Acceleration of Graph Neural Network-Based Prediction Models in Chemistry via Co-Design Optimization on Intelligence Processing Units.

Atomic structure prediction and associated property calculations are the bedrock of chemical physics. Since high-fidelity ab initio modeling techniques for computing the structure and properties can be prohibitively expensive, this motivates the development of machine-learning (ML) models that make these predictions more efficiently. Training graph neural networks over large atomistic databases introduces unique computational challenges, such as the need to process millions of small graphs with variable size and support communication patterns that are distinct from learning over large graphs, such as social networks. We demonstrate a novel hardware-software codesign approach to scale up the training of atomistic graph neural networks (GNN) for structure and property prediction. First, to eliminate redundant computation and memory associated with alternative padding techniques and to improve throughput via minimizing communication, we formulate the effective coalescing of the batches of variable-size atomistic graphs as the bin packing problem and introduce a hardware-agnostic algorithm to pack these batches. In addition, we propose hardware-specific optimizations, including a planner and vectorization for the gather-scatter operations targeted for Graphcore's Intelligence Processing Unit (IPU), as well as model-specific optimizations such as merged communication collectives and optimized softplus. Putting these all together, we demonstrate the effectiveness of the proposed codesign approach by providing an implementation of a well-established atomistic GNN on the Graphcore IPUs. We evaluate the training performance on multiple atomistic graph databases with varying degrees of graph counts, sizes, and sparsity. We demonstrate that such a codesign approach can reduce the training time of atomistic GNNs and can improve their performance by up to 1.5× compared to the baseline implementation of the model on the IPUs. Additionally, we compare our IPU implementation with a Nvidia GPU-based implementation and show that our atomistic GNN implementation on the IPUs can run 1.8× faster on average compared to the execution time on the GPUs.

Proposed regulations for research with biospecimens: responses from stakeholders at CTSA consortium institutions.

Secondary research with biospecimens acquired through clinical care and through research is often conducted without the informed consent of individuals from whom the specimens were acquired. While such uses are consistent with the current federal regulations, surveys of the general public suggest that many individuals would prefer more information and choice regarding research use of biospecimens. The federal government issued an Advance Notice of Proposed Rulemaking (ANPRM) in 2011 that proposed a number of potential changes in the regulations governing human subjects. These proposed regulations are particularly pertinent to institutions committed to research involving human subjects-including institutions in the NIH-funded Clinical and Translational Science Awards (CTSA) consortium. In this study, we reviewed public responses by CTSA-funded institutions and CTSA-affiliated organizations and groups regarding the proposed changes in the ANPRM with respect to research with biospecimens. Our results indicate that the majority of responses to the ANPRM from CTSA institutions were not supportive of the proposed changes. While many responses acknowledge a need to change current research practices regarding biospecimens, the proposed changes in the ANPRM received only limited support from this subgroup of academic research institutions.

Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations.

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.

Assessment of U.S. heart transplantation equity as a function of race: Observational analyses of the OPTN database.

Background: Racial disparities in heart transplantation (HT) outcomes are suspected but uncertain. The additional impact of a recent change in donor allocation on disparities in HT in the United States (US) is unknown. We hypothesize racial disparities in HT are present and may be worsened by new allocation practices. Methods: Cohort: Adults listed for HT before and after a heart allocation policy change (Era 1: Oct 18th, 2015 - Oct 18th, 2018, Era 2: Oct 18th, 2018-June 30, 2021). The primary outcome was the rate of HT by race (Black vs. White), assessed using multivariable competing risk analysis (compete: waitlist removal for death or clinical deterioration). Final adjusted models included co-morbidities, SES and community-level Social Determinants of Health. The secondary outcome was waitlist removal for death or clinical deterioration. Results: Of 17,384 waitlist candidates (Era 1: 9,150, Era 2: 8,234), Black waitlist candidates had a lower rate of HT compared to White waitlist candidates in Era 1 (adjusted HR 0·90, 95 % CI 0·84-0·97, p = 0·0053) and in Era 2 (adjusted HR 0·81, 95 % CI 0·75-0·88, p <0·0001, era race interaction p=0·056). The rate of waitlist removal for death or deterioration was similar between races in Era 1 (adjusted HR 0·92, 95 % 0·77-1·1, p = 0·38), but increased for Black candidates in Era 2 (adjusted HR 1·34, 95 % CI 1·09-1·65, p = 0·0054, era race interaction p = 0·0051). Interpretation: Both the measured rate of transplantation and rate of delisting for death or clinical deterioration have worsened for Black compared to White waitlist candidates under the new allocation system. Causes for these disparities require further study. Funding: University of Minnesota Department of Cardiology funds.

HIF activation enhances FcγRIIb expression on mononuclear phagocytes impeding tumor targeting antibody immunotherapy.

BACKGROUND: Hypoxia is a hallmark of the tumor microenvironment (TME) and in addition to altering metabolism in cancer cells, it transforms tumor-associated stromal cells. Within the tumor stromal cell compartment, tumor-associated macrophages (TAMs) provide potent pro-tumoral support. However, TAMs can also be harnessed to destroy tumor cells by monoclonal antibody (mAb) immunotherapy, through antibody dependent cellular phagocytosis (ADCP). This is mediated via antibody-binding activating Fc gamma receptors (FcγR) and impaired by the single inhibitory FcγR, FcγRIIb. METHODS: We applied a multi-OMIC approach coupled with in vitro functional assays and murine tumor models to assess the effects of hypoxia inducible factor (HIF) activation on mAb mediated depletion of human and murine cancer cells. For mechanistic assessments, siRNA-mediated gene silencing, Western blotting and chromatin immune precipitation were utilized to assess the impact of identified regulators on FCGR2B gene transcription. RESULTS: We report that TAMs are FcγRIIbbright relative to healthy tissue counterparts and under hypoxic conditions, mononuclear phagocytes markedly upregulate FcγRIIb. This enhanced FcγRIIb expression is transcriptionally driven through HIFs and Activator protein 1 (AP-1). Importantly, this phenotype reduces the ability of macrophages to eliminate anti-CD20 monoclonal antibody (mAb) opsonized human chronic lymphocytic leukemia cells in vitro and EL4 lymphoma cells in vivo in human FcγRIIb+/+ transgenic mice. Furthermore, post-HIF activation, mAb mediated blockade of FcγRIIb can partially restore phagocytic function in human monocytes. CONCLUSION: Our findings provide a detailed molecular and cellular basis for hypoxia driven resistance to antitumor mAb immunotherapy, unveiling a hitherto unexplored aspect of the TME. These findings provide a mechanistic rationale for the modulation of FcγRIIb expression or its blockade as a promising strategy to enhance approved and novel mAb immunotherapies.

Remote Musculoskeletal Assessment Framework: A Guide for Primary Care.

Introduction Remote consulting has exploded into primary care following the initial COVID-19 surge as a measure to reduce potential cross-infection (staff-patient or patient-patient). Musculoskeletal (MSK) conditions comprise up to 21% of the annual primary care caseload in England. Established techniques for MSK examination, however, rely on face-to-face attendance. Evidence-based guidance for remote MSK assessment is required to ensure the quality of care is maintained with the move from face-to-face to virtual consultations. Method A literature review of published evidence and current guidelines was conducted. The most appropriate remote consultation techniques and MSK examinations were identified and where there was no evidence, modified examination tests were developed from established face-to-face examination techniques. A concise, accessible framework for remote MSK assessment in primary care was then created and tested on a non-medically trained volunteer. Results Over 2232 papers and articles were identified by search headings, reducing to 28 sources that had relevant content. At the time of searching, there was no published evidence relating to MSK remote consultation in a primary care setting. However, evidence was found in the physiotherapy and rehabilitation literature for the efficacy and practicality of MSK teleconsultation. MSK remote examination framework From this literature and with the addition of modified established examinations, an MSK assessment framework was constructed. This framework provides pre-consultation guidance and step-by-step remote examination instructions. Patient and clinician resources (including a patient information leaflet and photographic examples of examinations) were created as supplementary material. Conclusion Due to the frameshift away from face-to-face consultation, primary care clinicians have found themselves lacking an evidence base or practical guidance to support remote MSK assessment. This paper is a systematic literature review of MSK telemedicine from which practical advice and evidence-based MSK tests have been developed. Where there is no evidence, modified traditional tests are suggested to allow a complete framework for remote MSK examination - using a system approach of 'look, point, move' followed by modified special tests, for use in a primary care setting as a 'ready-to-use' practical guide to remote MSK assessment, presented in a downloadable format. What did this add? With 21% of primary care consultations relating to MSK conditions and limited means of performing face-to-face MSK examination due to COVID-19, there needs to be a recognised framework for assessing the MSK system remotely. To the best of our knowledge, this evidence does not exist for primary care remote MSK examination. This paper demonstrates evidence-based practical advice (from non-primary care settings) and modified MSK examinations to be used in a primary care MSK remote consultation.

The validation of a new scoring method for assessing ego development based on three dimensions of language.

