OsPEX1, an extensin-like protein, negatively regulates root growth in a gibberellin-mediated manner in rice.

Leucine-rich repeat extensins (LRXs) are required for plant growth and development through affecting cell growth and cell wall formation. LRX gene family can be classified into two categories: predominantly vegetative-expressed LRX and reproductive-expressed PEX. In contrast to the tissue specificity of Arabidopsis PEX genes in reproductive organs, rice OsPEX1 is also highly expressed in roots in addition to reproductive tissue. However, whether and how OsPEX1 affects root growth is unclear. Here, we found that overexpression of OsPEX1 retarded root growth by reducing cell elongation likely caused by an increase of lignin deposition, whereas knockdown of OsPEX1 had an opposite effect on root growth, indicating that OsPEX1 negatively regulated root growth in rice. Further investigation uncovered the existence of a feedback loop between OsPEX1 expression level and GA biosynthesis for proper root growth. This was supported by the facts that exogenous GA3 application downregulated transcript levels of OsPEX1 and lignin-related genes and rescued the root developmental defects of the OsPEX1 overexpression mutant, whereas OsPEX1 overexpression reduced GA level and the expression of GA biosynthesis genes. Moreover, OsPEX1 and GA showed antagonistic action on the lignin biosynthesis in root. OsPEX1 overexpression upregulated transcript levels of lignin-related genes, whereas exogenous GA3 application downregulated their expression. Taken together, this study reveals a possible molecular pathway of OsPEX1mediated regulation of root growth through coordinate modulation of lignin deposition via a negative feedback regulation between OsPEX1 expression and GA biosynthesis.

Application of machine learning in predicting survival outcomes involving real-world data: a scoping review.

BACKGROUND: Despite the interest in machine learning (ML) algorithms for analyzing real-world data (RWD) in healthcare, the use of ML in predicting time-to-event data, a common scenario in clinical practice, is less explored. ML models are capable of algorithmically learning from large, complex datasets and can offer advantages in predicting time-to-event data. We reviewed the recent applications of ML for survival analysis using RWD in healthcare. METHODS: PUBMED and EMBASE were searched from database inception through March 2023 to identify peer-reviewed English-language studies of ML models for predicting time-to-event outcomes using the RWD. Two reviewers extracted information on the data source, patient population, survival outcome, ML algorithms, and the Area Under the Curve (AUC). RESULTS: Of 257 citations, 28 publications were included. Random survival forests (N = 16, 57%) and neural networks (N = 11, 39%) were the most popular ML algorithms. There was variability across AUC for these ML models (median 0.789, range 0.6-0.950). ML algorithms were predominately considered for predicting overall survival in oncology (N = 12, 43%). ML survival models were often used to predict disease prognosis or clinical events (N = 27, 96%) in the oncology, while less were used for treatment outcomes (N = 1, 4%). CONCLUSIONS: The ML algorithms, random survival forests and neural networks, are mainly used for RWD to predict survival outcomes such as disease prognosis or clinical events in the oncology. This review shows that more opportunities remain to apply these ML algorithms to inform treatment decision-making in clinical practice. More methodological work is also needed to ensure the utility and applicability of ML models in survival outcomes.

Association of cash payment with intensity of opioid prescriptions.

BACKGROUND: It is difficult to track use and outcomes in patients who pay cash for their prescriptions at the pharmacy. In Texas, 14% of all opioid prescriptions are paid with cash, often by uninsured patients and pharmacy shoppers. OBJECTIVE: To evaluate the association of cash payment with intensity of opioid prescriptions. METHODS: Using a prescription drug monitoring program and the U.S. Census data for the 2019 calendar year, this cross-sectional descriptive study analyzed more than 4 million opioid prescriptions in Texas residents aged 18-64 years. The payment type was coded as insurance if the prescription was paid in whole or in part by a health plan and as cash otherwise. Daily morphine milligram equivalent (MME) dose was used to compare the intensity of opioid prescriptions. The association of uninsured rates with mean daily MME and the number of opioid prescriptions paid with cash per 100,000 persons were assessed at a county level. RESULTS: Cash payment was associated with 30% higher mean daily MME (59 vs. 45; P < 0.001) than insurance payment. This difference was driven by the prescriptions for patients aged 25-34 years and from the highest decile of prescribers based on the percentage of opioid prescriptions paid by cash. For instance, cash payment was associated with 82% higher mean daily MME (91 vs. 50; P < 0.001) when patients aged 25-34 years obtained their prescriptions from the highest decile of prescribers. At a county level, uninsured rates were not associated with mean daily MMEs or the number of opioid prescriptions paid with cash. CONCLUSION: Cash payment was associated with a higher intensity of opioid prescriptions, mirroring the rates of drug overdose deaths across the patient age groups. Further research and policy actions need to address unmet pain management needs in uninsured patients and potential pharmacy shopping with cash payment and fraudulent identifications.

