A scalable approach to assess the safety of recently marketed systemic treatments for atopic dermatitis in clinical practice.

Targeted systemic immune-modulating drugs (IMDs) to treat atopic dermatitis (AD) were highly efficacious in randomized trials. Trials with limited number of subjects leave questions about their safety. We describe a data and analytics structure for the production of timely, high-quality evidence on the comparative safety of recently approved IMDs in patients with AD in clinical practice. We established a series of sequential propensity score (PS)-balanced cohorts that grow in size with each annual data refresh. Nine health outcomes of interest plus conjunctivitis as a positive tracer outcome were identified. The initial treatment comparison was dupilumab, an interleukin-4/13 inhibitor, or tralokinumab, an interleukin-13 inhibitor, versus abrocitinib/upadacitinib, both JAK inhibitors. The first analysis cycle (December 2021-February 2023) compared 269 patients initiating JAK inhibitors and 2,650 initiating IL-4/IL-13 inhibitors. Patient characteristics were well balanced after PS-matching. Outpatient infections within 180 days occurred in 18% of JAK-1 inhibitor initiators versus 12% of dupilumab/ tralokinumab initiators (RR=1.50; 0.96 to 2.33) whereas acne risks were 7% vs. 3%, respectively (RR=2.29, 0.96 to 5.46). This sequential monitoring system will produce essential knowledge on the safety of IMDs to treat AD based on its growing study size of patients observed in clinical practice.

Nitrite-driven anaerobic ethane oxidation.

Ethane, the second most abundant gaseous hydrocarbon in vast anoxic environments, is an overlooked greenhouse gas. Microbial anaerobic oxidation of ethane can be driven by available electron acceptors such as sulfate and nitrate. However, despite nitrite being a more thermodynamically feasible electron acceptor than sulfate or nitrate, little is known about nitrite-driven anaerobic ethane oxidation. In this study, a microbial culture capable of nitrite-driven anaerobic ethane oxidation was enriched through the long-term operation of a nitrite-and-ethane-fed bioreactor. During continuous operation, the nitrite removal rate and the theoretical ethane oxidation rate remained stable at approximately 25.0 mg NO2 -N L-1 d-1 and 11.48 mg C2H6 L-1 d-1, respectively. Batch tests demonstrated that ethane is essential for nitrite removal in this microbial culture. Metabolic function analysis revealed that a species affiliated with a novel genus within the family Rhodocyclaceae, designated as 'Candidatus Alkanivoras nitrosoreducens', may perform the nitrite-driven anaerobic ethane oxidation. In the proposed metabolic model, despite the absence of known genes for ethane conversion to ethyl-succinate and succinate-CoA ligase, 'Ca. A. nitrosoreducens' encodes a prospective fumarate addition pathway for anaerobic ethane oxidation and a complete denitrification pathway for nitrite reduction to nitrogen. These findings advance our understanding of nitrite-driven anaerobic ethane oxidation, highlighting the previously overlooked impact of anaerobic ethane oxidation in natural ecosystems.

The bioremediation of the typical persistent organic pollutants (POPs) by microalgae-bacteria consortia: A systematic review.

With industrialisation and the rapidly growing agricultural demand, many organic compounds have been leaked into the environment, causing serious damage to the biosphere. Persistent organic pollutants (POPs) are a type of toxic chemicals that are resistant to degradation through normal chemical, biological or photolytic approaches. With their stable chemical structures, POPs can be accumulated in the environment, and transported through wind and water, causing global environmental issues. Many researches have been conducted to remediate POPs contamination using various kinds of biological methods, and significant results have been seen. Microalgae-bacteria consortium is a newly developed concept for biological technology in contamination treatment, with the synergetic effects between microalgae and bacteria, their potential for pollutants degradation can be further released. In this review, two types of POPs (polychlorinated biphenyls and polycyclic aromatic hydrocarbons) are selected as the targeted pollutants to give a systematic analysis of the biodegradation through microalgae and bacteria, including the species selection, the identification of dominant enzymes, as well as the real application performance of the consortia. In the end, some outlooks and suggestions are given to further guide the development of applying microalgae-bacteria consortia in remediating POPs contamination. In general, the coculturing of microalgae and bacteria is a novel and efficient way to fulfil the advanced treatment of POPs in soil or liquid phase, and both monooxygenase and dioxygenase belonging to oxygenase play a vital role in the biodegradation of PCBs and PAHs. This review provides a general guide in the future investigation of biological treatment of POPs.

