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Reports of T cell malignancies after CAR-T cell therapy should be investigated, but existing data from follow-up studies suggest a low risk compared with other cancer treatments.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.

ABSTRACTThe availability of the genomic sequence of the malaria mosquito Anopheles gambiaehas in recent years sparked the development of transgenic technologies with the potential to be used as novel vector control tools. These technologies rely on genome editing that confer traits able to affect vectorial capacity. This can be achieved by either reducing the mosquito population or by making mosquitoes refractory to the parasite infection. For any genetically modified organism that is regarded for release, molecular characterization of the transgene and flanking sites are essential for their safety assessment and post-release monitoring. Despite great advancements, Whole-Genome Sequencing data are still subject to limitations due to the presence of repetitive and unannotated DNA sequences. Faced with this challenge, we describe a number of techniques that were used to identify the genomic location of a transgene in the male bias mosquito strain Ag(PMB)1 considered for potential field application. While the initial inverse PCR identified the most likely insertion site on Chromosome 3 R 36D, reassessment of the data showed a high repetitiveness in those sequences and multiple genomic locations as potential insertion sites of the transgene. Here we used a combination of DNA sequencing analysis and in-situ hybridization to clearly identify the integration of the transgene in a poorly annotated centromeric region of Chromosome 2 R 19D. This study emphasizes the need for accuracy in sequencing data for the genome of organisms of medical importance such as Anophelesmosquitoes and other tools available that can support genomic locations of transgenes.

Introduction: AOD01 is a novel, fully human immunoglobulin (Ig) G1 neutralizing monoclonal antibody that was developed as a therapeutic against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AOD01 in healthy volunteers. Methods: Intravenous doses of AOD01 were evaluated in escalating cohorts [four single-dose cohorts (2, 5, 10, and 20 mg/kg) and one two-dose cohort (two doses of 20 mg/kg, 24 h apart)]. Results: Twenty-three subjects were randomized to receive AOD01 or a placebo in blinded fashion. A total of 34 treatment-emergent adverse events (TEAEs) were reported; all were mild in severity. Related events (headache and diarrhea) were reported in one subject each. No event of infusion reactions, serious adverse event (SAE), or discontinuation due to AE were reported. The changes in laboratory parameters, vital signs, and electrocardiograms were minimal. Dose-related exposure was seen from doses 2 to 20 mg/kg as confirmed by Cmaxand AUC0–tlast. The median Tmaxwas 1.5–3 h. Clearance was dose independent. Study results revealed long half-lives (163–465 h). Antidrug antibodies (ADA) to AOD01 were not detected among subjects, except in one subject of the two-dose cohort on day 92. Sustained ex vivo neutralization of SARS-CoV-2 was recorded until day 29 with single doses from 2 to 20 mg/kg and until day 43 with two doses of 20 mg/kg. Conclusions: AOD01 was safe and well tolerated, demonstrated dose-related PK, non-immunogenic status, and sustained ex vivo neutralization of SARS-CoV-2 after single intravenous dose ranging from 2 to 20 mg/kg and two doses of 20 mg/kg and show good potential for treatment of SARS-CoV-2 infection.

We estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results.

AbstractSupport for social distancing measures was, globally, high at the early stages of the COVID-19 pandemic but increasingly came under pressure. Focusing on the UK, this article provides a rigorous exploration of the drivers of public support for social distancing at their formative stage, via mixed methods. Synthesizing insights from crisis management and securitization theory, thematic analysis is employed to map the main frames promoted by the government and other actors on the nature/severity, blame/responsibility, and appropriate response to the pandemic, which ‘follows the science’. The impact of these on public attitudes is examined via a series of regression analyses, drawing on a representative survey of the UK population (n = 2100). Findings challenge the prevailing understanding that support for measures is driven by personal health considerations, socio-economic circumstances, and political influences. Instead, crisis framing dynamics, which the government is well-positioned to dominate, have the greatest impact on driving public attitudes.