Does Pollen Trigger Urological Chronic Pelvic Pain Syndrome Flares? A Case-Crossover Analysis in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network.

PURPOSE: We sought to determine whether pollen triggers urological chronic pelvic pain syndrome flares. MATERIALS AND METHODS: We assessed flare status every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain case-crossover analysis of flare triggers (NCT01098279). Flare symptoms, flare start date and exposures in the 3 days before a flare were queried for the first 3 flares and at 3 randomly selected nonflare times. These data were linked to daily pollen count by date and the first 3 digits of participants' zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to nonflare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the 3 weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders. RESULTS: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (OR 1.31, 95% CI 1.04-1.66) and full longitudinal (RR 1.23, 95% CI 1.03-1.46) samples. CONCLUSIONS: We found some evidence to suggest that rising pollen count may trigger flares of urological chronic pelvic pain syndrome. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention and treatment, and control over the unpredictability of flares.

Does weather trigger urologic chronic pelvic pain syndrome flares? A case-crossover analysis in the multidisciplinary approach to the study of the chronic pelvic pain research network.

BACKGROUND: To investigate whether meteorological factors (temperature, barometric pressure, relative humidity, ultraviolet index [UVI], and seasons) trigger flares in male and female urologic chronic pelvic pain patients. METHODS: We assessed flare status every 2 weeks in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain 1-year longitudinal study. Flare symptoms, flare start date, and exposures in the 3 days preceding a flare or the date of questionnaire completion were assessed for the first three flares and at three randomly selected nonflare times. We linked these data to daily temperature, barometric pressure, relative humidity, and UVI values by participants' first 3 zip code digits. Values in the 3 days before and the day of a flare, as well as changes in these values, were compared to nonflare values by conditional logistic regression. Differences in flare rates by astronomical and growing seasons were investigated by Poisson regression in the full study population. RESULTS: A total of 574 flare and 792 nonflare assessments (290 participants) were included in the case-crossover analysis, and 966 flare and 5389 nonflare (409 participants) were included in the full study analysis. Overall, no statistically significant associations were observed for daily weather, no patterns of associations were observed for weather changes, and no differences in flare rates were observed by season. CONCLUSIONS: We found minimal evidence to suggest that weather triggers flares, although we cannot rule out the possibility that a small subset of patients is susceptible.

Real-world adherence and persistence for newly-prescribed HIV treatment: single versus multiple tablet regimen comparison among US medicaid beneficiaries.