Real-World Treatment Effectiveness of Disease-Modifying Antirheumatic Drugs by Serostatus Among Patients With Rheumatoid Arthritis.

OBJECTIVE: The objective of this study was to compare the clinical effectiveness of biologic disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) among seropositive versus seronegative patients with rheumatoid arthritis (RA) in a real-world setting. METHODS: We used Optum's deidentified Clinformatics Data Mart Database (January 1, 2004, to March 31, 2021) linked with outpatient laboratory test results. The study population was adult patients with RA who initiated a bDMARD or JAKi. The index date was the dispensing of the first-ever study drug. At least 1-year continuous enrollment before and after the index date was required. Disenrollment due to death after the index date was allowed. Serostatus was defined using laboratory test results or the International Classification of Diseases, 10th Revision code M05x or M06.0x any time prior to the index date. Treatment effectiveness was measured based on a claims-based composite endpoint at 1-year post index, including nonoccurrence of any of the following: addition of conventional synthetic DMARDs, addition of or switching to new bDMARDs/JAKi, initiation of glucocorticoids, increased glucocorticoid dose, or death. Log-binomial regression models were constructed to estimate the risk ratio (RR) with 95% confidence interval (CI) comparing seropositive patients with seronegative patients, adjusting for more than 60 baseline covariates. RESULTS: We identified a total of 7813 seropositive patients and 4202 seronegative patients. The mean (±SD) age was 56.7 (±14.0) years; 77.9% were female. The risk of 1-year treatment effectiveness was 70.2% among seropositive patients and 69.8% among seronegative patients. The adjusted RR (95% CI) was 1.00 (0.98-1.02). CONCLUSION: In this real-world cohort study, seropositive and seronegative patients with RA had similar 1-year treatment effectiveness after initiating a bDMARD/JAKi.

Comparison of EHR Data-Completeness in Patients with Different Types of Medical Insurance Coverage in the United States.

Prior studies have demonstrated that misclassification of study variables due to electronic health record (EHR)-discontinuity can be mitigated by restricting EHR-based analyses to subjects with high predicted EHR-continuity based on a simple algorithm. In this study, we compared EHR continuity in populations covered by Medicare, Medicaid, or commercial insurance. Using claims-linked EHRs from a multicenter network in Massachusetts, including Medicare (MA EHR-Medicare cohort) and Medicaid (MA EHR-Medicaid cohort) claims data; and TriNetX (TriNetX cohort) claims-linked EHR data from 11 US-based healthcare organizations, we assessed (1) EHR-continuity quantified by proportion of encounters captured by EHR (capture proportion (CP)); (2) area under receiver operating curve (AUROC) of previously validated model to identify patients with high EHR-continuity (CP ≥ 0.6); (3) misclassification of 40 patient characteristics, quantified by average standardized absolute mean difference (ASAMD). Study participants were ≥ 65 years (Medicare) or ≥ 18 years (Medicaid, TriNetX) with ≥ 365 days of continuous insurance enrollment overlapping with an EHR encounter. We found that the mean CP was 0.30, 0.18, and 0.19 and AUROC of the prediction model to identify patients with high EHR-continuity was 0.92, 0.89, and 0.77 in the MA EHR-Medicare, MA EHR-Medicaid, and TriNetX cohorts, respectively. Restricting to patients with predicted EHR-continuity percentile of top 20%, 50%, and 50% in MA EHR-Medicare, MA EHR-Medicaid, and TriNetX cohorts resulted in acceptable levels of misclassification (ASAMD < 0.1). Using a prediction model to identify cohorts with high EHR-continuity can improve validity, but cutoffs to achieve this goal vary by population.

The Impact of Longitudinal Data-Completeness of Electronic Health Record Data on the Prediction Performance of Clinical Risk Scores.

