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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]

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]

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]

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]

We used social media data from "covid19positive" subreddit, from 03/2020 to 03/2022 to identify COVID-19 cases and extract their reported symptoms automatically using natural language processing (NLP). We trained a Bidirectional Encoder Representations from Transformers classification model with chunking to identify COVID-19 cases; also, we developed a novel QuadArm model, which incorporates Question-answering, dual-corpus expansion, Adaptive rotation clustering, and mapping, to extract symptoms. Our classification model achieved a 91.2% accuracy for the early period (03/2020-05/2020) and was applied to the Delta (07/2021–09/2021) and Omicron (12/2021–03/2022) periods for case identification. We identified 310, 8794, and 12,094 COVID-positive authors in the three periods, respectively. The top five common symptoms extracted in the early period were coughing (57%), fever (55%), loss of sense of smell (41%), headache (40%), and sore throat (40%). During the Delta period, these symptoms remained as the top five symptoms with percent authors reporting symptoms reduced to half or fewer than the early period. During the Omicron period, loss of sense of smell was reported less while sore throat was reported more. Our study demonstrated that NLP can be used to identify COVID-19 cases accurately and extracted symptoms efficiently. [ABSTRACT FROM AUTHOR]

We used social media data from "covid19positive" subreddit, from 03/2020 to 03/2022 to identify COVID-19 cases and extract their reported symptoms automatically using natural language processing (NLP). We trained a Bidirectional Encoder Representations from Transformers classification model with chunking to identify COVID-19 cases; also, we developed a novel QuadArm model, which incorporates Question-answering, dual-corpus expansion, Adaptive rotation clustering, and mapping, to extract symptoms. Our classification model achieved a 91.2% accuracy for the early period (03/2020-05/2020) and was applied to the Delta (07/2021–09/2021) and Omicron (12/2021–03/2022) periods for case identification. We identified 310, 8794, and 12,094 COVID-positive authors in the three periods, respectively. The top five common symptoms extracted in the early period were coughing (57%), fever (55%), loss of sense of smell (41%), headache (40%), and sore throat (40%). During the Delta period, these symptoms remained as the top five symptoms with percent authors reporting symptoms reduced to half or fewer than the early period. During the Omicron period, loss of sense of smell was reported less while sore throat was reported more. Our study demonstrated that NLP can be used to identify COVID-19 cases accurately and extracted symptoms efficiently. [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]

Data on angioedema risk among sacubitril-valsartan (SV) users in real-world settings are limited. We sought to evaluate the risk of angioedema among SV new users compared with angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor-blocker (ARB) new users separately. We conducted a propensity score–matched cohort study, comparing SV new users (no use of SV, ACE inhibitor, ARB 6 months before) and SV new users with prior use (within 183 or 14 days) of ACE inhibitor or ARB (ACE inhibitor–SV and ARB-SV users; recent ACE inhibitor–SV and recent ARB-SV users, respectively) vs ACE inhibitor and ARB new users separately. Compared with ACE inhibitor, SV new (HR: 0.18; 95% CI: 0.11-0.29) and ACE inhibitor–SV users (HR: 0.31; 95% CI: 0.23-0.43) showed lower risk of angioedema. On the other hand, there was no difference in angioedema risk when SV new users (HR: 0.59; 95% CI: 0.35-1.01) or ARB-SV users (HR: 0.85; 95% CI: 0.58-1.26) were compared with ARB new users. Compared with SV new users, ACE inhibitor–SV users (HR: 1.62; 95% CI: 0.91-2.89) trended toward higher angioedema risk, which intensified when the ACE inhibitor to SV switch occurred within 14 days (recent ACE inhibitor–SV) (HR: 1.98; 95% CI: 1.11-3.53). Similarly, ARB-SV users (HR: 2.03; 95% CI: 1.16-3.54) experienced an increased risk compared with SV new users, which intensified for the more recent switchers (recent ARB-SV) (HR: 2.45; 95% CI: 1.36-4.43). We did not observe an increased risk of angioedema among SV new users compared with ACE inhibitor or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACE inhibitor or ARB compared with SV new users. [Display omitted] [ABSTRACT FROM AUTHOR]

Importance: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older.Objective: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older.Design, Setting, and Participants: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older.Exposure: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older.Main Outcome(S) and Measure(S): Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older.Results: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older.Conclusions and Relevance: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S. Medicare beneficiaries with chronic obstructive pulmonary disease.Case-crossover study conducted among U.S. Fee-for-Service Medicare beneficiaries with chronic obstructive pulmonary disease hospitalized with ARF, from January 1, 2007, through December 31, 2019.Oral antipsychotics.Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for ARF requiring invasive mechanical ventilation associated with the use of antipsychotics in the case period (days -14 to -1) compared to the control period (days -75 to -88).We identified 145,018 cases (mean age 69.4 years, 57.2% female). Of these, 2,003 had antipsychotic use only during the case period and 1,728 only during the control period. The aOR of ARF within 14 days after antipsychotic use was 1.13 (95% CI, 1.06, 1.20). The risk increased with increasing age, being statistically significant in patients ages 75–84 years (aOR: 1.37 [95% CI, 1.17, 1.60]) and 85 + years (aOR: 1.50 [95% CI, 1.20, 1.89]), but not in beneficiaries under 75 years of age (aOR 18–49 years: 1.01 [95% CI, 0.85, 1.20]; 50–64 years: 1.03 [95% CI, 0.92, 1.15]; 65–74 years: 1.12 [95% CI, 0.98, 1.27]).Recent antipsychotic use by Medicare beneficiaries with chronic obstructive pulmonary disease was associated with an increased risk of ARF in those aged 75 years and older. [ABSTRACT FROM AUTHOR]

