Molecular contribution to embryonic aneuploidy and karyotypic complexity in initial cleavage divisions of mammalian development.

Embryonic aneuploidy is highly complex, often leading to developmental arrest, implantation failure or spontaneous miscarriage in both natural and assisted reproduction. Despite our knowledge of mitotic mis-segregation in somatic cells, the molecular pathways regulating chromosome fidelity during the error-prone cleavage-stage of mammalian embryogenesis remain largely undefined. Using bovine embryos and live-cell fluorescent imaging, we observed frequent micro-/multi-nucleation of mis-segregated chromosomes in initial mitotic divisions that underwent unilateral inheritance, re-fused with the primary nucleus or formed a chromatin bridge with neighboring cells. A correlation between a lack of syngamy, multipolar divisions and asymmetric genome partitioning was also revealed, and single-cell DNA-seq showed propagation of primarily non-reciprocal mitotic errors. Depletion of the mitotic checkpoint protein BUB1B (also known as BUBR1) resulted in similarly abnormal nuclear structures and cell divisions, as well as chaotic aneuploidy and dysregulation of the kinase-substrate network that mediates mitotic progression, all before zygotic genome activation. This demonstrates that embryonic micronuclei sustain multiple fates, provides an explanation for blastomeres with uniparental origins, and substantiates defective checkpoints and likely other maternally derived factors as major contributors to the karyotypic complexity afflicting mammalian preimplantation development.

Single-cell sequencing of primate preimplantation embryos reveals chromosome elimination via cellular fragmentation and blastomere exclusion.

Aneuploidy that arises during meiosis and/or mitosis is a major contributor to early embryo loss. We previously showed that human preimplantation embryos encapsulate missegregated chromosomes into micronuclei while undergoing cellular fragmentation and that fragments can contain chromosomal material, but the source of this DNA was unknown. Here, we leveraged the use of a nonhuman primate model and single-cell DNA-sequencing (scDNA-seq) to examine the chromosomal content of 471 individual samples comprising 254 blastomeres, 42 polar bodies, and 175 cellular fragments from a large number (N = 50) of disassembled rhesus cleavage-stage embryos. Our analysis revealed that the aneuploidy and micronucleation frequency is conserved between humans and macaques, and that fragments encapsulate whole and/or partial chromosomes lost from blastomeres. Single-cell/fragment genotyping showed that these chromosome-containing cellular fragments (CCFs) can be maternally or paternally derived and display double-stranded DNA breaks. DNA breakage was further indicated by reciprocal subchromosomal losses/gains between blastomeres and large segmental errors primarily detected at the terminal ends of chromosomes. By combining time-lapse imaging with scDNA-seq, we determined that multipolar divisions at the zygote or two-cell stage were associated with CCFs and generated a random mixture of chromosomally normal and abnormal blastomeres with uniparental or biparental origins. Despite frequent chromosome missegregation at the cleavage-stage, we show that CCFs and nondividing aneuploid blastomeres showing extensive DNA damage are prevented from incorporation into blastocysts. These findings suggest that embryos respond to chromosomal errors by encapsulation into micronuclei, elimination via cellular fragmentation, and selection against highly aneuploid blastomeres to overcome chromosome instability during preimplantation development.

VariantQC: a visual quality control report for variant evaluation.

SUMMARY: Large scale genomic studies produce millions of sequence variants, generating datasets far too massive for manual inspection. To ensure variant and genotype data are consistent and accurate, it is necessary to evaluate variants prior to downstream analysis using quality control (QC) reports. Variant call format (VCF) files are the standard format for representing variant data; however, generating summary statistics from these files is not always straightforward. While tools to summarize variant data exist, they generally produce simple text file tables, which still require additional processing and interpretation. VariantQC fills this gap as a user friendly, interactive visual QC report that generates and concisely summarizes statistics from VCF files. The report aggregates and summarizes variants by dataset, chromosome, sample and filter type. The VariantQC report is useful for high-level dataset summary, quality control and helps flag outliers. Furthermore, VariantQC operates on VCF files, so it can be easily integrated into many existing variant pipelines. AVAILABILITY AND IMPLEMENTATION: DISCVRSeq's VariantQC tool is freely available as a Java program, with the compiled JAR and source code available from https://github.com/BimberLab/DISCVRSeq/. Documentation and example reports are available at https://bimberlab.github.io/DISCVRSeq/.

mGAP: the macaque genotype and phenotype resource, a framework for accessing and interpreting macaque variant data, and identifying new models of human disease.

