Decentralized Clinical Trials as a New Paradigm of Trial Delivery to Improve Equity of Access.

Importance: The need to maintain clinical trial recruitment during the COVID-19 pandemic has precipitated the rapid uptake of digital health for the conduct of clinical trials. Different terms are used in different jurisdictions and clinical contexts, including digital trials, networked trials, teletrials (TT), and decentralized clinical trials (DCT) with a need to agree to terms. Observations: This clinical care review summarized publications and gray literature, including government policies for the safe conduct of clinical trials using digital health. It compares 2 frequently used methodologies, DCT and TT, first developed before the COVID-19 pandemic by trialists and stakeholders in Australia to improve access to cancer clinical trials for geographically dispersed populations. TT uses a networked approach to implement clinical trials to share care between facilities and uses an agreement between sites or a supervision plan to improve governance and safety. Government regulators have adapted existing regulations and invested in the rollout of the TT model. The term DCT emerged in the northern hemisphere and has been the subject of guidance from regulatory agencies. DCT uses digital health to deliver care in nontraditional sites, such as participants' homes, but does not mandate a networked approach between health facilities or require a supervision plan to be in place. Conclusions and Relevance: TT can be considered as a specific type of DCT with several potential advantages, including upskilling across a network. DCT is a new paradigm for the use of digital health in the safe conduct of clinical trials and is a transformative issue in cancer care, addressing disparities in access to clinical trials and improving clinical outcomes.

Preclinical proof of concept for VivoVec, a lentiviral-based platform for in vivo CAR T-cell engineering.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence. In the presence of exogenous rapamycin, non-transduced immune cells are suppressed, while the RACR system in transduced cells converts rapamycin binding to an interleukin (IL)-2/IL-15 signal to promote proliferation. METHODS: UB-VV100 was administered to peripheral blood mononuclear cells (PBMCs) from healthy donors and from patients with B-cell malignancy without additional stimulation. Cultures were assessed for CAR T-cell transduction and function. Biodistribution was evaluated in CD34-humanized mice and in canines. In vivo efficacy was evaluated against normal B cells in CD34-humanized mice and against systemic tumor xenografts in PBMC-humanized mice. RESULTS: In vitro, administration of UB-VV100 resulted in dose-dependent and anti-CD3 scFv-dependent T-cell activation and CAR T-cell transduction. The resulting CAR T cells exhibited selective expansion in rapamycin and antigen-dependent activity against malignant B-cell targets. In humanized mouse and canine studies, UB-VV100 demonstrated a favorable biodistribution profile, with transduction events limited to the immune compartment after intranodal or intraperitoneal administration. Administration of UB-VV100 to humanized mice engrafted with B-cell tumors resulted in CAR T-cell transduction, expansion, and elimination of systemic malignancy. CONCLUSIONS: These findings demonstrate that UB-VV100 generates functional CAR T cells in vivo, which could expand patient access to CAR T technology in both hematological and solid tumors without the need for ex vivo cell manufacturing.

"Who is going to take care of these grandkids if I go?": End-of-life planning by caregivers in grandparent-headed households.

This qualitative study applied thematic analysis to semi-structured interviews with 15 key informants who self-identified as primary caregivers to at least one grandchild. Using Family Systems Theory and Theory of Planned Behavior as guiding frameworks, this study reports grandparent caregivers' end-of-life planning behaviors while illuminating factors influencing these behaviors. The analysis revealed two themes related to grandparents' communicative behaviors surrounding end-of-life planning (formal and informal behaviors) and four themes related to factors that influence grandparents' end-of-life planning (emotional paradoxes, legal/custodial conundrums, concerns about child wellbeing, and resources needed to plan). Findings extend end-of-life planning literature to often overlooked nontraditional family populations.

Mapping haemodynamic changes with rapid sequence induction agents in the emergency department.

OBJECTIVE: Patients intubated in the ED are at an increased risk of post-intubation hypotension. However, evidence regarding the most appropriate induction agent is lacking. The present study aims to describe and compare the haemodynamic effect of propofol, ketamine and thiopentone during rapid sequence induction. METHODS: This is an observational study using data prospectively collected from the Australian and New Zealand Emergency Department Airway Registry between June 2012 and March 2019. The distribution of induction agents across medical and trauma patients were obtained with descriptive statistics. The relationship between induction agent, dose and change in pre- and post-intubation systolic blood pressure (SBP) was described using multivariable logistic regression. The SBP pre- and post-intubation was the primary measure of haemodynamic stability. RESULTS: From the 5063 intubation episodes, 2229 met the inclusion criteria. Of those, 785 (35.2%) patients were induced with thiopentone, 773 (34.7%) with propofol and 671 (30.1%) with ketamine. Of the included population, 396 (17.8%) patients experienced a reduction in pre-intubation SBP exceeding 20%. Both propofol (P = 0.01) and ketamine (P = 0.01) had an independent and dose-dependent association with hypotension, noting that a higher proportion of patients induced with ketamine had a shock index exceeding 0.9. CONCLUSION: Propofol was associated with post-intubation hypotension and it is recommended clinicians consider using the lowest effective dose to reduce this risk. Reflecting its perceived haemodynamic stability, patients who received ketamine were more likely to have a higher shock index; however, there was also an association with post-intubation hypotension.

