Seamless Integration of Computer-Adaptive Patient Reported Outcomes into an Electronic Health Record.

BACKGROUND: Patient-reported outcome (PRO) measures have become an essential component of quality measurement, quality improvement, and capturing the voice of the patient in clinical care. In 2004, the National Institutes of Health endorsed the importance of PROs by initiating the Patient-Reported Outcomes Measurement Information System (PROMIS), which leverages computer-adaptive tests (CATs) to reduce patient burden while maintaining measurement precision. Historically, PROMIS CATs have been used in a large number of research studies outside the electronic health record (EHR), but growing demand for clinical use of PROs requires creative information technology solutions for integration into the EHR. OBJECTIVES: This paper describes the introduction of PROMIS CATs into the Epic Systems EHR at a large academic medical center using a tight integration; we describe the process of creating a secure, automatic connection between the application programming interface (API) which scores and selects CAT items and Epic. METHODS: The overarching strategy was to make CATs appear indistinguishable from conventional measures to clinical users, patients, and the EHR software itself. We implemented CATs in Epic without compromising patient data security by creating custom middleware software within the organization's existing middleware framework. This software communicated between the Assessment Center API for item selection and scoring and Epic for item presentation and results. The middleware software seamlessly administered CATs alongside fixed-length, conventional PROs while maintaining the display characteristics and functions of other Epic measures, including automatic display of PROMIS scores in the patient's chart. Pilot implementation revealed differing workflows for clinicians using the software. RESULTS: The middleware software was adopted in 27 clinics across the hospital system. In the first 2 years of hospital-wide implementation, 793 providers collected 70,446 PROs from patients using this system. CONCLUSION: This project demonstrated the importance of regular communication across interdisciplinary teams in the design and development of clinical software. It also demonstrated that implementation relies on buy-in from clinical partners as they integrate new tools into their existing clinical workflow.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

Takotsubo Cardiomyopathy: An ST-Elevation Myocardial Infarction Mimic.

Takotsubo cardiomyopathy (TC), a rare syndrome often preceded by an emotional or physical trigger, which earned the nickname broken heart syndrome, was first diagnosed in 1990. Takotsubo cardiomyopathy can mimic an ST-elevation myocardial infarction (STEMI). Originally, TC was thought to be self-limiting and benign. However, there is a 4%-5% mortality rate, which is associated with serious complications. The majority of people diagnosed with TC are postmenopausal women, but it can affect all ages. Patients will often present to the emergency department with chest pain and dyspnea. An electrocardiogram (ECG) often demonstrates ST elevation. There is no definitive way to differentiate between TC and STEMI on an ECG. Therefore, all patients need to have emergent coronary angiography with left ventriculography.

Symptom and needs assessment screening in oncology patients: Alternate outreach methods during COVID-19.

Patients with cancer are ideally screened for symptoms, including distress, using patient-reported outcome measures (PROMs). This initiative was developed to ensure patients without access to an electronic portal were screened for distress and related symptoms during the COVID-19 pandemic. Prior to the pandemic, these patients could complete screening in clinic. However, many visits transitioned to telehealth. We implemented a standardized telephone outreach process targeting patients without active electronic portal accounts to improve remote symptom monitoring. Outreach resulted in 172 completed screens, identifying 110 needs for 63 individuals. Twenty-eight patients completed patient portal enrollment. Outreach calls captured a higher percentage of Black patients (34%) and a higher percentage of 61-80 year olds (69%) compared to portal users. Telephone outreach during the pandemic captured data that otherwise would have been missed in elderly and minority patients without electronic patient portal access. Patient engagement is vital to the distress screening process.

Leveraging Patient Reported Outcomes Measurement via the Electronic Health Record to Connect Patients with Cancer to Smoking Cessation Treatment.

