A High-Fidelity Combined ATC-Rxnorm Drug Hierarchy for Large-Scale Observational Research.

Observational research utilizes patient information from many disparate databases worldwide. To be able to systematically analyze data and compare the results of such research studies, information about exposure to drugs or classes of drugs needs to be harmonized across these data. The NLM's RxNorm drug terminology and WHO's ATC classification serve these needs but are currently not satisfactorily combined into a common system. Creating such system is hampered by a number of challenges, resulting from different approaches to representing attributes of drugs and ontological rules. Here, we present a combined ATC-RxNorm drug hierarchy, allowing to use ATC classes for retrieval of drug information in large scale observational data. We present the heuristic for maintaining this resource and evaluate it in a real world database containing drug and drug classification information.

Real-World Patient Characteristics, Utilization Patterns, and Outcomes of US Patients with HR+, HER2- Metastatic Breast Cancer Treated with Abemaciclib.

BACKGROUND: Abemaciclib is the most recent oral cyclin-dependent kinase 4 and 6 inhibitor (CDK4 & 6i) to receive US Food and Drug Administration (FDA) approval to treat hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC). Administrative claims data were used to describe patient characteristics and select clinical and economic outcomes in US patients treated in routine clinical practice. Prior analyses from electronic health records data indicate approximately 25% of patients received either palbociclib or ribociclib for MBC before initiating abemaciclib treatment; this work further explored these findings and associated outcomes. METHODS: This retrospective study analyzed medical and pharmacy claims from the IBM® MarketScan® Research Databases between 1 January 2007 to 31 January 2020. Patients with HR+, HER2- MBC newly initiating abemaciclib between 1 September 2017 and 31 October 2019 were included and grouped by concomitant therapy (+aromatase inhibitor (AI), +fulvestrant (F), 200 mg abemaciclib monotherapy (Mono), or +other), and outcomes were analyzed by prior CDK4 & 6i use. Patient and treatment characteristics were summarized with descriptive statistics. Kaplan-Meier methods assessed time-to-discontinuation (TTD; i.e., persistency) and time-to-chemotherapy (TTC). Adherence (defined by the medication possession ratio) and drug wastage were determined. RESULTS: This analysis included 454 patients (mean age 57.7 years), with 35.0% (n = 159) in the +F group, 29.3% (n = 133) in the +AI group, 10.4% (n = 47) in the 200 mg Mono group, and 25.3% (n = 115) in the +other group. Prior chemotherapy and CDK 4 & 6i use were present in 23.8% and 49.8% of all patients, respectively. Visceral metastases were present at abemaciclib initiation in 50.4% in the +AI group; 49.7% in the +F group; and 55.3% in the 200 mg Mono group. Liver metastases were present in 33.7% of the overall population. Among patients without prior CDK4 & 6i use, the median TTD for patients receiving abemaciclib + AI was not reached [95% CI 430-not reached (NR) days], abemaciclib + F [531 days (95% CI 281-NR)], and abemaciclib mono [141 days (95% CI 80-NR)]. Median TTC for abemaciclib + AI and abemaciclib + F groups were not reached and the median TTC for abemaciclib mono was 535 days (95% CI 181-NR). Medication adherence was 88.7% and medication wastage costs among those with at least one dose modification were $808.12 and $452.2 per patient per month based on amount paid and wholesale acquisition cost (WAC), respectively. Mean length of follow-up for all patients was 350 days (SD 187). CONCLUSION: These real-world data complement clinical trial results by examining abemaciclib use among patients treated in routine clinical practice. The sizeable number of patients treated with prior CDK4 & 6i, chemotherapy, and/or visceral metastases at abemaciclib initiation suggest that many patients had very advanced disease and/or were in later stages of their treatment. These data confirm a higher percentage of patients treated with previous CDK4 & 6i than reported previously, reinforcing the importance of the ongoing, prospective clinical trials evaluating outcomes following progression on CDK4 & 6i.

Comparative Effectiveness of Dexamethasone in Hospitalized COVID-19 Patients in the United States.

