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Background Although immunotherapies represent an encouraging approach against cancer, to date none translated to the clinical benefit in Glioblastoma (GBM). One aspect contributing to this failure is the highly immunosuppressive GBM microenvironment. Our approach to overcome immunosuppression is to increase anti-tumor immune responses via adenovirus (AdV)-mediated delivery of the MHC-II Transactivator (CIITA) gene. CIITA-induced MHC-II expression is anticipated to convert GBM cells into surrogate antigen presenting cells able to prime T helper cells, therefore promoting CD4+ and CD8+ mediated immunity. Material and Methods We generated AdVs containing wild type CIITA (Ad-CIITA) using a replication-defective serotype5 adenoviral backbone. AdVs containing a mutated, non-functional version of CIITA (Ad-CIITA mutant) and an empty CMV promoter (Ad-null) were used as controls. AdV-mediated MHC-II expression was monitored at mRNA, protein and cell surface level. For the functional assessment of anti-tumor immune responses, we developed an advanced human GBM organoid model system consisting of tumor organoids co-cultured with either human peripheral blood mononuclear cells (PBMCs) or isolated CD3+ T cells. T cell mediated tumor cell killing was monitored over time via live cell imaging and flow cytometry. Results We successfully constructed and produced a CIITA-armed AdV that induces MHC-II expression in infected GBM cells, indicating the efficient expression of transcriptionally active CIITA for at least six days post infection. In immunocompetent human GBM organoids, Ad-CIITA infection of tumor cells led to prominent organoid disruption and tumor cell death, an effect that was not observed in the absence of PBMCs or CD3+ T cells. Tumor organoids infected with Ad-CIITA mutant remained intact, demonstrating the implication of cell surface MHC-II molecules in the observed phenotype. Conclusion Our results demonstrate that AdV-mediated delivery of CIITA is a promising strategy to increase T cell mediated immunity against glioblastoma.

The COVID-19 pandemic is a crisis which called for two crucial modes of social regulation

The Pharmacogenomics Knowledgebase (PharmGKB) is an integrated online knowledge resource for the understanding of how genetic variation contributes to variation in drug response. Our focus includes not only pharmacogenomic information useful for clinical implementation (e.g., drug dosing guidelines and annotated drug labels), but also information to catalyze scientific research and drug discovery (e.g., variant-drug annotations and drug-centered pathways). As of April 2021, the annotated content of PharmGKB spans 715 drugs, 1761 genes, 227 diseases, 165 clinical guidelines, and 784 drug labels. We have manually curated data from more than 9000 published papers to generate the content of PharmGKB. Recently, we have also implemented an automated natural language processing (NLP) tool to broaden our coverage of the pharmacogenomic literature. This article contains a basic protocol describing how to navigate the PharmGKB website to retrieve information on how genes and genetic variations affect drug efficacy and toxicity. It also includes a protocol on how to use PharmGKB to facilitate interpretation of findings for a pharmacogenomic variant genotype or metabolizer phenotype. PharmGKB is freely available at http://www.pharmgkb.org. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Navigating the homepage of PharmGKB and searching by drug Basic Protocol 2: Using PharmGKB to facilitate interpretation of pharmacogenomic variant genotypes or metabolizer phenotypes.

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs, including nonsteroidal anti-inflammatory drugs, phenytoin, antidiabetic agents, and angiotensin receptor blockers. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium.

Genome-enabled biotechnologies have the potential to accelerate breeding efforts in long-lived perennial crop species. Despite the transformative potential of molecular tools in pecan and other outcrossing tree species, highly heterozygous genomes, significant presence–absence gene content variation, and histories of interspecific hybridization have constrained breeding efforts. To overcome these challenges, here, we present diploid genome assemblies and annotations of four outbred pecan genotypes, including a PacBio HiFi chromosome-scale assembly of both haplotypes of the ‘Pawnee’ cultivar. Comparative analysis and pan-genome integration reveal substantial and likely adaptive interspecific genomic introgressions, including an over-retained haplotype introgressed from bitternut hickory into pecan breeding pedigrees. Further, by leveraging our pan-genome presence–absence and functional annotation database among genomes and within the two outbred haplotypes of the ‘Lakota’ genome, we identify candidate genes for pest and pathogen resistance. Combined, these analyses and resources highlight significant progress towards functional and quantitative genomics in highly diverse and outbred crops., Pecan is an important specialty crop that has experienced extensive interspecific hybridization and nearly-obligate outcrossing. Here, the authors assemble diploid genomes of four outbred genotypes, identify interspecific introgressions through comparative genomics analyses, and map QTLs associated with pest resistance.