BACKGROUND: Non-human primates (NHPs), particularly macaques, serve as critical and highly relevant pre-clinical models of human disease. The similarity in human and macaque natural disease susceptibility, along with parallel genetic risk alleles, underscores the value of macaques in the development of effective treatment strategies. Nonetheless, there are limited genomic resources available to support the exploration and discovery of macaque models of inherited disease. Notably, there are few public databases tailored to searching NHP sequence variants, and no other database making use of centralized variant calling, or providing genotype-level data and predicted pathogenic effects for each variant. RESULTS: The macaque Genotype And Phenotype (mGAP) resource is the first public website providing searchable, annotated macaque variant data. The mGAP resource includes a catalog of high confidence variants, derived from whole genome sequence (WGS). The current mGAP release at time of publication (1.7) contains 17,087,212 variants based on the sequence analysis of 293 rhesus macaques. A custom pipeline was developed to enable annotation of the macaque variants, leveraging human data sources that include regulatory elements (ENCODE, RegulomeDB), known disease- or phenotype-associated variants (GRASP), predicted impact (SIFT, PolyPhen2), and sequence conservation (Phylop, PhastCons). Currently mGAP includes 2767 variants that are identical to alleles listed in the human ClinVar database, of which 276 variants, spanning 258 genes, are identified as pathogenic. An additional 12,472 variants are predicted as high impact (SnpEff) and 13,129 are predicted as damaging (PolyPhen2). In total, these variants are predicted to be associated with more than 2000 human disease or phenotype entries reported in OMIM (Online Mendelian Inheritance in Man). Importantly, mGAP also provides genotype-level data for all subjects, allowing identification of specific individuals harboring alleles of interest. CONCLUSIONS: The mGAP resource provides variant and genotype data from hundreds of rhesus macaques, processed in a consistent manner across all subjects ( https://mgap.ohsu.edu ). Together with the extensive variant annotations, mGAP presents unprecedented opportunity to investigate potential genetic associations with currently characterized disease models, and to uncover new macaque models based on parallels with human risk alleles.

Predictors of Survival in Patients with Advanced Gastrointestinal Malignancies Admitted to the Intensive Care Unit.

BACKGROUND: Patients with cancer have a high use of health care utilization at the end of life, which can frequently involve admissions to the intensive care unit (ICU). We sought to evaluate the predictors for outcome in patients with gastrointestinal (GI) cancer admitted to the ICU for nonsurgical conditions. PATIENTS AND METHODS: The primary objective was to determine the predictors of hospital mortality. Secondary objectives included investigating the predictors of ICU mortality and hospital overall survival (OS). All patients with GI cancer admitted to the ICU at the University of Texas MD Anderson Cancer Center between November 2012 and February 2015 were retrospectively analyzed. Cancer characteristics, treatment characteristics, and Sequential Organ Failure Assessment (SOFA) scores were analyzed for their effects on survival. RESULTS: The characteristics of the 200 patients were as follows: 64.5% male, mean age of 60 years, median SOFA score of 6.7, and tumor types of intestinal (37.5%), hepatobiliary/pancreatic (36%), and gastroesophageal (24%). The hospital mortality was 41%, and overall 6-month mortality was 75%. In multivariate analysis, high admission SOFA score > 5, poor tumor differentiation, and duration of metastatic disease ≤7 months were associated with increased hospital mortality. For OS, high admission SOFA score > 5, poor tumor differentiation, and patients who were not on active chemotherapy because of poor performance had worse outcome. In multivariate analysis, SOFA score remained significant for OS even after excluding patients who died in the ICU. CONCLUSION: For patients with metastatic GI cancer admitted to the ICU, SOFA score was predictive for both acute and long-term survival. A patient's chemotherapy treatment status was not predictive for hospital mortality but was for OS. The SOFA score should be utilized in all patients with GI cancer upon ICU admission for prognostication. IMPLICATIONS FOR PRACTICE: Patients with cancer have a high use of health care utilization at the end of life, which can frequently involve admissions to the intensive care unit (ICU). Although there have been substantial increases in duration of survival for patients with advanced metastatic cancer, their mortality after an ICU admission remains high. GI malignancy is considered one of the top three lethal cancers estimated in 2017. Survival of critically ill patients with advanced GI cancer should be evaluated to help guide treatment planning.