The impact of electronic health record (EHR) discontinuity (i.e., receiving care outside of a given EHR system) on EHR-based risk prediction is unknown. We aimed to assess the impact of EHR-continuity on the performance of clinical risk scores. The study cohort consisted of patients aged ≥ 65 years with ≥ 1 EHR encounter in the 2 networks in Massachusetts (MA; 2007/1/1-2017/12/31, internal training and validation dataset), and one network in North Carolina (NC; 2007/1/1-2016/12/31, external validation dataset) that were linked with Medicare claims data. Risk scores were calculated using EHR data alone vs. linked EHR-claims data (not subject to misclassification due to EHR-discontinuity): (i) combined comorbidity score (CCS), (ii) claim-based frailty score (CFI), (iii) CHAD2 DS2 -VASc, and (iv) Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile, Elderly, and Drugs (HAS-BLED). We assessed the performance of CCS and CFI predicting death, CHAD2 DS2 -VASc predicting ischemic stroke, and HAS-BLED predicting bleeding by area under receiver operating characteristic curve (AUROC), stratified by quartiles of predicted EHR-continuity (Q1-4). There were 319,740 patients in the MA systems and 125,380 in the NC system. In the external validation dataset, AUROC for EHR-based CCS predicting 1-year risk of death was 0.583 in Q1 (lowest) EHR-continuity group, which increased to 0.739 in Q4 (highest) EHR-continuity group. The corresponding improvement in AUROC was 0.539 to 0.647 for CFI, 0.556 to 0.637 for CHAD2 DS2 -VASc, and 0.517 to 0.556 for HAS-BLED. The AUROC in Q4 EHR-continuity group based on EHR alone approximates that based on EHR-claims data. The prediction performance of four clinical risk scores was substantially worse in patients with lower vs. high EHR-continuity.

Risk of Infection in Children With Psoriasis Receiving Treatment With Ustekinumab, Etanercept, or Methotrexate Before and After Labeling Expansion.

Importance: Psoriasis in children is increasingly treated with systemic medications, yet their risk of serious infection is not well characterized in clinical practice. Pediatric clinical trials for these medications were often small and placebo controlled. Objective: To estimate the 6-month rate of infections among children with psoriasis who started treatment with ustekinumab, etanercept, or methotrexate. Design, Setting, and Participants: This cohort study used insurance claims data from clinical practices across the US on children aged 17 years or younger with psoriasis who were receiving treatment with a topical medication for psoriasis and started new treatment with ustekinumab, etanercept, or methotrexate. The analysis was stratified by the time before pediatric labeling (2009-2015) and after pediatric approval (2016-2021). Patient follow-up started 1 day after initiating treatment and ended at 6 months. Exposures: New treatment with ustekinumab, etanercept, and methotrexate. Main Outcomes and Measures: During follow-up, the frequency of inpatient serious infections and outpatient infections requiring treatment was compared. Event rates and rate ratios were estimated after propensity score decile stratification. Results: After exclusions, we identified 2338 patients (1368 girls [57.8%]) who initiated new treatment with a targeted immunomodulating agent. In all, 379 patients started treatment with ustekinumab, 779 patients started treatment with etanercept, and 1180 patients started treatment with methotrexate from 2009 through 2021. The propensity score-adjusted incidence rate of serious infection was 18.4 per 1000 person-years (3 events) for ustekinumab users, 25.6 per 1000 person-years (9 events) for etanercept users, and 14.9 per 1000 person-years (8 events) for methotrexate users. The adjusted rate of outpatient infections was 254.9 per 1000 person-years (39 events) for ustekinumab users, 435.7 per 1000 person-years (139 events) for etanercept users, and 433.6 per 1000 person-years (209 events) for methotrexate users. The adjusted rate ratio of outpatient infections was 0.58 (95% CI, 0.41-0.83) for ustekinumab vs etanercept, 0.66 (95% CI, 0.48-0.91) for ustekinumab vs methotrexate, and 0.95 (95% CI, 0.75-1.21) for etanercept vs methotrexate. Rate ratios were similar during the off-label use era and after pediatric labeling. Conclusions and Relevance: Among children with psoriasis who started treatment with immunomodulating agents, serious infections were infrequent. This cohort study suggests that there was no increase in the risk of outpatient infections for children who started treatment with ustekinumab compared with etanercept or methotrexate.

Real-world patient characteristics and use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: a cross-national study.

