The Helping Everyone Achieve Long Term Health Passport: exploring potential use of the HEALTH Passport in primary and secondary schools.

BACKGROUND: Chronic disease is a significant burden on the global population. The Helping Everyone Achieve Long Term Health (HEALTH) Passport is a paper-based approach previously utilized to help adults modify clinical risk factors through lifestyle, which may be effective in improving the long-term health of school-age children. This study investigates the feasibility of in-school use by engaging trainee teachers in primary and secondary education. METHODS: Two hundred and fifty six unique responses were collated to evaluate current teaching of the main health risk factors and HEALTH Passports specifically adapted for schools. Trainees attended workshops with pre- and post-questionnaires used to measure training efficacy and evaluate the Passports' suitability for in-school use. Narrative analysis of feedback was performed. RESULTS: Feedback received for both Passports was positive overall. Trainees highlighted the need for the Passports to be further age differentiated. Significantly increased confidence (P < 0.01) in knowledge of exercise, type 2 diabetes, weight and blood pressure was shown. Confidence in smoking, drugs and alcohol knowledge was reduced highlighting the requirement for further teacher training. CONCLUSIONS: The HEALTH Passport has potential as an intervention to improve health literacy in school-age children. Age adaptation is needed with references to weight measures removed. Emotional well-being should be focused on, and data management stringently assessed for child protection.

Fertility preservation, its effectiveness and its impact on disease status in pre-menopausal women with breast cancer: A systematic review and meta-analysis.

INTRODUCTION: Preservation of reproductive function is a key concern for many premenopausal women with breast cancer, given the known gonadotoxic effects of treatments. The present systematic review aimed to investigate the effectiveness and safety of fertility preservation strategies in pre-menopausal women with breast cancer. METHODS: Primary research assessing fertility preservation strategies of any type was identified. Markers of preservation of fertility including return of menstrual function, clinical pregnancy rates and live birth rates were selected as main outcome measures. An additional analysis of safety data was also performed. RESULTS: Fertility preservation interventions were overall associated with higher fertility outcomes: with a pooled odds ratio 4.14 (95% CI 3.59-4.77) for any kind of fertility preservation intervention. This was seen both for return of menstruation and for clinical pregnancy rate, but not for live birth rates. Fertility preservation was associated with a reduced rate of disease recurrence (OR 0.63 (95% CI 0.49-0.81)), while there was no significant difference in disease free survival (OR 0.88 (95% CI 0.74-1.05)) or in overall survival (OR 0.9 (95% CI 0.74-1.10)) between the fertility preservation group and those who had not undergone fertility preservation. CONCLUSION: Fertility preservation is both effective in preserving reproductive function, and safe with regard to disease recurrence, disease free survival and overall survival in premenopausal women with breast cancer.

Generation of human parallel chimeric antigen receptor (pCAR) T cells to achieve synergistic T cell co-stimulation.

Dual co-stimulation may be harnessed using parallel chimeric antigen receptors (pCARs) in which two distinct co-stimulatory units are adjacently localized on the plasma membrane. This protocol summarizes construct design, human T cell isolation, retroviral transduction, tissue culture expansion, and preclinical testing of pCAR T cells, exemplified by receptors that co-target avb6 integrin and ErbB dimers. For complete details on the use and execution of this protocol, please refer to Muliaditan et al. (2021).

Lymphodepletion strategies to potentiate adoptive T-cell immunotherapy - what are we doing; where are we going?

INTRODUCTION: Adoptive immunotherapy of cancer has evolved from the use of ex vivo expanded lymphokine-activated killer cells and tumor-infiltrating lymphocytes to an increasing array of approaches involving genetically engineered T-cells. A pivotal advance in the enablement of these therapies has been the conditioning of patients with lymphodepleting chemotherapy.A broad range of lymphodepleting regimens has been employed in an effort to improve response rates, without any single consistent approach having emerged. Only a limited number of studies involving small numbers of patients has directly compared two or more regimens, making it challenging to infer which are the preferred agents and dosing schedules. This difficulty is compounded by the fact that both response rate and toxicity appear to be disease-, patient- and T-cell product specific. EXPERT OPINION: This article surveys clinical experience with lymphodepleting regimens that have been used in conjunction with adoptive T-cell immunotherapy, focussing in particular on studies where different approaches have been employed. Harnessing this limited and evolving clinical experience, we set out to provide potential insights into how an optimal balance may be achieved between efficacy and safety. Intermediate dose fludarabine-based regimens are emerging as an increasingly popular option in an attempt to achieve this goal, although further studies are required to provide definitive evidence.

Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.

Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs.