Unexpected Toxicities When Nivolumab Was Given as Maintenance Therapy following Allogeneic Stem Cell Transplantation.

Treatment options are limited for patients with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We conducted a pilot study to assess the tolerability and efficacy of low-dose nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT. Of the 4 patients enrolled in the study, all rapidly developed immune-related adverse events (irAEs); 2 patients experienced serious adverse events, including grade 4 neutropenia and grade 3 autoimmune encephalopathy. As a result of these unexpected severe toxicities, the study was closed to further enrollment. Even at low doses, nivolumab maintenance in the post allo-SCT setting can cause serious irAEs beyond graft-versus-host disease, and further studies of dosage and timing after allo-SCT are needed.

Deciphering the exact breakpoints of structural variations using long sequencing reads with DeBreak.

Long-read sequencing has demonstrated great potential for characterizing all types of structural variations (SVs). However, existing algorithms have insufficient sensitivity and precision. To address these limitations, we present DeBreak, a computational method for comprehensive and accurate SV discovery. Based on alignment results, DeBreak employs a density-based approach for clustering SV candidates together with a local de novo assembly approach for reconstructing long insertions. A partial order alignment algorithm ensures precise SV breakpoints with single base-pair resolution, and a k-means clustering method can report multi-allele SV events. DeBreak outperforms existing tools on both simulated and real long-read sequencing data from both PacBio and Nanopore platforms. An important application of DeBreak is analyzing cancer genomes for potentially tumor-driving SVs. DeBreak can also be used for supplementing whole-genome assembly-based SV discovery.

Accurate long-read de novo assembly evaluation with Inspector.

Long-read de novo genome assembly continues to advance rapidly. However, there is a lack of effective tools to accurately evaluate the assembly results, especially for structural errors. We present Inspector, a reference-free long-read de novo assembly evaluator which faithfully reports types of errors and their precise locations. Notably, Inspector can correct the assembly errors based on consensus sequences derived from raw reads covering erroneous regions. Based on in silico and long-read assembly results from multiple long-read data and assemblers, we demonstrate that in addition to providing generic metrics, Inspector can accurately identify both large-scale and small-scale assembly errors.

Development of a COVID-19 Application Ontology for the ACT Network.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that that are critical to COVID-19 research. The ontology contains over 50,000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for SARS-CoV-2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of nine academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.

Development of a Coronavirus Disease 2019 (COVID-19) Application Ontology for the Accrual to Clinical Trials (ACT) network.

Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that are critical to COVID-19 research. The ontology contains over 50 000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for severe acute respiratory syndrome coronavirus 2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of 9 academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.

Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults.

Adolescents and young adults (AYAs) with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) represent a unique patient population with a disproportionate survival disadvantage compared with younger children. Substantial progress has been made as we began to understand and address the multifaceted drivers behind this outcome disparity. New insights into the biology of B-cell ALL have uncovered distinct genetic characteristics more commonly found in AYAs that affect prognosis. Dramatic improvements in survival have been achieved with the use of pediatric-inspired protocols in the front-line setting, as well as antibody-based and chimeric antigen receptor T-cell therapies in the relapsed and refractory setting. Guided by the incorporation of minimal residual disease testing to inform clinical decision making, these represent major paradigm shifts in management. Efforts to design clinical trials geared toward AYAs and to enroll AYAs in available clinical trials will ensure ongoing progress. Holistic care of AYAs with ALL further involves recognition of psychosocial issues arising as a consequence of their diagnosis and the delivery of age-appropriate supportive care.

AllergyMap: An Open Source Corpus of Allergy Mention Normalizations.

Allergy mention normalization is challenging because of the wide range of possible allergens including medications, foods, plants, animals, and consumer products. This paper describes the process of mapping free-text allergy information from an electronic health record (EHR) system in a university hospital to standard terminologies and migration of those data into an enterprise EHR system. The review, mapping, and migration revealed interesting issues and challenges with the free-text allergy information and the mapping in preparation for implementation in the new EHR system. These findings provide insights that can form the basis of guidelines for future mapping and migration efforts involving free-text allergy data. As part of this process, we generate and make freely available AllergyMap, a mapping between free-text entered allergy medication to standard non-proprietary ontologies. To our knowledge, this is the first such mapping available and could serve as a public resource for allergy mention normalization and system evaluation.

The past, present, and future of CRM1/XPO1 inhibitors.

Therapies targeted at inhibiting nucleo-cytoplasmic transport have found broad applications in the field of oncology. Chromosome region maintenance 1 (CRM1), better known as exportin 1 (XPO1), is the protein transporter responsible for the nucleo-cytoplasmic shuttling of most of the tumor suppressor proteins (TSP) and growth regulatory factors. XPO1 is also upregulated in many malignancies and associated with a poor prognosis. Its inhibition has been a target of therapy, and hence, the selective inhibitors of nuclear transport (SINE) compounds were developed as a novel class of anti-cancer agents. The most well-known SINE agent is selinexor (KPT-330) and has been widely tested in phase I and II clinical trials in both solid tumors and hematologic malignancies. This review discusses how dysregulation of XPO1 promotes tumorigenesis, the historical considerations in the development of SINE compounds, and their role in current clinical therapies.