The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected by patients’ baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) effects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the benefit–risk profile of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist. Electronic supplementary material The online version of this article (10.1007/s40262-019-00840-7) contains supplementary material, which is available to authorized users.

In 2009, the Clinical Pharmacogenetics Implementation Consortium (CPIC; www.cpicpgx.org), a shared project between Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) and the National Institutes of Health (NIH), was created to provide freely available, evidence-based, peer-reviewed, and updated pharmacogenetic clinical practice guidelines. To date, CPIC has published 23 guidelines (of which 11 have been updated), covering 19 genes and 46 drugs across several therapeutic areas. CPIC also now provides additional resources to facilitate the implementation of pharmacogenetics into routine clinical practice and the electronic health record. Furthermore, since its inception, CPIC’s interactions with other resources, databases, websites and genomic communities have grown. This purpose of this paper is to highlight the progress of CPIC over the past 10 years.

Pharmacogenomics (PGx) decision support and return of results is an active area of precision medicine. One challenge of implementing PGx is extracting genomic variants and assigning haplotypes in order to apply prescribing recommendations and information from the Clinical Pharmacogenetics Implementation Consortium (CPIC), the US Food and Drug Administration (FDA), the Pharmacogenomics Knowledgebase (PharmGKB), etc. Pharmacogenomics Clinical Annotation Tool (PharmCAT) (i) extracts variants specified in guidelines from a genetic data set derived from sequencing or genotyping technologies, (ii) infers haplotypes and diplotypes, and (iii) generates a report containing genotype/diplotype-based annotations and guideline recommendations. We describe PharmCAT and a pilot validation project comparing results for 1000 Genomes Project sequences of Coriell samples with corresponding Genetic Testing Reference Materials Coordination Program (GeT-RM) sample characterization. PharmCAT was highly concordant with the GeT-RM data. PharmCAT is available in GitHub to evaluate, test, and report results back to the community. As precision medicine becomes more prevalent, our ability to consistently, accurately, and clearly define and report PGx annotations and prescribing recommendations is critical.

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10−54; CES1 G143E, P = 1.3 × 10−16; CYP2C19*17, P = 9.5 × 10−10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10−4; CYP2B6 516 G > T, P = 1.0 × 10−3; CYP2C9*2, P = 1.2 × 10−3; and CYP2C9*3, P = 1.5 × 10−3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14–2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35–14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. Conclusion Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

Liquid metal (LM) plasma-facing components (PFCs) may provide a resolution to the challenging fusion environment, particularly the first wall and divertor surfaces. Transforming these conce...

Background: Preoperative emotional distress has been shown to negatively influence joint arthroplasty and spine surgery, but limited data exist for foot and ankle outcomes. Emotional distress can be captured through modern tools like the Patient-Reported Outcomes Instrument Measurement System (PROMIS) anxiety domain. We hypothesized that patients with greater preoperative PROMIS anxiety scores would report greater pain and less function after foot and ankle surgery than patients with lower preoperative anxiety levels. Methods: Elective foot and ankle surgeries from May 2016 to December 2017 were retrospectively identified. PROMIS anxiety, pain interference (PI), and physical function (PF) scores were collected before and after surgery. Patients were grouped based on preoperative PROMIS scores greater or less than 59.4. A cutoff of PROMIS anxiety above 59.4 was selected as the threshold that corresponds to traditional measures of anxiety. Results: Compared to patients with less preoperative anxiety (average: 47.2, n=146), patients with higher preoperative anxiety (average: 63.9, n=59) had greater preoperative pain (PROMIS PI: 63.5 vs 59.1, P < .001) and lower physical function (PROMIS PF: 37.9 vs 42.0, P = .001). Postoperatively, patients with higher preoperative anxiety had more residual pain and greater functional disability as compared to patients with less preoperative emotional distress (PROMIS PI: 58.6 vs 52.9, P < .001; PROMIS PF: 39.8 vs 44.4, P < .001; respectively). Conclusion: Our evidence showed that preoperative emotional anxiety predicted worse pain and function at early operative follow-up. Measures of preoperative anxiety could be useful in identifying patients at risk for poorer operative outcomes, but continued study is necessary. Level of Evidence: Level III, retrospective comparative study.

