Sample efficient reinforcement learning with active learning for molecular design.

Reinforcement learning (RL) is a powerful and flexible paradigm for searching for solutions in high-dimensional action spaces. However, bridging the gap between playing computer games with thousands of simulated episodes and solving real scientific problems with complex and involved environments (up to actual laboratory experiments) requires improvements in terms of sample efficiency to make the most of expensive information. The discovery of new drugs is a major commercial application of RL, motivated by the very large nature of the chemical space and the need to perform multiparameter optimization (MPO) across different properties. In silico methods, such as virtual library screening (VS) and de novo molecular generation with RL, show great promise in accelerating this search. However, incorporation of increasingly complex computational models in these workflows requires increasing sample efficiency. Here, we introduce an active learning system linked with an RL model (RL-AL) for molecular design, which aims to improve the sample-efficiency of the optimization process. We identity and characterize unique challenges combining RL and AL, investigate the interplay between the systems, and develop a novel AL approach to solve the MPO problem. Our approach greatly expedites the search for novel solutions relative to baseline-RL for simple ligand- and structure-based oracle functions, with a 5-66-fold increase in hits generated for a fixed oracle budget and a 4-64-fold reduction in computational time to find a specific number of hits. Furthermore, compounds discovered through RL-AL display substantial enrichment of a multi-parameter scoring objective, indicating superior efficacy in curating high-scoring compounds, without a reduction in output diversity. This significant acceleration improves the feasibility of oracle functions that have largely been overlooked in RL due to high computational costs, for example free energy perturbation methods, and in principle is applicable to any RL domain.

Factors Associated with Statin Discontinuation Following Metabolic and Bariatric Surgery: A Retrospective Analysis of 2012-2021 Electronic Medical Records Network Data.

BACKGROUND: Bariatric surgery has been shown to improve hyperlipidemia, decreasing the need for statin medications. Although maintaining statin therapy post-surgery for those with a history of atherosclerotic cardiovascular disease (ASCVD) is advised, it is uncertain if discontinuation risks differ between those with and without ASCVD history. AIM: The study aims to analyze the rate and reasons for statin cessation post-bariatric surgery in the US using real-world data. METHODS: Using the TriNetX electronic medical records network from 2012 to 2021, the study involved patients aged 18 or older on statins at the time of bariatric surgery. They were categorized into primary and secondary prevention groups based on prior ASCVD. Statin discontinuation was defined as a 90-day gap post the last statin dosage. The Cox model assessed factors influencing statin cessation. RESULTS: Seven hundred and thirty-three statin users undergoing bariatric surgery were identified, with 564 (77%) in primary prevention. Six months post-surgery, 48% of primary prevention patients and 34.5% of secondary ones stopped statins. Primary prevention patients had a 30% higher likelihood of cessation compared to secondary prevention (hazard ratio, 1.30; 95% CI, 1.06-1.60) as shown by multivariable analysis. CONCLUSIONS: Post-bariatric surgery, primary prevention patients are more likely to discontinue statins than secondary prevention patients.

Bayesian Optimization for Chemical Reactions.

Reaction optimization is challenging and traditionally delegated to domain experts who iteratively propose increasingly optimal experiments. Problematically, the reaction landscape is complex and often requires hundreds of experiments to reach convergence, representing an enormous resource sink. Bayesian optimization (BO) is an optimization algorithm that recommends the next experiment based on previous observations and has recently gained considerable interest in the general chemistry community. The application of BO for chemical reactions has been demonstrated to increase efficiency in optimization campaigns and can recommend favorable reaction conditions amidst many possibilities. Moreover, its ability to jointly optimize desired objectives such as yield and stereoselectivity makes it an attractive alternative or at least complementary to domain expert-guided optimization. With the democratization of BO software, the barrier of entry to applying BO for chemical reactions has drastically lowered. The intersection between the paradigms will see advancements at an ever-rapid pace. In this review, we discuss how chemical reactions can be transformed into machine-readable formats which can be learned by machine learning (ML) models. We present a foundation for BO and how it has already been applied to optimize chemical reaction outcomes. The important message we convey is that realizing the full potential of ML-augmented reaction optimization will require close collaboration between experimentalists and computational scientists.

Metabolic and Bariatric Surgery Utilization Trends in the United States: Evidence From 2012 to 2021 National Electronic Medical Records Network.

