Exploiting Multi-Level Parallelism in Streaming Applications for Heterogeneous Platforms with GPUs

Heterogeneous computing platforms support the traditional types of parallelism, such as e.g., instruction-level, data, task, and pipeline parallelism, and provide the opportunity to exploit a combination of different types of parallelism at different platform levels. The architectural diversity of platform components makes tapping into the platform potential a challenging programming task. This thesis makes an important step in this direction by introducing a novel methodology for automatic generation of structured, multi-level parallel programs from sequential applications. We introduce a novel hierarchical intermediate program representation (HiPRDG) that captures the notions of structure and hierarchy in the polyhedral model used for compile-time program transformation and code generation. Using the HiPRDG as the starting point, we present a novel method for generation of multi-level programs (MLPs) featuring different types of parallelism, such as task, data, and pipeline parallelism. Moreover, we introduce concepts and techniques for data parallelism identification, GPU code generation, and asynchronous data-driven execution on heterogeneous platforms with efficient overlapping of host-accelerator communication and computation. By enabling the modular, hybrid parallelization of program model components via HiPRDG, this thesis opens the door for highly efficient tailor-made parallel program generation and auto-tuning for next generations of multi-level heterogeneous platforms with diverse accelerators.Computer Systems, Imagery and Medi

Exploiting Multi-Level Parallelism in Streaming Applications for Heterogeneous Platforms with GPUs

Heterogeneous computing platforms support the traditional types of parallelism, such as e.g., instruction-level, data, task, and pipeline parallelism, and provide the opportunity to exploit a combination of different types of parallelism at different platform levels. The architectural diversity of platform components makes tapping into the platform potential a challenging programming task. This thesis makes an important step in this direction by introducing a novel methodology for automatic generation of structured, multi-level parallel programs from sequential applications. We introduce a novel hierarchical intermediate program representation (HiPRDG) that captures the notions of structure and hierarchy in the polyhedral model used for compile-time program transformation and code generation. Using the HiPRDG as the starting point, we present a novel method for generation of multi-level programs (MLPs) featuring different types of parallelism, such as task, data, and pipeline parallelism. Moreover, we introduce concepts and techniques for data parallelism identification, GPU code generation, and asynchronous data-driven execution on heterogeneous platforms with efficient overlapping of host-accelerator communication and computation. By enabling the modular, hybrid parallelization of program model components via HiPRDG, this thesis opens the door for highly efficient tailor-made parallel program generation and auto-tuning for next generations of multi-level heterogeneous platforms with diverse accelerators.</table

Azathioprine metabolite levels and outcomes during pregnancies with rheumatic disease

Objective Despite widespread use of azathioprine (AZA) during pregnancy, no studies evaluated the impact of pregnancy on AZA metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN) disposition in rheumatic diseases. This study characterises changes in AZA metabolite concentrations throughout pregnancy in women with rheumatic disease and explores relationships between metabolite concentrations, maternal disease activity, and neonatal outcomes.Methods Patients with rheumatic disease from a single centre prescribed AZA prior to pregnancy and ≥1 blood sample during pregnancy (5/2016 to 4/2022) were included. Commercial laboratories quantified AZA metabolite concentrations. The upper safety limit for 6-MMPN was &gt;5700 pmol/8×108 RBC. The therapeutic target for 6-TGN was ≥159 pmol/8×108 RBC. Repeated correlation measures were used to evaluate the relationship between metabolite concentrations and pregnancy duration, and the relationship between 6-TGN concentration and SLE Physician Global Assessment (PGA). The relationship between pregnancy average 6-TGN and neonatal gestational age at birth was analysed using linear regression.Results Thirty-seven pregnancies in 35 women with 108 serum samples were included. There was no significant difference in dose-adjusted 6-TGN concentrations across pregnancy and peripartum, whereas 6-MMPN concentrations appeared higher during pregnancy. No elevated transaminases or cholestasis were observed concurrently with 6-MMPN above 5700 pmol/8×108 RBC. Metabolite concentrations were related to total AZA dosage, weight-based dosage and TPMT phenotype. In pregnant women with SLE achieving average 6-TGN in the therapeutic range, we observed a non-significant reduction in PGA and increase in neonatal gestational age at birth.Conclusions In this exploratory study, we did not observe systematic changes in 6-TGN concentrations throughout pregnancy and peripartum, whereas 6-MMPN concentrations were higher during pregnancy. Monitoring AZA metabolite concentrations in pregnancy is a potential tool to identify medication non-adherence as well as patients with high 6-MMPN in whom dosage adjustment or close laboratory monitoring may optimise safety

Adverse Reactions in a Phase 1 Trial of the Anti-Malarial DM1157: An Example of Pharmacokinetic Modeling and Simulation Guiding Clinical Trial Decisions

Introduction: There is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P. falciparum from heme toxicity. We describe a first-in-human, phase 1 trial of DM1157 in healthy adult volunteers that was halted early because of significant toxicity. Methods: Adverse events were summarized using descriptive statistics. We used pharmacokinetic modeling to quantitatively assess whether the DM1157 exposure needed for P. falciparum inhibition was achievable at safe doses. Results: We found that there was no dose where both the safety and efficacy target were simultaneously achieved; conversely, the model predicted that 27 mg was the highest dosage at which patients would consistently maintain safe exposure with multiple dosing. By pre-defining dose escalation stopping rules and conducting an interim pharmacokinetic/pharmacodynamic analysis, we determined that the study would be unable to safely achieve a dosage needed to observe an anti-malarial effect, thereby providing strong rationale to halt the study. Conclusion: This study provides an important example of the risks and challenges of conducting early phase research as well as the role of modeling and simulation to optimize participant safety (ClinicalTrials.gov, NCT03490162)

Increasing contraception use among women receiving teratogenic medications in a rheumatology clinic

Teratogenic medications are often prescribed to women of childbearing age with autoimmune diseases. Literature suggests that appropriate use of contraception among these women is low, potentially resulting in high-risk unintended pregnancies. Preliminary review in our clinic showed suboptimal documentation of women’s contraceptive use. We therefore designed a quality improvement initiative to target three process measures: documentation of contraception usage and type, contraception counselling and provider action after counselling. We reviewed charts of rheumatology clinic female patients aged 18–45 over the course of 10 months; for those who were on teratogenic medications (methotrexate, leflunomide, mycophenolate and cyclophosphamide), we looked for evidence of documentation of contraception use. We executed multiple plan-do-study-act (PDSA) cycles to develop and evaluate interventions, which centred on interprofessional provider education, modification of electronic medical record (EMR) templates, periodic provider reminders, patient screening questionnaires and frequent feedback to providers on performance. Among eligible patients (n=181), the baseline rate of documentation of contraception type was 46%, the rate of counselling was 30% and interventions after counselling occurred in 33% of cases. Averaged intervention data demonstrated increased provider performance in all three domains: documentation of contraception type increased to 64%, counselling to 45% and provider action to 46%. Of the patients with documented contraceptives, 50% used highly effective, 27% used effective and 23% used ineffective contraception methods. During this project, one unintentional pregnancy occurred in a patient on methotrexate not on contraception. Our interventions improved three measures related to contraception counselling and documentation, but there remains a need for ongoing quality improvement efforts in our clinic. This high-risk population requires increased provider engagement to improve contraception compliance, coupled with system-wide EMR changes to increase sustainability

Delivering clinical trials at home: protocol, design and implementation of a direct-to-family paediatric lupus trial

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302)