Background: This study estimated operating room surface contamination rates during aseptic vs septic total joint arthroplasty and evaluated the similarity between clinically infecting organisms and those isolated from contaminated surfaces. Methods: Patients undergoing total hip and knee revision arthroplasties were identified, and surface and tissue samples were collected. Cases were classified aseptic or septic based on Musculoskeletal Infection Society criteria for prosthetic joint infection. Positive surface cultures were compared with intraoperative tissue cultures. Positive cultures were speciated and tested for antimicrobial sensitivity. Results: Samples were collected from 31 aseptic and 18 septic cases. Patients had similar demographics and time to explantation. Surface contamination rates for septic revisions were greater than those for aseptic revisions (77% vs 13%). During septic revisions, when intraoperative tissue cultures were positive, the surgical field was contaminated in 14 of 15 cases. The kappa correlation statistic for positive surgical cultures matching the surface sample was 0.9 (95% confidence interval: 0.78-1). Conclusions: Septic revisions had a significantly higher rate of surgical field contamination than aseptic revisions. Cultures suggest that bacteria contaminating the septic revision surgical field likely originated from the infected joint. Although this observation seems obvious, it is an important piece of information when discussing best practices during a single-stage exchange revision. Further clinical studies will demonstrate the use of a preparation and reset period during a single-stage revision to remove contaminated surfaces. Keywords: Total joint revision, Contamination, Prosthetic joint infection

Pharmacogenomics aims to associate human genetic variability with differences in drug phenotypes in order to tailor drug treatment to individual patients. The massive amount of genetic data generated from large cohorts of patients with variable drug phenotypes have led to advances in this field. Understanding the application of pharmacogenomics in dermatology could inform clinical practice and provide insight for future research. The Pharmacogenomics Knowledge Base and the Clinical Pharmacogenetics Implementation Consortium are among the resources to help clinicians and researchers navigate the many gene-drug associations that have already been discovered. The implementation of clinical pharmacogenomics within health care systems remains an area of ongoing development. This review provides an introduction to the field of pharmacogenomics and to current pharmacogenomics resources using examples of gene-drug associations relevant to the field of dermatology.