Background: Bariatric surgery has evolved over the past 2 decades yet assessing trends of bariatric surgery utilization in the growing eligible population is lacking. Aim: This study aimed to update the trends in bariatric surgery utilization, changes in types of procedures performed, and the characteristics of patients who underwent bariatric surgery in the United States, using real-world data. Method: This retrospective descriptive observational study was conducted using the TriNetX, a federated electronic medical records network from 2012 to 2021, for adult patients 18 years old or older who had bariatric surgery. Descriptive statistical analysis was conducted to assess patients' demographics and characteristics. Annual secular trend analyses were conducted for the annual rate of bariatric surgery, and the specific procedural types and proportions of laparoscopic surgeries. Results: A steady increase in the number of procedures performed in the United States over the first 6 years of the study, a plateau for the following 2 years, and then a decline in 2020 and 2021 (during the coronavirus disease 2019 pandemic). The annual rate of bariatric surgery was lowest in 2012 at 59.2 and highest in 2018 at 79.6 surgeries per 100,000 adults. During the study period, 96.2% to 98.8% of procedures performed annually were conducted laparoscopically as opposed to the open technique. Beginning in 2012, the Roux-en-Y gastric bypass (RYGB) procedure fell to represent only 17.1% of cases in 2018, along with a sharp decline in the adjustable gastric band (AGB) procedure, replaced by a sharp increase in the sleeve gastrectomy (SG) procedure to represent over 74% of cases in 2018. Conclusions: Bariatric surgery utilization in the United States showed a moderate decline in the number of RYGB procedures, which was offset by a substantial increase in the number of SG procedures and a precipitous drop in the annual number of AGB procedures.

Utilization, reimbursement, and price trends for Hepatitis C virus medications in the US Medicaid programs: 2001-2021.

Background: Hepatitis C Virus (HCV) remains a challenging health problem worldwide, with increasing incidence despite being curable with Direct Acting Antiviral (DAA) agents. Objective: This study aimed to describe the utilization, reimbursement, and price trends of HCV treatments and evaluate the influence of treatment guidelines and policies. Methods: A retrospective, descriptive drug utilization study conducted using the outpatient pharmacy data extracted from the Centers for Medicaid and Medicare Services State Drug Utilization Data between 2001 and 2021. All HCV treatments approved in the US were included, conventional therapy (CT), and DAA agents. The annual secular trends were calculated for each medication's total number of prescriptions, reimbursements, and prices. The average reimbursement per prescription was calculated and utilized as a proxy of prices. The HCV treatment guideline and policies and legislation were evaluated overtime to measure the impact on the trends. Results: Despite CT having a higher total utilization, DAA agents commanded significantly greater reimbursements, with 4.1 billion USD for CT and 19.45 billion USD for DAA agents. CT utilization increased rapidly and dominated the market until 2011, peaking at 379,696 prescriptions in 2003 but declining afterward. DAA agents' utilization increased rapidly in their first year: i.e., sofosbuvir reached 50,377 prescriptions with 1.3 billion USD in 2014, while ledipasvir/sofosbuvir reached 79,387 prescriptions with 2 billion USD in 2015. The average price per prescription was high for the DAA agents, like 24,992 USD for sofosbuvir and 22,787 USD for ledipasvir/sofosbuvir, compared to CT medications ribavirin, around 500 USD, and pegINF, around 3000 USD. The new DAA agents replaced CT, and initiating market competition among DAA agents. Conclusion: The introduction of multiple DAA agents slightly changed their prescription prices but remained high during the study period. The recent increase in HCV incidence cases indicates accessibility issues for costly and effective DAA agents, with treatment guidelines and policies playing a critical role in shaping these trends.

Reporting, handling, and interpretation of time-varying drug treatments in observational studies using routinely collected healthcare data.

