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New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

PURPOSE: Patients with triple negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin, and to identify molecular alterations and/or immune gene signatures predicting pCR. EXPERIMENTAL DESIGN: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles. RESULTS: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend towards higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80, versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteosome were upregulated in pre-treatment samples from patients who achieved pCR. CONCLUSIONS: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR. TRIAL REGISTRATION: Clinical trial information: NCT02124902, Registered 24 April 2014, & NCT02547987, Registered 10 September 2015.

The psychosocial benefits of participating in sports have long been appreciated. However, athletes are often faced with circumstances that make them susceptible to psychological challenges unique to the athletic population. One such circumstance is injury in sport, which can be a source of notable distress and may precipitate the emergence of new or exacerbation of underlying psychological disorders. In athletes who are injured, particularly those undergoing surgical intervention, psychological factors play a substantial role in the recovery process. A more comprehensive understanding of the complex interplay between psychological and physical health in the setting of an injury is essential to optimize patient care. The aim of this review was to highlight the impact of psychological factors on measurable outcomes after orthopaedic surgical interventions and to explore interventions that can be implemented to improve surgical outcomes and the overall care of injured athletes.

Background This study evaluated synchronous audiovisual telehealth and audio-only visits for patients with inflammatory bowel disease (IBD) to determine frequency of successful telehealth visits and determine what factors increase the likelihood of completion. Methods Data were collected from March to July 2020 in a tertiary care adult IBD clinic that was transitioned to a fully telehealth model. A protocol for telehealth was implemented. A retrospective analysis was performed using electronic medical record (EMR) data. All patients were scheduled for video telehealth. If this failed, providers attempted to conduct the visit as audio only. Results Between March and July 2020, 2571 telehealth visits were scheduled for adult patients with IBD. Of these, 2498 (99%) were successfully completed by video or phone. Sixty percent were female, and the median age was 41 years. Eighty six percent of the population was white, 8% black, 2% other, and 4% were missing. Seventy-five percent had commercial insurance, 15% had Medicare, 5% had Medicaid, and 5% had other insurance. No significant factors were found for an attempted but completely failed visit. Using a multivariate logistic regression model, increasing age (odds ratio, 1.80; 95% CI, 1.55–2.08; P Conclusions There is a high success rate for telehealth within an IBD population with defined clinic protocols. Certain patient characteristics such as age, race, and health insurance type increase the risk of failure of a video visit.

Purpose: In a head and neck squamous cell carcinoma (HNSCC) “window of opportunity” clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples. Experimental Design: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing. Results: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity. Conclusions: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.

Literacy is an important predictor of health care utilization and outcomes. We examine literacy among people seeking care in a state funded mental health clinic (Site 1) and a safety-net hospital clinic (Site 2). Limited literacy was defined as literacy at or below the 8th grade level. At Site 1, 53% of participants had limited reading literacy and 78% had limited aural literacy. At Site 2, 72% had limited reading and 90% had limited aural literacy. Regression analyses examined associations among limited literacy and psychiatric, neurocognitive and sociodemographic characteristics. Few associations among psychiatric and neurocognitive factors, and literacy were found. At Site 2, black and "other" race participants had higher odds for limited literacy compared to white participants suggesting that limited literacy may be an under-examined mechanism in understanding racial disparities in mental health. Work is needed to understand the relationships among literacy, mental health and mental health care.

The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that provides information on drug-gene interactions and druggable genes from publications, databases, and other web-based sources. Drug, gene, and interaction data are normalized and merged into conceptual groups. The information contained in this resource is available to users through a straightforward search interface, an application programming interface (API), and TSV data downloads. DGIdb 4.0 is the latest major version release of this database. A primary focus of this update was integration with crowdsourced efforts, leveraging the Drug Target Commons for community-contributed interaction data, Wikidata to facilitate term normalization, and export to NDEx for drug-gene interaction network representations. Seven new sources have been added since the last major version release, bringing the total number of sources included to 41. Of the previously aggregated sources, 15 have been updated. DGIdb 4.0 also includes improvements to the process of drug normalization and grouping of imported sources. Other notable updates include the introduction of a more sophisticated Query Score for interaction search results, an updated Interaction Score, the inclusion of interaction directionality, and several additional improvements to search features, data releases, licensing documentation and the application framework.

Background The purpose of this study was for the authors to describe their patient selection, surgical technique, and results with the alar rotation flap for surgical defects of the nasal ala. Methods The authors performed a retrospective analysis of all alar rotation flaps performed between June of 2006 and February of 2019. Three hundred ninety-four patients were identified, and follow-up encounters were reviewed to assess for complications and need for revision procedures. Results The alar rotation flap was performed on 394 patients over a 13-year period. The mean defect size was 9.3 ± 2.8 mm by 7.2 ± 2.3 mm. Three hundred nineteen patients (81 percent) were evaluated postoperatively, with a mean average duration of follow-up of 2.3 years (range, 6 days to 11.9 years). Complications included hemorrhagic crust along the incision line [n = 9 (3 percent)], flap edema [n = 7 (2 percent)], internal nasal valve dysfunction [n = 3 (1 percent)], depressed surgical scar [n = 2 (1 percent)], hematoma [n = 1 (0.5 percent)], and paresthesia [n = 1 (0.5 percent)]. Conclusion The alar rotation flap is a reliable one-stage flap for small- to medium-size partial-thickness defects of the nasal ala that can produce topographic restoration with minimal risk of aesthetic or functional complication. Clinical question/level of evidence Therapeutic, IV.

Background Intralesional injection of sterile medications remains a mainstay in dermatology, enabling a tailored, low-cost, in-office therapy. After the 2012 United States outbreak of fungal meningitis from contaminated intrathecally administered corticosteroids, there has been increased regulation of in-office compounding, regardless of the administration route. Studies demonstrating the safety data of in-office corticosteroid compounding for intradermal or subcutaneous use are lacking. Objective To assess the incidence of infection caused by compounded in-office intralesional triamcinolone. Methods A retrospective medical record review identified patients who received in-office intralesional corticosteroid injections in 2016. Medical documentation within 30 days of injection was reviewed for suspected infection. Results The records of 4370 intralesional triamcinolone injections were assessed, of which 2780 (64%) were compounded triamcinolone with bacteriostatic saline. We identified 11 (0.25%) suspected localized infections, with 4 of the 11 in the compounding cohort. Of these, 7 of 11 occurred after injection of an “inflamed cyst.” No hospitalizations or deaths occurred. No temporal or locational relationships were identified. Limitations This study was limited to 2 academic institutions. A 30-day postinjection time frame was used. Conclusion In-office compounding for intralesional dermal and subcutaneous administration is safe when sterile products are used by medical practitioners. There is no increased risk of compounded triamcinolone relative to noncompounded triamcinolone.

