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Three novel sesquiterpenoid heterodimers, designated as auckcostusolides A–C (1 – 3), were isolated from Aucklandia costus leaves. The structures of compounds 1 – 3 were elucidated through comprehensive spectroscopic analysis, with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism (ECD) calculations. Notably, compounds 1 and 2 , despite sharing identical planar structures derived from two identical sesquiterpenoids, exhibited opposite configurations at C-11 and C-8′. This configurational difference can be attributed to distinct Diels−Alder cycloaddition processes between the sesquiterpenoid monomers. Additionally, the cytotoxic effects of compounds 1 – 3 were evaluated against colorectal cancer HCT116 cells, fibrosarcoma HT1080 cells, and hepatocellular carcinoma HepG2 cells. Compounds 1 – 3 induced cell death was characterized by endoplasmic reticulum (ER) swelling and cytoplasmic vacuolization, typical morphological changes associated with paraptosis. Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of reactive oxygen species (ROS), activation of ER stress, and stimulation of the MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). Methods: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time‐series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. Results: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post‐rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre‐period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre‐period and 2090 visits occurred in the post‐period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. Conclusions: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre‐rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine‐involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts. [ABSTRACT FROM AUTHOR]

Objectives Automated phenotyping algorithms can reduce development time and operator dependence compared to manually developed algorithms. One such approach, PheNorm, has performed well for identifying chronic health conditions, but its performance for acute conditions is largely unknown. Herein, we implement and evaluate PheNorm applied to symptomatic COVID-19 disease to investigate its potential feasibility for rapid phenotyping of acute health conditions. Materials and methods PheNorm is a general-purpose automated approach to creating computable phenotype algorithms based on natural language processing, machine learning, and (low cost) silver-standard training labels. We applied PheNorm to cohorts of potential COVID-19 patients from 2 institutions and used gold-standard manual chart review data to investigate the impact on performance of alternative feature engineering options and implementing externally trained models without local retraining. Results Models at each institution achieved AUC, sensitivity, and positive predictive value of 0.853, 0.879, 0.851 and 0.804, 0.976, and 0.885, respectively, at quantiles of model-predicted risk that maximize F1. We report performance metrics for all combinations of silver labels, feature engineering options, and models trained internally versus externally. Discussion Phenotyping algorithms developed using PheNorm performed well at both institutions. Performance varied with different silver-standard labels and feature engineering options. Models developed locally at one site also worked well when implemented externally at the other site. Conclusion PheNorm models successfully identified an acute health condition, symptomatic COVID-19. The simplicity of the PheNorm approach allows it to be applied at multiple study sites with substantially reduced overhead compared to traditional approaches. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is there a difference in risk of severe hypocalcemia among female dialysis-dependent Medicare patients treated for osteoporosis with denosumab vs oral bisphosphonates? Findings: In this cohort study of 1523 dialysis-dependent patients initiating denosumab and 1281 initiating oral bisphosphonates, the weighted cumulative incidence of severe hypocalcemia (ie, <7.5 mg/dL [1.88 mmol/L] or emergent care) at 12 weeks was 41.1% with denosumab, 60 mg, vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]). Meaning: Treatment of older female dialysis-dependent patients with denosumab was associated with a statistically and clinically significant increased risk of severe hypocalcemia compared with oral bisphosphonates. Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease–mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate–treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring. This cohort study assesses the incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older receiving denosumab compared with oral bisphosphonates. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of increased federal restrictions on hydrocodone combination product (HCP) utilization, misuse, abuse, and overdose death. Methods: We assessed utilization, misuse, abuse, and overdose death trends involving hydrocodone versus select opioid analgesics (OAs) and heroin using descriptive and interrupted time‐series (ITS) analyses during the nine quarters before and after the October 2014 rescheduling of HCPs from a less restrictive (CIII) to more restrictive (CII) category. Results: Hydrocodone dispensing declined >30% over the study period, and declines accelerated after rescheduling. ITS analyses showed that immediately postrescheduling, quarterly hydrocodone dispensing decreased by 177M dosage units while codeine, oxycodone, and morphine dispensing increased by 49M, 62M, and 4M dosage units, respectively. Postrescheduling, hydrocodone‐involved misuse/abuse poison center (PC) case rates had a statistically significant immediate drop but a deceleration of preperiod declines. There were small level increases in codeine‐involved PC misuse/abuse and overdose death rates immediately after HCP's rescheduling, but these were smaller than level decreases in rates for hydrocodone. Heroin‐involved PC case rates and overdose death rates increased across the study period, with exponential increases in PC case rates beginning 2015. Conclusions: HCP rescheduling was associated with accelerated declines in hydrocodone dispensing, only partially offset by smaller increases in codeine, oxycodone, and morphine dispensing. The net impact on hydrocodone and other OA‐involved misuse/abuse and fatal overdose was unclear. We did not detect an immediate impact on heroin abuse or overdose death rates; however, the dynamic nature of the crisis and data limitations present challenges to causal inference. [ABSTRACT FROM AUTHOR]