BACKGROUND: Once-daily, single-tablet regimens (STRs) have been associated with improved patient outcomes compared to multi-tablet regimens (MTRs). This study evaluated real world adherence and persistence of HIV antiretroviral therapy (ART), comparing STRs and MTRs. METHODS: Adult Medicaid beneficiaries (aged ≥ 18 years) initiating ART with ≥ 2 ART claims during the identification period (January 1, 2015-December 31, 2016) and continuous health plan enrollment for a 12-month baseline period were included. For STRs, the first ART claim date was defined as the index date; for MTRs, the prescription fill claim date for the last drug in the regimen was defined as the index date, and prescription fills were required to occur within a 5-day window. Adherence was assessed in 30-day intervals over a 6-month period, with adherence defined as having less than a 5-day gap between fills. Persistence was evaluated as median number of days on therapy and percent persistence at 12 months. Cox Proportional Hazard models were used to evaluate risk of discontinuation, controlling for baseline and clinical characteristics. RESULTS: A total of 1,744 (STR = 1290; MTR = 454) and 2409 (STR = 1782; MTR = 627) patients newly prescribed ART had available data concerning adherence and persistence, respectively. Average age ranged 40-42 years. The patient population was predominantly male. Adherence assessments showed 22.7% of STR initiators were adherent to their index regimens over a 6-month period compared to 11.7% of MTR initiators. Unadjusted persistence analysis showed 36.3% of STR initiators discontinued first-line therapy compared to 48.8% for MTR initiators over the 2-year study period. Controlling for baseline demographic and clinical characteristics, MTR initiators had a higher risk of treatment discontinuation (hazard ratio [HR] = 1.6, p < 0.0001). Among STRs, compared to the referent elvitegravir(EVG)/cobicistat(COBI)/emtricitabine(FTC)/tenofovir alafenamide(TAF), risk of discontinuation was higher for efavirenz(EFV)/FTC/tenofovir disoproxil fumarate(TDF) (HR = 3.6, p < 0.0001), EVG/COBI/FTC/TDF (HR = 2.8, p < 0.0001), and abacavir (ABC)/lamivudine (3TC)/dolutegravir (DTG) (HR = 1.8, p = 0.004). Among backbones, FTC/TAF was associated with lower risk of discontinuation than FTC/TDF (HR = 4.4, p < 0.0001) and ABC/3TC (HR = 2.2, p < 0.0001). CONCLUSIONS: Among patients newly prescribed ART, STR initiators were significantly less likely to discontinue therapy and had greater adherence and persistence compared to MTR initiators. Regimens containing FTC/TAF as a backbone had higher persistence than those consisting of other backbones.

Controlling the ferroelectric and resistive switching properties of a BiFeO3 thin film prepared using sub-5 nm dimension nanoparticles.

In recent years, BiFeO3 has attracted significant attention as an interesting multiferroic material in the exploration of fundamental science and development of novel applications. Our previous study (Phys. Chem. Chem. Phys.18, 2016, 25409) highlighted the interesting physicochemical features of BiFeO3 of sub-5 nm dimension. The study also accentuated the existence of weak ferroelectricity at sub-5 nm dimensions in BiFeO3. Based on this feature, we have prepared thin films using sub-5 nm BiFeO3 nanoparticles and explored various physicochemical properties of the thin film. We report that during the formation of the thin film, the nanoparticles aggregated; particularly, annihilation of their nanotwinning nature was observed. Qualitatively, the Gibbs free energy change ΔG governed the abovementioned processes. The thin film exhibited an R3c phase and enhanced Bi-O-Fe coordination as compared to the sub-5 nm nanoparticles. Raman spectroscopy under the influence of a magnetic field shows a magnetoelectric effect, spin phonon coupling, and magnetic anisotropy. We report room-temperature ferroelectric behavior in the thin film, which enhances with the application of a magnetic field; this confirms the multiferroic nature of the thin film. The thin film shows polarization switching ability at multiple voltages and read-write operation at low bias (±0.5 V). Furthermore, the thin film shows negative differential-complementary resistive switching behavior in the nano-microampere current range. We report nearly stable 1-bit operation for 102 cycles, 105 voltage pulses, and 105 s, demonstrating the paradigm device applications. The observed results thus show that the thin films prepared using sub-5 nm BiFeO3 nanoparticles are a promising candidate for future spintronics and memory applications. The reported approach can also be pertinent to explore the physicochemical properties and develop potential applications of several other nanoparticles.

Observation of nanotwinning and room temperature ferromagnetism in sub-5 nm BiFeO3 nanoparticles: a combined experimental and theoretical study.