OBJECTIVES Methods for pharmacoepidemiologic studies of large-scale data repositories are established. Although clinical cohorts of older adults often contain critical information to advance our understanding of medication risk and benefit, the methods best suited to manage medication data in these samples are sometimes unclear and their degree of validation unknown. We sought to provide researchers, in the context of a clinical cohort study of delirium in older adults, with guidance on the methodological tools to use data from clinical cohorts to better understand medication risk factors and outcomes. DESIGN Prospective cohort study. SETTING The Successful Aging After Elective Surgery (SAGES) prospective cohort. PARTICIPANTS A total of 560 older adults (aged ≥70 years) without dementia undergoing elective major surgery. MEASUREMENTS Using the SAGES clinical cohort, methods used to characterize medications were identified, reviewed, analyzed, and distinguished by appropriateness and degree of validation for characterizing pharmacoepidemiologic data in smaller clinical data sets. RESULTS Medication coding is essential; the American Hospital Formulary System, most often used in the United States, is not preferred over others. Use of equivalent dosing scales (e.g., morphine equivalents) for a single medication class (e.g., opioids) is preferred over multiclass analgesic equivalency scales. Medication aggregation from the same class (e.g., benzodiazepines) is well established; the optimal prevalence breakout for aggregation remains unclear. Validated scale(s) to combine structurally dissimilar medications (e.g., anticholinergics) should be used with caution; a lack of consensus exists regarding the optimal scale. Directed acyclic graph(s) are an accepted method to conceptualize causative frameworks when identifying potential confounders. Modeling-based strategies should be used with evidence-based, a priori variable-selection strategies. CONCLUSION As highlighted in the SAGES cohort, the methods used to classify and analyze medication data in clinically rich cohort studies vary in the rigor by which they have been developed and validated.

Continuous video electroencephalography (CEEG) monitoring of critically ill infants and children has expanded rapidly in recent years. Indications for CEEG include evaluation of patients with altered mental status, characterization of paroxysmal events, and detection of electrographic seizures, including monitoring of patients with limited neurological examination or conditions that put them at high risk for electrographic seizures (e.g., cardiac arrest or extracorporeal membrane oxygenation cannulation). Depending on the inclusion criteria and clinical characteristics of the population studied, the percentage of pediatric patients with electrographic seizures varies from 7% to 46% and with electrographic status epilepticus from 1% to 23%. There is also evidence that epileptiform and background CEEG patterns may provide important information about prognosis in certain clinical populations. Quantitative EEG techniques are emerging as a tool to enhance the value of CEEG to provide real-time bedside data for management and prognosis. Continued research is needed to understand the clinical value of seizure detection and identification of other CEEG patterns on the outcomes of critically ill infants and children.

Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAT) in triple negative breast cancer (TNBC) patients yields a pathological complete response (pCR) rate of approximately 45%. Anthracyclines can lead to long-term toxicities including congestive heart failure and leukemia. TNBC patients achieving pCR have excellent long-term outcomes irrespective of NAT regimen. This study was designed to evaluate the efficacy of a non-anthracycline NAT regimen with carboplatin and docetaxel in TNBC. Correlative studies include detecting and tracking plasma circulating tumor DNA (ctDNA) to determine if it will predict clinical outcomes, and whole exome sequencing (WES) on tissue samples to decipher the genomic architecture of those who achieve pCR versus those who do not. Methods: This is a joint analysis of two identical multicenter trials. Eligible patients with AJCC 7 clinical stages II and III TNBC received docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks X 6 cycles. Following NAT, all patients underwent definitive surgery. The primary endpoint is pCR (no invasive tumor in the breast and axilla). Secondary objectives include evaluating ctDNA as a prognostic biomarker that may be used in identifying TNBC patients at a high risk of disease relapse, and evaluating differences in the genomic architecture between pCR and non-pCR patients. Patients have a research biopsy at baseline, cycle 1 day 3 (optional), and at definitive surgery for those with residual disease. Plasma for ctDNA is collected at baseline, cycle 1 day 3, at definitive surgery, and every 6 months for 5 years. Results: Between 2014 and 2019, 103 patients have been registered. Median age is 53 years (range 25-74), 27.2%: African-American, 77.7%: clinical stage II. Ninety-nine have completed NAT and have had surgery. In the intent to treat population, the preliminary pCR rate is 46.5% (95% CI 36.9% - 56.2%). Nine (8.7%) have developed recurrent disease, and 7 (6.8%) have died. Preliminary ctDNA results from 6 patients (4 non-pCR, 2 pCR) show that ctDNA is detectable in 67%. We identified 627 somatic variants by exome analysis. Of these, 10 variants overlapped with the Swift panel (Accel-Amplicon™ 56G Oncology Panel v2) used for ctDNA sequencing and variant detection. TP53 variants were identified in all 6 patients’ tumor tissue samples. At least one TP53 variant was identified in 4 patients’ baseline pre-chemotherapy ctDNA. Both pCR patients had either no detectable ctDNA TP53 mutations, or clearance of ctDNA following chemotherapy. Three non-PCR patients had persistent TP53 mutations in ctDNA during the treatment course. WES and ctDNA analysis on all patients is currently ongoing. Conclusions: We report a very encouraging pCR rate of 46.5% in TNBC patients with carboplatin and docetaxel NAT. This rate is similar to observed rates with anthracycline- and taxane-based NAT and may represent an option for treatment for TNBC patients. Correlative genomic and ctDNA studies are ongoing. Clinical trial information: NCT02124902 & NCT02547987. Citation Format: FOLUSO O ADEMUYIWA, Mothaffar F Rimawi, Tracy Summa, Jingqin Luo, Tao Wang, Rama Suresh, Lindsay Peterson, Michael Naughton, Ashley Frith, Leonel Hernandez-Aya, Katherine Weilbaecher, Cynthia Ma, Aadel A Chaudhuri, Yang-Yang Feng, Zachary L Skidmore, Obi L Griffith, Malachi Griffith, Matthew Ellis. Neoadjuvant treatment of triple negative breast cancer patients with docetaxel and carboplatin to assess anti-tumor activity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-03.