We sought to determine if maternal body mass index (BMI; kg/m2) identifies newborns with abnormal fetal growth (small for gestational age [SGA], large for gestational age [LGA], or macrosomia) at ≥37 weeks. Singletons with reliable gestational age and without diabetes or hypertension were analyzed. Areas under the receiver-operating characteristic (AUC) curves were calculated for BMI (first visit, delivery, and the change during pregnancy) to identify abnormal growth. If the AUC was ≤0.75 then the diagnostic test was not useful. Among 3582 cohorts, SGA occurred in 10%, LGA in 9%, and 11% were macrosomic. AUC indicates that BMI at delivery is significantly better than BMI at first visit for identification of aberrant growth, but their AUCs were less than 0.75, indicating it is not a useful diagnostic test. Maternal BMIs (at first visit, delivery, or the change during pregnancy) are poor predictors of abnormal fetal growth. [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]

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]

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]

Background: There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. Objective: To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. Design: Observational case-control study. Participants: Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. Main Measures: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. Results: A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5–12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92–0.98; OR for ARBs 0.94, 95% CI 0.90–0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04–1.14), ARBs (OR 1.10, 95% CI 1.05–1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03–1.19). Conclusions: ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding. [ABSTRACT FROM AUTHOR]

Introduction: Nearly 90% of drugs dispensed in the US are generic products.Objective: The aim of this study was to develop and implement a tool for analyzing manufacturer-level drug utilization and switching patterns within the US Food and Drug Administration's Sentinel system.Methods: A descriptive tool was designed to analyze data in the Sentinel common data model and was tested with two case studies-metoprolol extended release (ER) and lamotrigine ER-using claims data from four Sentinel data partners. We plotted initiators of each brand and generic product over time. For metoprolol ER, we evaluated rates of switching from generics around the time of manufacturing issues. For lamotrigine ER, we examined rates of switching back to the brand among those who switched from brand to generic.Results: We identified 1,651,285 initiators of metoprolol ER products between July 2008 and September 2015. We observed a large decrease in monthly metoprolol ER initiators (from 25,465 in December 2008 to 13,128 in February 2009), corresponding to recalls by generic manufacturers. We observed simultaneous increases in utilization of the authorized generic and brand products. We identified 4266 initiators of lamotrigine ER with an epilepsy diagnosis between January 2012 and September 2015. Among those who switched from brand to generic, the cumulative incidence of switching back was close to 20% at 2 years. Switchback rates were higher for the first available generic products.Conclusions: This developed tool was able to elucidate novel utilization and switching patterns in two case studies. Such information can be used to support surveillance of generic drugs and biosimilars. [ABSTRACT FROM AUTHOR]

Alpha-1 adrenergic receptor antagonists prevent cytokine storm in mouse sepsis models. This led to the hypothesis that alpha-1 blockers may prevent severe coronavirus disease 2019 (COVID-19), which is characterized by hypercytokinemia and progressive respiratory failure. We performed an observational case-control study in male Medicare beneficiaries aged 65 years or older, with or without benign prostatic hyperplasia (BPH), and treated with alpha-1 receptor blockers or 5-alpha reductase inhibitors. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated for outcomes of uncomplicated and severe COVID-19 hospitalization (intensive care unit admission, invasive mechanical ventilation, or death). There were 20,963 cases of hospitalized COVID-19 matched to 101,161 controls on calendar date and neighborhood of residence. In the primary analysis (males with BPH), there was no difference in risk of uncomplicated COVID-19 hospitalization (aOR 1.08, 95% CI 0.996-1.17) or hospitalization with severe complications (aOR 0.97, 95% CI 0.88-1.08). In the secondary analysis (males with or without BPH), the corresponding aORs were 1.02 (95% CI, 0.96-1.09) (uncomplicated) and 0.99 (95% CI, 0.91-1.07) (complicated), respectively. Subgroup and sensitivity analyses yielded similar results. Of note, there was no difference in risk of severe COVID-19 hospitalization when comparing non-selective vs selective alpha-1 blocker use (aOR 0.98, 95% CI 0.86-1.10), higher- vs lower-dose alpha-1 blocker use (aOR 0.96, 95% CI 0.86-1.08), or current vs remote alpha-1 blocker use (aOR 1.04, 95% CI 0.91-1.18). Prevalent use of alpha-1 receptor blockers was not associated with a protective or harmful effect on risk of uncomplicated or severe hospitalized COVID-19. [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]

The purpose of this study was to examine the effects of polycystic ovary syndrome (PCOS) and body mass index (BMI) on selected indicators of IVF or intracytoplasmic sperm injection (ICSI) treatment success. A retrospective cohort study was conducted using existing data on 69 IVF/ICSI treatment cycles undergone by PCOS women and an individually matched sample of 69 IVF/ICSI treatment cycles undergone by non-PCOS women at a major fertility treatment centre. BMI (kg/m²) was analysed as a continuous and categorical (<25, 25-29.9, ≥30) variable. Results indicated that PCOS was directly associated with the number of oocytes retrieved. Irrespective of PCOS status, continuous BMI was inversely associated with total and mature oocytes retrieved. Multiple linear regression analyses indicated no significant effects of PCOS or continuous BMI on the number of mature oocytes fertilized per mature oocyte retrieved or inseminated. Similarly, multiple logistic regression analyses suggested no significant effect of PCOS and continuous BMI on the odds of pregnancy, miscarriage or live birth. Furthermore, categorical BMI did not influence process and outcome measures of IVF/ICSI treatment success. PCOS and continuous BMI appear to have significant and distinct effects on early stages, but not on later stages, of IVF/ICSI treatment. [ABSTRACT FROM AUTHOR]

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]