INTRODUCTION: Rheumatoid arthritis (RA) is associated with significant morbidity and economic burden. This study aimed to compare baseline characteristics and patterns of anti-inflammatory drug use and disease-modifying anti-rheumatic drug (DMARD) use among patients with RA in Southern Italy versus the United States. METHOD: Using Caserta Local Health Unit (Italy) and Optum's de-identified Clinformatics® Data Mart (United States) claims databases, patients with ≥ 2 diagnosis codes for RA during the study period (Caserta: 2010-2018; Optum: 2010-2019) were identified. Baseline patient characteristics, as well as proportion of RA patients untreated/treated with NSAIDs/glucocorticoids/conventional DMARDs (csDMARDs)/biological/targeted synthetic DMARDs (b/tsDMARDs) during the first year of follow-up, and the proportion of RA patients with ≥ 1 switch/add-on between the first and the second year of follow-up, were calculated. These analyses were then stratified by age group (< 65; ≥ 65). RESULTS: A total of 9227 RA patients from Caserta and 195,951 from Optum databases were identified (two-thirds were females). During the first year of follow-up, 45.9% RA patients from Optum versus 79.9% from Caserta were exclusively treated with NSAIDs/glucocorticoids; 17.2% versus 11.3% from Optum and Caserta, respectively, were treated with csDMARDs, mostly methotrexate or hydroxychloroquine in both cohorts. Compared to 0.6% of RA patients from Caserta, 3.2% of the Optum cohort received ≥ 1 b/tsDMARD dispensing. Moreover, 61,655 (33.7%) patients from Optum cohort remained untreated compared to 748 (8.3%) patients from the Caserta cohort. The subgroup analyses stratified by age showed that 42,989 (39.8%) of elderly RA patients were untreated compared to 18,666 (24.9%) young adult RA patients in Optum during the first year of follow-up. Moreover, a higher proportion of young adult RA patients was treated with b/tsDMARDs, with and without csDMARDs, compared to elderly RA patients (Optum<65: 6.4%; Optum≥65: 1.0%; P-value < 0.001; Caserta<65: 0.8%; Caserta≥65: 0.1%; P-value < 0.001). Among RA patients untreated during the first year after ID, 41.2% and 48.4% RA patients from Caserta and Optum, respectively, received NSAIDs, glucocorticoids, and cs/b/tsDMARDs within the second year of follow-up. Stratifying the analysis by age groups, 50.6% of untreated young RA patients received study drug dispensing within the second year of follow-up, compared to only 36.7% of elderly RA patients in Optum. Interestingly, more young adult RA patients treated with csDMARDs during the first year after ID received a therapy escalation to b/tsDMARD within the second year after ID in both cohorts, compared to elderly RA patients (Optum<65: 7.8%; Optum≥65: 1.8%; Caserta<65: 3.2%; Caserta≥65: 0.6%). CONCLUSIONS: Most of RA patients, with heterogeneous baseline characteristics in Optum and Caserta cohorts, were treated with anti-inflammatory/csDMARDs rather than bDMARDs/tsDMARDs during the first year post-diagnosis, especially in elderly RA patients, suggesting a need for better understanding and dealing with barriers in the use of these agents for RA patients. Key Points • Substantial heterogeneity in baseline characteristics and access to bDMARD or tsDMARD drugs between RA patients from the United States and Italy exists. • Most of RA patients seem to be treated with anti-inflammatory/csDMARD drugs rather than bDMARD/tsDMARD drugs during the first year post-diagnosis. • RA treatment escalation is less frequent in old RA patients than in young adult RA patients. • An appropriate use of DMARDs should be considered to achieve RA disease remission or low disease activity.

Grape seed extract proanthocyanidin antagonizes aristolochic acid I-induced liver injury in rats by activating PI3K-AKT pathway.

Aristolochic acid is internationally recognized as a carcinogen. It has been shown that the main toxic mechanism of aristolochic acid on the liver and kidney is the induction of ROS-induced oxidative stress damage. To investigate whether proanthocyanidins (GSPE), a natural antioxidant product from grape seed extract, could antagonize AA-I-induced liver injury. Thirty-two SD rats were selected and divided into aristolochic acid exposure group (AA-I), normal control group, GSPE group and GSPE intervention group. The protective effects of GSPE on AA-I liver injury were evaluated by examining the body weight, liver index, liver function and liver pathological sections of rats. The results of body weight, liver index, liver function and liver pathological sections of rats showed that GSPE had antagonistic effects on AA-I-induced liver injury. antioxidant enzyme activity in the GSPE intervention group was significantly higher than that in the aristolochic acid group, apoptotic cells were significantly lower than that in the aristolochic acid group, protein and mRNA expression of PI3K-AKT and BCL-2 were significantly higher than that in the aristolochic acid group, BAX, The protein and mRNA expression of BAX, CASPAES-3, CASPAES-9 were significantly lower than those of the aristolochic acid group. GSPE can antagonize aristolochic acid-induced hepatotoxicity, and its mechanism of action is to antagonize aristolochic acid I-induced liver injury by inhibiting PI3K-AKT pathway-mediated hepatocyte apoptosis.

Advancing an Algorithm for the Identification of Patients with High Data-Continuity in Electronic Health Records.

