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ObjectivesGenerating and using real-world evidence (RWE) is a pragmatic solution for evaluating health technologies. RWE is recognized by regulators, health technology assessors, clinicians, and manufacturers as a valid source of information to support their decision-making. Well-designed registries can provide RWE and become more powerful when linked with electronic health records and administrative databases in coordinated registry networks (CRNs). Our objective was to create a framework of maturity of CRNs and registries, so guiding their development and the prioritization of funding.Design setting and participantsWe invited 52 stakeholders from diverse backgrounds including patient advocacy groups, academic, clinical, industry and regulatory experts to participate on a Delphi survey. Of those invited, 42 participated in the survey to provide feedback on the maturity framework for CRNs and registries. An expert panel reviewed the responses to refine the framework until the target consensus of 80% was reached. Two rounds of the Delphi were distributed via Qualtrics online platform from July to August 2020 and from October to November 2020.Main outcome measuresConsensus on the maturity framework for CRNs and registries consisted of seven domains (unique device identification, efficient data collection, data quality, product life cycle approach, governance and sustainability, quality improvement, and patient-reported outcomes), each presented with five levels of maturity.ResultsOf 52 invited experts, 41 (79.9%) responded to round 1; all 41 responded to round 2; and consensus was reached for most domains. The expert panel resolved the disagreements and final consensus estimates ranged from 80.5% to 92.7% for seven domains.ConclusionsWe have developed a robust framework to assess the maturity of any CRN (or registry) to provide reliable RWE. This framework will promote harmonization of approaches to RWE generation across different disciplines and health systems. The domains and their levels may evolve over time as new solutions become available.

BackgroundCongenital cytomegalovirus (CMV) infection is the most common infectious cause of birth defects and neurological damage in newborns. Despite a well-established role for natural killer (NK) cells in control of CMV infection in older children and adults, it remains unknown whether fetal NK cells can sense and respond to CMV infection acquired in utero.MethodsHere, we investigate the impact of congenital CMV infection on the neonatal NK-cell repertoire by assessing the frequency, phenotype, and functional profile of NK cells in cord blood samples from newborns with congenital CMV and from uninfected controls enrolled in a birth cohort of Ugandan mothers and infants.ResultsWe find that neonatal NK cells from congenitally CMV infected newborns show increased expression of cytotoxic mediators, signs of maturation and activation, and an expansion of mature CD56- NK cells, an NK-cell subset associated with chronic viral infections in adults. Activation was particularly prominent in NK cell subsets expressing the Fcγ receptor CD16, indicating a role for antibody-mediated immunity against CMV in utero.ConclusionsThese findings demonstrate that NK cells can be activated in utero and suggest that NK cells may be an important component of the fetal and infant immune response against CMV.Clinical trials registrationNCT02793622.

This research investigated the effectiveness of reading short stories to develop three particular dimensions of Byram's (1997) intercultural communicative competence (ICC): interpreting and identifying; comparing and relating; and attitude and openness. The study utilized a twelve-session design, and analyzed the cultural themes of three short stories written by and about native English speakers (NES). Data was collected through a mixed-method approach and included pre- and posttests, and semi-structured interviews. The participants were ten secondary-one (grade 7) students at an international school in Bangkok, Thailand. Results indicated that reading and discussing short stories helped develop ICC in all three of the dimensions studied. By far, the largest increases recorded occurred in the students' interpreting and identifying abilities, while relatively small increases were seen in both the comparing and relating dimension and the attitude and openness dimension. Despite the small increases, some students reported that reading short stories broadened their means for comparing and relating; and their preexisting openness to NES cultures helps explain their low development of the attitude dimension. Consequently, this paper puts forward that EFL teachers in Thailand should utilize short stories mindfully, i.e., to focus specifically on those aspects of ICC deemed most crucial to their students.

Background Indigenous communities worldwide lead calls for all evaluations of research, programmes and policies affecting their communities to reflect the values, priorities and perspectives of the Indigenous peoples and communities involved. Tools, such as the Quality Appraisal Tool (QAT), are available to assess research quality through an Indigenous cultural lens. Good evaluation requires that evaluation efforts be evaluated. We found that critical reflection on the quality of evaluations from an Indigenous perspective is largely absent from the published literature. To ensure that we strive for quality in evaluation as determined by Indigenous people with whom we work, we examined the quality of our own evaluation of an Indigenous health research collaboration by conducting a reflexive dialogue.Methods The QAT was used to assess our evaluation according to Indigenous health research principles. Our qualitative study used analytical coautoethnography to generate data through a series of reflexive dialogue sessions with Indigenous and non-Indigenous members of the research collaboration, using the QAT criteria as discussion prompts. Our ideas and reflections were compared and contrasted through a collaborative and iterative writing process, multiple review cycles and discussions.Results We documented our findings against the QAT framework. We found examples that each QAT principle had, to some extent, been adhered to, but constantly needed to assess whether the principles were fully achieved to our satisfaction. Strengths of the evaluation included being adaptable and responsive to emerging issues for the research collaboration, while areas for improvement included more Indigenous leadership of, and involvement in, evaluation.Conclusions Although reflexive evaluation practice is not always comfortable, it does provide an opportunity to generate insights for improvement. Reflecting as we did—in a partnership between Indigenous and non-Indigenous colleagues—enabled deeper insights and meaning. We anticipate that our process models how other research in Indigenous contexts might better advance ethical, quality Indigenous research through working in collaboration with Indigenous researchers and communities.