BACKGROUND: Time-varying drug treatments are common in studies using routinely collected health data (RCD) for assessing treatment effects. This study aimed to examine how these studies reported, handled, and interpreted time-varying drug treatments. METHODS: A systematic search was conducted on PubMed from 2018 to 2020. Eligible studies were those used RCD to explore drug treatment effects. We summarized the reporting characteristics and methods employed for handling time-varying treatments. Logistic regressions were performed to investigate the association between study characteristics and the reporting of time-varying treatments. RESULTS: Two hundred and fifty-six studies were included, and 225 (87.9%) studies involved time-varying treatments. Of these, 24 (10.7%) reported the proportion of time-varying treatments and 105 (46.7%) reported methods used to handle time-varying treatments. Multivariable logistic regression showed that medical studies, prespecified protocol, and involvement of methodologists were associated with a higher likelihood of reporting the methods applied to handle time-varying treatments. Among the 105 studies that reported methods, as-treated analyses were the most commonly used analysis sets, which were employed in 73.9%, 75.3% and 88.2% of studies that reported approaches for treatment discontinuation, treatment switching and treatment add-on. Among the 225 studies involved time-varying treatments, 27 (12.0%) acknowledged the potential bias introduced by treatment change, of which 14 (51.9%) suggested that potential biases may impact acceptance or rejection of the null hypothesis. CONCLUSIONS: Among observational studies using RCD, the underreporting about the presence and methods for handling time-varying treatments was largely common. The potential biases due to time-varying treatments have frequently been disregarded. Collaborative endeavors are strongly needed to enhance the prevailing practices.

Effectiveness and safety of edoxaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies.

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia type. Patients with AF are often administered anticoagulants to reduce the risk of ischemic stroke due to an irregular heartbeat. We evaluated the efficacy and safety of edoxaban versus warfarin in patients with nonvalvular AF by conducting an updated meta-analysis of real-world studies. Methods: In this comprehensive meta-analysis, we searched two databases, PubMed and EMBASE, and included retrospective cohort observational studies that compared edoxaban with warfarin in patients with nonvalvular AF from 1 January 2009, to 30 September 2023. The effectiveness and safety outcomes were ischemic stroke and major bleeding, respectively. In the final analysis, six retrospective observational studies involving 87,236 patients treated with warfarin and 40,933 patients treated with edoxaban were included. To analyze the data, we used a random-effects model to calculate the hazard ratio (HR). Results: Patients treated with edoxaban had a significantly lower risk of ischemic stroke [hazard ratio (HR) = 0.66; 95% confidence interval (CI) = 0.61-0.70; p < 0.0001] and major bleeding (HR = 0.58; 95% CI = 0.49-0.69; p < 0.0001) than those treated with warfarin. The sensitivity analysis results for ischemic stroke and major bleeding were as follows: HR = 0.66; 95% CI = 0.61-0.70; p < 0.0001 and HR = 0.58; 95% CI = 0.49-0.69; p < 0.0001, respectively. Conclusion: Our findings revealed that edoxaban performed better than warfarin against major bleeding and ischemic stroke.

Safety profile and signal detection of phosphodiesterase type 5 inhibitors for erectile dysfunction: a Food and Drug Administration Adverse Event Reporting System analysis.

Background: Phosphodiesterase type 5 inhibitors (PDE5Is) are generally well tolerated but have been associated with uncommon and significant adverse events (AEs). Aim: This study aims to investigate and compare the characteristics of AEs associated with PDE5Is used for erectile dysfunction and identify any safety signals in a postmarketing surveillance database between 2010 and 2021. Methods: A descriptive analysis was conducted for all AEs reported to the Food and Drug Administration Adverse Event Reporting System for 4 PDE5Is-avanafil, sildenafil, tadalafil, and vardenafil-indicated for erectile dysfunction between January 2010 and December 2021. The frequency of the most reported AEs and outcomes were identified. A disproportionality analysis based on proportional reporting ratio (PRR) and reporting odds ratio (ROR) was conducted for the most common and clinically important AEs to identify signals to gain insights into potential differences in safety profiles. Outcomes: The outcome measures of the study are frequency of reported AEs and outcomes following AE. Results: A total of 29 236 AEs were reported for PDE5Is during the study period. The most reported AE was "drug ineffective" with 7115 reports (24.3%). Eight safety signals were detected across the 4 drugs. Key signals were sexual disorders (PRR, 3.13 [95% CI, 2.69-3.65]; ROR, 3.24 [95% CI, 2.77-3.79]) and death (PRR, 3.17 [2.5-4.01]; ROR, 3.211 [2.52-4.06]) for sildenafil, priapism (PRR, 3.63 [2.11-6.24]; ROR, 3.64 [2.12-6.26]) for tadalafil, and drug administration error (PRR, 2.54 [1.84-3.52]; ROR, 2.6 [1.86-3.63]) for vardenafil. The most reported outcomes were other serious events with 6685 events (67.2%) and hospitalization with 1939 events (19.5%). Clinical Implications: The commonly reported AEs and detected signals may guide clinicians in treatment decision making for men with erectile dysfunction. Strengths and Limitations: This is the first comprehensive report and disproportionality analysis on all types of AEs associated with PDE5Is used for erectile dysfunction in the United States. The findings should be interpreted cautiously due to limitations in the Adverse Event Reporting System, which includes self-reports, duplicate and incomplete reports, and biases in reporting and selection. Therefore, establishing a causal relationship between the reported AEs and the use of PDE5Is is uncertain, and the data may be confounded by other medications and indications. Conclusion: PDE5Is demonstrate significantly increased risks of reporting certain clinically important AEs. While these events are not common, it is imperative to continually monitor PDE5I use at the levels of primary care to national surveillance to ensure safe utilization.