Particle size significantly affects the properties and therefore the potential applications of multiferroics. However, is there special particle size effect in BiFeO3, which has a spiral modulated spin structure? This is still under investigation for sub-5 nm BiFeO3. In this report, the structural, electronic and magnetic properties are investigated for chemically synthesized BiFeO3 nanoparticles with an average size of 3 nm. We observed nanotwinning features in the specific size regime of the nanoparticles (2-4 nm). A weak Bi-O-Fe coordination and weak covalent nature has been observed in the nanoparticles through high-resolution electron energy loss spectroscopy and theoretical analysis, confirming that BiFeO3 nanoparticles a retain rudimentary R3c phase even at sub-5 nm dimensions. The R3c phase of sub-5 nm BiFeO3 nanoparticles has also been confirmed using Raman spectroscopy and Raman mapping of the vibrational modes. The nanoparticles display cluster spin glass, room temperature ferromagnetism, and a metamictization-davidite phase. The observation of weak magnetic entropy features confirmed the presence of a weak correlation between the magnetic and ferroelectric components. To support our experimental observations, we have simulated a sub-5 nm BiFeO3 nanocluster. Using density functional theory, the ferromagnetic ground state and the presence of a weak covalent nature in the nanocluster is established considering the first Brillouin zone, thus confirming our experimental results. Finding of new physicochemical features in sub-5 nm BiFeO3 would be beneficial for the understanding of the fundamental physical and chemical science as well as potential device development.

Formation of filamentous aerobic granules: role of pH and mechanism.

Filamentous overgrowth in aerobic granular sludge processes can cause reactor failure. In this work, aerobic granules were cultivated in five identical sequencing batch reactors with acetate or glucose as the carbon source with various values of influent pH (4.5-8). Microscopic observations revealed that acidic pH, rather than the species of carbon source, epistatically controls the aerobic granules with filamentous structure. An acidic pH shifted the structure of the microbial community in the granules, such that the fungus Geotrichum fragrans was the predominant filamentous microorganism therein. The acidic pH reduced the intracellular cyclic diguanylate (c-di-GMP) content for increasing the motility of the bacteria to washout and increase the growth rate of G. fragrans on glucose or acetate, together causing overgrowth of the fungus. Maintaining the suspension under alkaline condition is proposed as an effective way to suppress filamentous overgrowth and maintain granule stability.

Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis.

BACKGROUND: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. OBJECTIVES: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. METHODS: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. RESULTS: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. CONCLUSIONS: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.

Incremental health care expenditures for non-Hodgkin lymphoma in comparison with other cancers: Analysis of national survey data.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is among the most common cancers in the United States, with an estimated annual incidence of more than 80,000 and a high survival rate. However, limited national data exist regarding the health care burden of NHL. OBJECTIVE: To evaluate the incremental health care expenditures among patients with NHL using the Medical Expenditure Panel Survey (MEPS) data compared with patients with other cancers. METHODS: This observational cross-sectional study included all patients with NHL (≥ 18 years) and all individuals diagnosed with other cancers from the MEPS 2014-2019. The components of health care expenditures included hospital inpatient care, office-based visits, outpatient care, emergency department, prescription medications, dental, home health, and other expenditures. Patients with NHL and those diagnosed with other cancers were identified from the full-year consolidated MEPS Household Component 2014-2019. Descriptive weighted analysis was used to compare the health care expenditure components between individuals with NHL and all other cancers. A 2-part model using probit and generalized linear models with a log link function was used to estimate the incremental increase in total health care expenditures for NHL compared with all other cancers. RESULTS: According to the MEPS, there were 0.74 million patients with NHL (95% CI = 0.62-0.86) and 27.91 million patients with other cancers (95% CI = 26.69-29.13) annually. Most of the patients with NHL were White (78.36%), male (60.67%), and older than 65 years (45.8%). The unadjusted analysis indicated a total annual expenditure of $21,698 (95% CI = $16,752-$26,645) for NHL, which was significantly higher than the annual expenditure for patients with other cancers ($15,029 [95% CI = $14,476-$15,582]). Most of the total health expenditure of both the NHL group and the other cancers group was distributed in 3 categories of hospital inpatient care (29.15% vs 26.29%), office-based visits (28.10% vs 25.08%), and prescription medications (19.03% vs 22.57%). Based on the 2-part model adjusted for all covariates, the annual health care expenditure for NHL was $7,284 (95% CI = $1,432-$13,135), higher than the expenditure of patients diagnosed with all other cancers. Among the health care expenditure components, the office-based visits were $2,641 higher for patients with NHL compared with the other cancers group (95% CI = $1,129-$4,153). CONCLUSIONS: The economic burden of NHL is higher compared with other cancers. Most of the NHL expenditures were attributable to hospital inpatient services and office-based visits. The study findings can inform value-based care considerations because of a better understanding of utilization and care patterns for NHL. DISCLOSURES: Dr Aparasu has received research funding from Astellas Inc., Incyte Corp., Gilead, and Novartis Inc. for projects unrelated to the current work. The other authors declare no conflicts of interest for this article. We confirm that this work is original and has not been published elsewhere, nor is it currently under consideration for publication elsewhere.