Aim. To find out the cause of inhibition of the IL2-STAT5 signaling pathway in chronic lymphocytic leukemia (CLL) cells. Methods.CLL cells were isolated from peripheral blood, using gradient centrifugation on a ficoll-verografin mixture. Expression of the STAT1-6 genes at the mRNA level was analyzed, using the Oncomine database. Expression, phosphorylation status and cellular localization of the STAT5 protein were studied by fluorescence microscopy, using specific antibodies. Results.Unlike B-cells of healthy donors, expression of the STAT5A protein was low in the patient CLL cells. As we have previously shown, the IL-2-STAT5 (JAK-STAT5) signaling pathway is inhibited in CLL cells. Now we demonstrated a low level of phosphorylation of the STAT5 protein, or a complete lack of phosphorylation in CLL cells. The STAT5A protein shows cytoplasmic localization, indicating the absence of complexes in the nucleus that activate/repress transcription of the STAT5-dependent genes. Conclusions. Inhibition of the IL-2-STAT5 pathway in CLL cells is caused by a lack of the STAT5 proteins phosphorylation and/or the absence of the active STAT5A transcription complexes in the nucleus of CLL cells. Мета. Встановити причину блокування сигнального шляху IL2-STAT5 у клітинах крові хворих на хронічний ліфмолейкоз (ХЛЛ). Методи. Клітини ХЛЛ виділяли з периферичної крові пацієнтів, хворих на ХЛЛ, за допомогою центрифугування у градієнтіфікол-верографін. Експресію генів STAT1-6 на рівні мРНК аналізували за допомогою бази даних Oncomine. Експресію, статус фосфорилювання і клітинну локалізацію білка STAT5 вивчали методом флуоресцентної мікроскопії з використаннім специфічних антитіл. Результати. Навідмінувід В-клітин здорових людей, експресія білка STAT5А була низькою у клітинах хворих на ХЛЛ. Як нами було встановлено раніше, сигнальний шлях IL-2-STAT5 (JAK-STAT5) інгібовано у клітинах ХЛЛ. Нами було показано низький рівень фосфорилювання білків STAT5, або повну відсутність фосфорильованої форми протеїнів в лейкемічних клітинах. Протеїн STAT5А показує цитоплазматичну локалізацію, що вказує н авідсутність у ядрікомплексів, активуючих транскрипцію генів, залежних від фактора транскрипції STAT5. Висновки. Інгибування сигнального клітинного шляху IL-2-STAT5 в клітинах крові хворих на ХЛЛ реалізується за рахунок гіпофосфорилювання протеїнів STAT5 та/або відсутності активних комплексів транскрипції STAT5А у ядрі лейкемичних клітин. Цель. Установить причину блокирования сигнального пути IL2-STAT5 в клетках крови больных хроническим лимфолейкозом (ХЛЛ). Методы. Лейкемические клетки выделяли из периферической крови с помощью центрифугирования в градиенте плотности фиколл-верографин. Экспрессию генов STAT1-6 на уровне мРНК анализировали с помощью базы данных Oncomine. Экспрессию, статус фосфорилирования и клеточную локализацию белка STAT5 изучали методом флуоресцентной микроскопии с использованием специфических антител. Результаты. В отличие от В-клеток здоровых людей, экспрессия белка STAT5А была низкой в клетках больных ХЛЛ. Как нами было установлено ранее, сигнальный путь IL-2-STAT5 (JAK-STAT5) ингибирован в клетках ХЛЛ. Намибылпоказаннизкийуровеньфосфорилированиябелков STAT5 или полное отсутствие фосфорилированной формы протеинов в лейкемических клетках. Протеин STAT5А показывает цитоплазматическую локализацию, что указывает на отсутствие в ядре комплексов, активирующих транскрипцию генов, зависимых от фактора транскрипции STAT5. Выводы. Ингибирование сигнального клеточного пути IL-2-STAT5 в клетках крови больных ХЛЛ происходит за счёт гипофосфорилирования белков STAT5 и/или отсутствия активных комплексов транскрипции STAT5А в ядре лейкемических клеток.

Background: In node negative and 1-3 positive nodes breast cancer patients with hormone receptor positive (HR+), HER2-negative (HER2-) early-stage breast cancer the indication for chemotherapy is based on clinical and pathologic risk stratification (tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67). For further decision-making, the EndoPredict test, which combines a molecular signature with the clinical risk factors tumor size and nodal status, stratifies patients into “low risk" or “high risk” groups. Level I-B- evidence demonstrates, that EndoPredict predicts the 10 year cumulative risk of relapse and metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment. Aim: In the RESCUE-Trial we document distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) events in patients who had an EndoPredict test. The primary objective is to show that 10-year DMFS of patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone is >90 %. Secondary endpoints among others include DMFS, DFS, OS in patients with EPclin “low risk” versus “high risk”. Also the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors (like tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67 level) with respect to survival will also be assessed. Eligibility: Patient with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes will be eligible, if they had an EndoPredict test within three months before inclusion. Methods: The EndoPredict test results, tumor board decision and anti-tumor therapy will be assessed. After one year, annually (for 10 years), patients will be evaluated for treatment compliance, recurrence, metastases, and survival. The primary endpoint will be analyzed by a Kaplan-Meyer estimate for which a one-sided lower 95 % confidence interval will be given. Several secondary endpoints will be assessed in three interim analyses after completion of the 1st, 3rd, 5th year and then finally after 10 years. Accrual: Start of accrual is planned for July 2018. At least 26 sites in Germany and one site in Switzerland will be active. Sponsor: The study is sponsored by the North-Eastern-German Society of Gynecological Oncology (NOGGO) e.V. Contact Information: For further information, contact NOGGO via studies@noggo.de or the leading physician Dr. Johannes Ettl via johannes.ettl@tum.de. Citation Format: Ettl J, Blohmer J-U, Denkert C, Keller M, Klein E, Kronenwett R, Neuser P, Paepke S, Schade-Brittinger C, Schnuppe K, Untch M, Wittenberg M, Kiechle M. RESCUE: Reaching for Evidence-baSed Chemotherapy Use in Endocrine sensitive breast cancer - A prospective health care study on risk assessment by the clinicomolecular test EndoPredict® and long-term patient outcome in early luminal breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-03.