Background: Identifying high data-continuity patients in an electronic health record (EHR) system may facilitate selecting cohorts with a lower degree of variable misclassification and promote study validity. We updated a previously developed algorithm for identifying patients with high EHR data-completeness by adding demographic and health utilization factors to improve adaptability to networks serving patients of diverse backgrounds. We also expanded the algorithm to accommodate data in the ICD-10 era. Methods: We used Medicare claims linked with EHR data to identify individuals aged ≥65 years. EHR-continuity was defined as the proportion of encounters captured in EHR data relative to claims. We compared the model with additional demographic factors and their interaction terms with other predictors with the original algorithm and assessed the performance by area under the ROC curve (AUC) and net reclassification index (NRI). Results: The study cohort consisted of 264,099 subjects. The updated prediction model had an AUC of 0.93 in the validation set. Compared to the previous model, the new model had an NRI of 37.4% (p<0.001) for EHR-continuity classification. Interaction terms between demographic variables and other predictors did not improve the performance. Patients within the top 20% of predicted EHR-continuity had four times less misclassification of key variables compared to the remaining population. Conclusion: Adding demographic and healthcare utilization variables significantly improved the model performance. Patients with high predicted EHR-continuity had less misclassification of study variables compared to the remaining population in both ICD-9 and 10 eras.

Occurrence of inflammatory bowel disease in patients with chronic inflammatory skin diseases: a cohort study: Classification: Epidemiology.

BACKGROUND: Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) in a range of data sources with mixed conclusions. OBJECTIVES: We compared the incidence of IBD - ulcerative colitis (UC) and Crohn disease (CD) - in patients with a CISD vs. similar persons without a CISD. METHODS: In this cohort study using nationwide, longitudinal, commercial insurance claims data from the USA, we identified adults and children who were seen by a dermatologist between 2004 and 2020, and diagnosed with either psoriasis, atopic dermatitis, alopecia areata, vitiligo or hidradenitis suppurativa. Comparator patients were identified through risk-set sampling; they were eligible if they were seen by a dermatologist at least twice and not diagnosed with a CISD. Patient follow-up lasted until either IBD diagnosis, death, disenrolment or end of data stream, whichever came first. IBD events, UC or CD, were identified via validated algorithms: hospitalization or diagnosis with endoscopic confirmation. Incidence rates were computed before and after adjustment via propensity-score decile stratification to account for IBD risk factors. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated to compare the incidence of IBD in CISD vs. non-CISD. RESULTS: We identified patients with atopic dermatitis (n = 123 614), psoriasis (n = 83 049), alopecia areata (n = 18 135), vitiligo (n = 9003) or hidradenitis suppurativa (n = 6806), and comparator patients without a CISD (n = 2 376 120). During a median follow-up time of 718 days, and after applying propensity-score adjustment for IBD risk factors, we observed increased risk of both UC (HRUC 2·30, 95% CI 1·61-3·28) and CD (HRCD 2·70, 1·69-4·32) in patients with hidradenitis suppurativa, an increased risk of CD (HRCD 1·23, 1·03-1·46) but not UC (HRUC 1·01, 0·89-1·14) in psoriasis, and no increased risk of IBD in atopic dermatitis (HRUC 1·02, 0·92-1·12; HRCD 1·08, 0·94-1·23), alopecia areata (HRUC 1·18, 0·89-1·56; HRCD 1·26, 0·86-1·86) or vitiligo (HRUC 1·14, 0·77-1·68; HRCD 1·45, 0·87-2·41). CONCLUSIONS: IBD was increased in patients with hidradenitis suppurativa. CD alone was increased in patients with psoriasis. Neither UC nor CD was increased in patients with atopic dermatitis, alopecia areata or vitiligo. What is already known about this topic? Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) utilizing a range of data sources, with mixed conclusions. What does this study add? This large-scale, claims-based cohort study expands current knowledge by providing background rates for IBD across multiple CISDs using consistent methods and within a single, nationally representative patient population. We observed a relative increased risk of IBD in patients with hidradenitis suppurativa, but the overall incidence rate difference of IBD was generally low. Crohn disease alone was significantly increased in patients with psoriasis, and neither ulcerative colitis nor Crohn disease was increased in patients with atopic dermatitis, vitiligo or alopecia areata.

Predictors of Treatment Change Among Patients with Rheumatoid Arthritis Treated with TNF Inhibitors as First-Line Biologic Agent in the USA: A Cohort Study from Longitudinal Electronic Health Records.