The popularity of green building and BIM technology has increased globally, with strong government support in China. However, the integration of green requirements into interior decoration poses practical difficulties. Despite the few studies on the combination of green evaluation and BIM in building decoration, current methods largely rely on expert scores after completion. This research proposes a green evaluation index system for building interior decoration, examining the inter-index relationships and contribute to the final green degree of the project. Additionally, a green evaluation method based on BIM technology and the Bayesian network is explored, aimed at evaluating the green degree of design schemes, providing feedback, and supporting the realization of green interior decoration. With a focus on green evaluation, the current methods that rely solely on expert scores after completion will be improved. The results will provide technical support for the realization of green decoration and offer a reference for the improvement of green evaluation methods in the future. [ABSTRACT FROM AUTHOR]

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015–2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events. [ABSTRACT FROM AUTHOR]

Purpose: It is a priority of the US Food and Drug Administration (FDA) to monitor the safety of medications used during pregnancy. Pregnancy exposure registries and cohort studies utilizing electronic health record data are primary sources of information but are limited by small sample sizes and limited outcome assessment. TreeScan™, a statistical data mining tool, can be applied within the FDA Sentinel System to simultaneously identify multiple potential adverse neonatal and infant outcomes after maternal medication exposure. Methods: We implemented TreeScan using the Sentinel analytic tools in a cohort of linked live birth deliveries and infants nested in the IBM MarketScan® Research Database. As a case study, we compared first trimester fluoroquinolone use and cephalosporin use. We used the Bernoulli and Poisson TreeScan statistics with compatible propensity score‐based study designs for confounding control (matching and stratification) and used multiple propensity score models with various strategies for confounding control to inform best practices. We developed a hierarchical outcome tree including major congenital malformations and outcomes of gestational length and birth weight. Results: A total of 1791 fluoroquinolone‐exposed and 8739 cephalosporin‐exposed mother‐infant pairs were eligible for analysis. Both TreeScan analysis methods resulted in single alerts that were deemed to be due to uncontrolled confounding or otherwise not warranting follow‐up. Conclusions: In this implementation of TreeScan using Sentinel analytic tools, we did not observe any new safety signals for fluoroquinolone use in the first trimester. TreeScan, with tailored or high‐dimensional propensity scores for confounding control, is a valuable tool in addition to current safety surveillance methods for medications used during pregnancy. [ABSTRACT FROM AUTHOR]