A novel online survey approach designed to measure consumer sunscreen application thickness-implications for estimating environmental emissions.

BACKGROUND: The effects of ultraviolet (UV) filters in the aquatic environment have been well studied, but environmental exposures remain unclear and understudied. Consumer usage directly influences the amount of sunscreen products, and subsequently UV filters, potentially released into the environment. OBJECTIVE: To conduct a literature review of previous research into sunscreen application thickness, develop a questionnaire protocol designed to semi-quantify sunscreen usage by US consumers, and conduct a large-scale survey to determine a sunscreen application thickness (to face and body) that is more refined than conservative defaults. The United States Food & Drug Administration (US FDA) recommends a sunscreen application rate of 2 mg/cm2. This value is typically used as a worst-case assumption in environmental exposure assessments of UV filters. METHODS: Designed a novel approach to estimate lotion sunscreen application thickness using an online questionnaire protocol employing visual references and self-reported height and weight of the respondents. A literature review was also conducted to collect historical sunscreen usage. RESULTS: Over 9000 people were surveyed in the US, and after the dataset was refined, their sunscreen application thickness was estimated based on calculated body surface area and reported sunscreen amounts. The mean and median values for survey respondents are 3.00 and 1.78 mg/cm2, respectively, for facial application thickness and 1.52 and 1.35 mg/cm2, respectively, for body application thickness. Earlier research from 1985-2020 reported 36 of the 38 values are below the US FDA's recommended application thickness of 2 mg/cm2 (range 0.2-5 mg/cm2). IMPACT STATEMENT: This web-based survey is the first of its kind, designed specifically to quantify sunscreen application in a large and diverse set of consumers. This method provides a greater reach to larger populations thus enabling more granular data analysis and understanding. Exposure assessments of sunscreen ingredients typically use conservative parameters. These data can refine those assessments and allow for more informed and science-based risk management decisions.

Drug Expenditure, Price, and Utilization in US Medicaid: A Trend Analysis for New Multiple Myeloma Medications from 2016 to 2022.

INTRODUCTION: Multiple myeloma (MM) is the most common plasma cell tumor type. In late 2015, the FDA approved three new medications for MM. These medications were ixazomib, daratumumab, and elotuzumab. However, their utilization, reimbursement, and price in the Medicaid program have not been analyzed before. METHODS: A retrospective drug utilization study using the national Medicaid pharmacy claims data from 2016 to 2022 in the US. The primary metrics of analysis were utilization (number of prescriptions), reimbursement (total spending), and price (reimbursement per prescription). RESULTS: The overall Medicaid utilization of MM medications increased from 1671 prescriptions in 2016 to 34,583 prescriptions in 2022 (1970% increase). Moreover, the overall Medicaid reimbursement for the new MM medications increased from USD 9,250,000 in 2016 to over USD 214,449,000 in 2022 (2218% increase). Daratumumab had much higher utilization, reimbursement, and market shares than its competitors. Ixazomib was the most expensive medication compared to daratumumab and elotuzumab. CONCLUSION: The results of this study demonstrate that CMS utilization and spending on MM medications have significantly grown since 2016. Daratumumab has by far the highest utilization, spending, and market share. The utilization of and spending on specific pharmaceuticals are clearly impacted by policy and clinical guideline recommendations.