Interface terminologies: bridging the gap between theory and reality for Africa.

In the United States and Europe, electronic health records (EHRs) allow information technology and decision-support to facilitate the activities of clinicians and are considered an important component of health care improvement. However, actual adoption of EHRs by physicians has been slow and the use of decision support has been minimal. Part of the difficulty lies in the challenges that users face in capturing structured clinical information. Reference and administrative terminologies have been in use for many years and provide a critical infrastructure to support reimbursement, decision-support and data analysis. The problem is that physicians do not think and work using reference terminologies. Interface terminologies bridge the gap between information that is in the physician's mind and information that can be interpreted by computer applications. The maps from interface terminologies to appropriate reference terminologies enable advanced functionality in clinical information systems. The conflict between the need for timely adoption of health information technology and the need for standardization is also relevant to the problems faced by health information technology in Africa. The problem of clinicians having to communicate and/or record information in a format that is acceptable to someone else, somewhere else, leaves the true benefits of these systems beyond the reach of most in Africa. There is a growing effort in the United States to produce clinically-relevant interface terminologies mapped to standards. These interface terminologies can be expanded to incorporate the languages and clinical requirements of clinicians in Africa. The adoption of interface terminologies will help bring the value of standard terminology and the resulting benefits of decision-support, data analysis and information retrieval to parts of the world where they are needed most.

A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia.

BACKGROUND: Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents. METHODS: We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito). RESULTS: Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction. CONCLUSION: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m2/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015.

Classifying Clinical Trial Eligibility Criteria to Facilitate Phased Cohort Identification Using Clinical Data Repositories.

A major challenge in using electronic health record repositories for research is the difficulty matching subject eligibility criteria to query capabilities of the repositories. We propose categories for study criteria corresponding to the effort needed for querying those criteria: "easy" (supporting automated queries), mixed (initial automated querying with manual review), "hard" (fully manual record review), and "impossible" or "point of enrollment" (not typically in health repositories). We obtained a sample of 292 criteria from 20 studies from ClinicalTrials.gov. Six independent reviewers, three each from two academic research institutions, rated criteria according to our four types. We observed high interrater reliability both within and between institutions. The analysis demonstrated typical features of criteria that map with varying levels of difficulty to repositories. We propose using these features to improve enrollment workflow through more standardized study criteria, self-service repository queries, and analyst-mediated retrievals.

Characterizing Teamwork in Cardiovascular Care Outcomes: A Network Analytics Approach.

BACKGROUND: The nature of teamwork in healthcare is complex and interdisciplinary, and provider collaboration based on shared patient encounters is crucial to its success. Characterizing the intensity of working relationships with risk-adjusted patient outcomes supplies insight into provider interactions in a hospital environment. METHODS AND RESULTS: We extracted 4 years of patient, provider, and activity data for encounters in an inpatient cardiology unit from Northwestern Medicine's Enterprise Data Warehouse. We then created a provider-patient network to identify healthcare providers who jointly participated in patient encounters and calculated satisfaction rates for provider-provider pairs. We demonstrated the application of a novel parameter, the shared positive outcome ratio, a measure that assesses the strength of a patient-sharing relationship between 2 providers based on risk-adjusted encounter outcomes. We compared an observed collaboration network of 334 providers and 3453 relationships to 1000 networks with shared positive outcome ratio scores based on randomized outcomes and found 188 collaborative relationships between pairs of providers that showed significantly higher than expected patient satisfaction ratings. A group of 22 providers performed exceptionally in terms of patient satisfaction. Our results indicate high variability in collaboration scores across the network and highlight our ability to identify relationships with both higher and lower than expected scores across a set of shared patient encounters. CONCLUSIONS: Satisfaction rates seem to vary across different teams of providers. Team collaboration can be quantified using a composite measure of collaboration across provider pairs. Tracking provider pair outcomes over a sufficient set of shared encounters may inform quality improvement strategies such as optimizing team staffing, identifying characteristics and practices of high-performing teams, developing evidence-based team guidelines, and redesigning inpatient care processes.

Community-acquired meningitis in older adults: clinical features, etiology, and prognostic factors.

OBJECTIVES: To investigate the epidemiology and outcomes of community-acquired meningitis in older adults. DESIGN: Retrospective study. SETTING: Participants adults in Houston, Texas, with community-acquired meningitis hospitalized between January 1, 2005, and January 1, 2010 (N = 619; n = 54, 8.7%, aged ≥65; n = 565 aged <65). METHODS: An adverse clinical outcome was defined as a Glasgow Outcome Scale score of 4 or less. RESULTS: Older adults had higher rates of comorbidities, abnormal neurological and laboratory (serum white blood cell count >12,000/µL, and cerebrospinal fluid protein >100 mg/dL) findings (P < .001), abnormalities on computed tomography and magnetic resonance imaging of the head (P = .002), and adverse clinical outcomes (ACOs) (P < .001). The majority of participants (65.8%) had meningitis of unknown etiology. Bacterial meningitis was an infrequent cause of community-acquired meningitis (7.4%). Of the known causes, bacterial meningitis and West Nile virus were more common in older than younger adults; younger participants more frequently had cryptococcal and viral meningitis. On logistic regression, female sex was predictive of a poor outcome in the older participants (P = .002), whereas abnormal neurological examination (P < .001), fever (P = .01), and a cerebrospinal fluid glucose level less than 45 mg/dL (P = .002) were significant poor prognostic factors in younger participants. CONCLUSION: Most cases of community-acquired meningitis are of unknown origin. Older adults are more likely than younger adults to have bacterial meningitis and West Nile virus infection when a cause can be identified. They also have more neurological abnormalities, laboratory and imaging abnormalities, and adverse clinical outcomes.

