Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.

Background: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response [1,2]. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) [3] Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD. Methods: We conducted a descriptive cohort study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11 th June 2020 and are iteratively updated via GitHub [4]. Findings: We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19 , and 113,627 hospitalized with COVID-19 requiring intensive services . All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts, and are available in an interactive website: https://data.ohdsi.org/Covid19CharacterizationCharybdis/. Interpretation: CHARYBDIS findings provide benchmarks that contribute to our understanding of COVID-19 progression, management and evolution over time. This can enable timely assessment of real-world outcomes of preventative and therapeutic options as they are introduced in clinical practice.

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

In response to the rapidly changing occupational health environment, Bangkok DusitMedical Services (BDMS) has recognized a need to increase the quality and availabilityof occupational health services. This manuscript describes the evolution of aninternational health alliance, based on the “twinning” framework, to achieve acollaborative goal of developing an Occupational Health Center of Excellence(COE-OH) in Thailand. Through this alliance, the COE-OH has supported thedevelopment of programs in the areas of health promotion, training and research. Thetwinning framework was applied as the alliance moved through initiation, implementation,monitoring and evaluation. Project evaluation was viewed as an iterative process thatinformed next steps in the process as the collaboration developed. Initial products ofthis alliance include adaptation of the “Let’s Get Healthy!” health promotion and datacollection tool for use as part of the Thai employee check-up; development andimplementation of occupational health trainings for various levels of clinical staff;student exchange opportunities; and the creation of the infrastructure to supportstanding up of a fully human subjects compliant data repository for research. Threeyears into this alliance, the COE-OH has reached a point where feasibility has beenestablished and the immense opportunities of future joint work have become apparent.

IntroductionIt is not clear how to effectively recruit healthy research volunteers.MethodsWe developed an electronic health record (EHR)-based algorithm to identify healthy subjects, who were randomly assigned to receive an invitation to join a research registry via the EHR's patient portal, letters, or phone calls. A follow-up survey assessed contact preferences.ResultsThe EHR algorithm accurately identified 858 healthy subjects. Recruitment rates were low, but occurred more quickly via the EHR patient portal than letters or phone calls (2.7 vs. 19.3 or 10.4 d). Effort and costs per enrolled subject were lower for the EHR patient portal (3.0 vs. 17.3 or 13.6 h, $113 vs. $559 or $435). Most healthy subjects indicated a preference for contact via electronic methods.ConclusionsHealthy subjects can be accurately identified from EHR data, and it is faster and more cost-effective to recruit healthy research volunteers using an EHR patient portal.

Clinical integrated data repositories (IDRs) are poised to become a foundational element of biomedical and translational research by providing the coordinated data sources necessary to conduct retrospective analytic research and to identify and recruit prospective research subjects. The Clinical and Translational Science Award (CTSA) consortium's Informatics IDR Group conducted a survey of 2010 consortium members to evaluate recent trends in IDR implementation and use to support research between 2008 and 2010. A web-based survey based in part on a prior 2008 survey was developed and deployed to 46 national CTSA centers. A total of 35 separate organizations completed the survey (74%), representing 28 CTSAs and the National Institutes of Health Clinical Center. Survey results suggest that individual organizations are progressing in their approaches to the development, management, and use of IDRs as a means to support a broad array of research. We describe the major trends and emerging practices below.

Objective: Elevated levels of C-reactive protein (CBP) and D-dimer (DD) have been associated with the presence and progression of various forms of atherosclerotic disease, particularly coronary heart disease. We hypothesize that there is a relationship between elevated levels of baseline CRP and DD and progression of peripheral arterial disease (PAD) in patients with symptomatic PAD. The current study is a prospective evaluation of this hypothesis.Methods. Between 1996 and 2003, 384 subjects were enrolled in a National Institutes of Health-sponsored blinded, prospective trial evaluating the effects of multiple atherosclerotic risk factors on progression of symptomatic PAD. Baseline levels of CRP and D-dimer were obtained in 332 subjects. Subjects were followed every 6 months with clinical history and exam, ankle-brachial pressure index (ABI), and carotid artery duplex scanning (CDS). The primary study end point was a composite of ABI progression, CDS progression, stroke, myocardial infarction, amputation, and death from cardiovascular disease. Secondary end points included each of the components of the primary end point. The relationship between time to the various endpoints and baseline CRP and DD levels was examined by life-table analysis and Cox proportional hazards analysis.Results: Adequate baseline samples for CRP and DD were available in 332 subjects (mean age, 67 years; 57.8% men) with mean follow-up of 38.4 months (range, 1 to 99 months). Mean baseline levels (+/- SD) for CRP were 0.8 +/- 1.14 (range, 0.03 to 13.0), and mean DD levels were 227.4 +/- 303.3 (range, 1.9 to 2744.8). Progression, as defined by the primary end point, occurred in 48.5% of subjects. Subjects with elevated CRP (highest tertile) were no more likely to have any of the progression end points than those with the lowest values (lowest tertile) (P = NS, log-rank test, for all comparisons). By univariate analysis, subjects with elevated DD (highest tertile) were significantly more likely to die from any cause compared with subjects with the lowest DD values (lowest tertile) (P =.03, log-rank test). They were, however, no more likely to reach any of the other progression end points, including the primary end point (P = NS, log-rank test for all other comparisons). Multivariate analysis showed that DD level was a significant independent variable associated with occurrence of myocardial infarction (hazard ratio, 2.3; P =.02).Conclusions. In subjects with symptomatic PAD, elevated baseline DD, a marker of thrombotic activity, was significantly associated with the occurrence of myocardial infarction. This study did not confirm a relationship between progression of PAD and baseline DD or CRP during the first 3 years. Baseline DD and CRP do not provide useful risk stratification in patients at high risk for progression of symptomatic PAD. Future studies should evaluate serial levels of these markers to assess their utility in predicting progression of symptomatic PAD.