Older Patients With Hepatocellular Carcinoma Have More Advanced Disease, Lower Rates of Treatment, and Lower Survival.

GOALS: To evaluate age-specific disparities in cancer stage at diagnosis, receipt of treatment, and survival among adults with hepatocellular carcinoma (HCC). BACKGROUND: HCC has become the fastest rising cause of cancer-related deaths in the United States. The aging population coupled with the rising incidence of HCC will result in an emerging cohort of older patients with HCC placing significant burden health care systems. STUDY: Using 2003 to 2011 Surveillance, Epidemiology, and End Results data, a US population-based cancer registry, we retrospectively evaluated age-specific disparities in cancer stage at diagnosis, receipt of treatment, and survival among adults with HCC. Multivariate logistic regression models evaluated HCC stage at diagnosis and HCC treatment received. Multivariate Cox proportional hazard models evaluated long-term survival. RESULTS: Compared with HCC patients below 50 years old, patients aged 70 years or older were less likely to have HCC within Milan criteria [odds ratio, 0.58; confidence interval (CI), 0.54-0.63; P<0.001]. Older age was also associated with significantly lower rates of receiving HCC treatment. Even after adjusting for stage of disease, patients aged 70 years or older had the lowest odds of receiving any HCC treatment compared with patients below 50 years old (odds ratio, 0.52; CI, 0.46-0.60; P<0.001). On multivariate Cox regression, HCC patients aged 70 years or older had significantly lower survival compared with patients below 50 years old (hazards ratio, 1.22; CI, 1.15-1.30; P<0.001). CONCLUSIONS: Among US adults with HCC, patients aged 70 years or older were less likely to have HCC within Milan criteria at diagnosis, less likely to receive any HCC treatment, and had significantly lower long-term survival.

Race/ethnicity-specific disparities in cancer incidence, burden of disease, and overall survival among patients with hepatocellular carcinoma in the United States.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the fastest rising causes of cancer-related deaths in the United States, with disparities observed in cancer incidence and survival between ethnic groups. This report provides updated analyses on race-specific disparities in US HCC trends. METHODS: This large, population-based cohort study was conducted using Surveillance, Epidemiology, and End Results cancer registry data from 2003 to 2011 to investigate race-specific disparities in HCC incidence and survival. Survival was analyzed using Kaplan-Meier methods and multivariate Cox proportional-hazards models. RESULTS: From 2003 to 2011, Asians had the highest HCC incidence, followed by blacks, Hispanics, and non-Hispanic whites. During the same period, Hispanics had the greatest increase in HCC incidence (+35.8%), whereas Asians experienced a 5.5% decrease. Although patients aged ≥65 years had the highest HCC incidence among all racial/ethnic groups, the higher HCC incidence in Asians was observed only for patients ages <50 and ≥65 years, whereas HCC incidence among patients ages 50 to 64 years was similar among Asians, blacks, and Hispanics. The overall 5-year HCC survival rate was highest among Asians (26.1%; 95% confidence interval [CI], 24.5%-27.6%) and lowest among blacks (21.3%; 95% CI, 19.5%-23.1%). On multivariate regression, Asians (hazard ratio, 0.83; 95% CI, 0.79-0.87; P < .001) and blacks (hazard ratio, 0.94; 95% CI, 0.89-0.99; P = .01) had significantly higher survival compared with non-Hispanic whites. CONCLUSIONS: Asians were the only group to demonstrate a declining HCC incidence in the form of a shift from advanced HCC to more localized HCC. These findings most likely reflect improved screening and surveillance efforts for this group. Cancer 2016;122:2512-23. © 2016 American Cancer Society.

Birth cohort-specific disparities in hepatocellular carcinoma stage at diagnosis, treatment, and long-term survival.

