symmetry as 12-fold quasicrystals.

We construct fourteen complex periodic two-dimensional (2D) photonic structures with different structural symmetries by arranging the small portions of a 12-fold quasicrystal on square or hexagonal lattices. The corresponding reciprocal lattices confirm that all of them demonstrate the 12-fold-like characteristics due to the analogue short-range arrangements. We then investigate their photonic bandgap properties at different dielectric contrast levels (dielectric rods in air background). Our results suggest that all structures possess analogue transverse magnetic (TM) gaps in both Si and glass photonic crystals due to the similarity of their local geometries. However, the arrangements of the basic elements, total symmetries, and the coupling between the local and the lattice symmetries have greater impact on the glass photonic crystals, which show much larger deviation of gap sizes from different structures. Furthermore, we find that the minimal dielectric contrast to achieve the TM gap in the complex lattices (dielectric-in-air) can be as low as epsilon = 1.44, whereas the inverse structures may open a 2D complete gap in silicon nitride (epsilon = 4.1).

Real-world use of procalcitonin and other biomarkers among sepsis hospitalizations in the United States: A retrospective, observational study.

BACKGROUND: Sepsis management guidelines endorse use of biomarkers to support clinical assessment and treatment decisions in septic patients. The impact of biomarkers on improving patient outcomes remains uncertain. METHODS: Retrospective observational study of adult sepsis discharges between January 1, 2012, and December 31, 2015, from Premier Healthcare Database hospitals. Sepsis was defined by an All Patients Refined Diagnosis-Related Group code of 720 (septicemia and disseminated infections). Use of four biomarker strategies was evaluated based on hospital records: (i) >1 procalcitonin (PCT), (ii) 1 PCT, (iii) no PCT but ≥1 C-reactive protein (CRP) and/or lactate and (iv) no sepsis biomarkers. Associations between biomarker use and clinical and cost outcomes were examined. The primary outcome was impact of biomarker strategy on hospital costs per day. RESULTS: Among 933,591 adult sepsis discharges during the study period, 731,392 (78%) had biomarker tests ordered. In multivariable analyses, discharges with >1 PCT had higher hospital costs per day ($1,904; 95% confidence interval [CI] $1,896-$1,911) compared with discharges with no sepsis biomarkers ($1,606; 95% CI $1,658-$1,664). Discharges with >1 PCT also had greater illness severity and antimicrobial exposure compared with other biomarker-use groups. The adjusted odds of dying during hospital stay compared with being discharged were significantly lower for sepsis discharges with >1 PCT (0.64; 95% CI 0.61-0.67) and 1 PCT (0.88; 95% CI 0.85-0.91) compared with no sepsis biomarker use. The proportion of discharges with ≥1 PCT increased almost six-fold during the study; use of other biomarkers remained constant. CONCLUSIONS: Between 2012 and 2015, PCT use among sepsis discharges increased six-fold while lactate and CRP use remained unchanged. PCT use was associated with decreased odds of in-hospital mortality but increased hospital costs per day. Serial biomarker monitoring may be associated with improved patient outcomes in the most critically ill septic patients.

Distortion of 3D SU8 photonic structures fabricated by four-beam holographic lithography withumbrella configuration.

We present a quantitative study of the distortion from a threeterm diamond-like structure fabricated in SU8 polymer by four-beam holographic lithography. In the study of the refraction effect, theory suggests that the lattice in SU8 should be elongated in the [111] direction but have no distortion in the (111) plane, and each triangular-like hole array in the (111) plane would rotate by ~30 degrees away from that in air. Our experiments agree with the prediction on the periodicity in the (111) plane and the rotation due to refraction effect, however, we find that the film shrinkage during lithographic process has nearly compensated the predicted elongation in the [111] direction. In study of photonic bandgap (PBG) properties of silicon photonic crystals templated by the SU8 structure, we find that the distortion has decreased quality of PBG.