B-cell-directed CAR T-cell therapy activates CD8+ cytotoxic CARneg bystander T cells in patients and nonhuman primates.

ABSTRACT: Chimeric antigen receptor (CAR) T cells hold promise as a therapy for B-cell-derived malignancies, and despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. Although recent studies have explored the mechanisms of in vivo CAR T-cell function, little is understood about the activation of surrounding CARneg bystander T cells and their potential to enhance tumor responses. We performed single-cell RNA sequencing on nonhuman primate (NHP) and patient-derived T cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T cells following B-cell-targeted CAR T-cell therapy. Using a highly translatable CD20 CAR NHP model, we observed a distinct population of activated CD8+ CARneg T cells emerging during CAR T-cell expansion. These bystander CD8+ CARneg T cells exhibited a unique transcriptional signature with upregulation of natural killer-cell markers (KIR3DL2, CD160, and KLRD1), chemokines, and chemokine receptors (CCL5, XCL1, and CCR9), and downregulation of naïve T-cell-associated genes (SELL and CD28). A transcriptionally similar population was identified in patients after a tisagenlecleucel infusion. Mechanistic studies revealed that interleukin-2 (IL-2) and IL-15 exposure induced bystander-like CD8+ T cells in a dose-dependent manner. In vitro activated and patient-derived T cells with a bystander phenotype efficiently killed leukemic cells through a T-cell receptor-independent mechanism. Collectively, to our knowledge, these data provide the first comprehensive identification and profiling of CARneg bystander CD8+ T cells following B-cell-targeting CAR T-cell therapy and suggest a novel mechanism through which CAR T-cell infusion might trigger enhanced antileukemic responses. Patient samples were obtained from the trial #NCT03369353, registered at www.ClinicalTrials.gov.

2020 family medicine postgraduate examinations at The University of the West Indies: successes and challenges in the time of COVID-19 pandemic.

Little has been published regarding postgraduate assessments during the COVID-19 pandemic. There is an urgent need to graduate well-trained specialists including family physicians who play a key role in patient care. The successes and challenges encountered in mounting qualifying 2020 Family Medicine examinations during the COVID-19 pandemic at the University of the West Indies are described in this paper. Human resource, planning, use of technology and virtual environments are discussed, which enabled successful examinations at this multicampus regional site.

Family Medicine at the University of the West Indies: a model for the developing world.

Context and background: To describe the Family Medicine (FM) postgraduate training programme at the University of the West Indies (UWI). Actions and activities: This paper was created through a review of documents, and discussions with past and present coordinators and key stakeholders at four campuses in the English-speaking Caribbean (ESC). LESSONS LEARNED: Despite intermittent setbacks the FM programme in the ESC has grown due to: (1) The presence of an umbrella institution in the UWI. (2) The role of the Caribbean College of Family Physicians providing a unifying force of advocacy and cooperation. (3) Collaboration of staff across four sites despite large distances, differing departmental and campus structures and financial models; and varying levels of local medical and public health support. (4) The use of a modular design for academic content, which means that students have comparable learning experiences. (5) Streamlining of exit examinations, thus sharing resources in the assessment process. (6) A strong presence of FM in the undergraduate curriculum. CONCLUSIONS: Despite a variety of timelines in programme development and funding mechanisms, over 150 physicians have graduated in FM in the past five years. We identify the unifying strategies and institutions which made this possible and present this model as an option for new programmes in the developing world.

A Phenomenological Exploration of Experiences Related to Learning Styles Among Undergraduate Medical Students in a Barbadian Medical School.

Introduction: Learning style (LS) frameworks have been implemented by educators to promote participatory learning in order to strengthen learner engagement and to enhance learning outcomes. Self-efficacy has been shown to have an association with learning style and is a predictor of clinical performance and other qualities in medical students. This study examined the perspectives of second and final year medical students in a Caribbean-based medical school, relative to their learning approaches, teaching exposures and preparation for assessments. Methods: An interpretivist qualitative approach was used to analyze data from two focus groups, conducted as part of a sequential mixed-methods study (November 2018-February 2019) with medical students in the second and final year of study. Discussions were audio-recorded, transcribed verbatim, and inductively coded with in-depth thematic analysis assisted by NVivo software. Results: Six Year 2 (Female: Male = 5:1) and seven Year 5 (Female: Male = 5:2) participants, ranging between 18 and 34 years and with a range of LS were recruited into the study. Analysis and data reduction produced three organizing themes: "Dynamics of information delivery and acquisition", "Pivoting", and "LS identification, awareness and mutability", and the global construct "Individual and environmental factors modulate the influence of LS preference in triggering self-efficacy". In managing information received in class, students used textbooks, YouTube videos, and collaborative learning to augment perceived gaps in lectures and their personal notes. Learning style self-awareness is useful for facilitating self-efficacy throughout medical school, especially at points of transition within the programme of study. Conclusion: LS theory and testing appear to be useful for student and teacher awareness. In practice, honing students' adaptability to varying learning settings may be more relevant in helping students achieve self-efficacy.