Background Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature. Methods To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we propose the use of text mining approaches to extract these clinically relevant biomarkers from all available published literature. To this end, a group of cancer genomics experts annotated sentences that discussed biomarkers with their clinical associations and achieved good inter-annotator agreement. We then used a supervised learning approach to construct the CIViCmine knowledgebase. Results We extracted 121,589 relevant sentences from PubMed abstracts and PubMed Central Open Access full-text papers. CIViCmine contains over 87,412 biomarkers associated with 8035 genes, 337 drugs, and 572 cancer types, representing 25,818 abstracts and 39,795 full-text publications. Conclusions Through integration with CIVIC, we provide a prioritized list of curatable clinically relevant cancer biomarkers as well as a resource that is valuable to other knowledgebases and precision cancer analysts in general. All data is publically available and distributed with a Creative Commons Zero license. The CIViCmine knowledgebase is available at http://bionlp.bcgsc.ca/civicmine/.

Aims and objectives: Smoking is a risk factor for idiopathic pulmonary fibrosis (IPF), but the associated mechanism remains unknown. Our aim was to study the RNA-regulatory networks of the stress-responsive RNA-binding protein HuR and what impact it has on the disease pathology. Methods: TGF-β1-activated human lung fibroblasts were used to study the effect of cigarette smoke extract (CSE) stimulation on the translocation HuR from the nucleus to the cytoplasm. HuR-specific RNA-interactions in the nuclear and cytoplasmic cell fractions were analyzed by CLIP (cross-linking and immunoprecipitation) and subsequent high-throughput sequencing. Results: We showed that CSE induces HuR translocation from the nucleus to the cytoplasm in TGF-β1-activated lung fibroblasts. CLIP data revealed several fibrotic genes, including COL1A1 and COL1A2, among the most frequently bound HuR-targets in the cytoplasm. Evaluation of HuR-bound RNA sequences showed a difference in 4-meric binding motifs between nuclear and cytoplasmic HuR fractions, with increased binding to polyU-rich RNA motifs in the cytoplasm. Interestingly, the polyU-rich binding was reduced upon TGF-β1/CSE stimulation. Additionally, the TGF-β1/CSE stimulation led to reduced binding of cytoplasmic HuR to 3’UTR RNA regions and increased interaction with the coding regions. Conclusions: Our data suggests a global shift of HuR function from 3’UTR-dependent RNA stabilization, potentially in the direction of translational regulation of genes associated with fibrosis.

Contains fulltext : 238683.pdf (Publisher’s version ) (Open Access) Social determinants of health may affect ICU outcome, but the association between social determinants of health and delirium remains unclear. We evaluated the association between three social determinants of health and delirium occurrence and duration in critically ill adults. DESIGN: Secondary, subgroup analysis of a cohort study. SETTING: Single, 36-bed mixed medical-surgical ICU in the Netherlands. PATIENTS: Nine hundred fifty-six adults consecutively admitted from July 2016 to February 2020. Patients admitted after elective surgery, residing in a nursing home, or not expected to survive greater than or equal to 48 hours were excluded. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Four factors related to three Center for Disease Control social determinants of health domains (social/community context [ethnicity], education access/quality [educational level], and economic stability [employment status and monthly income]) were collected at ICU admission from patients (or families). Well-trained ICU nurses evaluated patients without coma (Richmond Agitation Sedation Scale, -4, -5) and with the Confusion Assessment Method-ICU and/or a delirium day was defined by greater than or equal to 1 + Confusion Assessment Method-ICU and/or scheduled antipsychotic use. Multivariable logistic regression models controlling for ICU days and 10 delirium risk variables (before-ICU: age, Charlson, cognitive impairment, any antidepressant, antipsychotic, or benzodiazepine use; ICU baseline: Acute Physiology and Chronic Health Evaluation IV and admission type; daily ICU: Sequential Organ Failure Assessment, restraint use, coma, benzodiazepine, or opioid use) evaluated associations between each social determinant of health factor and both ICU delirium occurrence and duration. Delirium occurred in 393/956 patients (45.4%) for 2 days (1-5 d). Patients with low (vs high) income had more ICU delirium (p = 0.05). Multivariate analyses revealed no social determinants of health to be significantly associated with increased delirium occurrence or duration. Low (vs high) income was weakly associated with increased delirium occurrence (adjusted odds ratio, 1.83; 95% CI, 0.91-3.89). Low (vs high) education (adjusted relative risk, 1.21; 95% CI, 0.97-1.53) was weakly associated with a longer delirium duration. CONCLUSIONS: Social determinants of health did not affect ICU delirium in one Dutch region. Additional research across different countries/regions and where additional social determinants of health are considered is needed to define the association between social determinants of health and ICU delirium.

Rationale: It is unclear whether opioid use increases the risk of ICU delirium. Prior studies have not accounted for confounding, including daily severity of illness, pain, and competing events that may preclude delirium detection.Objectives: To evaluate the association between ICU opioid exposure, opioid dose, and delirium occurrence.Methods: In consecutive adults admitted for more than 24 hours to the ICU, daily mental status was classified as awake without delirium, delirium, or unarousable. A first-order Markov model with multinomial logistic regression analysis considered four possible next-day outcomes (i.e., awake without delirium, delirium, unarousable, and ICU discharge or death) and 11 delirium-related covariables (baseline: admission type, age, sex, Acute Physiology and Chronic Health Evaluation IV score, and Charlson comorbidity score; daily: ICU day, modified Sequential Organ Failure Assessment, ventilation use, benzodiazepine use, and severe pain). This model was used to quantify the associationbetween opioid use, opioid dose, and delirium occurrence the next day.Measurements and Main Results: The 4,075 adults had 26,250 ICU days; an opioid was administered on 57.0% (n = 14,975), severe pain occurred on 7.0% (n = 1,829), and delirium occurred on 23.5% (n = 6,176). Severe pain was inversely associated with a transition to delirium (odds ratio [OR] 0.72; 95% confidence interval [CI], 0.53-0.97). Any opioid administration in awake patients without delirium was associated with an increased risk for delirium the next day [OR, 1.45; 95% CI, 1.24-1.69]. Each daily 10-mg intravenous morphine-equivalent dose was associated with a 2.4% increased risk for delirium the next day.Conclusions: The receipt of an opioid in the ICU increases the odds of transitioning to delirium in a dose-dependent fashion.