This paper discusses both challenges and opportunities for using inquiry-based learning in public administration postgraduate education in a context of internationalisation. In particular, we discuss the appropriateness of inquiry-based learning for teaching diverse groups of students from varied international backgrounds. Inquiry-based learning has been widely promoted in the United Kingdom higher education sector and seems intuitively appealing as a pedagogical approach for an applied subject such as public administration. However, there are challenges associated with using inquiry-based learning with postgraduate international students who have a short time to assimilate complex theories and concepts in a second language, and have often been educated previously in contexts with a more didactic tradition of education. With the increasing internationalisation of the United Kingdom higher education sector, we suggest there is tension between some of the teaching and learning methods that are being promoted nationally and the needs of an increasingly diverse international student body. Reflecting on our own experiences as teachers of international students on public administration programmes, we outline both the benefits and limitations of teaching with inquiry-based learning but also suggest ways in which this type of approach could be assimilated within the broader set of pedagogical practices used with international postgraduate students.

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process.

IMPORTANCE: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count. OBJECTIVE: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count. DESIGN, SETTING, AND PARTICIPANTS: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children’s Hospital of Philadelphia from January 1, 1998, to December 31, 2020. EXPOSURE: The rs2814778-CC genotype. MAIN OUTCOMES AND MEASURES: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result. RESULTS: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001). CONCLUSIONS AND RELEVANCE: In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.

Advanced, late-stage Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) is incurable, and its treatment remains a clinical and therapeutic challenge. Results from a phase II clinical trial in advanced NPC patients employing a combined chemotherapy and EBV-specific T cell (EBVST) immunotherapy regimen showed a response rate of 71.4%. Longitudinal analysis of patient samples showed that an increase in EBV DNA plasma concentrations and the peripheral monocyte-to-lymphocyte ratio negatively correlated with overall survival. These parameters were combined into a multivariate analysis to stratify patients according to risk of death. Immunophenotyping at serial time points showed that low-risk individuals displayed significantly decreased amounts of monocytic myeloid-derived suppressor cells postchemotherapy, which subsequently influenced successful cytotoxic T-lymphocyte (CTL) immunotherapy. Examination of the low-risk group, 2 weeks post-EBVST infusion, showed that individuals with a greater overall survival possessed an increased frequency of CD8 central and effector memory T cells, together with higher levels of plasma interferon (IFN)-γ, and cytotoxic lymphocyte-associated transcripts. These results highlight the importance of the rational selection of chemotherapeutic agents and consideration of their impact on both systemic immune responses and downstream cellular immunotherapy outcomes.

IMPORTANCE: Previous observational studies have suggested that fluoroquinolones are associated with aortic aneurysm or dissection, but these studies may be subject to confounding by indication or surveillance bias. OBJECTIVE: To assess the association of fluoroquinolones with risk of aortic aneurysm or aortic dissection (AA/AD) while accounting for potential confounding by fluoroquinolone indication and bias owing to differential surveillance. DESIGN, SETTING, AND PARTICIPANTS: In an observational cohort study using a US commercial claims database, 2 pairwise 1:1 propensity score–matched cohorts were identified: patients aged 50 years or older with a diagnosis of pneumonia 3 days or less before initiating treatment with a fluoroquinolone or azithromycin and patients aged 50 years or older with a urinary tract infection (UTI) diagnosis 3 days or less before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole. Hazard ratios (HRs) and 95% CIs were estimated controlling for 85 baseline confounders. In a secondary analysis, patients receiving fluoroquinolones were compared with those receiving amoxicillin, both with and without considering baseline aortic imaging, to address differences in detection of AA/AD before antibiotic use. Data on patients within the database from January 1, 2003, through September 30, 2015, were analyzed. Data analysis was conducted from July 23, 2019, to July 6, 2020. MAIN OUTCOMES AND MEASURES: Hospitalization for AA/AD occurring within 60 days following treatment initiation. RESULTS: After propensity score matching, patient characteristics were well balanced, with 279 554 patients (mean [SD] age, 63.66 [10.93] years; 149 976 women [53.6%]) in the pneumonia cohort and 948 364 patients (mean [SD] age, 62.06 [10.33] years; 823 667 women [86.9%]) in the UTI cohort. Initiators of fluoroquinolones (n = 139 772 pairs in the pneumonia cohort and n = 474 182 pairs in the UTI cohort) had an increased rate of AA/AD compared with initiators of azithromycin (HR, 2.57; 95% CI, 1.36-4.86; incidence, 0.03% for fluoroquinolones vs 0.01% for azithromycin) but no increased rate compared with initiators of combined trimethoprim and sulfamethoxazole (HR, 0.99; 95% CI, 0.62-1.57; incidence, <0.01% in both UTI groups). Secondary analysis using amoxicillin as a comparator (n = 3 976 162 pairs) produced results consistent with those from earlier studies (HR, 1.54; 95% CI, 1.33-1.79; incidence, <0.01% in both groups). Requiring baseline imaging in this cohort (n = 542 649 pairs) to address surveillance bias attenuated the increased rate (HR, 1.13; 95% CI, 0.96-1.33; incidence, 0.06% for fluoroquinolones vs 0.05% for amoxicillin). CONCLUSIONS AND RELEVANCE: The findings of this nationwide cohort study of adults with pneumonia or UTI suggest an increased relative rate of AA/AD associated with fluoroquinolones within the pneumonia cohort but not within the UTI cohort. In both cohorts, the absolute rate of AA/AD appeared to be low (<0.1%). The increased relative rate observed in the pneumonia cohort may be due to residual confounding or surveillance bias.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKEmutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