Assessing treatment switch among patients with multiple sclerosis: A machine learning approach.

Background: Patients with multiple sclerosis (MS) frequently switch their Disease-Modifying Agents (DMA) for effectiveness and safety concerns. This study aimed to develop and compare the random forest (RF) machine learning (ML) model with the logistic regression (LR) model for predicting DMA switching among MS patients. Methods: This retrospective longitudinal study used the TriNetX data from a federated electronic medical records (EMR) network. Between September 2010 and May 2017, adults (aged ≥18) MS patients with ≥1 DMA prescription were identified, and the earliest DMA date was assigned as the index date. Patients prescribed any DMAs different from their index DMAs were considered as treatment switch. . The RF and LR models were built with 72 baseline characteristics and trained with 70% of the randomly split data after up-sampling. Area Under the Curves (AUC), accuracy, recall, G-measure, and F-1 score were used to evaluate the model performance. Results: In this study, 7258 MS patients with ≥1 DMA were identified. Within two years, 16% of MS patients switched to a different DMA. The RF model obtained significantly better discrimination than the LR model (AUC = 0.65 vs. 0.63, p < 0.0001); however, the RF model had a similar predictive performance to the LR model with respect to F- and G-measures (RF: 72% and 73% vs. LR: 72% and 73%, respectively). The most influential features identified from the RF model were age, type of index medication, and year of index. Conclusions: Compared to the LR model, RF performed better in predicting DMA switch in MS patients based on AUC measures; however, judged by F- and G-measures, the RF model performed similarly to LR. Further research is needed to understand the role of ML techniques in predicting treatment outcomes for the decision-making process to achieve optimal treatment goals.

Comparative adherence trajectories of oral disease-modifying agents in multiple sclerosis.

STUDY OBJECTIVE: This study compared the adherence trajectories of fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users with multiple sclerosis (MS) as there is limited evidence regarding the comparative adherence patterns of different oral disease-modifying agents (DMAs). DESIGN: A retrospective cohort study DATA SOURCE: 2015-2019 IBM MarketScan Commercial Claims Database. PATIENTS: Adults (≥18 years) with MS (International Classification of Diseases [ICD]-9/10-Clinical Modification [CM]:340/G35) diagnosis and ≥1 DMA prescription. INTERVENTION: Incident FIN-, TER-, or DMF use based on the index DMA with 1 year of washout period. MEASUREMENTS: The DMA adherence trajectories based on the proportion of days covered (PDC) were examined using the Group-Based Trajectory Modeling (GBTM) one year after the treatment initiation. Generalized boosting models (GBM)-based inverse probability treatment weights (IPTW) were incorporated in multinomial logistic regression to assess the comparative adherence trajectories across oral DMAs with FIN group as a reference category. MEASUREMENTS AND MAIN RESULTS: The study cohort consisted of 1913 patients with MS who were initiated with FIN (24.2%, n = 462), TER (24.0%, n = 458), and DMF (51.9%, n = 993) during 2016-2018. The adherence rate (PDC ≥ 0.8) among FIN, TER, and DMF users was found to be 70.8% (n = 327), 59.6% (n = 273), and 61.0% (n = 606), respectively. The GBTM grouped patients into three adherence trajectories: Complete Adherers-59.1%, Slow Decliners-22.6%, and Rapid Discontinuers-18.3%. The multinomial logistic regression model involving GBM-based IPTW revealed that DMF (adjusted odds ratio [aOR]: 2.32, 95% confidence interval [CI]:1.57-3.42) and TER (aOR: 2.50, 95% CI: 1.62-3.88) users had higher odds to be rapid discontinuers relative to FIN users. In addition, TER users were more likely (aOR: 1.50, 95% CI: 1.06-2.13) to be slow decliners compared with FIN users. CONCLUSION: Teriflunomide and DMF were associated with poorer adherence trajectories than FIN. More research is needed to evaluate the clinical implications of these adherence trajectories of oral DMAs to optimize the management of MS.