Safety reporting of Essure medical device: a qualitative and quantitative assessment on the FDA manufacturer and user facility device experience database in 2018.

Background: There have been numerous cases of adverse events since the introduction of Essure medical devices for sterilization in 2002. This study analyzed the safety event reports of the Essure reported in the Manufacturer and User Facility Device Experience (MAUDE). Methods: A retrospective analysis examined the MAUDE reports between Jan-1, 2018, and Oct-31, 2018 and focused on safety reports related to the Essure device. Safety reports were categorized and analyzed by their event type, device problem, patients' symptoms and the level of harm. Of this study cohort, 10% of samples were randomly selected for quantitative analyses. Thematic analysis was conducted for reports included death cases. Results: A total of 4,994 eligible reports were analyzed. There were ten reports associated with individuals' deaths, and the main themes of safety reports from qualitative analysis were pains, bleeding, surgery, migraine, and infection. Quantitative analysis of 500 randomly selected samples showed that 98% of adverse event reports were associated with different injuries such as surgery, pain, bleeding, hysterectomy, and menorrhagia. Additionally, more than 90% of reports were submitted by the manufacturer. Conclusion: These findings indicated several safety issues of Essure. More meaningful pre- and post-marketing surveillance and regulation are warranted in the medical device market to ensure safety and effectiveness, including investigating complaints, promptly sharing relevant information with regulators and users, and implementing corrective actions.

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Spending, Utilization, and Price Trends for Immune Checkpoint Inhibitors in US Medicaid Programs: An Empirical Analysis from 2011 to 2021.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a cornerstone in cancer treatment. With high treatment costs and an increasing number of young and low-income patients with cancer, there is a need to determine the current spending and utilization of ICIs in a real-world population. The objective of this study was to outline the drug spending, utilization, and price trends of ICIs for US Medicaid programs from 2011 to 2021. METHODS: A retrospective descriptive analysis was conducted using the Medicaid State Drug Utilization pharmacy summary files managed by the Centers for Medicare and Medicaid Services. Six ICIs for this study include ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and cemiplimab. Yearly reimbursement and prescription numbers were calculated for six ICIs billed through Medicaid between 2011 and 2021. The average spending per prescription was calculated as a proxy for drug prices. RESULTS: Overall spending and utilization on ICIs have risen exponentially over the past decade. Between 2011 and 2021, expenditures increased from $2.8 million to $4.1 billion. Utilization increased from 94 prescriptions to 462,049 prescriptions in 2021 with six ICIs. The average spending per prescription, or average drug price, decreased 70%, from $29,795.88 in 2011 to $8914.69 in 2021. CONCLUSIONS: Spending on and utilization of ICIs have increased dramatically over the past decade. These findings shed new light on the impact of ICIs on state Medicaid programs and may provide insight into potential cost drivers that need to be addressed through policy.

Impact of Introducing Infliximab Biosimilars on Total Infliximab Consumption and Originator Infliximab Prices in Eight Regions: An Interrupted Time-Series Analysis.

OBJECTIVE: We aimed to assess whether the introduction of the first infliximab biosimilar was associated with changes in overall infliximab consumption (originator and biosimilars) and price changes to the originator infliximab. METHODS: An interrupted time series analysis using infliximab sales data from 2010 to 2020 from the IQVIA Multinational Integrated Data Analysis System for eight selected regions: Australia, Canada, Hong Kong, Korea, India, Japan, the UK, and the USA. Quarterly measures of infliximab consumption and list prices were respectively defined as the number of standard units (SU)/1000 inhabitants and as 2020 USA dollars (USD)/SU. RESULTS: Following the introduction of infliximab biosimilars, overall infliximab consumption increased in Australia [immediate change: 0.145 SU/1000 inhabitants (P = 0.014); long-term change: 0.022 SU/1000 inhabitants per quarter (P < 0.001)], Canada [immediate change 0.415 (P = 0.008)], the UK [long-term change 0.024 (P < 0.001)], and Hong Kong [immediate change: 0.042 (P < 0.001)]. The list price of originator infliximab also decreased following biosimilar introduction in Australia [immediate change: - 187.84 USD/SU (P < 0.001); long-term change - 6.46 USD/SU per quarter (P = 0.043)], Canada [immediate change: - 145.58 (P < 0.001)], the UK [immediate change: - 34.95 (P = 0.010); long-term change: - 4.77 (P < 0.001)], and Hong Kong [long-term change: - 4.065 (P = 0.046)]. Consumption and price changes were inconsistent in India, Japan, Korea, and the USA. CONCLUSIONS: Introduction of the first infliximab biosimilar was not consistently associated with increased consumption across regions. Additional policy and healthcare system interventions to support biosimilar infliximab adoption are needed.