INTRODUCTION: To compare the mortality of hospitalized patients with COVID-19 between those that required supplemental oxygen and received dexamethasone with a comparable set of patients who did not receive dexamethasone. METHODS: We utilized the Premier Health Database to identify hospitalized adult patients with COVID-19 from July 1, 2020-January 31, 2021. Index date was when patients first initiated oxygen therapy. The primary endpoint was in-hospital mortality for patients receiving dexamethasone versus those not receiving dexamethasone 1-day pre- to 1-day post-index period. Secondary endpoints included 28-day mortality, time to in-hospital mortality, progression to invasive mechanical ventilation or death, time to discharge, and proportion discharged alive by day 28. Twenty-three models using weighting, matching, stratification, and regression were deployed through the concept of frequentist model average (FMA) to estimate the effect of dexamethasone on all-cause mortality up to the 28-day hospitalization period. RESULTS: A total of 1,208,881 patients with COVID-19 were screened; as an inpatient 255,216 used oxygen, and 251,536 were included in the analysis. In the dexamethasone group, odds of in-hospital mortality were higher than those of the comparator (FMA: odds ratio [OR] 1.15, 95% CI 1.08, 1.22). Using a best fit model, OR for in-hospital mortality was non-significant for the dexamethasone group compared with the comparator (OR 1.02, 95% CI 0.92, 1.14). Dexamethasone treatment was associated with poorer outcomes versus the comparator group across the majority of secondary endpoints, except for number of days in hospital, which was lower in the dexamethasone group versus the comparator group (mean difference - 2.14, 95% CI - 2.43, - 1.47). CONCLUSIONS: Hospitalized adult patients with COVID-19 who required supplemental oxygen and received dexamethasone did not have a survival benefit versus similar patients not receiving dexamethasone. The dexamethasone group was not associated with favorable responses for outcomes such as progression to death or mechanical ventilation and time to in-hospital death.

A review of stakeholder recommendations for defining fit-for-purpose real-world evidence algorithms.

Aim: The credibility and value of real-world evidence (RWE) are either supported or undermined by the algorithms (i.e., operational definitions) used. Methods: We conducted a targeted evidence review of key RWE decision makers' published recommendations on RWE algorithms through April 2021. Stakeholders were regulatory bodies, other governmental agencies and payer organizations. Results: Our review identified recommended criteria: relevance, validity, reliability, responsiveness, transparency and replicability, safety, feasibility and quality process. Stakeholders routinely recommended accuracy measures, subgroups evaluation and specific considerations for assessing exposures and covariates and the underlying real-world data (RWD) quality. Conclusion: The importance of stakeholder guidance on fit-for-purpose RWE algorithms is growing. We highlight gaps that future guidance and stakeholder recommendations could address.

Inpatient Hospital Costs for COVID-19 Patients in the United States.

INTRODUCTION: Reliable cost and resource use data for COVID-19 hospitalizations are crucial to better inform local healthcare resource decisions; however, available data are limited and vary significantly. METHODS: COVID-19 hospital admissions data from the Premier Healthcare Database were evaluated to estimate hospital costs, length of stay (LOS), and discharge status. Adult COVID-19 patients (ICD-10-CM: U07.1) hospitalized in the US from April 1 to December 31, 2020, were identified. Analyses were stratified by patient and hospital characteristics, levels of care during hospitalization, and discharge status. Factors associated with changes in costs, LOS, and discharge status were estimated using regression analyses. Monthly trends in costs, LOS, and discharge status were examined. RESULTS: Of the 247,590 hospitalized COVID-19 patients, 49% were women, 76% were aged ≥ 50, and 36% were admitted to intensive care units (ICU). Overall median hospital LOS, cost, and cost/day were 6 days, US$11,267, and $1772, respectively; overall median ICU LOS, cost, and cost/day were 5 days, $13,443, and $2902, respectively. Patients requiring mechanical ventilation had the highest hospital and ICU median costs ($47,454 and $41,510) and LOS (16 and 11 days), respectively. Overall, 14% of patients died in hospital and 52% were discharged home. Older age, Black and Caucasian race, hypertension and obesity, treatment with extracorporeal membrane oxygenation, and discharge to long-term care facilities were major drivers of costs, LOS, and risk of death. Admissions in December had significantly lower median hospital and ICU costs and LOS compared to April. CONCLUSION: The burden from COVID-19 in terms of hospital and ICU costs and LOS has been substantial, though significant decreases in cost and LOS and increases in the share of hospital discharges to home were observed from April to December 2020. These estimates will be useful for inputs to economic models, disease burden forecasts, and local healthcare resource planning.