Identification of key genes responsible for green and white colored spathes in Anthurium andraeanum (Hort.).

Modern anthuriums, Anthurium andraeanum (Hort.) are among the most popular flowering plants and widely used for interior decoration. Their popularity is largely attributed to the exotic spathes with different colors. Previous studies have reported color development in red spathe cultivars, but limited information is available on key genes regulating white and green colored spathes. This study analyzed anthocyanin, chlorophyll, and carotenoid contents as well as transcript differences in spathes of eight cultivars that differed in spathe colors ranging from red to white and green. Results showed that increased expression of a transcription factor AaMYB2 was associated with elevated levels of anthocyanin in spathes, but decreased expression of AaMYB2 and increased expression of AaLAR (leucoanthocyanidin reductase) and AaANR (anthocyanidin reductase) were accompanied with the accumulation of colorless proanthocyanidin, thus the white spathe. As to the green colored spathe, chlorophyll content in the green spathe cultivar was substantially higher than the other cultivars. Correspondingly, transcripts of chlorophyll biosynthesis-related genes AaHemB (porphobilinogen synthase) and AaPor (protochlorophyllide oxidoreductase) were highly upregulated but almost undetectable in white and red spathes. The increased expression of AaHemB and AaPor was correlated with the expression of transcription factor AaMYB124. Subsequently, qRT-PCR analysis confirmed their expression levels in nine additional cultivars with red, white, and green spathes. A working model for the formation of white and green spathes was proposed. White colored spathes are likely due to the decreased expression of AaMYB2 which results in increased expression of AaLAR and AaANR, and the green spathes are attributed to AaMYB124 enhanced expression of AaHemB and AaPor. Further research is warranted to test this working model.

Cloning and expression of a novel trans-anethole oxygenase gene from Paraburkholderia sp. MR185.

trans-Anethole oxygenase (TAO) is the key enzyme responsible for the oxidation of trans-anethole to p-anisaldehyde. A strain, Paraburkholderia sp. MR185, was isolated from soil in Yulin star anise-planting regions using trans-anethole as a sole carbon source and a gene which encodes a protein with high similarities to a hypothetical protein of Paraburkholderia sp. MM5384-R2 which shows 61.27% identies with TAO from Pseudomonas putida JYR-1 was cloned and sequenced. The gene, tao, was expressed in E. coli cells and its protein product was purified by affinity chromatography through regenerated amorphous cellulose (RAC). SDS-PAGE analysis indicated a clear band of recombinant protein TAO, and its molecular weight, 38.3 kDa, was consistent with the theoretical value. Its enzyme activity of producing p-anisaldehyde from trans-anethole was detected by DNPH (2,4-dinitrophenylhydrazine) chromogenic reaction and HPLC, and the specific activity of TAO reached 3.93 U/mg protein. Immobilized TAO on RAC was used to catalyze the production of p-anisaldehyde from trans-anethole, and the enzyme retained more than 60% of its initial activity after 10 uses. This is the first report on Paraburkholderia TAO.

Medical insurance and physician-induced demand in China: the case of hemorrhoid treatments.

In October 2015, the Guangdong government of China enacted a so-called unified medical insurance payment for patients residing in Guangdong province, which fundamentally simplifies reimbursement procedures of medical insurance for the involved cross-city in-patients. Using a unique confidential dataset from 2013 to 2018 on hemorrhoid treatments at a renowned hospital in Guangzhou, the provincial capital of Guangdong, and exploiting difference-in-differences estimations based on the abovementioned policy, we document that the physicians' incentives are a negative externality of the full medical insurance policy for cross-city in-patients and account for a 49% probability increase in improper treatments; and neither increasing the communication between physicians and patients nor enhancing the education level of patients reduces the physician-induced demand for improper treatments. A series of robustness tests indicate our findings are solid. In summary, we highlight the substantial roles of medical insurance as a driver of physician-induced demand in an emerging economy such as China.

Health-related quality of life of patients with multiple sclerosis: Analysis of ten years of national data.