The creation of visualizations to interpret genomics data remains an important aspect of data science within computational biology. The GenVisR Bioconductor package was created to lower the entry point for publication-quality graphics and has remained a popular suite of tools within this domain. GenVisR supports visualizations covering a breadth of topics including functions to produce visual summaries of copy-number alterations, somatic variants, sequence quality metrics, and more. Recently, the GenVisR package has undergone significant updates to increase performance and functionality. To demonstrate the utility of GenVisR, we present protocols for use of the updated Waterfall() function to create a customizable Oncoprint-style plot of the mutational landscape of a tumor cohort. We explain the basics of installation, data import, configuration, plotting, clinical annotation, and customization. A companion online workshop describing the GenVisR library, Waterfall() function, and other genomic visualization tools is available at genviz.org. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generating a Waterfall() plot from original mutation data Basic Protocol 2: Adding clinical data to a Waterfall() plot Basic Protocol 3: Customizing mutation burden in Waterfall() plots Basic Protocol 4: Brief exploration of customizable options Support Protocol 1: Installing GenVisR.

Psychological resilience is an important construct that can enhance athletic performance and foster valuable life skills. Through positive adaptation to adversity and stressors in the athletic arena, athletes are able to cultivate their ability to effectively respond to negative stimuli, ultimately evolving to personal growth. For young female athletes, development of resilience may be particularly important. Young female athletes face distinct challenges in sport including sport inequity, body image issues, eating disorders, increased mental distress, and internalization of emotions. The aim of this review is to define and describe the construct of resilience and discuss the implications and applications relevant to young female athletes. By understanding how to foster resilience strategies in this population, we can enhance sport performance and enjoyment, as well as bolster valuable life skills that facilitate personal growth.

Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab–resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab–resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab–resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ–mTORC1–Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. Implications: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.

Elder mistreatment, affecting an estimated one in ten older adults, has devastating consequences for individuals, families and communities. The magnitude of the issue and known barriers to addressing it through formal systems necessitate innovative approaches to identification and response. This study explores network composition change following elder mistreatment in order to assess the viability of leveraging network members in future intervention efforts. Multiply imputed linear regression models show associations between elder mistreatment and small increases in net change and the number of specific network additions. No association between elder mistreatment and network member losses or network density were found. These findings highlight the complexity of social network change in older adulthood and point to a need for future research considering the influence of Adult Protective Service intervention as well as qualitative work assessing older adults’ own perceptions of mistreatment and network change.

Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.

Systems savvy, a new construct derived from foundations of practical intelligence, is the capacity to see the interdependence of technological and social/organizational systems and to construct synergies between them. Understanding systems savvy is valuable for managing the changes that go along with rapidly evolving technical and social/organizational systems that are part of the group decision and negotiation landscape. We first define the construct of systems savvy and position it in recent research on practical intelligence and tacit knowledge. We differentiate it from several other individual characteristics often used in research and practice. We use a critical incident technique with 13 subject matter experts to create a situational judgment test measure of systems savvy that can be used for research or assessments to support training. Preliminary validation of the measure uses a sample of 39 successful professionals and 182 novices. Systems savvy represents a contribution to research streams focused on understanding technology with implications at the team and organizational levels of analysis. We conclude with a discussion of the limitations of the current research and offer possible next steps toward using the systems savvy construct for understanding and supporting the future of work, especially within teams.

Objectives Haloperidol is commonly administered in the ICU to reduce the burden of delirium and its related symptoms despite no clear evidence showing haloperidol helps to resolve delirium or improve survival. We evaluated the association between haloperidol, when used to treat incident ICU delirium and its symptoms, and mortality. Design Post hoc cohort analysis of a randomized, double-blind, placebo-controlled, delirium prevention trial. Setting Fourteen Dutch ICUs between July 2013 and December 2016. Patients One-thousand four-hundred ninety-five critically ill adults free from delirium at ICU admission having an expected ICU stay greater than or equal to 2 days. Interventions Patients received preventive haloperidol or placebo for up to 28 days until delirium occurrence, death, or ICU discharge. If delirium occurred, treatment with open-label IV haloperidol 2 mg tid (up to 5 mg tid per delirium symptoms) was administered at clinician discretion. Measurements and main results Patients were evaluated tid for delirium and coma for 28 days. Time-varying Cox hazards models were constructed for 28-day and 90-day mortality, controlling for study-arm, delirium and coma days, age, Acute Physiology and Chronic Health Evaluation-II score, sepsis, mechanical ventilation, and ICU length of stay. Among the 1,495 patients, 542 (36%) developed delirium within 28 days (median [interquartile range] with delirium 4 d [2-7 d]). A total of 477 of 542 (88%) received treatment haloperidol (2.1 mg [1.0-3.8 mg] daily) for 6 days (3-11 d). Each milligram of treatment haloperidol administered daily was associated with decreased mortality at 28 days (hazard ratio, 0.93; 95% CI, 0.91-0.95) and 90 days (hazard ratio, 0.97; 95% CI, 0.96-0.98). Treatment haloperidol administered later in the ICU course was less protective of death. Results were stable by prevention study-arm, predelirium haloperidol exposure, and haloperidol treatment protocol adherence. Conclusions Treatment of incident delirium and its symptoms with haloperidol may be associated with a dose-dependent improvement in survival. Future randomized trials need to confirm these results.

A 7-year-old boy presented with acute-onset headache, vomiting, and confusion during summer. Two months previously, he developed right thigh pain, causing intermittent limping. Three days before admission, he developed headache; 1 day later, he experienced fatigue, nausea, and vomiting. On the day of presentation, symptoms included behavioral change (showered 15 times), unsteadiness, and new palmoplantar rash. He presented with confusion and lethargy and was transferred to our facility. His father had a recent gastrointestinal illness, but there were no other sick contacts. There were no recent weight changes, fever, tick/animal exposure, or travel. Past medical history included prior herpes simplex virus (HSV)–positive facial lesion (at 5 years old). The patient took no medications, had no known allergies, was developmentally normal, and was appropriately vaccinated. On general examination, he was somnolent and irritable, and had a palpable right thigh mass and palmar/solar petechiae. Neurologically, he was arousable to light touch, followed only simple midline commands, answered yes/no to orientation questions and responded to all naming questions with “I don't know.” Cranial nerves were intact. He had normal muscle bulk/tone and at least 3/5 strength throughout, but encephalopathy limited assessment. He had normal sensation to light touch and muscle stretch reflexes, neutral plantar responses, and no dysmetria. The patient sat in bed independently but refused to stand or walk.