Trends in utilization, reimbursement, and price for DOACs and warfarin in the US Medicaid population from 2000 to 2020.

The use of direct oral anticoagulants (DOACs) is widely increasing in the United States (US). Warfarin has been the conventional anticoagulant used in the past few decades, but it has been gradually replaced by DOACs. The objective of the study was to analyze trends in utilization, reimbursement, and price for those anticoagulants in the US Medicaid population. Retrospective data analysis was conducted using the National Summary Files for the Medicaid State Drug Utilization Data. Study drugs included dabigatran, rivaroxaban, apixaban, edoxaban and warfarin. The study assessed secular trends of utilization, reimbursement, and per-prescription price. The data was collected from the first quarter of 2000 through to the second quarter of 2020 restricted for outpatient prescriptions only. During the 21-year study period, a substantial rise in total expenditures on warfarin and DOACs was observed from $144 million in 2000 to $694 million in 2020. Moreover, the utilization of DOACs has increased significantly since the first approval of Xarelto in 2010 from 1079 in 2011 to 1.5 million in 2019. The per-prescription price of DOACs increased from an average of $200 in 2011 to $407 in 2020. Conversely, the total number of prescriptions of Warfarin and branded Coumadin decreased from 2.4 million to 1.4 million and from 3.9 million to less than a million, respectively. The present study demonstrated a change in the trends of US expenditure and utilization for warfarin and DOACs with DOACs representing the majority of market share of both spending per prescription and reimbursement.

The Utilization, Expenditure, and Price of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in the US Medicaid Programs: Trends Over a 31 Year Period.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are used for several indications including hypertension. Our aim is to evaluate the utilization, expenditure, and drug price of ACEIs and ARBs in the US Medicaid population. METHODS: A retrospective descriptive trend analysis was conducted using Medicaid State Drug Utilization outpatient pharmacy summary files managed by the Centers for Medicare and Medicaid Services from 1991 to 2021. Study drugs included ACEIs (e.g., captopril) and ARBs (e.g., losartan). Annual reimbursement and utilization were calculated for both classes. The average reimbursement per prescription was calculated as a proxy for drug prices. Market share competition between ACEIs and ARBs was analyzed over time. RESULTS: ACEI and ARB utilization rose by 25% from 1991 to 2021. Brand ACEIs utilization peaked in 2002 with 28 million prescriptions while brand ARBs utilization continued to increase until 2005 with over 23 million prescriptions. However, generic products took the lead and exceeded brand ACEI and ARB utilization in 2006 and 2012 respectively. Medicaid spent over $ 33.7 billion on ACEIs and ARBs over 31-year. Brand ACEIs and ARBs average prices increased sharply to $8,104 and $6,908 respectively in 2021. The total prescription market share for ACEIs was 68% compared to 32% of ARBs over the entire study. CONCLUSION: ACEIs and ARBs utilization increased over the last 31 years. Brand utilization switched over to generic resulting in less reimbursement. The average prices of brand ACEIs and ARBs continue to increase even after generics were introduced to the market.

Icolos: a workflow manager for structure-based post-processing of de novo generated small molecules.

SUMMARY: We present Icolos, a workflow manager written in Python as a tool for automating complex structure-based workflows for drug design. Icolos can be used as a standalone tool, for example in virtual screening campaigns, or can be used in conjunction with deep learning-based molecular generation facilitated for example by REINVENT, a previously published molecular de novo design package. In this publication, we focus on the internal structure and general capabilities of Icolos, using molecular docking experiments as an illustrative example. AVAILABILITY AND IMPLEMENTATION: The source code is freely available at https://github.com/MolecularAI/Icolos under the Apache 2.0 license. Tutorial notebooks containing minimal working examples can be found at https://github.com/MolecularAI/IcolosCommunity. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Impact of time-varying exposure on estimated effects in observational studies using routinely collected data: protocol for a cross-sectional study.