BACKGROUND: Previous observational studies utilizing administrative claims data have largely been unable to consider clinical factors that may be related to patterns of drug use among patients with rheumatoid arthritis (RA). OBJECTIVE: To understand predictors of treatment changes following initiation of a tumor necrosis factor inhibitor (TNFi) using nation-wide electronic health record (EHR) data in the USA. METHODS: The Optum Immunology Condition EHR data (01/01/2011-09/30/2019) was used to identify a population of adult patients with RA initiating a TNFi as the first line biologic disease-modifying anti-rheumatic drug (DMARD). The primary outcome was any treatment change during the 1-year post-index period defined as cycling to a different TNFi or switching to non-TNFi biologic or targeted synthetic DMARDs. Secondary outcomes were the individual components of TNFi cycling and switching, examined separately. To identify predictors of DMARD treatment changes, we used a least absolute shrinkage and selection operator (LASSO) regression model. Model c-statistics and odds ratios (ORs, 95% confidence intervals (CIs)) of predictors were reported. RESULTS: We identified 24,871 patients with RA who initiated a TNFi. The mean age was 55.5 (± 13.7) years and 77.2% were female. Among the TNFi initiators, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Predictors that are associated with higher likelihood of TNFi cycling or switching included female gender (OR: 1.26, 95% CI: 1.16-1.36) and glucocorticoid use (OR: 1.30, 95% CI: 1.21-1.40). In contrast, inflammatory bowel disease (OR: 0.62, 95% CI: 0.48-0.78), psoriasis (OR: 0.82, 95% CI: 0.70-0.95), recent use of methotrexate (OR: 0.89, 95% CI: 0.81-0.97), and vitamin D intake (OR: 0.92, 95% CI: 0.85-0.99) were negatively associated with TNFi cycling or switch. CONCLUSIONS: Gender, glucocorticoid use, inflammatory bowel disease, psoriasis, and vitamin D intake were identified as significant predictors of TNFi cycling or switching for TNFi initiators in the RA population. Predicting treatment change remains challenging even with large detailed EHR data. This study aimed to identify key determinants of treatment changes among patients with rheumatoid arthritis (RA) initiating a tumor necrosis factor inhibitor (TNFi) as their first-line biologic disease-modifying antirheumatic drug (DMARD) in routine care settings using a US nation-wide longitudinal electronic health record (EHR). Among 24,871 patients with RA who initiated a TNFi, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Female patients and those who used glucocorticoids were more likely to experience TNFi cycling or switching, whereas inflammatory bowel disease, psoriasis, recent methotrexate use, and vitamin D intake were negatively associated with the outcome. However, predicting treatment change remains challenging even with larger detailed EHR data potentially due to unmeasured factors such as prescriber's preference or patient's belief in the medication.

Rotenone induces hepatotoxicity in rats by activating the mitochondrial pathway of apoptosis.

As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.

Impact of longitudinal data-completeness of electronic health record data on risk score misclassification.

BACKGROUND: Electric health record (EHR) discontinuity, that is, receiving care outside of a given EHR system, can lead to substantial information bias. We aimed to determine whether a previously described EHR-continuity prediction model can reduce the misclassification of 4 commonly used risk scores in pharmacoepidemiology. METHODS: The study cohort consists of patients aged ≥ 65 years identified in 2 US EHR systems linked with Medicare claims data from 2007 to 2017. We calculated 4 risk scores, CHAD2DS2-VASc, HAS-BLED, combined comorbidity score (CCS), claims-based frailty index (CFI) based on information recorded in the 365 days before cohort entry, and assessed their misclassification by comparing score values based on EHR data alone versus the linked EHR-claims data. CHAD2DS2-VASc and HAS-BLED were assessed in atrial fibrillation (AF) patients, whereas CCS and CFI were assessed in the general population. RESULTS: Our study cohort included 204 014 patients (26 537 with nonvalvular AF) in system 1 and 115 726 patients (15 529 with nonvalvular AF) in system 2. Comparing the low versus high predicted EHR continuity in system 1, the proportion of patients with misclassification of ≥2 categories improved from 55% to 16% for CHAD2DS2-VASc, from 55% to 12% for HAS-BLED, from 37% to 16% for CCS, and from 10% to 2% for CFI. A similar pattern was found in system 2. CONCLUSIONS: Using a previously described prediction model to identify patients with high EHR continuity may significantly reduce misclassification for the commonly used risk scores in EHR-based comparative studies.