Currently, the interaction of the consumer and the retail market on the basis of the digital technologies could be described from the point of view of open innovation concept. The article aims to prove the advantages of mixing two separate formats of the interaction between the seller and the consumer in online and offline. The scientific approach to the developing of the so-called phygital environment (physical plus digital) could be considered as a research gap. The definition of the phygital environment regards the innovational concept being used in marketing practice but has not been described in scientific publication yet. The article examines the peculiarities of interaction between consumers and sellers in the framework of their interaction in the phygital environment. The concept of pop-up stores is analyzed as a new format of advertising interaction with the consumer. The authors have proposed a model of an end-to-end analytics system for assessing the effectiveness of a pop-up store in the framework of the interaction of participants in the turnover in a phygital environment. The proposed model has been tested and the efficiency of opening a pop-up store has been evaluated with and without the proposed model. The main marketing indicators and potential effects from the implementation of the proposed system for the company’s activities, in general, in the field of marketing are evaluated. The authors have studied the prospects for both development and automation, as well as the formation of the system of personalized marketing for companies, which implements the concept of interaction with consumers within the framework of the phygital environment.

PurposeTobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes.Experimental DesignWhole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings.ResultsLow expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations.ConclusionsIn HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobacco’s primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

Objective Telehealth (TH) use in endocrinology was limited before the COVID-19 pandemic but will remain a major modality of care postpandemic. Reimbursement policies have been limited historically due to concerns of overutilization of visits and testing. Additionally, there is limited literature on endocrinology care delivered via TH for conditions other than diabetes. We assess real-world TH use for endocrinology in a prepandemic environment with the hypothesis that TH would not increase the utilization of total visits or related ancillary testing services compared with conventional (CVL) face-to-face office visits. Methods A single-institution retrospective cohort study assessing the prepandemic use of TH in endocrinology, consisting of 75 patients seen via TH and 225 patients seen in CVL visits. For most patients, TH was conducted via a clinic-to-clinic model. Outcomes measured were total endocrine visit frequency and frequency of related laboratory and radiology testing per patient, hemoglobin A1C, microalbumin, low-density lipoprotein, thyroid-stimulating hormone, thyroglobulin, and thyroid ultrasounds. Results For all endocrine visits, TH patients had a median of 0.24 (interquartile range, 0.015-0.36) visits per month. CVL patients had a median of 0.20 visits per month (interquartile range, 0.11-0.37). Total visits per month did not vary significantly between groups (P = .051). Hemoglobin A1C outcomes were equivalent and there was no increase in ancillary laboratory testing for the TH group. Conclusion Our observations demonstrate that, in a prepandemic health care setting, TH visits can provide equivalent care for endocrinology patients, without increasing utilization of total visits or ancillary services.

Community and stakeholder engagement is increasingly recognized as essential to science at the nexus of food, energy, and water systems (FEWS) to address complex issues surrounding food and energy production and water provision for society. Yet no comprehensive framework exists for supporting best practices in community and stakeholder engagement for FEWS. A review and meta-synthesis were undertaken of a broad range of existing models, frameworks, and toolkits for community and stakeholder engagement. A framework is proposed that comprises situational awareness of the FEWS place or problem, creation of a suitable culture for engagement, focus on power-sharing in the engagement process, co-ownership, co-generation of knowledge and outcomes, the technical process of integration, the monitoring processes of reflective and reflexive experiences, and formative evaluation. The framework is discussed as a scaffolding for supporting the development and application of best practices in community and stakeholder engagement in ways that are arguably essential for sound FEWS science and sustainable management.

PURPOSE: Seizures occur in 10% to 40% of critically ill children. We describe a phenomenon seen on color density spectral array but not raw EEG associated with seizures and acquired brain injury in pediatric patients. METHODS: We reviewed EEGs of 541 children admitted to an intensive care unit between October 2015 and August 2018. We identified 38 children (7%) with a periodic pattern on color density spectral array that oscillates every 2 to 5 minutes and was not apparent on the raw EEG tracing, termed macroperiodic oscillations (MOs). Internal validity measures and interrater agreement were assessed. We compared demographic and clinical data between those with and without MOs. RESULTS: Interrater reliability yielded a strong agreement for MOs identification (kappa: 0.778 [0.542–1.000]; P < 0.0001). There was a 76% overlap in the start and stop times of MOs among reviewers. All patients with MOs had seizures as opposed to 22.5% of the general intensive care unit monitoring population (P < 0.0001). Macroperiodic oscillations occurred before or in the midst of recurrent seizures. Patients with MOs were younger (median of 8 vs. 208 days; P < 0.001), with indications for EEG monitoring more likely to be clinical seizures (42 vs. 16%; P < 0.001) or traumatic brain injury (16 vs. 5%, P < 0.01) and had fewer premorbid neurologic conditions (10.5 vs. 33%; P < 0.01). CONCLUSIONS: Macroperiodic oscillations are a slow periodic pattern occurring over a longer time scale than periodic discharges in pediatric intensive care unit patients. This pattern is associated with seizures in young patients with acquired brain injuries.

The COVID‐19 pandemic has transformed healthcare for both clinicians and patients. This conceptual article uses ideas from the moral distress literature to understand the challenges MedFTs and physicians face during the COVID‐19 pandemic. The authors highlight earlier themes from the moral distress literature and share current reflections to illustrate similar challenges. Some clinicians who were already experiencing a rise in burnout due to the mass digitization of healthcare are now facing increased moral distress due to ethical dilemmas, pervasive uncertainty, boundary ambiguity, isolation, and burnout brought about by emerging COVID‐19 policies. Fears about personal safety, exposing loved ones, financial concerns, self‐doubt, and frustrations with telehealth have contributed to increased moral distress during the COVID‐19 pandemic. Building resilience by setting one's personal moral compass can help clinicians avoid the pitfalls of moral distress. Five steps for developing resilience and implications for guiding trainees in developing resilience are discussed.