Polygenic risk scores (PRS) have potential to improve health care by identifying individuals that have elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and health care systems. The electronic Medical Records and Genomics (eMERGE) network is conducting a collaborative study which will return PRS to 25,000 pediatric and adult participants. All participants will receive a risk report, potentially classifying them as high risk (∼2-10% per condition) for 1 or more of 10 conditions based on PRS. The study population is enriched by participants from racial and ethnic minority populations, underserved populations, and populations who experience poorer medical outcomes.

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.

Supplemental Digital Content is available in the text.Asthma is the leading chronic disease in children. Several studies have identified genetic biomarkers associated with susceptibility and severity in both adult and pediatric cases. In this study, we evaluated outcomes in 400 African American and European American pediatric cases all of whom were regular users of inhaled corticosteroids. Patients were stratified by genotype using two single nucleotide polymorphisms in the β-2-adrenergic receptor (ADRB2) gene – rs1042713 and rs1042714, previously associated with asthma outcome. These correspond to nonsynonymous single nucleotide polymorphisms at positions 16 [arginine to glycine (Arg16Gly); rs1042713] and 27 [glutamic acid to glutamine (Glu27Gln); rs1042714], which are relatively common (minor allele frequencies ∼40–50%), and have been well characterized in asthma pharmacogenetics. We controlled for adherence to the National Heart, Lung and Blood Institute guidelines using deep mining of electronic health record data to determine treatment course. We found no significant effect for rs1042713 (Arg16Gly) but did identify an effect for rs1042714, where participants homozygous for Gln27 had increased exacerbations while taking inhaled corticosteroids in comparison with those who were either heterozygous or homozygous for Glu27. This is consistent with previous studies and demonstrates for the first time that the Glu27 variant in the ADRB2gene is associated with increased frequencies of asthma exacerbations. Moreover, this study also lends an important proof-of-principle on how electronic health records linked to genotype can be efficiently and systematically mined to delineate health outcomes.

This article addresses the role and opportunities for public administration and public affairs education in North Cyprus. The context of the research is situated within a transnational education partnership between the University of the West of Scotland and the Management Centre of the Mediterranean (Nicosia, North Cyprus). The dominant narrative of the article is, based on the case of North Cyprus, to provide key insights into why public administration and public affairs education is a force for development in governance and civil society terms. The political context of North Cyprus is such that it is in the midst of significant change based on the twin governance challenges of, first, uncertainty regarding its international status (following the Cypriot coup d’etat and Turkish intervention in 1974 that led to North declaring independence in 1983 and becoming the Turkish Republic of North Cyprus) and, second, efforts to accommodate ‘acquis communautaire’ in order to progress towards EU accession (subject to successful reunification with the South). An underpinning reflective consideration in the article relates to how such educational programmes, based on a franchised model, address aspects of ‘good governance’ (often based on a Western paradigm) but, at the same time, are also suitably responsive to local civil society and political contexts.