Development of a Medicare Claims-Based Model to Predict Persistent High-Dose Opioid Use After Total Knee Replacement.

OBJECTIVE: To develop a claims-based model to predict persistent high-dose opioid use among patients undergoing total knee replacement (TKR). METHODS: Using Medicare claims (2010-2014), we identified patients ages ≥65 years who underwent TKR with no history of high-dose opioid use (mean >25 morphine milligram equivalents [MMEs]/day) in the year prior to TKR. We used group-based trajectory modeling to identify distinct opioid use patterns. The primary outcome was persistent high-dose opioid use in the year after TKR. We split the data into training (2010-2013) and test (2014) sets and used logistic regression with least absolute shrinkage and selection operator regularization, utilizing a total of 83 preoperative patient characteristics as candidate predictors. A reduced model with 10 prespecified variables, which included demographic characteristics, opioid use, and medication history was also considered. RESULTS: The final study cohort included 142,089 patients who underwent TKR. The group-based trajectory model identified 4 distinct trajectories of opioid use (group 1: short-term, low-dose; group 2: moderate-duration, low-dose; group 3: moderate-duration, high-dose; and group 4: persistent high-dose). The model predicting persistent high-dose opioid use achieved high discrimination (receiver operating characteristic area under the curve [AUC] 0.85 [95% confidence interval (95% CI) 0.84-0.86]) in the test set. The reduced model with 10 predictors performed equally well (AUC 0.84 [95% CI 0.84-0.85]). CONCLUSION: In this cohort of older patients, 10.6% became persistent high-dose (mean 22.4 MME/day) opioid users after TKR. Our model with 10 readily available clinical factors may help identify patients at high risk of future adverse outcomes from persistent opioid use after TKR.

Giant cell arteritis treatment patterns and rates of serious infections.

OBJECTIVES: Giant cell arteritis (GCA) afflicts older adults who may have age- and comorbidity-related risks for infection and is treated with immunosuppressants that increase risk of infection. We examined GCA treatment patterns and rates of serious infections in two real-world cohorts in the U.S. METHODS: We identified two GCA cohorts using two U.S. health insurance databases, Medicare (public, 2007-2017) and MarketScan (commercial, 2015-2019), by applying a validated claims-based algorithm with positive predictive value 79.0% for GCA. We required age ≥50 years and assessed baseline comorbidities, dispensing of immunosuppressants and prophylactic antibiotics, and vaccine administration. We calculated incidence rates (IR) of serious infections, defined as bacterial or viral infections requiring hospitalisation based on primary inpatient diagnosis code. Multivariable Cox proportional hazards models estimated hazard ratios for risk of serious infection for prespecified covariates. RESULTS: The Medicare cohort included 734 patients, 28% male, mean age 77.1; the MarketScan cohort included 1022 patients, 30% male, mean age 68.4. More than 85% used prednisone ≥60mg daily at index date and <10% used tocilizumab. Serious infections developed in 27.9% of Medicare and 7.2% of MarketScan patients: IR per 100 person-years = 10.7 (95% CI 9.3, 12.2) in Medicare and 6.3 (95% CI 5.0, 7.9) in MarketScan. Older age and higher frailty score were significantly associated with increased risk for serious infection. CONCLUSIONS: In these two U.S. GCA cohorts, high-dose glucocorticoids were the most common initial treatment, and over 25% of Medicare and 7% of MarketScan patients developed serious infection during follow-up. Older age and higher frailty score were associated with higher risk of serious infections, though maximum daily prednisone dose was not. Pneumocystis jiroveci pneumonia was rare in two GCA cohorts despite infrequent use of prophylactic antibiotics.

Risk of Hospitalization for Serious Infection After Initiation of Ustekinumab or Other Biologics in Patients With Psoriasis or Psoriatic Arthritis.