INTRODUCTION: Time-varying exposure is an important issue that should be addressed in longitudinal observational studies using routinely collected data (RCD) for drug treatment effects. How well investigators designed, analysed and reported time-varying exposure, and to what extent the divergence that can be observed between different methods used for handling time-varying exposure in these studies remains uncertain. We will conduct a cross-sectional study to comprehensively address this question. METHODS AND ANALYSIS: We have developed a comprehensive search strategy to identify all studies exploring drug treatment effects including both effectiveness and safety that used RCD and were published in core journals between 2018 and 2020. We will collect information regarding general study characteristics, data source profile, methods for handling time-varying exposure, results and the interpretation of findings from each eligibility. Paired reviewers will screen and extract data, resolving disagreements through discussion. We will describe the characteristics of included studies, and summarise the method used for handling time-varying exposure in primary analysis and sensitivity analysis. We will also compare the divergence between different approaches for handling time-varying exposure using ratio of risk ratios. ETHICS AND DISSEMINATION: No ethical approval is required because the data we will use do not include individual patient data. Findings will be disseminated through peer-reviewed publications.

Utilization, Spending, and Price of Opioid Medications in the US Medicaid Programs Between 1991 and 2019.

Background: The opioid epidemic and drug abuse are critical public health challenges in the United States. The number of deaths from exceeding the recommended opioid dose is increasing. Objective: To describe the recent trends in utilization, spending, and cost of opioid medications in the US Medicaid population between 1991 and 2019. Methods: This retrospective, descriptive study was designed to evaluate the utilization of, spending on, and cost of opioids from 1991 to 2019 in the Medicaid population. We extracted data from the Centers for Medicare & Medicaid Services national Medicaid pharmacy files. The opioids received included fentanyl, meperidine, morphine, hydromorphone, oxymorphone, hydrocodone, hydrocodone plus acetaminophen, oxycodone, oxycodone plus acetaminophen, tapentadol, and tramadol. The number of prescriptions and reimbursement spending were calculated for each medication per quarter year. The average per-prescription reimbursement as a proxy of drug price was calculated as the reimbursement amount divided by the number of prescriptions per quarter year. The market shares by spending and utilization were also calculated for each opioid medication. Results: The number of all opioid prescriptions in Medicaid increased from approximately 2.1 million in 1991 to approximately 41.6 million in 2015, and then reduced to approximately 19.1 million in 2019. During this 29-year study period, the opioid medications that were used as monotherapy were hydrocodone (246.8 million prescriptions), oxycodone (111.9 million prescriptions), and tramadol (75.2 million prescriptions). The total spending in the Medicaid population on opioids was $19.4 billion, including approximately $7.3 billion spending on oxycodone, approximately $3.7 billion on fentanyl, and approximately $3.3 billion on hydrocodone. The majority of opioid prices increased over time, and the highest average costs per opioid prescription in 2019 were $1188 for oxymorphone, $641 for tapentadol, and $198 for fentanyl. Conclusions: The utilization of and spending on opioid medications in Medicaid increased over time, peaked in 2015, and then declined with the initiation of nationwide programs to combat the opioid epidemic. Effective cost-containment strategies and programs to combat the abuse of opioids are warranted in Medicaid programs.

Glutamate in primary afferents is required for itch transmission.

Whether glutamate or itch-selective neurotransmitters are used to confer itch specificity is still under debate. We focused on an itch-selective population of primary afferents expressing MRGPRA3, which highly expresses Vglut2 and the neuropeptide neuromedin B (Nmb), to investigate this question. Optogenetic stimulation of MRGPRA3+ afferents triggers scratching and other itch-related avoidance behaviors. Using a combination of optogenetics, spinal cord slice recordings, Vglut2 conditional knockout mice, and behavior assays, we showed that glutamate is essential for MRGPRA3+ afferents to transmit itch. We further demonstrated that MRGPRA3+ afferents form monosynaptic connections with both NMBR+ and NMBR- neurons and that NMB and glutamate together can enhance the activity of NMBR+ spinal DH neurons. Moreover, Nmb in MRGPRA3+ afferents and NMBR+ DH neurons are required for chloroquine-induced scratching. Together, our results establish a new model in which glutamate is an essential neurotransmitter in primary afferents for itch transmission, whereas NMB signaling enhances its activities.