Background Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD. Methods A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions–Improvement scale of “much improved” or “very much improved.” Results Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, −3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions–Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan. Conclusions At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits., B.P.C. acknowledges funding from Abigail Wexner Research Institute at Nationwide Children’s Hospital; T.H. Nyrönen acknowledges funding from Academy of Finland grant #31996; A.M.-J., K.N., T.F.B., O.M.H., and Z.S. acknowledge funding from Australian Medical Research Future Fund; M.S. acknowledges funding from Biobank Japan; D. Bujold and S.J.M.J. acknowledge funding from Canada Foundation for Innovation; L.J.D. acknowledges funding from Canada Foundation for Innovation Cyber Infrastructure grant #34860; D. Bujold and G.B. acknowledge funding from CANARIE; L.J.D. acknowledges funding from CANARIE Research Data Management contract #RDM-090 (CHORD) and #RDM2-053 (ClinDIG); K.K.-L. acknowledges funding from CanSHARE; T.L.T. acknowledges funding from Chan Zuckerberg Initiative; T. Burdett acknowledges funding from Chan Zuckerberg Initiative grant #2017-171671; D. Bujold, G.B., and L.D.S. acknowledge funding from CIHR; L.J.D. acknowledges funding from CIHR grant #404896; M.J.S.B. acknowledges funding from CIHR grant #SBD-163124; M. Courtot and M. Linden acknowledge funding from CINECA project EU Horizon 2020 grant #825775; D. Bujold and G.B. acknowledge funding from Compute Canada; F.M.-G. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – NFDI 1/1 “GHGA – German Human Genome-Phenome Archive; R.M.H.-S. acknowledges funding from Duke-Margolis Center for Health Policy; S.B. and A.J.B. acknowledge funding from EJP-RD EU Horizon 2020 grant #825575; A. Niewielska, A.K., D.S., G.I.S., J.A.T., J.R., M.A.K., M. Baudis, M. Linden, S.B., S.S., T.H. Nyrönen, and T.M.K. acknowledge funding from ELIXIR; A. Niewielska acknowledges funding from EOSC-Life EU Horizon 2020 grant #824087; J.-P.H. acknowledges funding from ETH Domain Strategic Focal Area “Personalized Health and Related Technologies (PHRT)” grant #2017-201; F.M.-G. acknowledges funding from EUCANCan EU Horizon 2020 grant #825835; B.M.K., D. Bujold, G.B., L.D.S., M.J.S.B., N.S., S.E.W., and Y.J. acknowledge funding from Genome Canada; B.M.K., M.J.S.B., S.E.W., and Y.J. acknowledge funding from Genome Quebec; F.M.-G. acknowledges funding from German Human Genome-Phenome Archive; C. Voisin acknowledges funding from Google; A.J.B. acknowledges funding from Health Data Research UK Substantive Site Award; D.H. acknowledges funding from Howard Hughes Medical Institute; S.B. acknowledges funding from Instituto de Salud Carlos III; S.-S.K. and K.T. acknowledge funding from Japan Agency for Medical Research and Development (AMED); S. Ogishima acknowledges funding from Japan Agency for Medical Research and Development (AMED) grant #20kk0205014h0005; C.Y. and K. Kosaki acknowledge funding from Japan Agency for Medical Research and Development (AMED) grant #JP18kk0205012; GEM Japan acknowledges funding from Japan Agency for Medical Research and Development (AMED) grants #19kk0205014h0004, #20kk0205014h0005, #20kk0205013h0005, #20kk0205012h0005, #20km0405401h0003, and #19km0405001h0104; J.R. acknowledges funding from La Caixa Foundation under project #LCF/PR/GN13/50260009; R.R.F. acknowledges funding from Mayo Clinic Center for Individualized Medicine; Y.J. and S.E.W. acknowledge funding from Ministère de l’Économie et de l’Innovation du Québec for the Can-SHARE Connect Project; S.E.W. and S.O.M.D. acknowledge funding from Ministère de l’Économie et de l’Innovation du Québec for the Can-SHARE grant #141210; M.A.H., M.C.M.-T., J.O.J., H.E.P., and P.N.R. acknowledge funding from Monarch Initiative grant #R24OD011883 and Phenomics First NHGRI grant #1RM1HG010860; A.L.M. and E.B. acknowledge funding from MRC grant #MC_PC_19024; P.T. acknowledges funding from National University of Singapore and Agency for Science, Technology and Research; J.M.C. acknowledges funding from NHGRI; A.H.W. acknowledges funding from NHGRI awards K99HG010157, R00HG010157, and R35HG011949; A.M.-J., K.N., D.P.H., O.M.H., T.F.B., and Z.S. acknowledge funding from NHMRC grants #GNT1113531 and #GNT2000001; D.L.C. acknowledges funding from NHMRC Ideas grant #1188098; A.B.S. acknowledges funding from NHMRC Investigator Fellowship grant #APP177524; J.M.C. and L.D.S. acknowledge funding from NIH; A.A.P. acknowledges funding from NIH Anvil; A.V.S. acknowledges funding from NIH contract #HHSN268201800002I (TOPMed Informatics Research Center); S.U. acknowledges funding from NIH ENCODE grant #UM1HG009443; M.C.M.-T. and M.A.H. acknowledge funding from NIH grant #1U13CA221044; R.J.C. acknowledges funding from NIH grants #1U24HG010262 and #1U2COD023196; M.G. acknowledges funding from NIH grant #R00HG007940; J.B.A., S.L., P.G., E.B., H.L.R., and L.S. acknowledge funding from NIH grant #U24HG011025; K.P.E. acknowledges funding from NIH grant #U2C-RM-160010; J.A.E. acknowledges funding from NIH NCATS grant #U24TR002306; M.M. acknowledges funding from NIH NCI contract #HHSN261201400008c and ID/IQ Agreement #17X146 under contract #HHSN2612015000031 and #75N91019D00024; R.M.C.-D. acknowledges funding from NIH NCI grant #R01CA237118; M. Cline acknowledges funding from NIH NCI grant #U01CA242954; K.P.E. acknowledges funding from NIH NCI ITCR grant #1U24CA231877-01; O.L.G. acknowledges funding from NIH NCI ITCR grant #U24CA237719; R.L.G. acknowledges funding from NIH NCI task order #17X147F10 under contract #HHSN261200800001E; A.F.R. acknowledges funding from NIH NHGRI grant #RM1HG010461; N.M. and L.J.Z. acknowledge funding from NIH NHGRI grant #U24HG006941; R.R.F., T.H. Nelson, L.J.B., and H.L.R. acknowledge funding from NIH NHGRI grant #U41HG006834; B.J.W. acknowledges funding from NIH NHGRI grant #UM1HG009443A; M. Cline acknowledges funding from NIH NHLBI BioData Catalyst Fellowship grant #5118777; M.M. acknowledges funding from NIH NHLBI BioData Catalyst Program grant #1OT3HL142478-01; N.C.S. acknowledges funding from NIH NIGMS grant #R35-GM128636; M.C.M.-T., M.A.H., P.N.R., and R.R.F. acknowledge funding from NIH NLM contract #75N97019P00280; E.B. and A.L.M. acknowledge funding from NIHR; R.G. acknowledges funding from Project Ris3CAT VEIS; S.B. acknowledges funding from RD-Connect, Seventh Framework Program grant #305444; J.K. acknowledges funding from Robertson Foundation; S.B. and A.J.B. acknowledge funding from Solve-RD, EU Horizon 2020 grant #779257; T.S. and S. Oesterle acknowledge funding from Swiss Institute of Bioinformatics (SIB) and Swiss Personalized Health Network (SPHN), supported by the Swiss State Secretariat for Education, Research and Innovation SERI; S.J.M.J. acknowledges funding from Terry Fox Research Institute; A.E.H., M.P.B., M. Cupak, M.F., and J.F. acknowledge funding from the Digital Technology Supercluster; D.F.V. acknowledges funding from the Australian Medical Research Future Fund, as part of the Genomics Health Futures Mission grant #76749; M. Baudis acknowledges funding from the BioMedIT Network project of Swiss Institute of Bioinformatics (SIB) and Swiss Personalized Health Network (SPHN); B.M.K. acknowledges funding from the Canada Research Chair in Law and Medicine and CIHR grant #SBD-163124; D.S., G.I.S., M.A.K., S.B., S.S., and T.H. Nyrönen acknowledge funding from the EU Horizon 2020 Beyond 1 Million Genomes (B1MG) Project grant #951724; P.F., A.D.Y., F.C., H.S., I.U.L., D. Gupta, M. Courtot, S.E.H., T. Burdett, T.M.K., and S.F. acknowledge funding from the European Molecular Biology Laboratory; Y.J. and S.E.W. acknowledge funding from the Government of Canada; P.G. acknowledges funding from the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-206); J.Z. acknowledges funding from the Government of Ontario; C.K.Y. acknowledges funding from the Government of Ontario, Canada Foundation for Innovation; C. Viner and M.M.H. acknowledge funding from the Natural Sciences and Engineering Research Council of Canada (grant #RGPIN-2015-03948 to M.M.H. and Alexander Graham Bell Canada Graduate Scholarship to C.V.); K.K.-L. acknowledges funding from the Program for Integrated Database of Clinical and Genomic Information; J.K. acknowledges funding from the Robertson Foundation; D.F.V. acknowledges funding from the Victorian State Government through the Operational Infrastructure Support (OIS) Program; A.M.L., R.N., and H.V.F. acknowledge funding from Wellcome (collaborative award); F.C., H.S., P.F., and S.E.H. acknowledge funding from Wellcome Trust grant #108749/Z/15/Z; A.D.Y., H.S., I.U.L., M. Courtot, H.E.P., P.F., and T.M.K. acknowledge funding from Wellcome Trust grant #201535/Z/16/Z; A.M., J.K.B., R.J.M., R.M.D., and T.M.K. acknowledge funding from Wellcome Trust grant #206194; E.B., P.F., P.G., and S.F. acknowledge funding from Wellcome Trust grant #220544/Z/20/Z; A. Hamosh acknowledges funding from NIH NHGRI grant U41HG006627 and U54HG006542; J.S.H. acknowledges funding from National Taiwan University #91F701-45C and #109T098-02; the work of K.W.R. was supported by the Intramural Research Program of the National Library of Medicine, NIH. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. H.V.F. acknowledges funding from Wellcome Grant 200990/A/16/Z ‘Designing, developing and delivering integrated foundations for genomic medicine'.