Objective: Synthetic meshes and acellular dermal matrices are increasingly used in implant based breast reconstruction. The objective of this study was to determine the incidence and severity of complications following the implantation of the partially absorbable bi-component soft mesh SERAGYN ® BR and assess risk factors for adverse operative outcomes. Methods: A retrospective clinical study was performed: The SERAGYN ® BR soft mesh was utilized in 148 operations (skin-sparing mastectomy, nipple-sparing mastectomy, breast conserving surgery, secondary reconstruction after mastectomy) in four different institutions in Germany from June 2012 to February 2014. We analyzed whether the results were affected by tumor morphology (e.g. grading), patient characteristics and co-morbidities, previous surgery or therapies and use of alloplastic materials. Results: The SERAGYN ® BR soft mesh was successfully implanted in 131 of 148 operations. The rate of reconstructive failure was 11.5 %. The most common complication was seroma (25.7 %), followed by hematoma and skin infection (each 14.2%). Wound healing issues were detected in 13.5% cases, secondary wound infections in 10.8%. 83.8% of operations had no severe complications. Independent predictors for reconstructive failure were wound healing issues, nipple- or skin necrosis, wound- or skin infections, a high volume of excised tissue, hematomas, seromas and sentinel lymph node excisions. A higher body mass index was correlated with a higher rate of infection. Conclusion: SERAGYN ® BR mesh can be used successfully in breast reconstructive surgery. Rates of major complications or reconstructive failure are comparable to the use of other synthetic or biological meshes. Citation Format: Machleidt A, Schmidt-Feuerheerd N, Blohmer J-U, Ohlinger R, Küper J, von Waldenfels G, Dittmer S, Paepke S, Klein E. Reconstructive breast surgery with partially absorbable bi-component Seragyn® BR soft mesh: An outcome analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-16-16.

In the past few decades, Rose rosette disease (RRD) has spread from its source in western North America through the Mid-West to the East coast. It now threatens to decimate the US rose industry. Garden roses, which form the cornerstone of the multi-billion dollar landscape industry, annually generate wholesale US domestic bare root and container production valued at around $ 400 million. RRD is caused by an emaravirus, Rose rosette virus (RRV), which is transmitted by wind-blown eriophyid mites (Phyllocoptes fructiphilus). Unlike other rose diseases, it can kill a rose within two to three years of infection. In collaboration with scientists from 6 states, private rose breeders, the American Rose Society, AmericanHort, and the rose industry, a project was initiated to develop a multidisciplinary approach to control the disease. In the short term, the project team is working to develop Best Management Practices and educational materials based on host, virus, and vector biology to minimize the effects of RRD. Key to this effort is the development of efficient user-friendly diagnostic tools. In the long term, roses are being assessed for resistance to RRD using both replicated field trials and observational data from collaborators. Marker-trait associations for RRD resistance and consistent flower productivity are being identified to move RRD resistance efficiently into elite rose germplasm. Economic and marketing studies are being done to assess the economic effect of RRD on the rose industry, improve our understanding of consumer preferences, and identify barriers to rose sales.