The purpose of this paper is to describe a new framework for representing and solving strategic game theory problems. This framework, called “Chemical Game Theory” (CGT), uses well-known, rigorous principles from chemistry and chemical engineering to solve strategic decision problems that could be analyzed using “Traditional Game Theory” (TGT). In strategic decisions, players each can choose from among two or more alternative possibilities, and the outcome depends upon the collective choices from all players. In this article we will analyze some of the premises of TGT as compared with CGT. In CGT, the players’ choices are treated as metaphorical molecules, and outcomes are calculated according to chemical reaction methods. The important concept of entropic choices is introduced, and pre-bias effects are included naturally as initial concentrations of reactants. CGT is not a generalization of TGT; rather, it represents contested decision problems differently, and gives different solutions. In this article we use the formalism of chemistry to provide a “knowlecular” approach to analyzing contested decisions. This approach has a rich capacity to represent decision-making scenarios and serve as a decision-making algorithm for contested decisions, where leadership power plays an important role.

Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization’s prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.

Background/Context Pickering v. Board of Education, decided by the U.S. Supreme Court in 1968, is considered the high-water mark in the constitutional protection of public employee free speech. Two significant decisions issued by that Court since Pickering have limited public employees’ expressive rights: Connick v. Myers and Garcetti v. Ceballos.Purpose/Objective The principal research questions which were the focus of this study are: is the adverse effect on free speech presumed by legal analysts following Connick and Garcetti having real effects in terms of judicial voting behavior and, if so, how has this occurred?Research Design We set up legal precedent and the judge's ideology as predictors of judicial voting behavior. The legal precedent variable delineates three intervals, namely the Pickering era [1968–1983], the Connick era [1983–2006) and the Garcetti era [2006–2014]. Two different measures of ideology are considered: party affiliation and the judge's DW-NOMINATE score. The dependent variable is the judge's individual vote in each case. Votes are categorized as pro-employer or pro-employee.Data Collection and Analysis Because our interest is specific to K–12 settings we analyze 507 judicial votes drawn from the 169 U.S. Courts of Appeals employer-employee free speech cases brought by school employees between the issuance of Pickering in 1968 and the post-Garcetti period into 2014. Since our dependent variable is dichotomous the statistical estimates are obtained via logistic regression.Conclusions/Recommendations We find that employee-plaintiffs are prevailing at lower rates at the U.S. Courts of Appeals in free speech claims against public school districts following the Garcetti decision. Since Garcetti, Courts of Appeals judges—those appointed by both Republican and Democratic presidents—have voted in an increasingly pro-employer direction. We contend this results from “doctrinal signaling,” here, the progressive curtailment in the Supreme Court of public employees’ free speech rights from Connick v. Myers in 1983 to Garcetti. We suggest this “signaling” is used by Courts of Appeals judges as an interpretive tool to give meaning to apparently ambiguous decisions such as Garcetti. Finally, the impact and implications of this negative trend for K–12 employees, as well as possible solutions, are considered.

This article reviews recent linked challenges to Scottish Local Government viewed through the lens of ‘governance’ in the post-Scottish independence referendum context. This is an appropriate juncture to consider the range of contemporaneous and linked issues and challenges that face this level of governance. The article includes an update on the debates associated public sector reform and the agenda to ‘renew local democracy’. Moreover, the article addresses recent developments with regards to empowerment as a result of the Community Empowerment Act (passed in June 2015). The article concludes by providing an update on the challenges associated with the democratic representation of Scottish local authorities. By drawing these themes and developments together, highlighting their historical roots, the article provides an important platform for a new research agenda in relation to local democracy and community empowerment in Scotland.

To ‘will as God wills’ is expected of Christians: ‘Thy will be done.’ But does this imply that one is expected to be content, even pleased, with whatever happens, since whatever happens is in some sensewhat God wills? Eleonore Stump labels such an expectation a ‘stern-minded attitude,’ and she claims to find it in the work of Meister Eckhart. Contrasting it with the positions taken by Bernard of Clairvaux and Thomas Aquinas, Stump rejects sternmindedness as too harsh on natural human feeling and based on a faulty concept of the will. I argue that Stump fails to situate some of Eckhart's admittedly extreme claims in the framework of his metaphysics and the larger context of his writings, which show he is clearly not stern-minded. Finally, I offer an explanation of Eckhart's injunction to ‘live without why/will.’