Tobacco use negatively impacts cancer treatment outcomes, yet too few providers actively support their patients in quitting. Barriers to consistently addressing tobacco use and referring to treatment include time constraints and lack of knowledge surrounding treatment options. Patient Reported Outcomes (PRO) measurement is best practice in cancer care and has potential to help address these barriers to tobacco cessation treatment. This descriptive program evaluation study reports preliminary results following implementation of a novel automated PRO tobacco use screener and referral system via the electronic health record (EHR) patient portal (MyChart) that was developed and implemented as a part of a population-based tobacco treatment program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Between 25 June 2019 and 6 April 2020, 4589 unique patients completed the screener and 164 (3.6%) unique patients screened positive for recent (past month) cigarette smoking. All patients who screened positive were automatically referred to a smoking cessation treatment program integrated within the Lurie Cancer Center, and 71 (49.7%) patients engaged in treatment, as defined by completing at least one behavioral counseling session. Preliminary results indicate that the PRO/MyChart system may improve smoker identification and increase offering of treatment and, despite the "cold call" following a positive screen, may result in a treatment engagement rate that is higher than rates of treatment engagement previously documented in oncology settings. Longer term evaluation with formal statistical testing is needed before drawing conclusions regarding effectiveness, but PRO measurement via the EHR patient portal may serve a potentially important role in a multi-component approach to reaching and engaging cancer patients in comprehensive tobacco cessation treatment.

Planning for patient-reported outcome implementation: Development of decision tools and practical experience across four clinics.

INTRODUCTION: Many institutions are attempting to implement patient-reported outcome (PRO) measures. Because PROs often change clinical workflows significantly for patients and providers, implementation choices can have major impact. While various implementation guides exist, a stepwise list of decision points covering the full implementation process and drawing explicitly on a sociotechnical conceptual framework does not exist. METHODS: To facilitate real-world implementation of PROs in electronic health records (EHRs) for use in clinical practice, members of the EHR Access to Seamless Integration of Patient-Reported Outcomes Measurement Information System (PROMIS) Consortium developed structured PRO implementation planning tools. Each institution pilot tested the tools. Joint meetings led to the identification of critical sociotechnical success factors. RESULTS: Three tools were developed and tested: (1) a PRO Planning Guide summarizes the empirical knowledge and guidance about PRO implementation in routine clinical care; (2) a Decision Log allows decision tracking; and (3) an Implementation Plan Template simplifies creation of a sharable implementation plan. Seven lessons learned during implementation underscore the iterative nature of planning and the importance of the clinician champion, as well as the need to understand aims, manage implementation barriers, minimize disruption, provide ample discussion time, and continuously engage key stakeholders. CONCLUSIONS: Highly structured planning tools, informed by a sociotechnical perspective, enabled the construction of clear, clinic-specific plans. By developing and testing three reusable tools (freely available for immediate use), our project addressed the need for consolidated guidance and created new materials for PRO implementation planning. We identified seven important lessons that, while common to technology implementation, are especially critical in PRO implementation.

Integration of Patient-reported Outcomes in a Total Joint Arthroplasty Program at a High-volume Academic Medical Center.

INTRODUCTION: Despite widely appreciated barriers to successful clinical implementation, the literature regarding how to operationalize electronic health record-integrated patient-reported outcomes (PROs) remains sparse. We offer a detailed summary of the implementation of PROs into the standard of care at a major tertiary academic medical center. METHODS: Collection of four Patient-Reported Outcomes Measurement Information System computer adaptive tests was piloted in a large academic orthopaedic surgery ambulatory clinic starting in October 2016. The Patient-Reported Outcomes Measurement Information System computer adaptive tests (Physical Function, Pain Intensity, Pain Interference, and Ability to Return to Social Roles and Activities) were initially implemented as manual order sets to be administered before surgery through 2 years after surgery. Completion rate over time, mean time to completion for all PRO domains, and the overall distribution of symptom severity were used to evaluate the success of the pilot. A subsequent optimization and redesign of the pilot was conducted using tablets, automation of questionnaire deployment, and improved results review to address obstacles encountered during the pilot phase. RESULTS: Two thousand nine distinct joint arthroplasty patients (mean age = 65) completed at least one set of PRO assessments, with overall completion rates reaching 68% and mean completion time of 3 minutes. Focal points during the implementation process included engagement and training of staff, selection of an appropriate patient population and outcome measures, and user friendly data displays for patients and providers. CONCLUSION: Our pilot program successfully demonstrated that PROs can be administered, scored, and made immediately available within the electronic health record to patients and their providers with minimal disruption of clinical workflows. Although considerable operational and technological challenges remain, we found that the implementation of PROs in clinical care within an ambulatory practice at an academic medical center can be achieved through a constellation of several key factors.