Heat stress on roses (Rosa spp.) negatively affects the plantRSQUOs performance and reduces the market value of the crop. The effect of heat on flower size was assessed through petal number in the field during the cool (~20°C) and warm (~30°C) seasons during 2013-2014 and through flower diameter and weight during 2015 for 9 interrelated diploid rose families, respectively. The elevated temperature caused a decrease in flower size for flower diameter (~16-18%), petal number (~23-17%), and flower weight (~17-32%). Flower size showed low to moderate (flower diameter, 0.24-0.38; petal number, 0.12-0.26; flower weight, 0.34-0.53) narrow sense heritability and moderate (flower diameter, 0.62-0.70; petal number, 0.74-0.91; flower weight, 0.76-0.88) broad sense heritability inferring a major non-additive genetic component for flower size. Differences in heat tolerance would indicate that roses respond differentially to the environment (heat stress). Thus in a genetic variance analysis, a high G×E variance would indicate genetic differences in heat stress. Among the three size parameters, flower diameter showed the largest G×E genetic variance. However, the G×E variance for flower diameter in the heat shock experiment explained less (6.3%) genetic variance as compared to the field experiment (37%) indicating that selection would be more effective under field conditions. We are now investigating the use of FlexQTL to analyze the phenotypic and genotypic data from these interrelated families to identify important QTL conditioning the changes in flower size and heat tolerance.

Cercospora leaf spot (Cercospora rosicola) is a fungal disease that is prevalent in the southeastern United States. It causes leaf spotting and plant weakening, which may lead to premature defoliation. The current cercospora management practice is repeated fungicide applications throughout the season. Replicated garden rose cultivar field trials in south central (College Station) and northeastern (Overton) Texas were rated monthly for the percent of leaves with cercospora lesions from April through November in 2016 to assess the relative resistance of rose cultivars to cercospora leaf spot. Although both sites had a wide range of cercospora lesion incidence on the roses, the Overton site had a greater average (2.66 vs. 0.44) cercospora leaf spot rating than College Station due to more favorable conditions. At the higher disease pressure location, of the 263 roses accessions evaluated, ~13% were highly susceptible with GROTERDAN50% of the leaves infected with cercospora and 6 cultivars showed no cercospora symptoms. A restricted estimated maximum likelihood (REML) genetic variance analysis of field ratings for cercospora incidence of 16 interrelated diploid estimated the narrow sense and broad sense heritabilities were 0.51 and 0.72, respectively. This indicates that the selection for cercospora resistant cultivars should be possible. Further work to determine markers associated with the resistance is ongoing.

Plant architecture, which is the result of both the plant organization and the interaction between the plant and the environment, affects the ornamental value and flower productivity of roses. Thus, it is helpful to understand the genetic basis of plant architecture so that breeding efforts can be directed towards improved architecture. To this end, six architectural traits (plant height, number and length of primary shoots, number of nodes on primary shoot, number of secondary and tertiary shoots per primary shoot) were evaluated in May and December of 2015 in College Station, TX, for 13 interrelated diploid rose populations segregating for plant architecture types. Three of the traits (number of primary shoots, length of primary shoots, and number of nodes on primary shoot) exhibited low to moderate narrow sense heritability but moderately high to high broad sense heritability, indicating an important non-additive genetic component. The number of nodes on the primary shoots and the number of secondary and tertiary shoots per primary shoot displayed a large genotype by environment interaction. A comparison of desirable and undesirable plant growth types indicated that desirable growth types have more than 30 primary shoots with multiple secondary/tertiary shoots. The 13 rose populations have been genotyped for single nucleotide polymorphisms (SNPs) and the next step will be to perform a quantitative trait loci (QTL) analysis using FlexQTL to identify markers for high numbers of primary shoots.