Safety code compliance checking before construction is a key step in risk control. However, the conventional safety compliance checking methods are static model-oriented, which can lead to both the low adaptability of the model to the dynamic construction process, and low checking efficiency. This paper develops a dynamic safety checking method based on BIM and topology for enhancing construction safety management, by incorporating actual construction processes. Firstly, based on the four stages of automatic safety checking, a comprehensive dynamic safety checking framework is proposed. Secondly, the object attributes and spatial location in the BIM model are extracted to form a dynamic topological relationship database. Following this, the dynamic safety checking method is designed, and the checking results are intuitively reported to users based on BIM software. An actual construction scenery is taken as an example to verify the feasibility of the method in the final stage. The results showed that the dynamic safety checking method, based on topology and rules, can help to accurately identify safety risks in the pre-construction stage and reduce the safety risks due to poor design considerations or construction process modification. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) is an enzyme that catalyzes acetylcholine into choline and acetic acid. Conventional pesticides, including organophosphates and carbamates target and inhibit the activity of AChE. To obtain more pesticide precursors that meet the safety requirements, more than 200 compounds were screened. Tirotundin and parthenolide identified as potential neurotoxins to nematodes were isolated from Tithonia diversifolia and Chrysanthemum parthenium, respectively. Their IC50 values were 6.89 ± 0.30 and 5.51 ± 0.23 μg/mL, respectively against the AChE isolated from Caenorhabditis elegans. AChE was inhibited in a dose-dependent manner using the two compounds. And the Lineweaver-Burk and Dixon plots indicated that tirotundin and parthenolide were reversible inhibitors against AChE, both inhibiting AChE in a mixed-type competitive manner and demonstrating these compounds may possess dual binding site AChE inhibitors. LC50 values of tirotundin and parthenolide against C. elegans were 9.16 ± 0.21 and 7.23 ± 0.48 μg/mL, respectively. These results provide a certain theoretical basis for the development and utilization of novel pesticides. [ABSTRACT FROM AUTHOR]

Warfarin was selected as a case study to examine confounding when comparing a product across different manufacturers because it is a narrow therapeutic index drug with prevalent beliefs for brand‐name superiority. Medicare beneficiaries aged ≥65 years with atrial fibrillation and an incident outpatient warfarin prescription from July 2006 through July 2015 were included in the study population (N = 746,098). Substantial imbalances were observed between brand‐name warfarin and generics for (i) clinical comorbidity, (ii) socioeconomic status, (iii) prescriber specialty, (iv) recent ambulatory and emergent care, (v) drug adherence, (vi) pharmacy setting (e.g., retail, mail‐order), and (vii) risk scores for bleeding and thrombosis. Patients receiving brand‐name warfarin were healthier than patients receiving generic manufactured warfarin. Utilization of generic warfarin products also differed by geographic region and pharmacy setting. Manufacturer‐level comparative‐safety studies for causal inference should carefully consider the presence of these imbalances and their potential for introducing healthy user bias. [ABSTRACT FROM AUTHOR]

Purpose The purpose of the study is to describe and compare the number and characteristics of opioid‐involved fatal cases captured in the National Poison Data System (NPDS) and in US death certificates. Methods: NPDS, which collects data on all calls to US poison control centers, and Drug‐Involved Mortality (DIM), which combines information from literal text of US death certificates and National Vital Statistics Systems, were queried for opioid‐involved fatal cases from 2010 to 2015. Characteristics of the two case series were compared. Results: DIM contained 154 016 opioid‐involved overdose deaths, and NPDS contained 2524 fatal opioid exposures, a ratio of 61:1. The number of opioid deaths remained stable in NPDS but increased in DIM over the 6‐year period. On average, deaths involving opioids with higher mean dosage strength (in morphine milligram equivalents) per unit among dispensed prescriptions were more likely to be captured in DIM relative to NPDS, as compared with those with a lower mean dosage strength per unit. The increase in fentanyl‐related deaths seen in DIM since 2013 was not observed in NPDS. Conclusions: NPDS is a valuable drug safety surveillance resource due to its timeliness and drug specificity. However, it captures only a small fraction of opioid‐involved fatal poisonings, and comparisons with data derived from death certificate literal text indicate that caution is warranted in making inferences about opioid‐involved fatality trends over time or comparisons across opioids. [ABSTRACT FROM AUTHOR]

In meta-analysis of clinical trials, standard statistical methods run into problems when the proportions of safety events are small. Motivated by the dataset used in a published analysis of cardiovascular safety in Rosiglitazone trials, this article proposes using a zero-inflated binomial model to handle the zero-event trials. The maximum likelihood estimates of the model parameters are obtained using the expectation and maximization algorithm. Via simulation studies, it is shown that the proposed methods provide estimates of odds ratios with less bias and variation, compared with both the Mantel–Hanszel method with continuity correction and Peto's method. The proposed methods are applied to the Rosiglitazone trials. for this article are available online. [ABSTRACT FROM AUTHOR]