We describe research on the validity of a new theoretical framework and scoring methodology, called STAGES, for sentence completion tests of meaning-making maturity or complexity (also called ego development or perspective-taking capacity). STAGES builds upon research on the substantially validated Washington University Sentence Completion Test of Jane Loevinger as updated by Susanne Cook-Greuter. STAGES proposes an underlying structural explanation for the Cook-Greuter system based on three dimensions. Two of these are polar factors: individual/collective, and passive/active; and the third is a categorization of the sophistication of the types of objects referred to (i.e. as concrete, subtle/abstract, or "metaware"). We describe two validation studies for the STAGES scoring method and model. The first is a replication study of concurrent validity, using 73 inventories to test the hypothesis that the STAGES scoring method replicates the Cook-Greuter scoring method. Using the weighted Kappa statistic, we demonstrate a very strong match between the two methods, confirming the first hypothesis. This study includes levels up to and including Strategist (i.e. a substantial percentage of test-takers from most populations). Levels above Strategist were validated using another method because (1) there is less Cook-Greuter data available at these levels, and (2) the two scoring methods diverge sufficiently, making comparison difficult. The second study, of 71 inventories, attempts to validate the STAGES scoring method at levels above Strategist by testing the inter-rater reliability among four scorers. The inter-rater reliability above Strategist, using the weighted Kappa statistic, was found to be moderate to substantial, indicating that the instrument and scoring method has internal validity for these four, rare higher levels. Additionally, the inter-rater reliability over all STAGES levels were found to be very strong.

BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression.

Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, MYC inhibitors have been difficult to develop. Alternatively, inhibitors of epigenetic/ transcriptional regulators, particularly the bromodomain and extraterminal (BET) family, have been used to modulate MYC. However, current benzodiazepine-derivative BET inhibitors (BETi) elicit disappointing responses and dose-limiting toxicity in relapsed/refractory lymphoma, potentially because of enrichment of high-risk molecular features and chemical backbone-associated toxicities. Consequently, novel nonbenzodiazepine BETi and improved mechanistic understanding are required. Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Both invoked BIM-dependent apoptosis and in vivo therapy, associated with miR-17∼92 repression, in murine Eµ-myc lymphomas, with PLX2853 exhibiting enhanced potency. Accordingly, exogenous BCL-2 expression abrogated these effects. Because high BCL-2 expression is common in diffuse large B-cell lymphoma (DLBCL), BETi were ineffective in driving apoptosis and in vivo therapy of DLBCL cell lines, mirroring clinical results. However, BETi-mediated BIM upregulation and miR-17∼92 repression remained intact. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL.

Preliminary experience of 99mTc-Aprotinin scintigraphy in amyloidosis.

BACKGROUND AND AIM: Radio-labelled Aprotinin has been shown to bind with amyloid fibrils in vitro as well as in vivo. The aim was to test the usefulness of 99mTc-Aprotinin imaging in systemic amyloidosis. METHODS: Thirty-five cases who had 99mTc-Aprotinin scans for the assessment of systemic amyloidosis were reviewed retrospectively. Eighteen had biopsy-proven amyloidosis and 17 were controls (amyloidosis was excluded by negative biopsies and non-invasive tests). Five of 18 patients with amyloidosis had final diagnosis of cardiac amyloid. RESULTS: Physiological uptake of 99mTc-Aprotinin was noted in the urinary tract (kidneys and bladder) and in the liver of all patients and controls; and non-specific uptake of 99mTc-Aprotinin was visualised in the spleen and oro-facial structures in the majority of both groups. Myocardial 99mTc-Aprotinin uptake was noted in all five patients with final diagnosis of cardiac amyloidosis and in none of the 30 subjects who did not have cardiac amyloid. The median heart to background uptake ratio was 2.0 in cardiac amyloid patients and 1.1 in subjects without cardiac amyloid (P = 0.0004). Single Photon Emission Tomography (SPECT) studies of the thorax confirmed that the site of uptake lay within the myocardium. In the amyloidosis group, site-specific 99mTc-Aprotinin uptake was also identified in the subcutaneous tissue of the legs and in a breast nodule shown to be positive for amyloidosis on biopsy. CONCLUSIONS: 99mTc-Aprotinin imaging may be a useful non-invasive method for the assessment of the presence and extent of extra-abdominal amyloid, particularly cardiac amyloidosis. It has little role in diagnosis of amyloidosis involving the oro-facial and abdominal structures.

Long-lived radiopharmaceuticals: dispensing from multidose vials.

We report the use of broth simulation as a means of validating the practice of sub-dispensing from stock vials of long-lived sterile radiopharmaceuticals. 'Matched' vials of nutrient broth accompanied the stock vials of long-lived sterile radiopharmaceuticals during their time in use and were subject to the same handling and storage procedures. At the end of the life of each radiopharmaceutical stock vial, the matching broth residue was sent for incubation and reporting. The results to date have yielded no reports of microbial contamination in any of the simulated broths (0 in 256).