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

Previous literature has suggested both MRI and ultrasound can accurately diagnose plantar plate tears. There is a significant cost difference between these two modalities, sparking interest for which should be the preferred method for diagnosis.The purpose of this study was to examine the diagnostic accuracy of MRI and dynamic, musculoskeletal ultrasound for lesser metatarsal plantar plate injuries using a systematic review and meta-analysis.MEDLINE, CINAHL, and Clinicaltrials.gov were searched thru May 2020. We included studies evaluating the diagnostic accuracy of MRI or ultrasound for detecting plantar plate tears, using intraoperative confirmation as the gold standard comparison. Sensitivity and specificity were obtained and pooled from included studies. Summary receiver operating curves were formed for each diagnostic test to compare accuracy. Study quality was assessed using the QUADAS-2 scoring system.Eleven studies met our inclusion criteria, representing 227 plantar plates for MRI and 238 plantar plates for ultrasound. MRI displayed a pooled sensitivity of 89% (95% CI 0.84, 0.93) and specificity of 83% (95% CI 0.64, 0.94). Ultrasound displayed a sensitivity and specificity of 95% (95% CI 0.91, 0.98) and 52% (95% CI 0.37, 0.68), respectively.MRI was superior to ultrasound in diagnosing plantar plate injuries overall, however, ultrasound was more sensitive than MRI, suggesting a negative ultrasound would likely rule out a plantar plate injury in the presence of an equivocal physical exam. Determining the grade of the injury is best served with MRI which can provide added insight into the joint's supporting structures (e.g. collateral ligaments) and integrity.

Pharmacogenomics (PGx) can be seen as a model for biomedical studies: it includes all disease areas of interest and spans in vitro studies to clinical trials, while focusing on the relationships between genes and drugs and the resulting phenotypes. This review will examine different characteristics of PGx study publications and provide examples of excellence in framing PGx questions and reporting their resulting data in a way that maximizes the knowledge that can be built on them.

Nociceptive and pruriceptive neurons in the dorsal root ganglia (DRG) convey sensations of pain and itch to the spinal cord, respectively. One subtype of mature DRG neurons, comprising 6% to 8% of neurons in the ganglia, is responsible for sensing mediators of acute itch and atopic dermatitis, including the cytokine IL-31. How itch-sensitive (pruriceptive) neurons are specified is unclear. Here, we show that transmembrane protein 184B (TMEM184B), a protein with roles in axon degeneration and nerve terminal maintenance, is required for the expression of a large cohort of itch receptors, including those for interleukin 31 (IL-31), leukotriene C4, and histamine. Male and female mice lacking TMEM184B show reduced responses to IL-31 but maintain normal responses to pain and mechanical force, indicating a specific behavioral defect in IL-31-induced pruriception. Calcium imaging experiments indicate that a reduction in IL-31-induced calcium entry is a likely contributor to this phenotype. We identified an early failure of proper Wnt-dependent transcriptional signatures and signaling components in Tmem184b mutant mice that may explain the improper DRG neuronal subtype specification. Accordingly, lentiviral re-expression of TMEM184B in mutant embryonic neurons restores Wnt signatures. Together, these data demonstrate that TMEM184B promotes adult somatosensation through developmental Wnt signaling and promotion of proper pruriceptive gene expression. Our data illuminate a new key regulatory step in the processes controlling the establishment of diversity in the somatosensory system.

Objective To compare end-to-end jejunal anastomoses with a one-layer (Utrecht) and two-layer (simple continuous/Cushing) patterns. Study design Experimental study. Animals Eight healthy adult horses. Methods Jejunal end-to-end anastomoses were performed in randomly assigned one-layer or two-layer patterns. Horses were recovered from surgery and monitored for complications. At 14 days, the opposite pattern was performed (cross-over design) prior to euthanasia. Duration of closures was compared between patterns. Serosal width was measured before harvesting anastomotic sites from the first procedure. Luminal diameter was measured, and sections were collected for histological evaluation of heating after routine and immunohistochemical staining. Results One-layer closure was faster (716 ± 86 s) than two-layer closures (1136 ± 111 s). Postoperative complications were minimal. No difference was detected in lumen size between groups. The lumen was reduced by 18% after one-layer and 15% after two-layer closures (p = .34). Serosal adhesions to the mesentery without clinical evidence of obstruction were observed in two horses with two-layer closure. Histopathological scores for inflammation, infection, and healing did not differ between groups. Conclusion Jejunal anastomosis with one-layer Utrecht technique was about 7 min faster and led to similar luminal reduction and histological healing scores as two-layer jejunojejunostomies. Clinical significance The outcomes of one-layer Utrecht jejunojejunostomies in healthy horses justify clinical evaluation of this technique.