A likelihood ratio test, recently developed for the detection of signals of adverse events for a drug of interest in the FDA Adverse Events Reporting System database, is extended to detect signals of adverse events simultaneously for all the drugs in a drug class. The extended likelihood ratio test methods, based on Poisson model (Ext-LRT) and zero-inflated Poisson model (Ext-ZIP-LRT), are discussed and are analytically shown, like the likelihood ratio test method, to control the type-I error and false discovery rate. Simulation studies are performed to evaluate the performance characteristics of Ext-LRT and Ext-ZIP-LRT. The proposed methods are applied to the Gadolinium drug class in FAERS database. An in-house likelihood ratio test tool, incorporating the Ext-LRT methodology, is being developed in the Food and Drug Administration. [ABSTRACT FROM AUTHOR]

• Trigonochinene E (TE) promotes lysosomal biogenesis and autophagy via TFEB/TFE3. • TE activates TFEB/TFE3 in a mTOR/PKC/ROS-independent manner. • ER stress mediates TE-induced TFEB/TFE3 activation. • Autophagy triggered by TE protects degenerative NP cells from oxidative stress. Macroautophagy (henceforth autophagy) is the major form of autophagy, which delivers intracellular cargo to lysosomes for degradation. Considerable research has revealed that the impairment of lysosomal biogenesis and autophagic flux exacerbates the development of autophagy-related diseases. Therefore, reparative medicines restoring lysosomal biogenesis and autophagic flux in cells may have therapeutic potential against the increasing prevalence of these diseases. The aim of the present study was thus to explore the effect of trigonochinene E (TE), an aromatic tetranorditerpene isolated from Trigonostemon flavidus , on lysosomal biogenesis and autophagy and to elucidate the potential underlying mechanism. Four human cell lines, HepG2, nucleus pulposus (NP), HeLa and HEK293 cells were applied in this study. The cytotoxicity of TE was evaluated by MTT assay. Lysosomal biogenesis and autophagic flux induced by 40 μM TE were analyzed using gene transfer techniques, western blotting, real-time PCR and confocal microscopy. Immunofluorescence, immunoblotting and pharmacological inhibitors/activators were applied to determine the changes in the protein expression levels in mTOR, PKC, PERK, and IRE1α signaling pathways. Our results showed that TE promotes lysosomal biogenesis and autophagic flux by activating the transcription factors of lysosomes, transcription factor EB (TFEB) and transcription factor E3 (TFE3). Mechanistically, TE induces TFEB and TFE3 nuclear translocation through an mTOR/PKC/ROS-independent and endoplasmic reticulum (ER) stress-mediated pathway. The PERK and IRE1α branches of ER stress are crucial for TE-induced autophagy and lysosomal biogenesis. Whereas TE activated PERK, which mediated calcineurin dephosphorylation of TFEB/TFE3, IRE1α was activated and led to inactivation of STAT3, which further enhanced autophagy and lysosomal biogenesis. Functionally, knockdown of TFEB or TFE3 impairs TE-induced lysosomal biogenesis and autophagic flux. Furthermore, TE-induced autophagy protects NP cells from oxidative stress to ameliorate intervertebral disc degeneration (IVDD). Here, our study showed that TE can induce TFEB/TFE3-dependent lysosomal biogenesis and autophagy via the PERK-calcineurin axis and IRE1α-STAT3 axis. Unlike other agents regulating lysosomal biogenesis and autophagy, TE showed limited cytotoxicity, thereby providing a new direction for therapeutic opportunities to use TE to treat diseases with impaired autophagy-lysosomal pathways, including IVDD. [Display omitted] [ABSTRACT FROM AUTHOR]