BACKGROUND & AIMS: Individuals born between 1945 and 1965 account for nearly 75% of hepatitis C virus (HCV) infections in the United States. As this cohort ages, progressive HCV-related liver disease leading to cirrhosis and hepatocellular carcinoma (HCC) will place a significant burden on the healthcare system. We aim to evaluate birth cohort-specific disparities in HCC stage at diagnosis, treatment rates, and overall survival with a focus on the 1945-1965 birth cohort. METHODS: A population-based retrospective cohort study of adult patients with HCC identified in the Surveillance, Epidemiology, and End Results 2003-2011 registry evaluated birth cohort-specific disparities in the prevalence and outcomes of HCC, including multivariate logistic regression models to evaluate disparities in HCC stage at diagnosis and HCC treatment received. Birth cohort-specific survival was evaluated with Kaplan-Meier methods and multivariate Cox proportional hazard models. RESULTS: The proportion of HCC represented by the 1945-1965 cohort increased by 64% from 2003-2011, and accounted for 57.4% of all HCC in 2011. Compared to patients born after 1965, the 1945-1965 cohort were more likely to have HCC within Milan criteria (OR, 3.66; 95% CI, 3.13-4.28; p<0.001). However, among patients with HCC within Milan criteria, the 1945-1965 cohort had no difference in receipt of surgical treatment, but had higher overall long-term survival (HR, 0.82; 95% CI, 0.69-0.97; p<0.03). CONCLUSIONS: The 1945-1965 birth cohort accounts for the majority of HCC in the United States. Despite earlier HCC stage at diagnosis, no difference in receipt of surgical treatment was observed, but higher overall survival was achieved.

Race/Ethnicity-specific Disparities in Hepatocellular Carcinoma Stage at Diagnosis and its Impact on Receipt of Curative Therapies.

GOALS: To evaluate race/ethnicity-specific disparities in hepatocellular carcinoma (HCC) stage at diagnosis and how this impacts receiving curative therapies. BACKGROUND: HCC is a leading cause of morbidity and mortality worldwide. The highest incidence of HCC is seen among ethnic minorities in the United States. STUDY: Using the 2003-2011 Surveillance, Epidemiology, and End Results database and United Network of Organ Sharing, population-based registries for cancer and liver transplantation (LT) in the United States, race/ethnicity-specific cancer stage at diagnosis and treatment received among adults with HCC were evaluated. RESULTS: Compared with non-Hispanic whites, blacks had significantly more advanced HCC at diagnosis [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.10-1.30; P<0.001], whereas Asians were less likely to have advanced disease (OR, 0.87; CI, 0.80-0.94; P<0.001). Among patients with HCC meeting Milan criteria, Hispanics (OR, 0.64; 95% CI, 0.57-0.71; P<0.001) and blacks (OR, 0.67; 95% CI, 0.59-0.76; P<0.001) were significantly less likely to receive curative therapy (resection or LT), whereas Asians were more likely to receive curative therapy (OR, 1.22; 95% CI, 1.10-1.35; P<0.001) compared with non-Hispanic whites. However, Asians (OR, 0.49; 95% CI, 0.42-0.58; P<0.001) and Hispanics (OR, 0.51; 95% CI, 0.44-0.60; P<0.001) were less likely to receive LT. CONCLUSIONS: Among US adults with HCC, blacks consistently had more advanced stage at diagnosis and lower rates of receiving treatment. After correcting for cancer stage and evaluating the subset of patients eligible for curative therapies, blacks and Hispanics had significantly lower rates of curative HCC treatment.

The first wave of the 1918 influenza pandemic among soldiers of the Canadian expeditionary force.

OBJECTIVES: This article evaluates the evidence for the presence of the first, mild wave of the 1918 influenza pandemic among soldiers in the Canadian Expeditionary Force (CEF). METHODS: Death records for soldiers in the CEF who died in Canada in 1917 and 1918 were extracted from the Commonwealth War Graves Commission and record-linked to the Canada War Graves Registers, Circumstances of Casualty database. Monthly mortality rates from pneumonia and influenza (P&I) were compared with mortality rates from all other causes for 1917 and 1918, and by region for 1918. RESULTS: The herald wave of influenza was present among CEF soldiers in 1918. P&I mortality was significantly higher in March and April 1918 than during the same period in 1917. P&I mortality rates varied across the country and were significantly higher among soldiers who died in the Maritime region of Canada. In March, Maritime P&I mortality was significantly higher than its counterpart in the West; in April it was significantly higher than P&I mortality in both the Central and Western regions. CONCLUSIONS: The CEF findings suggest that local, geographic heterogeneity characterized the first wave of the 1918 influenza pandemic in Canada and illustrate the ways in which well-established, historical patterns of cross-border social contact with the United States, coupled with the special conditions created by warfare, disproportionately funnelled influenza into particular regions. Identification of the mild first wave among soldiers in the CEF calls for more research on the civilian experience of both waves of influenza in Canada.