Diabetes prevention in the Caribbean using Lifestyle Intervention and Metformin Escalation (LIME): Protocol for a hybrid Type-1 effectiveness-implementation trial using a quasi-experimental study design.

BACKGROUND: Globally, several diabetes prevention interventions have been shown to be cost-effective, yet they have had limited adaptation, implementation, and evaluation in the Caribbean and among Caribbean-descent individuals, where the burden of type 2 diabetes is high. We report on the protocol for the Lifestyle Intervention with Metformin Escalation (LIME) study - an evidence-based diabetes prevention intervention to reduce the incidence of diabetes among Caribbean-descent individuals with prediabetes. METHODS: LIME is a hybrid type-I effectiveness-implementation quasi-experimental study taking place in 4 clinical sites in Barbados, Trinidad, the U.S. Virgin Islands, and Puerto Rico. LIME targets individuals who self-identify as Caribbean or Caribbean-descent and have high-risk prediabetes with a hemoglobin A1c (HbA1c) between 6 and 6.4%. Eligible participants in the intervention arm are enrolled in a six-week lifestyle modification workshop. Six months later, individuals who have not lost at least 5% of their bodyweight or continue to have an HbA1c of 6% or higher are prescribed metformin medication. In total, participants are followed for one year. The primary effectiveness outcome is proportion of individuals who lower their HbA1c below 6%. DISCUSSION: LIME is a unique diabetes prevention intervention for Caribbean and Caribbean-descent individuals. LIME utilizes a tailored lifestyle change curriculum, incorporates appropriate metformin prescribing when lifestyle change alone is insufficient, targets the highest-risk individuals with prediabetes, and is based in a clinical setting to ensure sustainability.

Does peak expiratory flow measured sitting differ from that measured standing? A cross-over study in primary care in Barbados.

BACKGROUND: Several authorities recommend measuring peak expiratory flow (PEF) standing. Limited evidence suggests that PEF obtained sitting is similar in magnitude but there are no studies in African populations. AIM: To determine in adults aged 18-60 years if PEF measured sitting differs from that measured standing. DESIGN & SETTING: Crossover design with alternating position of initial measurement in people attending primary care clinics in Barbados. METHOD: Quota sampling by age, sex, and clinic of adults aged 18-60 years was done and an interviewer-administered questionnaire was completed. PEF sitting and standing was measured with an European Union (EU) scale Mini-Wright® meter. The highest of three readings in each position was used and the difference in means tested for significance using the paired sample t-test. RESULTS: Characteristics of the 199 participants were 44% male; 96.5% of African descent; mean age 37 years (standard deviation [SD] 12.8); 22% with an asthma diagnosis; 23% tobacco users; and 22% marijuana users. Mean PEF standing was 438.4 versus 429.7 lmin-1 sitting, mean difference 8.7 (95% confidence interval [CI] = 3.6 to 13.8). For men, mean PEF standing was 518.7 versus 506.3 lmin-1 sitting, mean difference 12.4 (95% CI = 3.3 to 21.5). For women, mean PEF was 374.7 standing versus 368.9 lmin-1 sitting, mean difference 5.8 (95% CI = 0.11 to 11.5). A Bland-Altman plot accounting for trend and a Lin's correlation coefficient of 0.935 demonstrated good agreement between standing and sitting PEF. CONCLUSION: PEF measurements are reduced when performed sitting compared to standing. The difference is small and unlikely to alter clinical management in most cases.

The supply of antibiotics by NHS walk-in centre nurses using PGDs.

Patient group directions (PGDs) have become a feature of NHS walk-in centres enabling nurses to supply and administer drugs in response to the generalised direction of a doctor. In light of the issues surrounding the use of antibiotics a clinical audit was undertaken to assess nurses' competence and record-keeping in relation to supplying antibiotics according to PGDs. This study goes some way to demonstrate that nurses are supplying and administering antibiotics judiciously and safely according to local PGDs.