Olanzapine treatment is associated with reduced high molecular weight adiponectin in serum: a potential mechanism for olanzapine-induced insulin resistance in patients with schizophrenia.

Treatment of schizophrenia with olanzapine and other atypical antipsychotic agents is associated with insulin resistance and diabetes mellitus. The mechanism for this is not understood. Adiponectin is an insulin-sensitizing cytokine secreted by adipocytes. It is present in serum in multimers of varying size. Trimers and hexamers are referred to as low molecular weight (LMW) adiponectin. Larger multimers (12-, 18-, and 24-mers) have been designated high molecular weight (HMW) adiponectin and seem responsible for the insulin-sensitizing action of this adipokine. The aim of this study was to examine total adiponectin and LMW and HMW multimers in serum from patients with schizophrenia treated with either olanzapine (n = 9) or other typical antipsychotics (n = 9) and compare results with 16 healthy sex-, body mass index-, and age-matched controls. The effects of olanzapine on adiponectin protein expression and secretion in in vitro-differentiated primary human adipocytes were also examined. Patients receiving olanzapine had significantly lower total serum adiponectin as compared with those on conventional treatment and controls (5.23 +/- 1.53 ng/mL vs. 8.20 +/- 3.77 ng/mL and 8.78 +/- 3.8 ng/mL; P < 0.05 and P < 0.01, respectively). The HMW adiponectin was also reduced in patients on olanzapine as compared with the disease and healthy control groups (1.67 +/- 0.96 ng/mL vs. 3.87 +/- 2.69 ng/mL and 4.07 +/- 3.2 ng/mL; P < 0.05 for both). The LMW adiponectin was not different between patient groups (P = 0.15) but lower in patients on olanzapine as compared with controls (3.56 +/- 0.85 ng/mL vs. 4.70 +/- 1.4 ng/mL; P < 0.05). In vitro, short duration (up to 7 days) olanzapine exposure had no effect on total adiponectin expression or multimer composition of secreted protein. In summary, this study demonstrates a correlation between olanzapine treatment and reduced serum adiponectin, particularly HMW multimers. This may not be a direct effect of olanzapine on adipocyte expression or secretion of adiponectin. These observations provide insights into possible mechanisms for the association between olanzapine treatment and insulin resistance.

High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection.

BACKGROUND: Obesity is recognized as a cofactor in hepatitis C (HCV) liver injury. Adipokines may be the link between increasing body mass index (BMI) and disease progression in HCV. Adiponectin is an anti-inflammatory adipokine that is present in serum in a range of multimeric forms that appear to have different metabolic functions. METHODS: We studied 30 male patients with untreated chronic HCV (15 each with genotypes 1 and 3) and 12 controls. The three groups were matched for age and BMI. Total adiponectin and high (HMW) and low (LMW) molecular weight adiponectin multimers were measured. The relationships between adiponectin, BMI, insulin sensitivity, and liver histology were examined. RESULTS: Genotype 3 was associated with greater hepatic steatosis and inflammation than genotype 1. Patients with genotype 1 were less insulin sensitive than genotype 3, who had similar insulin sensitivity to controls. Insulin resistance was associated with a decrease in total and HMW adiponectin in both HCV and controls, while LMW adiponectin was unchanged. When the effect of genotype was examined, this association was present with genotype 3 but not genotype 1 infection. CONCLUSIONS: These data demonstrate that the relationship between insulin resistance and adiponectin is similar in controls and patients with genotype 3 but not genotype 1 infection. The greater degree of insulin resistance in genotype 1 appears to be a genotype-specific effect.

The SNOMED clinical terms development process: refinement and analysis of content.

SNOMED Clinical Terms is a comprehensive concept-based health care terminology that was created by merging SNOMED RT and Clinical Terms Version 3. Following the mapping of concepts and descriptions into a merged database, the terminology was further refined by adding new content, modeling the relationships of individual concepts, and reviewing the hierarchical structure. A quality control process was performed to ensure integrity of the data. Additional features such as subsets, qualifiers, and mappings to other coding systems were added or updated to facilitate usability. We then analyzed the content of the completed work. This paper describes the refinement processes and compares the actual content of SNOMED CT with the early data obtained from analysis of the description mapping process. As predicted, the majority of concepts in SNOMED CT originated from SNOMED RT or CTV3, but not both.