Baseline phenotype and 30-day outcomes of people tested for COVID-19: an international network cohort including >3.32 million people tested with real-time PCR and >219,000 tested positive for SARS-CoV-2 in South Korea, Spain and the United States.

Early identification of symptoms and comorbidities most predictive of COVID-19 is critical to identify infection, guide policies to effectively contain the pandemic, and improve health systems' response. Here, we characterised socio-demographics and comorbidity in 3,316,107persons tested and 219,072 persons tested positive for SARS-CoV-2 since January 2020, and their key health outcomes in the month following the first positive test. Routine care data from primary care electronic health records (EHR) from Spain, hospital EHR from the United States (US), and claims data from South Korea and the US were used. The majority of study participants were women aged 18-65 years old. Positive/tested ratio varied greatly geographically (2.2:100 to 31.2:100) and over time (from 50:100 in February-April to 6.8:100 in May-June). Fever, cough and dyspnoea were the most common symptoms at presentation. Between 4%-38% required admission and 1-10.5% died within a month from their first positive test. Observed disparity in testing practices led to variable baseline characteristics and outcomes, both nationally (US) and internationally. Our findings highlight the importance of large scale characterization of COVID-19 international cohorts to inform planning and resource allocation including testing as countries face a second wave.

Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.

Deep phenotyping of 34,128 patients hospitalised with COVID-19 and a comparison with 81,596 influenza patients in America, Europe and Asia: an international network study.

Background In this study we phenotyped individuals hospitalised with coronavirus disease 2019 (COVID-19) in depth, summarising entire medical histories, including medications, as captured in routinely collected data drawn from databases across three continents. We then compared individuals hospitalised with COVID-19 to those previously hospitalised with influenza. Methods We report demographics, previously recorded conditions and medication use of patients hospitalised with COVID-19 in the US (Columbia University Irving Medical Center [CUIMC], Premier Healthcare Database [PHD], UCHealth System Health Data Compass Database [UC HDC], and the Department of Veterans Affairs [VA OMOP]), in South Korea (Health Insurance Review & Assessment [HIRA]), and Spain (The Information System for Research in Primary Care [SIDIAP] and HM Hospitales [HM]). These patients were then compared with patients hospitalised with influenza in 2014-19. Results 34,128 (US: 8,362, South Korea: 7,341, Spain: 18,425) individuals hospitalised with COVID-19 were included. Between 4,811 (HM) and 11,643 (CUIMC) unique aggregate characteristics were extracted per patient, with all summarised in an accompanying interactive website (http://evidence.ohdsi.org/Covid19CharacterizationHospitalization/). Patients were majority male in the US (CUIMC: 52%, PHD: 52%, UC HDC: 54%, VA OMOP: 94%,) and Spain (SIDIAP: 54%, HM: 60%), but were predominantly female in South Korea (HIRA: 60%). Age profiles varied across data sources. Prevalence of asthma ranged from 4% to 15%, diabetes from 13% to 43%, and hypertensive disorder from 24% to 70% across data sources. Between 14% and 33% were taking drugs acting on the renin-angiotensin system in the 30 days prior to hospitalisation. Compared to 81,596 individuals hospitalised with influenza in 2014-19, patients admitted with COVID-19 were more typically male, younger, and healthier, with fewer comorbidities and lower medication use. Conclusions We provide a detailed characterisation of patients hospitalised with COVID-19. Protecting groups known to be vulnerable to influenza is a useful starting point to minimize the number of hospital admissions needed for COVID-19. However, such strategies will also likely need to be broadened so as to reflect the particular characteristics of individuals hospitalised with COVID-19.