Effect of Montmorency tart cherry juice on cognitive performance in older adults: a randomized controlled trial.

Hypertension, inflammation and oxidative stress are important factors in the development of cognitive impairment. Our previous study demonstrated that tart cherry juice can lower systolic blood pressure (BP) and improve inflammatory and oxidative stress status in older adults. As part of our previous trial, we explored whether daily consumption of tart cherry juice would improve cognitive abilities. In this randomized controlled trial, 37 adults between the ages of 65-80 with normal cognitive function were recruited and randomly assigned to consume two cups of Montmorency tart cherry juice for 12 weeks. Subjective memory and objective cognitive performance were assessed at baseline and after the 12-week juice supplementation using a validated subjective memory questionnaire and a standardized battery of tests. Daily caloric intake and physical activity levels were assessed throughout the study period. After the intervention, participants in the tart cherry group had higher contentment with memory scores (mean difference of 2.7; 95% CI: 1.2 to 4.2; p = 0.02), lowered their scores of movement time (mean difference of -10.4; 95% CI: -13.4 to -7.5; p = 0.03) as well as performed better on the paired associates learning task (mean difference of -8.5; 95% CI: -12.5 to -4.5; p = 0.02) compared to the control group. The within-group analysis showed that the visual sustained attention (p < 0.0001) and spatial working memory (p = 0.06) improved after the 12-week consumption of tart cherry juice compared with corresponding baseline values. Daily tart cherry juice consumption may improve cognitive abilities. This may be through anti-oxidative and anti-inflammatory properties of tart cherry and its ability to lower BP. Further research is needed to confirm these findings.

The Use of Ketamine for the Management of Acute Pain in the Emergency Department.

Ketamine has been used as an anesthetic agent for over 50 years. At the upper end of the dosing range, it displays dissociative anesthetic and amnestic effects, while at lower doses, it acts as an analgesic and demonstrates opioid-sparing capabilities. Ketamine is unique in its preservation of hemodynamic stability and respiratory function, and is used extensively in the emergency department (ED) for procedural sedation and the facilitation of brief painful procedures. Despite evidence supporting its safety and efficacy as an analgesic agent at sub-dissociative doses, its use in the ED for the management of acute pain remains uncommon. New guidelines were published in July 2018 by the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists that provide a framework for identifying patients who are likely to benefit from the use of Ketamine in an acute pain setting.

Quality Improvement in Ambulatory Surgery Centers: A Major National Effort Aimed at Reducing Infections and Other Surgical Complications.

BACKGROUND: Surgical volume has shifted significantly from inpatient to outpatient settings, including free-standing ambulatory surgery centers (ASCs). Approaches to quality improvement (QI) and surveillance used in hospitals are not always appropriate to the ambulatory setting. METHODS: We recruited 665 ASCs in 47 US states to participate in an intervention to improve safe practice through implementation of a surgical safety checklist and infection control practices. Areas for partner contribution included recruitment, project development, content development and delivery, clinical subject matter expertise, data analysis, and facility coaching. RESULTS: Barriers to implementation and data collection were encountered during the project, requiring revisions to the implementation plan. Project activities, such as facility recruitment, data measurement, and implementation strategies were modified to meet ASC-specific needs. Several ASC-specific tools were designed. CONCLUSIONS: The increasing number of patients being cared for in ASCs makes it essential to better understand how to implement quality improvement projects in that environment. Tailoring interventions to the ASC's unique needs is necessary.