Sepsis prediction, early detection, and identification using clinical text for machine learning: a systematic review.

OBJECTIVE: To determine the effects of using unstructured clinical text in machine learning (ML) for prediction, early detection, and identification of sepsis. MATERIALS AND METHODS: PubMed, Scopus, ACM DL, dblp, and IEEE Xplore databases were searched. Articles utilizing clinical text for ML or natural language processing (NLP) to detect, identify, recognize, diagnose, or predict the onset, development, progress, or prognosis of systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock were included. Sepsis definition, dataset, types of data, ML models, NLP techniques, and evaluation metrics were extracted. RESULTS: The clinical text used in models include narrative notes written by nurses, physicians, and specialists in varying situations. This is often combined with common structured data such as demographics, vital signs, laboratory data, and medications. Area under the receiver operating characteristic curve (AUC) comparison of ML methods showed that utilizing both text and structured data predicts sepsis earlier and more accurately than structured data alone. No meta-analysis was performed because of incomparable measurements among the 9 included studies. DISCUSSION: Studies focused on sepsis identification or early detection before onset; no studies used patient histories beyond the current episode of care to predict sepsis. Sepsis definition affects reporting methods, outcomes, and results. Many methods rely on continuous vital sign measurements in intensive care, making them not easily transferable to general ward units. CONCLUSIONS: Approaches were heterogeneous, but studies showed that utilizing both unstructured text and structured data in ML can improve identification and early detection of sepsis.

Clinical factors and outcomes of subsegmental pulmonary embolism in cancer patients.

In the cancer population, patients diagnosed with venous thromboembolism (VTE) are considered to have a threefold increased risk of mortality compared with those without VTE. With the advent of modern computed tomography (CT), the rate of diagnosis of subsegmental pulmonary embolism (SSPE) has increased, likely as a result of improved visualization of the peripheral pulmonary arteries. The clinical significance of SSPE remains unclear because of the lack of randomized controlled clinical trials. The aim of this study was to identify the incidence and risk factors of recurrent proximal PE within 12 months of diagnosis of SSPE in cancer. We performed a retrospective analysis of 206 adult cancer patients who were diagnosed with SSPE from 2014 to 2016 at the University of Texas MD Anderson Cancer Center. At the time of SSPE diagnosis, the majority had metastatic cancer, 108 patients (53.2%) were undergoing chemotherapy, and 23 patients (11.2%) had a history of VTE. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Sixty-seven percent of SSPE was discovered incidentally on restaging CT scans, with the majority being a single and isolated event (70.9%). Within 12 months of SSPE diagnosis, 18 patients (8.7%) were found to have a recurrent PE. The patients treated with anticoagulation had a lower rate of PE recurrence (8% vs 13% in those not treated with anticoagulation). Treatment with anticoagulation did not appear to have a significant impact on overall survival (P = .48) when adjusted for ECOG performance status and cancer stage.

Outcomes of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11 mutation.