Proof-of-concept study: Homomorphically encrypted data can support real-time learning in personalized cancer medicine.

BACKGROUND: The successful introduction of homomorphic encryption (HE) in clinical research holds promise for improving acceptance of data-sharing protocols, increasing sample sizes, and accelerating learning from real-world data (RWD). A well-scoped use case for HE would pave the way for more widespread adoption in healthcare applications. Determining the efficacy of targeted cancer treatments used off-label for a variety of genetically defined conditions is an excellent candidate for introduction of HE-based learning systems because of a significant unmet need to share and combine confidential data, the use of relatively simple algorithms, and an opportunity to reach large numbers of willing study participants. METHODS: We used published literature to estimate the numbers of patients who might be eligible to receive treatments approved for other indications based on molecular profiles. We then estimated the sample size and number of variables that would be required for a successful system to detect exceptional responses with sufficient power. We generated an appropriately sized, simulated dataset (n = 5000) and used an established HE algorithm to detect exceptional responses and calculate total drug exposure, while the data remained encrypted. RESULTS: Our results demonstrated the feasibility of using an HE-based system to identify exceptional responders and perform calculations on patient data during a hypothetical 3-year study. Although homomorphically encrypted computations are time consuming, the required basic computations (i.e., addition) do not pose a critical bottleneck to the analysis. CONCLUSION: In this proof-of-concept study, based on simulated data, we demonstrate that identifying exceptional responders to targeted cancer treatments represents a valuable and feasible use case. Past solutions to either completely anonymize data or restrict access through stringent data use agreements have limited the utility of abundant and valuable data. Because of its privacy protections, we believe that an HE-based learning system for real-world cancer treatment would entice thousands more patients to voluntarily contribute data through participation in research studies beyond the currently available secondary data populated from hospital electronic health records and administrative claims. Forming collaborations between technical experts, physicians, patient advocates, payers, and researchers, and testing the system on existing RWD are critical next steps to making HE-based learning a reality in healthcare.

The Historical Background of Plaster Cast.

The pivotal role of plaster of Paris (POP) cast as an immobilization tool to promote healing in complex and/or other types of fractures is irrefutable. We clearly know that Antonius Mathysen extensively applied plaster cast during Crimea and/or other wars and reportedly saved thousands of lives. However, the exact origin of using POP in orthopedic cast is yet to be clear. In his famous report from Bandar-e Rig, a city in Iran, William Eton paved the way for the conclusion that POP cast might have originated from the Persian Empire. In this paper, we provide more supporting evidences which make the aforementioned claim more probable.

Systematic review of the effectiveness of health-related behavioral interventions using portable activity sensing devices (PASDs).

BACKGROUND: Portable activity sensing devices (PASDs) have received significant interest as tools for objectively measuring activity-related parameters and promoting health-related outcomes. Studies of PASDs suggest the potential value of integrating them with behavioral interventions to improve intermediate and downstream clinical outcomes. OBJECTIVES: This systematic review describes and evaluates evidence from controlled studies of interventions using PASDs on their effectiveness in health-related outcomes. Study quality was also assessed. METHODS: A systematic literature search was performed of MEDLINE, Cochrane Central Register of Controlled Trials, PsycINFO, EMBASE, and CINAHL databases. We included English-language papers of controlled trials through 2015 reporting the effectiveness of PASDs in improving health-related outcomes in any population. We extracted and analyzed data on study characteristics including design, target population, interventions, and findings. RESULTS: Seventeen trials met the inclusion criteria from a total of 9553 unique records. Study objectives varied greatly, but most sought to increase physical activity. Studies with a "passive" intervention arm using a PASD with minimal behavioral support generally did not demonstrate effectiveness in improving health-related outcomes. Interventions integrating PASDs with multiple behavioral change techniques were more likely to be effective, particularly for intermediate outcomes such as physical activity and weight loss. Trials had small sample sizes but were generally free of bias, except for blinding and selection bias. CONCLUSION: There is insufficient evidence to draw a conclusion about the general health-related benefits of PASD interventions. PASD interventions may improve intermediate outcomes when coupled with multiple behavioral change techniques. Devices alone or with minimal behavioral change support are insufficient to change health-related outcomes.