BACKGROUND: Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system. Both the physical and mental burden of MS affect patients' health-related quality of life (HRQoL). However, there is limited research at the national level evaluating the humanistic burden among MS patients. OBJECTIVES: This study evaluated the HRQoL and functional limitations among MS patients using ten years of national survey data. METHODS: Guided by the conceptual framework of the Wilson and Cleary model, this study compared HRQoL between adults diagnosed with MS (Clinical Classification Code= "080″) and non-MS adults using the 2006-2015 Medical Expenditure Panel Survey (MEPS) data. The humanistic burden included HRQoL and functional limitations. The HRQoL was evaluated using physical component summary (PCS) and mental component summary (MCS) based on the Short Form Health Survey (SF-12). The study applied the multivariable Generalized Linear Models (GLM) to estimate the marginal differences in PCS and MCS based on the SF-12. In addition, seeking help for activities of daily living (ADL) and instrumental activities of daily living (IADL) were modeled with multivariable logistic regression. RESULTS: According to the MEPS, the estimated annual prevalence of MS was 0.52 million (95% Confidence Interval [CI]: 0.42-0.60). MS patients were mainly female (71.90%), middle aged (50-64 years, 40.21%), non-Hispanic whites (78.29%), and enrolled in private insurance plans (68.93%). The average PCS scores in MS and non-MS groups were 35.70 and 49.48, respectively. The average MCS scores were 45.58 and 51.25 for MS and non-MS groups, respectively. In addition, 18.26% of MS patients sought help for ADL, and 27.08% sought help for IADL. After adjusting for individual, biological, and environmental characteristics, the multivariable GLM with Poisson distribution indicated that the marginal difference of PCS score was 11.10 (95% CI: 9.50-12.61) units lower, and the MCS score was 4.89 (95% CI: 3.44-6.30) units lower among MS patients. In addition, MS patients were 17.32 (95% CI: 11.61-25.84) and 14.43 (95% CI: 10.09-20.65) times more likely to request assistance for ADL and IADL, respectively. CONCLUSIONS: MS was associated with lower physical and mental HRQoL than their non-MS counterparts and MS patients were more likely to request help for ADL and IADL. More work is needed to evaluate the effect of treatment strategies on improving the HRQoL and functional limitations in MS.

FACTORS ASSOCIATED WITH SWITCHING FROM INJECTABLE TO ORAL DISEASE MODIFYING AGENTS AMONG PATIENTS WITH MULTIPLE SCLEROSIS.

BACKGROUND: Since the introduction of oral disease-modifying agents (DMA) in 2010, the treatment options for multiple sclerosis (MS) have changed significantly. There is limited information regarding the factors associated with switching to oral DMA among prevalent injectable DMA users. OBJECTIVE: This study evaluated the factors associated with switching to oral DMAs among prevalent injectable DMA users with MS. METHODS: A retrospective observational cohort study using the TriNetX electronic medical records (EMR) data was conducted among patients with MS. The study included prevalent injectable DMA users with at least two injectable DMA (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, or glatiramer acetate) prescription records within 6 months between September 2010 and May 2018. The second injectable DMA prescription date was considered as the index date. Switching was defined as any oral DMA prescription record (fingolimod, dimethyl fumarate, or teriflunomide) within 12 months after the index date. Patients with any infusion DMA prescription after the first injectable DMA prescription, and those less than 18 years of age were excluded from the study. The Andersen Behavioral Model was used as the conceptual framework to identify predisposing, enabling, and need factors measured during the 1-year baseline period before the index date. A multivariable logistic regression model was used to examine the predisposing (age, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, MS-related medication, and healthcare utilization) associated with switching from injectable to oral DMAs. RESULTS: Among 2,943 prevalent injectable users included in this study, 8.09% (n=238) patients switched to oral DMAs. Patients who switched to oral DMAs were primarily younger adults aged 18-44 years (64.29%), females (82.77%), had sensory and visual symptoms, and had corticosteroid utilization during the one-year look-back period compared to non-switchers. Results from multivariable logistic regression model revealed that middle-aged adults (45-64 years, adjusted odds ratio [aOR]: 0.43, 95% Confidence Interval [CI]: 0.32-0.58), old adults (≥65 years, aOR: 0.30, 95% CI: 0.13-0.66) and men (aOR: 0.67, 95% CI: 0.47-0.96) were associated with decreased odds of switching to oral DMAs. Presence of MS-related sensory symptoms (aOR: 1.52, 95% CI: 1.07-2.16), visual symptoms (aOR: 1.59, 95% CI: 1.10-2.31), and corticosteroids usage (aOR: 1.44, 95% CI: 1.04-1.98) were associated with increased odds of switching to oral DMAs. CONCLUSION: The study found that about one in twelve prevalent injectable DMA users switched to oral DMA. Both demographic and clinical factors were associated with switching to oral DMAs. Further research is needed to evaluate the outcomes of switching to inform treatment decisions for MS management.