Effects of Tart Cherry Juice on Biomarkers of Inflammation and Oxidative Stress in Older Adults.

Inflammation and oxidative stress are important factors in the development of cardiovascular disease and atherosclerosis. The findings of our previous study suggest that 12 weeks consumption of tart cherry juice lowers the levels of systolic blood pressure (BP) and low-density lipoprotein (LDL) cholesterol in older adults. The present study investigated the effects of tart cherry juice on blood biomarkers of inflammation and oxidative stress. In this randomized-controlled clinical trial, a total of 37 men and women between the ages of 65⁻80 were randomly assigned to consume 480 mL of tart cherry juice or control drink daily for 12 weeks. Several blood biomarkers of inflammation and oxidative stress were assessed at baseline and after 12 weeks intervention. After the 12 weeks intervention, tart cherry juice significantly increased the plasma levels of DNA repair activity of 8-oxoguanine glycosylase (p < 0.0001) and lowered (p = 0.03) the mean c-reactive protein (CRP) level compared to the control group. There was a significant group effect observed for plasma CRP (p = 0.03) and malondialdehyde (MDA) (p = 0.03), and a borderline significant group effect observed for plasma oxidized low-density lipoprotein (OxLDL) (p = 0.07). Within group analysis showed that the plasma levels of CRP, MDA, and OxLDL decreased numerically by 25%, 3%, and 11%, respectively after 12 weeks of tart cherry juice consumption compared with corresponding baseline values. The present study suggests that the ability of tart cherry juice to reduce systolic BP and LDL cholesterol, in part, may be due to its anti-oxidative and anti-inflammatory properties. Larger and longer follow-up studies are needed to confirm these findings.

Impact of tart cherry juice on systolic blood pressure and low-density lipoprotein cholesterol in older adults: a randomized controlled trial.

Hypertension and dyslipidemia are major risk factors for cardiovascular disease (CVD). Common treatments for high blood pressure (BP) and dyslipidemia include medications, but there is question as to whether natural sources may be adequate to reduce CVD risk factors. We examined the effects of tart cherry juice on lipid profiles, BP, glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) in older adults. In this randomized-controlled clinical trial, 17 men and 20 women between the ages of 65-80 years were randomly assigned to consume 480 ml of tart cherry juice or control drink daily for 12 weeks. Control beverages were matched for energy and sugar content. Outcome variables were assessed at baseline and after 12 weeks of tart cherry juice or control drink. Systolic BP and low-density lipoprotein cholesterol (LDL) exhibited treatment × time interaction effects. At the end of the study, participants in the tart cherry group had lower levels of LDL cholesterol (difference of -20.6 with P = 0.001) and total cholesterol (difference of -19.11 with P = 0.01), and higher levels of glucose (difference of 7.94 with P = 0.001), triglycerides (difference of 6.66 with P = 0.01) and BMI (difference of 1.06 with P = 0.02) than in the control group. Neither tart cherry juice nor control significantly altered body weight, high-density lipoprotein cholesterol, diastolic BP, insulin and HOMA-IR. Our findings show that tart cherry juice can lower the levels of systolic BP and LDL cholesterol. However, larger and longer follow-up studies are needed to further assess cardio-protective effects of tart cherry juice.

A national collaborative approach to reduce catheter-associated urinary tract infections in nursing homes: A qualitative assessment.