Benefit-risk assessment is critical in evaluating the effectiveness of a new drug before and after the approval. Some benefit-risk measures depend on the probabilities of benefit-risk categories in which the subject-level benefit and risk outcomes are characterized. The existing benefit-risk methods for analyzing the categorical data depend only on the frequencies of mutually exclusive and collectively exhaustive categories that the subjects fall in, and thus ignore the subject-level differences. We propose a Bayesian method for analyzing the subject-level data with multiple visits. A generalized linear model is used to model the subject-level response probability, with respect to a “reference” category, assuming a logit model with subject-level category effects and multiple visit effects. The random longitudinal visit effects are modeled by a multivariate normal distribution with zero means and first-order autoregressive structured variance-covariance matrices. In the proposed Bayesian setup, a Dirichlet process is used as a prior for the subject-level category effect to catch the similarity among the subject responses. We develop an efficient Markov chain Monte Carlo algorithm for implementing the proposed method, and illustrate the estimation of individual benefit-risk profiles through simulation. The performance of the proposed model fit is evaluated using two model selection approaches, namely, the deviance information criterion (DIC) and the log-pseudo marginal likelihood (LPML). We analyze a clinical trial data using the proposed method to assess the subject-level or personalized benefit-risk in each arm, and to evaluate the aggregated benefit-risk difference between the treatments at different visits. [ABSTRACT FROM AUTHOR]

Objectives: Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications.Methods: We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRD(TM)) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest.Results: A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohn's disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies.Conclusions: Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed. [ABSTRACT FROM AUTHOR]

An important aspect of the drug evaluation process is to have an integrated benefit-risk assessment to determine, using some quantitative measures, whether the benefit outweighs the risk for the target population. Chuang-Stein et al. proposed a five-category random variable along with three global measures of benefit-risk assessment. Assuming the cell probabilities follow a multinomial distribution, we propose a Bayesian approach for the longitudinal assessment of benefit-risk using these three global measures and a new measure. A Dirichlet distribution is used as the natural conjugate prior for multinomial cell probabilities, and the posterior distributions of cell-probabilities are recursively derived as the data from multiple visits become available. In a more generalized approach, a power prior is used through the likelihood function to discount the information from previous visits, and, again, the posterior distributions of the cell-probabilities at multiple visits are derived. The estimates of the posterior means and credible intervals for the four global measures are derived, and the decision rules based on the credible intervals are applied for the assessment of the four global measures. Using two simulated datasets generated under two different scenarios—one where benefit outweighs risk and the other where benefit does not outweigh risk—the performances of the four measures are evaluated using a Markov chain Monte Carlo (MCMC) technique. We illustrate of the methodology using clinical trial data. [ABSTRACT FROM PUBLISHER]

Three new limonoids, walsurauias A-C (1–3), along with four known ones, were isolated from the leaves and twigs of Walsura yunnanensis C. Y. Wu. Their structures were determined on the basis of comprehensive spectroscopic data analysis. The new limonoids were screened for their cytotoxic activity (IC 50 0.81–5.73 μM) against four human cancer cell lines, including A549, HepG2, HCT116 p21KO and CNE-2. And α , β -unsaturated ketone moieties in rings A and B are essential for their cytotoxic activity. Selected compounds were further investigated. Compounds 1–3 effectively induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner in cancer cells. In addition, compounds 1–3 inhibited the colony formation and compounds 2 and 3 suppressed the migration of cancer cells. [Display omitted] • Three new limonoids walsurauias A-C with potent cytotoxicity against cancer cells were isolated from Walsura yunnanensis. • α , β -Unsaturated ketone moieties in ring A and B are essential for the cytotoxicity. • Walsurauias A-C effectively induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner in cancer cells. • Walsurauias A-C inhibited the colony formation and suppressed the migration of cancer cells. [ABSTRACT FROM AUTHOR]

Entropy indices, such as Shannon entropy and Gini-Simpson index, have been used for analysing biological diversities. However, these entropy indices are based on abundance of the species only and they do not take differences between the species into consideration. Rao's quadratic entropy has found many applications in different fields including ecology. Further, the quadratic entropy (QE) index is the only ecological diversity index that reflects both the differences and abundances of the species. The problem of testing of hypothesis of the equality of QEs is formulated as a problem of comparing practical equivalence intervals. Simulation experiments are used to compare various equivalence intervals. Previously analyzed dinosaur data are used to illustrate the methods for determining biodiversity. [ABSTRACT FROM PUBLISHER]