Time to Next Treatment, Health Care Resource Utilization, and Costs Associated with Ibrutinib Use Among U.S. Veterans with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Real-World Retrospective Analysis.

BACKGROUND: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common adult leukemia, accounting for ≈ 37% of all leukemias in the United States. Limited real-word evidence is available on the outcomes of ibrutinib use among previously untreated patients in the U.S. Veterans Health Administration (VHA) population diagnosed with CLL/SLL. OBJECTIVES: To (a) evaluate time to next treatment (TTNT) among U.S. veterans with CLL/SLL who initiated ibrutinib versus chemoimmunotherapy (CIT) in first line (1L) and 1L ibrutinib versus ibrutinib in later lines (2L+) and (b) compare health care resource utilization (HRU) and costs between the 1L ibrutinib and CIT cohorts. METHODS: Adults with CLL/SLL and claims for 1L single-agent ibrutinib or CIT (index date = first prescription claim date) were included from Veterans Health Administration Data (April 1, 2013-March 31, 2018). A subset of the CIT 1L cohort with evidence of ibrutinib in 2L/3L was defined as the ibrutinib 2L+ cohort. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate TTNT, and generalized linear models were used to determine all-cause per patient per month (PPPM) HRU and costs during 1L among propensity score-matched (PSM) cohorts. RESULTS: After PSM, 614 patients were included in each of the 1L ibrutinib and 1L CIT cohorts, and 149 were included in each of the 1L ibrutinib and 2L+ ibrutinib cohorts. The 1L ibrutinib cohort had significantly longer TTNT compared with each of the 1L CIT and 2L+ ibrutinib cohorts (P <0.0001 and P =0.0001, respectively) and was less likely to have a next line of treatment than the CIT 1L cohort (HR = 0.52; 95% CI = 0.42-0.65; P < 0.0001) and the 2L+ ibrutinib cohort (HR = 0.39; 95% CI = 0.22-0.69; P = 0.0012). The 1L ibrutinib cohort had significantly fewer inpatient visits (rate ratio [RR] = 0.38; 95% CI = 0.28-0.52; P ≤ 0.05) and outpatient visits PPPM (RR =0.72; 95% CI = 0.68-0.77; P ≤ 0.5) compared with the CIT 1L cohort. Additionally, the 1L ibrutinib cohort had $7,308 significantly lower monthly medical costs (95% CI = -$9,892 to -$4,895; P ≤ 0.05) versus the 1L CIT cohort, resulting in comparable monthly total health care cost (medical and pharmacy) between real-world 1L patients treated by ibrutinib and CIT (-$2,160; 95% CI = -$4,840-$347; P > 0.05). CONCLUSIONS: These findings demonstrate that among U.S. veterans with CLL/SLL, 1L ibrutinib use was associated with significantly longer TTNT versus that of 1L CIT. Similarly, early treatment with ibrutinib was associated with longer TTNT as compared to ibrutinib use in later lines of therapy. Moreover, 1L ibrutinib was associated with lower HRU and medical costs compared with 1L CIT, completely offsetting the higher pharmacy costs related to 1L ibrutinib treatment. DISCLOSURES: This research was sponsored by Janssen Scientific Affairs. The analyses were performed by STATinMED Research. Huang is an employee of Janssen Scientific Affairs and may own company stock. Sundaram was an employee of Janssen Scientific Affairs at the time this study was conducted. Borra and Janjan are employees of STATinMED Research, a paid consultant to the study sponsor. Wang, Li, and Shrestha were employees of STATinMED Research at the time this study was conducted.