BACKGROUND: Reducing health care-associated infections (HAIs), such as catheter-associated urinary tract infection (CAUTI), is a critical performance improvement target in nursing homes. The Agency for Healthcare Research and Quality Safety Program for Long-term Care: Health Care-Associated Infections/Catheter-Associated Urinary Tract Infection, a national performance improvement program, was designed to promote implementation of a CAUTI prevention program through state-based or regional collaboratives in more than 500 nursing homes across the United States. METHODS: Qualitative interviews were conducted with 8 purposefully selected organizational leads (who led implementation activities for a group of facilities) and 8 facility leads (who led implementation activities at a given facility) to understand implementation successes and challenges and experiences of participants involved in the program. Key themes were identified using a rapid analysis approach. RESULTS: Key themes related to general perceptions, changes due to program participation, and factors influencing program implementation were identified. In general, the program was viewed positively by organizational and facility leads with changes in catheter care practices, staff empowerment, and improvements in knowledge identified as benefits. Implementation challenges included the time required for program start-up as well as issues with staff and physician support, logistic barriers, and staffing turnover. CONCLUSIONS: Despite some challenges, the observed program success and positive views of those participating suggest that collaboratives are an important strategy for providing nursing homes with enhanced expertise and support to prevent HAIs and ensure resident safety.

Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial.

Animal and human studies indicate that electrical stimulation of dorsal root ganglion (DRG) neurons may modulate neuropathic pain signals. ACCURATE, a pivotal, prospective, multicenter, randomized comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (spinal cord stimulation, SCS). The primary end point was a composite of safety and efficacy at 3 months, and subjects were assessed through 12 months for long-term outcomes and adverse events. The predefined primary composite end point of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in visual analog scale score from preimplant baseline and who did not report any stimulation-related neurological deficits. No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥50% pain relief and treatment success was greater in the DRG arm (81.2%) than in the SCS arm (55.7%, P < 0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. Dorsal root ganglion stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (P < 0.001) and reduced extraneous stimulation in nonpainful areas (P = 0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities. As the largest prospective, randomized comparative effectiveness trial to date, the results show that DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Safety and Efficacy of Occipital Nerves Stimulation for the Treatment of Chronic Migraines: Randomized, Double-blind, Controlled Single-center Experience.

BACKGROUND: A recent multicenter study presented 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial for patients with chronic migraine (CM) undergoing peripheral nerve stimulation of the occipital nerves. We present the data from a single center of 20 patients enrolled at the Cleveland Clinic's Pain Management Department. METHODS: In this single center, 20 patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, Migraine Disability Assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life, satisfaction, and adverse events (AEs). RESULTS: Headache days per month were reduced by 8.51 (±9.81) days (P < 0.0001). The proportion of patients who achieved a 30% and 50% reduction in headache days and/or pain intensity was 60% and 35%, respectively. MIDAS and Zung PAD were reduced for all patients. Fifteen (75%) of the 20 patients at the site reported at least one AE. A total of 20 AEs were reported from the site. CONCLUSION: Our results support the 12-month efficacy of 20 CM patients receiving peripheral nerve stimulation of the occipital nerves in this single-center trial.

Tonic and burst spinal cord stimulation waveforms for the treatment of chronic, intractable pain: study protocol for a randomized controlled trial.

BACKGROUND: Burst stimulation is a novel form of neurostimulation for the treatment of chronic pain which has demonstrated promise in small uncontrolled studies, but has not yet gained approval for use in the U.S. We report the study methods for an ongoing multicenter, randomized, controlled, cross-over study designed to gain United States Food and Drug Administration (FDA) approval for burst stimulation. METHODS: Participants who are candidates for a currently approved neurostimulation device were enrolled and screened. Participants who fail a tonic trial evaluation, have significant depressive symptoms, or evidence lack of compliance with study procedures by failing to complete 7 days of a Pain Diary are excluded. Participants receiving a permanent implant are randomized to receive: (1) 12 weeks of tonic followed by 12 weeks of burst stimulation or (2) 12 weeks of burst stimulation followed by 12 weeks of tonic stimulation. Assessments occur at 6, 12, 18, and 24 weeks. After 24 weeks, participants choose their preferred therapy and are assessed every 6 months for up to 2 years. All patients had the device leads inserted at the site of a successful tonic stimulation trial. Assessments include: a Pain Diary using a Visual Analog Scale (VAS) for overall, trunk, and limb pain, the Beck Depression Inventory, the Pain Catastrophizing Scale, the Oswestry Disability Index, paresthesia, satisfaction, and therapy preference. Reported adverse events are collected throughout the study. The primary endpoint is the noninferiority of burst stimulation compared to tonic measured by the within-subject difference in the mean overall VAS score at the end of each 12-week stimulation period. DISCUSSION: This trial represents the largest controlled trial of burst stimulation to date, and is expected to yield important information regarding the safety and efficacy of burst stimulation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02011893 . Registered on 10 December 2013.