BACKGROUND: STK11 mutation (STK11m ) in patients (pts) with stage IV non-small cell lung cancer (NSCLC) is associated with inferior survival and poor response to immune checkpoint inhibitors (ICI). The significance of STK11m in stage III NSCLC pts treated with concurrent chemoradiation (CCRT) with or without consolidation ICI is unknown. METHODS: Stage III NSCLC patients who received CCRT and had known STK11 mutational status were included in this retrospective study. The data on the STK11m pts were collected from 4 cancer institutions. A cohort of pts with wild type STK11 (STK11w ) from the University of Iowa served as a comparison group. Patient demographics and clinical characteristics were collected. Cox regression models were used to explore the effect of STK11 mutation on survival. RESULTS: 75 pts with stage III NSCLC who had known STK11 mutational status were identified. 16/75 (21%) had STK11m . 5/16 with STK11 m did not receive CCRT so they were excluded from the analysis. The clinical and demographic characteristics for the 11 STK11m and 59 STK11w pts were not statistically different (STK11m vs. STK11w ): mean age: 57 vs. 64 yrs, non-squamous histology: 8/11 (73%) vs. 37/59 (63%), KRAS mutation: 3/11 (27%) vs. 11/59 (19%), TP53 mutation: 6/11 (55%) vs. 15/59 (25%), PD-L1 ≥50%: 1/8 (13%) vs. 10/32 (31%), and consolidation ICI 6/11 (55%) vs. 17/59 (29%). Regarding the 6 STK11m pts who received ICI (4 pembrolizumab, 2 durvalumab), the median number of ICI infusions was 8 (range, 3-17) vs. 6 (range, 1-25) in the 17 pts with STK11w who received ICI (durvalumab). After adjusting for performance status and cancer stage, multivariable analysis showed that progression free survival (PFS) for the STK11m pts was significantly worse than STK11 w pts (HR =2.25; 95% CI, 1.03-4.88, P=0.04), whereas overall survival (OS) showed no significant difference for STK11m vs. STK11w patients (HR 1.47, 95% CI, 0.49-4.38, P=0.49). CONCLUSIONS: In stage III NSCLC patients who received CCRT, STK11m was associated with worse PFS compared to STK11w . Larger studies are needed to further explore the prognostic implications of STK11m in stage III NSCLC and whether ICI impacts survival for this subgroup.

The Story of Angiogenesis Inhibitors in Non-small-cell Lung Cancer: The Past, Present, and Future.

The treatment of advanced non-small-lung cancer (NSCLC) has steadily evolved over the past 2 decades, and current therapy includes chemoimmunotherapy or targeted therapy with tyrosine kinase inhibitors (TKIs). Angiogenesis inhibitors were first approved in the mid-2000s in combination with chemotherapy for the treatment of NSCLC. The addition of anti-angiogenics to chemotherapy resulted in modest increases in survival when median overall survival was less than 1 year. More recently, the use of anti-angiogenics has fallen out of favor with the advent of checkpoint inhibitors and never-before-seen durable long-term responses. However, we postulate that there is still an important role for anti-angiogenics in this era of targeted therapy and checkpoint inhibitors in the treatment of NSCLC. Preclinical studies have shown that combination blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways leads to synergistic antitumor effects. These results have been replicated in the clinical setting in patients who harbor EGFR mutations, with VEGF inhibitor-TKI dual therapy leading to impressive survival outcomes. Similarly, combination treatment with checkpoint inhibitors and VEGF inhibitors have led to unprecedented survival outcomes in both advanced renal cell cancer as well as NSCLC. In this review, we explore the evolution of anti-angiogenic therapy in advanced NSCLC and discuss the clinical efficacy of angiogenesis inhibitors in combination with chemotherapy, TKI therapy, and checkpoint inhibitors.

Reducing patient and provider knowledge gaps: An evaluation of a community informed hepatitis C online course.

OBJECTIVES: Hepatitis C (HCV) knowledge gaps are associated with lower levels of engagement in (HCV) care which contributes to HCV-related morbidity and mortality. Knowledge gaps may be exacerbated by rapid changes in HCV care/treatment. Cost-effective, timely and easy-to-implement education is needed to address knowledge gaps and foster HCV engagement. METHODS: We developed a free, one-hour, online course for patients and providers. Online and facilitated course events were evaluated. Outcome measures included: pre/post-scores, perceived knowledge gains and increased capacity to educate/encourage engagement in HCV care. RESULTS: Total pre-post-test gains were significant (p < .001) across groups. Over 50% of participants reported: perceived knowledge gains of "A lot" or higher; the course increased their capacity to educate and encourage client engagement in care by "A lot" or higher. CONCLUSIONS: The evaluation confirmed ongoing patient and provider HCV knowledge gaps, significantly reduced those gaps, and increased provider's capacity to educate and encourage client engagement in HCV care. PRACTICE IMPLICATIONS: The course is an effective tool to address knowledge gaps that might lower engagement in care. It is available to patients to use in the privacy of their own home or for providers for their personal use, to use with individuals or patient groups.