An Interactive User Interface for Drug Labeling to Improve Readability and Decision-Making.

FDA-approved prescribing information (also known as product labeling or labels) contain critical safety information for health care professionals. Drug labels have often been criticized, however, for being overly complex, difficult to read, and rife with overwarning, leading to high cognitive load. In this project, we aimed to improve the usability of drug labels by increasing the 'signal-to-noise ratio' and providing meaningful information to care providers based on patient-specific comorbidities and concomitant medications. In the current paper, we describe the design process and resulting web application, known as myDrugLabel. Using the Structured Product Label documents as a base, we describe the process of label personalization, readability improvements, and integration of diverse evidence sources, including the medical literature from PubMed, pharmacovigilance reports from FDA adverse event reporting system (FAERS), and social media signals directly into the label.

The effect of renin angiotensin system on tamoxifen resistance.

Breast cancer is one of the most common forms of cancer observed in women and endogenous estrogens are thought to play a major role in its development. Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to treat and prevent breast cancer. Tamoxifen is an ER antagonist in the breast but an ER agonist in cardiovascular system (CVS) and some other tissues. Many patients experience resistance to tamoxifen. Several studies have indicated various mechanisms in tamoxifen resistance. Growth factors and their receptors, extracellular proteins, transcription factors, cell-cycle regulators, and signal-transduction molecules have been identified as being potentially involved in tamoxifen resistance. The aim of the present hypothesis is to provide evidences that may lead to this suggestion that renin-angiotensin system (RAS) may have a role in tamoxifen resistance. It has been established in numerous studies that RAS play a role in the progression of various cancers such as breast cancer. Besides, other studies have indicated that estrogen has an inhibitory effect on the RAS components levels in CVS and various tissues such as the adrenal and the pituitary. Therefore, it can be suggested that tamoxifen may increase RAS components levels in the breast tissue by its antagonistic effect on ER and causes resistance. Confirmation of this theory by experimental investigations may lead to this suggestion that combination of angiotensin-converting enzyme inhibitors or angiotensin receptor-1 blockers with tamoxifen may have a preventive effect on development of acquired tamoxifen resistance.

Role of endothelin-1 in tamoxifen resistance: Mechanism for a new possible treatment strategy in breast cancer.

Breast cancer is the prevalent cancer worldwide. Excessive exposure to endogenous estrogen across a woman's lifespan contributes to and may be a causal factor in breast cancer. Tamoxifen is a mixed estrogen agonist and antagonist, which is used in treatment and prevention of breast cancer as an estrogen antagonist. Many patients experience resistance to tamoxifen for which many mechanisms have been suggested. Endothelin-1 acts as a mitogen for human breast fibroblasts and it affects tumor cell proliferation, invasion, angiogenesis, neovascularization, mitogenesis, and apoptosis inhibition. Previous studies have shown that estradiol is effective in inhibiting endothelin synthesis in breast tissue and cardiovascular system. Tamoxifen as an estrogen receptor (ER) agonist in cardiovascular system has a cardioprotective effect and decreases endothelin level as a vasoconstrictor in cardiovascular system. But in breast tissue tamoxifen acts as an ER antagonist. According to the role of endothelin in breast cancer and inhibitory effect of estrogen on endothelin, we hypothesized that tamoxifen causes increasing in endothelin level or endothelin receptors probably by inhibitory effect on ER in breast tissue, leading to tamoxifen resistance. Therefore a combination of tamoxifen with endothelin antagonist seems to be a reasonable therapeutic strategy.