The charges on this task group (TG) were as follows: (a) provide specific procedural guidelines for performing the tests recommended in TG 142; (b) provide estimate of the range of time, appropriate personnel, and qualifications necessary to complete the tests in TG 142; and (c) provide sample daily, weekly, monthly, or annual quality assurance (QA) forms. Many of the guidelines in this report are drawn from the literature and are included in the references. When literature was not available, specific test methods reflect the experiences of the TG members (e.g., a test method for door interlock is self-evident with no literature necessary). In other cases, the technology is so new that no literature for test methods was available. Given broad clinical adaptation of volumetric modulated arc therapy (VMAT), which is not a specific topic of TG 142, several tests and criteria specific to VMAT were added.

Aminoglycosides are widely used antibiotics with notable side effects such as nephrotoxicity, vestibulotoxicity and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

Ice mass loss from both Antarctic Ice Sheet is increasing, accelerating its contribution to global sea level rise. Interactions between the ice shelves (the floating portions of the ice sheet) and the ocean are key processes in this mass loss. The large Ross Ice Shelf is presently stable but buttresses grounded ice equivalent to about 12 m of global sea level, and geological evidence points to large and sometimes rapid past changes. Recent ocean modeling and observations show that seasonal inflows of warmed upper-ocean water under a thin-ice corridor from Ross Island to Minna Bluff and at the ice front can produce locally high melt rates each summer, suggesting that future increases in summer upper-ocean ocean warming north of the ice front could accelerate ice-shelf flow speeds and mass loss. Recent GPS observations of Ross Ice Shelf velocity have shown seasonal flow variations of several meters per year over a large part of the ice shelf, accelerating in summer and decelerating in winter. A similar seasonal variability has been observed over the floating extension of Byrd glacier (one of the major tributary glaciers of Ross Ice Shelf) by processing Antarctic image pairs in the ITS_LIVE dataset. However, ice-sheet simulations driven by realistic annual cycles of basal melt rates near the ice front produce much smaller seasonal variations than observed, suggesting that other processes could be at play. Here, we investigate a new potential mechanism for a seasonal signal in ice flow: variations of sea surface height (SSH) driven by seasonal changes in thermodynamic and atmospheric forcing of ocean state under the ice shelf. Model annual cycle of SSH under Ross Ice Shelf has an amplitude of up to ~20 cm, with substantial spatial variability. These variations of sea level, similarly to tidal signal but with a longer period, can lead to changes in driving stress over the ice shelf as well as a migration of the grounding line due to hydrostatic adjustment and visco-elastic bending of the ice shelf in the grounding zone. By simulating these SSH variations in an ice-sheet model, we more accurately reproduce the variations observed at GPS stations on Ross Ice Shelf.

The Mw 8.3 2015 Illapel earthquake ruptured a 190 km long segment of the Chilean subduction zone. In the past, this area ruptured several times through large and great earthquakes, the most recent event before 2015 being a Mw 7.9 earthquake in 1943. Here, we combine continuous and survey GPS ground displacements to perform a kinematic inversion of the two-months afterslip following the mainshock. We show that the postseismic slip developed South and North of the coseismic rupture, but also overlaps the deeper part of it. We estimate that two months after the large mainshock, the postseismic moment released represents 13% of the coseismic moment (the mainshock released 3.16x1021 N.m whereas the afterslip released 3.98x1020 N.m). At a first order, seismicity and areas experiencing afterslip match together and are concentrated at the edges of the coseismic rupture between 25 and 45 km depth. One interesting feature is the occurrence of two moderate size aftershocks on November, 11th at shallow depth North of the rupture. We investigate the relationship between the evolution of afterslip and these aftershocks. Finally, we interpret the result in the light of past earthquakes history and calculate the moment balance through the last centuries.