Objectives: To examine the effect of polycystic ovary syndrome (PCOS), a marker of the metabolic syndrome, on selected indicators of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment success. Methods: A retrospective cohort study was conducted using existing data on 69 IVF/ICSI treatment cycles undergone by PCOS women and a caliper-matched sample of 69 IVF/ICSI treatment cycles undergone by non-PCOS women over a 7-year period at a major fertility treatment center. Matching criteria were age and date at IVF/ICSI treatment initiation. Process and outcome measures were used to define successful IVF/ICSI treatment. Statistical significance was determined at an alpha level of 0.05. Results: The total number of oocytes and the number of immature oocytes retrieved in the process of an IVF/ICSI cycle were significantly higher in the context of PCOS. No significant differences were observed among PCOS and non-PCOS groups on various IVF/ICSI cycle outcomes, including high-grade embryo, pregnancy achievement, miscarriage, and live birth status. Conclusions: Although IVF/ICSI yields more oocytes in the context of PCOS, IVF/ICSI outcomes do not differ significantly by PCOS status. Prospective cohort studies are needed to examine short-term and long-term health effects of PCOS in the context of IVF/ICSI. [ABSTRACT FROM AUTHOR]

Abstract: Background: Endometrial spotting and/or bleeding (ESB) occurs in levonorgestrel subcutaneous implant (LNG SI) users. Matrix metalloproteinases (MMPs) may play a role in ESB. Study Design: Women between 18 and 40 years with regular menstrual cycles had a baseline evaluation followed by LNG SI insertion and randomization to doxycycline (DOX; 20 mg) or placebo (PL) twice a day. MMP-2, MMP-9 and tissue inhibitor of MMP-1 (TIMP-1) in serum and the endometrium were estimated at baseline and at 1, 3 and 6 months after insertion. Results: LNG increased serum MMP-9, while DOX decreased MMP-9 levels compared to PL after 1 month (p<.05). DOX decreased endometrial MMP-9 at 1 and 6 months compared to baseline and PL (p<.05). DOX increased endometrial TIMP-1 at 6 months compared with baseline and PL (p<.05). MMP-2 levels were unchanged. Conclusion: LNG SI increased serum MMP-9 and TIMP-1 levels, while DOX decreased both serum and endometrial MMP-9 levels. [Copyright &y& Elsevier]

The objective of this retrospective cross-sectional study was to evaluate the value of basal serum anti-Müllerian hormone (AMH) levels as a predictor of ovarian response and pregnancy outcome in a donor egg program. The study showed that AMH was superior to other biomarkers of ovarian reserve in predicting low and high response in young women selected as oocyte donors, but that it was not predictive of embryo morphology or pregnancy outcome in the recipient population. [Copyright &y& Elsevier]

Background: There is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD)., Objective: To assess the risk for emergently treated hypocalcemia with denosumab by stage of CKD and presence of CKD-mineral and bone disorder (CKD-MBD)., Design: Target trial emulation., Setting: Medicare fee-for-service data with prescription drug coverage, 2012 to 2020., Participants: Female patients aged 65 years or older initiating denosumab, oral bisphosphonates, or intravenous (IV) bisphosphonates for osteoporosis., Measurements: Hospital and emergency department admissions (that is, emergent care) for hypocalcemia were assessed in the first 12 treatment weeks. Inverse probability of treatment weighted cumulative incidence and weighted risk differences (RDs) were calculated., Results: A total of 361 453 patients treated with denosumab, 829 044 treated with oral bisphosphonates, and 160 413 treated with IV bisphosphonates were identified. Risk for emergently treated hypocalcemia with denosumab versus oral bisphosphonates increased with worsening CKD stage ( P  < 0.001), with greatest risk among dialysis-dependent (DD) patients (3.01% vs. 0.00%; RD, 3.01% [95% CI, 2.27% to 3.77%]) and non-dialysis-dependent (NDD) patients with CKD stages 4 and 5 (0.57% vs. 0.03%; RD, 0.54% [CI, 0.41% to 0.68%]). Among patients with stages 4 and 5 CKD (NDD + DD), denosumab had a greater risk for emergently treated hypocalcemia versus oral bisphosphonates in those with CKD-MBD (1.53% vs. 0.02%; RD, 1.51% [CI, 1.21% to 1.78%]) than in those without CKD-MBD (0.22% vs. 0.03%; RD, 0.19% [CI, 0.08% to 0.31%]). Denosumab also showed increased risk compared with IV bisphosphonates., Limitation: Generalizability to men and non-Medicare populations., Conclusion: Risk for emergently treated hypocalcemia with denosumab increased with worsening CKD stage and was highest in DD patients and those with CKD-MBD., Primary Funding Source: U.S. Food and Drug Administration., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0013.