PURPOSEThere have been few studies of the natural history of peripheral arterial disease (PAD), and none have used serial noninvasive laboratory examinations for the objective quantification of disease progression. The relationship between the site of initial symptoms of PAD (lower-extremity disease [LED] vs cerebrovascular disease [CVD]) and the site of subsequent symptomatic progression (LED vs CVD vs coronary heart disease [CHD]) has not been examined.METHODSThis is a long-term, blinded prospective clinical research study of the relationship of PAD progression to multiple clinical, laboratory, and noninvasive vascular laboratory parameters. Patients with symptomatic LED, CVD, or both underwent comprehensive risk-factor assessment and were seen every 6 months for follow-up examinations. In addition to history and physical examination, all subjects underwent serial noninvasive lower-extremity and carotid artery testing. The relationship between the initial symptomatic site(s) and subsequent progression was examined by means of multivariate proportional hazards analysis, which was adjusted for age, diabetes mellitus, hypertension, smoking, cholesterol, homocysteine level, lowest initial ankle/brachial index (ABI), worst carotid stenosis, ABI progression, and carotid stenosis progression, because each of these factors was significantly associated with one or more aspects of progression.RESULTSThere were 397 study subjects (mean age, 66 years; 38% women) with a mean follow-up period of 48.5 months. LED was initially present in 88% of subjects and CVD in 37% of subjects (both were present in 25% of subjects). There were 78 deaths, 47 (60%) of which were caused by cardiovascular disease (18% mortality rate after 5 years by means of life table). Progression of disease as documented by means of vascular laboratory findings occurred in 90% of subjects by means of life table after 5 years (ABI progression, 31%; carotid stenosis progression, 40%). Symptomatic clinical progression of disease occurred in 52% of subjects by means of life table after 5 years (LED progression, 22%; CVD progression, 23%; CHD progression, 31%). By means of multivariate analysis, no significant relationship was found between the site of initial symptoms of PAD and the site(s) of subsequent symptomatic clinical progression (LED vs CVD vs CHD; P = not significant for all hazard ratios).CONCLUSIONPatients with symptomatic PAD experience symptoms of ongoing LED, CVD, and CHD with a frequency that is not influenced by the site(s) of their original symptoms. The hypothesis that lesions and resulting symptoms of systemic atherosclerosis occur at various anatomic sites as a matter of random chance should be tested with other studies.

BACKGROUND: Alternate tapping speed is widely used as a measure of bradykinesia in Parkinson's disease (PD). Tapping speed in normal control subjects and factors that might influence tapping speed have not been systematically examined.OBJECTIVE: To examine the effects of age, hand dominance, and gender on tapping speed in normal control subjects and to compare the effects of practice on tapping speed in normal and PD control subjects.METHODS: Tapping speed for three sequential trials in the dominant and nondominant hand was examined in 100 normal control subjects and 60 subjects with PD. The effect of hourly practice over 26 hours (19 trials) was investigated in 14 normal and 24 PD subjects.RESULTS: The speed with which normal subjects alternately tapped two counters was negatively correlated with age, was greater in the dominant hand, was not related to gender, and improved with short-term practice (three trials) and with continued practice over 26 hours. Parkinsonian subjects, in general, tapped more slowly than normal control subjects and more slowly in the more affected arm. Parkinsonian subjects benefited from short-term practice as much as normal control subjects but, unlike normal control subjects, did not improve with continued practice over 26 hours.CONCLUSIONS: Alternate tapping speed is influenced by age, hand dominance, Parkinson's disease, and practice. Subjects with PD do not benefit as much from continued practice as do normal subjects, suggesting some limitation or impairment of procedural (motor) learning in PD.

In the study reported here, a multidimensional work-sampling technique was used to estimate the proportion of time externs spent on Various activities and the amount of time pharmacy preceptors spent actively precepting students. Students were supplied with a study manual that consisted of an instruction sheet and an activity log and were given an adjustable random reminder device. When the beeper sounded, they were instructed to record their activity using a standard coding system. Students recorded 2,157 observations over the course of 226 study days. Students were alone over hair the time and spent very little time in contact with either prescribers or patients. Community-based externs had approximately ten times more contact with patients than hospital-based externs. Students spent the majority of their time in the dispensing area and were actively precepted 22.9 percent of the time during the study. Multidimensional work sampling can give externship coordinators information regarding student activities and preceptorship during externship rotations. This information can be used to monitor the externship to assure correlation between expected and actual activities, compare activities between sites, and provide important information regarding preceptor time commitments.

The distribution of drug product samples by pharmaceutical companies to a family medicine clinic was studied. Data on all deliveries of drug samples to the clinic site of a university-affiliated family medicine residency program from November 1992 through December 1993 were collected. In addition, the 11 faculty family physicians were surveyed about their experiences with the deliveries of samples. Forty-three manufacturers delivered samples of 331 drugs during the 14-month study period. There were 366 visits by the drug company representatives, who made 1117 separate deliveries. The total value of the samples, based on the average whole-sale price, was $240,782. Twenty-nine percent of the drugs were nonformulary, and only 49% were stocked by the pharmacy. The physicians surveyed indicated that they were either usually or always asked to sign for samples they did not in fact request, that they usually did not know what was recorded on the receipts for samples that they signed, and that they seldom verified what was actually delivered. Pharmaceutical manufactures delivered large quantities of drug samples during the study period, and many of the drugs were nonformulary or not stocked by the pharmacy. The physicians indicated that they were not well informed about delivered samples for which they signed receipts.