Background: The inflammatory changes that underlie the heterogeneous presentations of COVID-19 remain incompletely understood. In this study we aimed to identify inflammatory profiles that precede the development of severe COVID-19, that could serve as targets for optimised delivery of immunomodulatory therapies and provide insights for the development of new therapies. Methods: We included individuals sampled

IntroductionLymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency.MethodsWe retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m2 and cyclophosphamide 500 mg/m2 for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity.ResultsFrom June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin’s lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2–4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2–4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026).DiscussionAs the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.

IntroductionMaternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Maternal reproductive history is associated with differential risk of pregnancy complications. The molecular phenotypes and roles of these distinct monocyte/macrophage populations and the influence of gravidity on these phenotypes has not been systematically investigated.MethodsHere, we used RNA sequencing to study the transcriptional profiles of MIMs and HBCs in normal term pregnancies.ResultsOur analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidae compared to primigravidae. In HBCs, multigravidae displayed enrichment of gene pathways involved in cell-cell signaling and differentiation.DiscussionOur results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Furthermore, maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidae to pregnancy complications.

Actinobacteria is an ancient phylum of Gram-positive bacteria with a characteristic high GC content to their DNA. The ActinoBase Wiki is focused on the filamentous actinobacteria, such as Streptomyces species, and the techniques and growth conditions used to study them. These organisms are studied because of their complex developmental life cycles and diverse specialised metabolism which produces many of the antibiotics currently used in the clinic. ActinoBase is a community effort that provides valuable and freely accessible resources, including protocols and practical information about filamentous actinobacteria. It is aimed at enabling knowledge exchange between members of the international research community working with these fascinating bacteria. ActinoBase is an anchor platform that underpins worldwide efforts to understand the ecology, biology and metabolic potential of these organisms. There are two key differences that set ActinoBase apart from other Wiki-based platforms: [1] ActinoBase is specifically aimed at researchers working on filamentous actinobacteria and is tailored to help users overcome challenges working with these bacteria and [2] it provides a freely accessible resource with global networking opportunities for researchers with a broad range of experience in this field.

HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.

Public affairs programs have long aimed to advance public service education. First defined as preparing public servants for government employment, public affairs programs have expanded to advancing the public interest and governance across all sectors. While modern public affairs programs have become more expansive in how they define public service education and the mechanisms they use to advance education (e.g. applied learning, skills training, professionalization, service learning), they continue to follow a general model of limiting training to those who select into a singular disciplinary track. We outline a new approach to public service education -- Next Generation Service -- which seeks to cultivate public service education to undergraduates outside the core discipline and across campus. We call on public affairs programs to expand their service to the university and broader community by advancing public service values across campus regardless of major.

The authors discuss a course case study that focuses on diversity and inclusion in campus Greek life at a predominantly White institution. The course uses the lenses of race, racism, and heteronormativity to focus students' attention on the complex histories of Greek organizations and the experiences of female college students with marginalized identities. This course de-centralized the White, heterosexual sorority (cis)woman experience, created a bridge between student life and academic affairs, partnered with sorority-affiliated faculty members as change agents and role models, and engaged alumnae with diverse identities. The authors share course outcomes related to students' culminating feminist praxis project.

Although generating high neutralizing antibody levels is a key component of protective immunity after acute viral infection or vaccination, little is known about why some individuals generate high versus low neutralizing antibody titers. Here, we leverage the high-dimensional single-cell profiling capacity of mass cytometry to characterize the longitudinal cellular immune response to Zika virus (ZIKV) infection in viremic blood donors in Puerto Rico. During acute ZIKV infection, we identify widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated cell types during acute infection are associated with high titers of ZIKV neutralizing antibodies 6 months post-infection, while stable immune features suggesting a cytotoxic-skewed immune set point are associated with low titers. Our study offers insight into the coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials aimed at inducing high levels of antiviral neutralizing antibodies.

Correlates of Protection (CoP) are biomarkers above a defined threshold that can replace clinical outcomes as primary endpoints, predicting vaccine effectiveness to support the approval of new vaccines or follow up studies. In the context of COVID-19 vaccination, CoPs can help address challenges such as demonstrating vaccine effectiveness in special populations, against emerging SARS-CoV-2 variants or determining the durability of vaccine-elicited immunity. While anti-spike IgG titres and viral neutralising capacity have been characterised as CoPs for COVID-19 vaccination, the contribution of other components of the humoral immune response to immediate and long-term protective immunity is less well characterised. This review examines the evidence supporting the use of CoPs in COVID-19 clinical vaccine trials, and how they can be used to define a protective threshold of immunity. It also highlights alternative humoral immune biomarkers, including Fc effector function, mucosal immunity, and the generation of long-lived plasma and memory B cells and discuss how these can be applied to clinical studies and the tools available to study them.