There is a dearth of safety data on maternal outcomes after perinatal medication exposure. Data-mining for unexpected adverse event occurrence in existing datasets is a potentially useful approach. One method, the Poisson tree-based scan statistic (TBSS), assumes that the expected outcome counts, based on incidence of outcomes in the control group, are estimated without error. This assumption may be difficult to satisfy with a small control group. Our simulation study evaluated the effect of imprecise incidence proportions from the control group on TBSS' ability to identify maternal outcomes in pregnancy research. We simulated base case analyses with "true" expected incidence proportions and compared these to imprecise incidence proportions derived from sparse control samples. We varied parameters impacting Type I error and statistical power (exposure group size, outcome's incidence proportion, and effect size). We found that imprecise incidence proportions generated by a small control group resulted in inaccurate alerting, inflation of Type I error, and removal of very rare outcomes for TBSS analysis due to "zero" background counts. Ideally, the control size should be at least several times larger than the exposure size to limit the number of false positive alerts and retain statistical power for true alerts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses., Methods and Analysis: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids., Ethics and Dissemination: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public., Trial Registration Number: NCT04509115., Competing Interests: Competing interests: In the past three years, Dr. Jeffery has received unrelated grant funding from the Agency for Healthcare Research and Quality, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the American Cancer Society and the US Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938). Dr. Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International; in addition, Dr. Ross is an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Ms. Ritchie currently receives research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), and from the US Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938). Ms. Emanuel received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST) and from the US Food and Drug Administration for the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation (CERSI) (U01FD005938). Dr. Gilbert currently receives research support from the National Institutes of Health (U19DE028717). Dr. Bellolio received funding from the National Center for Complementary and Integrative Health, the National Institute on Aging, and Diagnostic Robotics. Dr. Heckmann reported receiving salary support from CMS to develop, implement, and maintain hospital performance outcome measures that are publicly reported, in addition to receiving research support through Yale as part of a Centers for Disease Control and Prevention project designed to strengthen prescription drug overdose prevention efforts, from Connecticut Department of Public Health as part of a public health project designed to assess the impact of Good Samaritan Laws, and from the Community Health Network of Connecticut for her work as a medical consultant. Dr Lipkind serves on the Pfizer independent external data monitoring committee for the COVID-19 vaccine. Since leaving the Yale-New Haven Center for Outcomes Research and Evaluation, Ms. Ciaccio has been employed part-time at Hugo Health., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia , inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Study Objectives: Early high school start times may contribute to insufficient sleep leading to increased teen crash rate. Virginia Beach (VB) and Chesapeake are adjacent, demographically similar cities. VB high schools start 75-80 minutes earlier than Chesapeake's. We hypothesized that VB teens would manifest a higher crash rate than Chesapeake teens., Methods: The Virginia Department of Motor Vehicles (DMV) provided de-identified, aggregate 2008 and 2007 data for weekday crashes and crash times in VB and Chesapeake for drivers aged 16-18 years ("teens"), and provided 2008 and 2007 crash data for all drivers. Data allowed comparisons of VB versus Chesapeake crash rates for teens (overall and hour-by-hour), and teens versus all other ages. We compared AM and PM traffic congestion (peak hours) in the two cities., Results: In 2008, there were 12,916 and 8,459 Virginia Beach and Chesapeake 16- to 18-year-old drivers, respectively. For VB and Chesapeake, teen drivers' crash rates in 2008 were 65.8/1000 and 46.6/1000 (p < 0.001), respectively, and in 2007 were 71.2/1000 and 55.6/1000. Teen drivers' crash peaks in the morning occurred one hour earlier in VB than Chesapeake, consistent with school commute time. Congestion data for VB and Chesapeake did not explain the different crash rates., Conclusions: A significantly increased teen crash rate for both 2008 and 2007 occurred in VB, the city with earlier high school start times. Future studies using individual level data may clarify if sleep restriction, circadian dyssynchrony, and sleep inertia might contribute to this increased crash rate.