Ethical Considerations about EHR-Mediated Results Disclosure and Pathology Information Presented via Patient Portals.

Electronic health records (EHR) now include patient portals where patients can obtain clinical reports, including notes, radiology reports, and laboratory/anatomic pathology results. Although portals increase patient access to information, no guidelines have been developed for hospitals about appropriate delays in posting different types of pathology reports to the EHR. Delays exist as a matter of policy to allow physicians time to answer questions and provide emotional support when discussing sensitive results with patients. Some types of results are more sensitive than others, however, including results of cancer, genetic, and HIV testing. Ethical questions about patient access to test results online are discussed.

Perceptions of Culture of Safety in Hemodialysis Centers.

Staff members, physicians, nurse practitioners, and physician assistants from a sample of hemodialysis facilities in Network 6 (North Carolina, South Carolina, and Georgia) and Network 11 (Michigan, Minnesota, North Dakota, South Dakota, and Wisconsin) completed a 10-item assessment with modified questions from the Hospital Survey on Patient Safety Culture, with an emphasis on safety culture related to vascular access infections. A composite score was constructed, which was the average of the percent-positive scores of the items. Overall, scores were high, indicating a positive patient safety culture. Composite scores varied by role type, with nurses, patient care technicians, and other technicians reporting the lowest composite scores. Network 6 participants reported higher scores on two of the survey items. Fewer staff within a facility were associated with higher composite scores.

Clonal evaluation of prostate cancer foci in biopsies with discontinuous tumor involvement by dual ERG/SPINK1 immunohistochemistry.

The presence of two or more prostate cancer foci separated by intervening benign tissue in a single core is a well-recognized finding on prostate biopsy. Cancer involvement can be measured by including intervening benign tissue or only including the actual cancer involved area. Importantly, this parameter is a common enrollment criterion for active surveillance protocols. We hypothesized that spatially distinct prostate cancer foci in biopsies may arise from separate clones, impacting cancer involvement assessment. Hence, we used dual ERG/SPINK1 immunohistochemistry to determine the frequency of separate clones-when separate tumor foci showed discordant ERG and/or SPINK1 status-in discontinuously involved prostate biopsy cores from two academic institutions. In our cohort of 97 prostate biopsy cores with spatially discrete tumor foci (from 80 patients), discontinuous cancer involvement including intervening tissue ranged from 20 to 100% and Gleason scores ranged from 6 to 9. Twenty-four (25%) of 97 discontinuously involved cores harbored clonally distinct cancer foci by discordant ERG and/or SPINK1 expression status: 58% (14/24) had one ERG(+) focus, and one ERG(-)/SPINK1(-) focus; 29% (7/24) had one SPINK1(+) focus and one ERG(-)/SPINK1(-) focus; and 13% (3/24) had one ERG(+) focus and one SPINK1(+) focus. ERG and SPINK1 overexpression were mutually exclusive in all tumor foci. In summary, our results show that ~25% of discontinuously involved prostate biopsy cores showed tumor foci with discordant ERG/SPINK1 status, consistent with multiclonal disease. The relatively frequent presence of multiclonality in discontinuously involved prostate biopsy cores warrants studies on the potential clinical impact of clonality assessment, particularly in cases where tumor volume in a discontinuous core may impact active surveillance eligibility.

Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza.

BACKGROUND: Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. METHODS: Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. RESULTS: Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. CONCLUSIONS: This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.