Purpose: N-803 is an IL15 receptor superagonist complex, designed to optimize in vivo persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8+ T cells. Monoclonal antibodies (mAbs) direct Fc receptor–bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously. Patients and Methods: Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression. Results: This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes. Conclusions: N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.

PURPOSE Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood. METHODS Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50). RESULTS In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration–approved drugs. CONCLUSION This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions.

Objectives Research examining the effect of changes in Medicaid dental benefits on emergency department (ED) use for dental conditions has had mixed results. We examined the effect of changes in Medicaid dental benefits on ED use for nontraumatic dental conditions (NTDCs) among adults in Massachusetts before and after Medicaid dental benefits for adults were eliminated (July 2010) and partially restored (January 2013). Methods We used 2009-2013 data from the Massachusetts All-Payer Claims Database. The study population included Medicaid enrollees aged ≥21 who made a visit to the ED for an NTDC that was paid for by Medicaid during the study period. We used an interrupted time-series study design and segmented regression model to assess the effect of the policy changes on ED use for NTDCs. We also conducted a subanalysis by patient age, sex, and geographic location. Results During the study period, 21 731 Medicaid enrollees aged ≥21 made 35 660 NTDC ED visits. Eliminating comprehensive dental benefits led to a significant increase in the use of EDs for NTDCs. This increase occurred over time (11% increase at 15 months after elimination of comprehensive dental benefits; estimate, 0.64 [95% CI, 0.07-1.21]; P = .03) rather than immediately after the policy change took effect. The partial restoration of certain dental benefits led to a significant decrease in the rate of ED visits for NTDCs over time (15.7% decrease at 5 months after partial restoration of certain dental benefits; estimate, –0.97 [95% CI, –1.83 to –0.11]; P = .03). Conclusion Strengthening dental coverage policies for adult Medicaid enrollees could decrease their reliance on EDs for NTDCs.