OBJECTIVE: To compare the risk of serious infections requiring hospitalization in patients with psoriasis (PsO) or psoriatic arthritis (PsA) initiating ustekinumab versus other biologics or apremilast. METHODS: In this multi-database cohort study, we identified patients with PsO/PsA who initiated therapy with adalimumab, apremilast, certolizumab, etanercept, golimumab, ixekizumab, secukinumab, or ustekinumab between 2009 and 2018. The primary outcome measure was hospitalizations due to serious infections, which included bacterial, viral, or opportunistic infections. We estimated hazard ratios (HRs) comparing each study drug to ustekinumab after applying propensity score fine stratification weights for confounding control in each database. Database-specific weighted HRs were combined by meta-analysis. RESULTS: We identified 123,383 patients with PsO/PsA who initiated one of the study drugs. During a total of 117,744 person-years of follow-up, 1,514 serious infections occurred with a crude incidence of 1.29 per 100 person-years. After propensity score fine stratification and weighting, the incidence rates of serious infection among ustekinumab initiators ranged from 0.59 to 0.95 per 100 person-years. Compared with ustekinumab, the combined weighted HRs (95% confidence interval [95% CI]) for serious infections were 1.66 (95% CI 1.34-2.06) for adalimumab, 1.42 (95% CI 1.02-1.96) for apremilast, 1.09 (95% CI 0.68-1.75) for certolizumab, 1.39 (95% CI 1.01-1.90) for etanercept, 1.74 (95% CI 1.00-3.03) for golimumab, 2.92 (95% CI 1.80-4.72) for infliximab, 2.98 (95% CI 1.20-7.41) for ixekizumab, and 1.84 (95% CI 1.24-2.72) for secukinumab. CONCLUSION: Other biologics and apremilast were associated with a 1.4- to 3-times higher risk of hospitalization for serious infections in PsO/PsA patients when compared to ustekinumab; this finding should be considered in the safety profile of these therapies when selecting appropriate treatment regimens in patients with PsO/PsA.

Longitudinal Data Discontinuity in Electronic Health Records and Consequences for Medication Effectiveness Studies.

Electronic health record (EHR) discontinuity (i.e., receiving care outside of the study EHR system), can lead to information bias in EHR-based real-world evidence (RWE) studies. An algorithm has been previously developed to identify patients with high EHR-continuity. We sought to assess whether applying this algorithm to patient selection for inclusion can reduce bias caused by data-discontinuity in four RWE examples. Among Medicare beneficiaries aged >=65 years from 2007 to 2014, we established 4 cohorts assessing drug effects on short-term or long-term outcomes, respectively. We linked claims data with two US EHR systems and calculated %bias of the multivariable-adjusted effect estimates based on only EHR vs. linked EHR-claims data because the linked data capture medical information recorded outside of the study EHR. Our study cohort included 77,288 patients in system 1 and 60,309 in system 2. We found the subcohort in the lowest quartile of EHR-continuity captured 72-81% of the short-term and only 21-31% of the long-term outcome events, leading to %bias of 6-99% for the short-term and 62-112% for the long-term outcome examples. This trend appeared to be more pronounced in the example using a nonuser comparison rather than an active comparison. We did not find significant treatment effect heterogeneity by EHR-continuity for most subgroups across empirical examples. In EHR-based RWE studies, investigators may consider excluding patients with low algorithm-predicted EHR-continuity as the EHR data capture relatively few of their actual outcomes, and treatment effect estimates in these patients may be unreliable.

Risk of Non-Vertebral Fracture in Gout Compared to Rheumatoid Arthritis.

OBJECTIVE: To evaluate the risk of non-vertebral fractures in patients with gout compared with those with rheumatoid arthritis (RA). METHODS: Using claims data from Medicare (2008-2015), we conducted a cohort study of patients with gout versus RA matched on age, sex, and index date with a 1:1 ratio. The primary outcome was a composite endpoint of non-vertebral fractures including hip, pelvis, humerus, and wrist identified with the validated algorithms. We also assessed hip fractures separately. Multivariable Cox proportional hazards regression estimated the hazard ratio (HR) for the outcomes in gout versus RA adjusted for 45 covariates. RESULTS: We included a total of 134,157 matched pairs of gout and RA patients (mean age: 73.7 years). Risk factors for fracture were more prevalent in RA, while other comorbidities including obesity, coronary heart disease, hypertension, and diabetes were more common in gout. Over the mean 2.8 years follow-up, the incidence rate (IR)/1000 person-year (PY) of non-vertebral fractures was 10.42 in gout and 15.01 in RA. For hip fractures, the IR/1000 PY was 4.86 in gout and 7.73 in RA. The multivariable HR associated with gout versus RA was 0.84 (95% confidence interval (CI) 0.80-0.88) for non-vertebral fractures and 0.76 (95% CI 0.71-0.82) for hip fractures. Stratified analyses by age, sex, prior fractures, steroid use, and TNF inhibitor use showed similar results. CONCLUSIONS: In this large cohort of older patients, gout was associated with a modestly decreased risk of non-vertebral or hip fractures versus RA. However, non-vertebral fractures occurred frequently in both gout and RA.