Persons living with HIV/AIDS (PLWH) are living long enough to need age-related and HIV-related nursing home (NH) care. Nursing home quality of care has been associated with risk for hospitalization, but it is unknown if quality of HIV care in NHs affects hospitalization in this population. We assessed HIV care quality with four national measures adapted for the NH setting. We applied the measures to 2011-2013 Medicare claims linked to Minimum Data Set assessments of resident health, prescription dispensing data, and national reports of NH characteristics. Cox proportional hazards models calculated the risk of all-cause and HIV/AIDS-related hospitalization by HIV care compliance. We identified 1,246 PLWH in 201 NHs with 382 all-cause and 63 HIV/AIDS-related hospitalizations. Nursing home HIV care compliance varied from 24.9% to 64.7%. After regression adjustment, we could detect no difference in all-cause or HIV/AIDS-related hospitalizations by NH HIV care compliance. We postulate that the lack of association may be due to inappropriate HIV care quality measures that do not accurately represent NHs ability to care for PLWH. There is urgent need to create valid NH HIV care quality measures.

PURPOSE The cancer research community is constantly evolving to better understand tumor biology, disease etiology, risk stratification, and pathways to novel treatments. Yet the clinical cancer genomics field has been hindered by redundant efforts to meaningfully collect and interpret disparate data types from multiple high-throughput modalities and integrate into clinical care processes. Bespoke data models, knowledgebases, and one-off customized resources for data analysis often lack adequate governance and quality control needed for these resources to be clinical grade. Many informatics efforts focused on genomic interpretation resources for neoplasms are underway to support data collection, deposition, curation, harmonization, integration, and analytics to support case review and treatment planning. METHODS In this review, we evaluate and summarize the landscape of available tools, resources, and evidence used in the evaluation of somatic and germline tumor variants within the context of molecular tumor boards. RESULTS Molecular tumor boards (MTBs) are collaborative efforts of multidisciplinary cancer experts equipped with genomic interpretation resources to aid in the delivery of accurate and timely clinical interpretations of complex genomic results for each patient, within an institution or hospital network. Virtual MTBs (VMTBs) provide an online forum for collaborative governance, provenance, and information sharing between experts outside a given hospital network with the potential to enhance MTB discussions. Knowledge sharing in VMTBs and communication with guideline-developing organizations can lead to progress evidenced by data harmonization across resources, crowd-sourced and expert-curated genomic assertions, and a more informed and explainable usage of artificial intelligence. CONCLUSION Advances in cancer genomics interpretation aid in better patient and disease classification, more streamlined identification of relevant literature, and a more thorough review of available treatments and predicted patient outcomes.

The Vanderbilt Health Affiliated Network (VHAN) is a collaborative alliance of physicians, health systems, and employers driving a new level of clinical innovation and teamwork to enhance patient care, contain costs, and improve the health of communities in Tennessee and surrounding states. The network includes more than 5,000 clinicians, 60 hospitals, 12 health systems, and hundreds of physician practices and clinics who work together to strengthen communities and improve quality of life across the Southeast through better health. The statin outreach service was piloted in one VHAN practice, the Vanderbilt Medical Group, a large primary care group at Vanderbilt University Medical Center (VUMC). VUMC is a tertiary care academic center. VUMC primary care providers (PCPs) are located in several practice locations, and one location was chosen to pilot this intervention. The PCPs included internal medicine residents and attending physicians. Before this project, there was no clinical pharmacy presence in this practice.

Context The potential for endocrine care via telemedicine has been recognized since the early 2000s when clinical outcome data demonstrated improvements in glycemic control with telemedicine. The widespread use of telemedicine during the COVID-19 pandemic has pushed telemedicine beyond diabetes care and into clinical areas with a paucity of published data. The evaluation and treatment of thyrotoxicosis heavily relies on laboratory assessment and imaging with physical exam playing a role to help differentiate the etiology and assess the severity of thyrotoxicosis. Case Description We describe a patient presenting for evaluation of new thyrotoxicosis via telemedicine, and describe modifications to consider for thorough, safe evaluation via telemedicine. Conclusion Telemedicine may be an ideal way to assess and treat patients with thyrotoxicosis who are not able to physically attend a visit with an endocrinologist but still have access to a laboratory for blood draws. Potential challenges include access to imaging and high-volume surgeons if needed. Clinical and economic outcomes of telemedicine care of thyrotoxicosis should be studied so that standards of care for endocrine telemedicine can be established.

PURPOSE Precision oncology depends on the matching of tumor variants to relevant knowledge describing the clinical significance of those variants. We recently developed the Clinical Interpretations for Variants in Cancer (CIViC; civicdb.org ) crowd-sourced, expert-moderated, and open-access knowledgebase. CIViC provides a structured framework for evaluating genomic variants of various types (eg, fusions, single-nucleotide variants) for their therapeutic, prognostic, predisposing, diagnostic, or functional utility. CIViC has a documented application programming interface for accessing CIViC records: assertions, evidence, variants, and genes. Third-party tools that analyze or access the contents of this knowledgebase programmatically must leverage this application programming interface, often reimplementing redundant functionality in the pursuit of common analysis tasks that are beyond the scope of the CIViC Web application. METHODS To address this limitation, we developed CIViCpy ( civicpy.org ), a software development kit for extracting and analyzing the contents of the CIViC knowledgebase. CIViCpy enables users to query CIViC content as dynamic objects in Python. We assess the viability of CIViCpy as a tool for advancing individualized patient care by using it to systematically match CIViC evidence to observed variants in patient cancer samples. RESULTS We used CIViCpy to evaluate variants from 59,437 sequenced tumors of the American Association for Cancer Research Project GENIE data set. We demonstrate that CIViCpy enables annotation of > 1,200 variants per second, resulting in precise variant matches to CIViC level A (professional guideline) or B (clinical trial) evidence for 38.6% of tumors. CONCLUSION The clinical interpretation of genomic variants in cancers requires high-throughput tools for interoperability and analysis of variant interpretation knowledge. These needs are met by CIViCpy, a software development kit for downstream applications and rapid analysis. CIViCpy is fully documented, open-source, and available free online.

SUMMARYBackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate.MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (NCT02296684), and is ongoing but closed to accrual.FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR ≥10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-γ pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%).ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical.FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

Wikidata is a community-maintained knowledge base that has been assembled from repositories in the fields of genomics, proteomics, genetic variants, pathways, chemical compounds, and diseases, and that adheres to the FAIR principles of findability, accessibility, interoperability and reusability. Here we describe the breadth and depth of the biomedical knowledge contained within Wikidata, and discuss the open-source tools we have built to add information to Wikidata and to synchronize it with source databases. We also demonstrate several use cases for Wikidata, including the crowdsourced curation of biomedical ontologies, phenotype-based diagnosis of disease, and drug repurposing.