"A Toxic Trend?": Generational Conflict and Connectivity in Twitter Discourse Under the #BoomerRemover Hashtag.

BACKGROUND AND OBJECTIVES: This study examines the #BoomerRemover hashtag on Twitter to understand discourses of intergenerational conflict and unity that emerged during the novel coronavirus disease 2019 global pandemic. The research highlights conflict and connection surrounding generational cohorts via social media, particularly in a time of crisis. RESEARCH DESIGN AND METHODS: The study used an inductive-dominant qualitative content analysis to examine 536 tweets collected between March 9 and April 9, 2020 under #BoomerRemover. RESULTS: Data analysis revealed five forms of conflictive generational discourse: derogatory endorsement of the #BoomerRemover moniker, conflict regarding the nature and origins of the moniker, conflict surrounding the virus, political conflict, and generational jabs. Two forms of intergenerationally unifying discourse were identified: implicit and explicit pleas for connectivity. DISCUSSION AND IMPLICATIONS: The analysis of discourse under #BoomerRemover revealed more nuanced expressions surrounding generational cohorts than widely reported in media outlets. Some users tweeted the hashtag in ways that reflected conflict, with #BoomerRemover acting as a vector through which stereotypes were perpetuated and magnified. However, a number of users tweeted the hashtag to call for intergenerational connectivity, highlighting the complexity of online discourse. These results yield implications for the study of online generational discourse, particularly in light of the unique circumstances surrounding the pandemic.

Can a child and family health service improve early childhood health outcomes in an urban Aboriginal community?

AIMS: To describe the engagement of a cohort of urban Aboriginal families with an Early Childhood Health Service, and to assess any association of engagement with the service with screening by the Edinburgh Post-Natal Depression Scale (EPDS), full breastfeeding rates and post-natal smoking status. METHODS: Routine electronic medical record data collected by a Child and Family Health Nurse between 2011 and 2014 was analysed retrospectively. Associations between use of the service and acceptance of EPDS, breastfeeding rates and post-natal smoking status were determined using binary and multinomial multiple logistic regression analyses. RESULTS: There were 424 Aboriginal babies and 215 mothers included in the study. Each occasion of service increased the odds of accepting screening with the EPDS (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = 0.04) and complete breastfeeding (OR 1.11, CI 1.01-1.23, P = 0.04), but not of quitting smoking (OR 0.99, CI 0.96-1.02, P = 0.34). Despite accounting for engagement with the service, overall uptake of the EPDS remained low; of 267 offers for EPDS screening, only 115 were accepted (43%). CONCLUSION: The service was accessed in increasing numbers during the study period. Mothers who utilised the service more frequently were more likely to accept EPDS screening and exclusively breastfeed; however, acceptance of EPDS screening remained low overall. Further research is recommended to investigate the low acceptance of EPDS in this Aboriginal population and whether those results are transferable to other communities.

Loss of RASSF2 Enhances Tumorigencity of Lung Cancer Cells and Confers Resistance to Chemotherapy.

RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation. Inactivation of RASSF2 enhances K-Ras-mediated transformation and overexpression of RASSF2 suppresses tumor cell growth. In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector. We adopted an RNAi approach to determine the effects of inactivation of RASSF2 on the transformed phenotype of lung cancer cells containing an oncogenic K-Ras. Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes. This enhanced transformed phenotype of the cells correlated with increased levels of activated AKT, indicating that RASSF2 can modulate Ras signaling pathways. Loss of RASSF2 expression also confers resistance to taxol and cisplatin, two frontline therapeutics for the treatment of lung cancer. Thus we have shown that inactivation of RASSF2, a process that occurs frequently in primary tumors, enhances the transforming potential of activated K-Ras and our data suggests that RASSF2 may be a novel candidate for epigenetic-based therapy in lung cancer.

Phenylethanolamine N-methyl transferase expression in mouse thymus and spleen.

Catecholamines usually are found in neurons and chromaffin cells of mammals. In this study, surprisingly high levels of the epinephrine synthesizing enzyme phenylethanolamine N-methyl transferase (PNMT) were detected in the thymus of young mice. Levels of PNMT activity in the thymus were comparable to levels in the brainstem and were suppressed by the PNMT inhibitor LY134046. PNMT mRNA was localized with in situ hybridization throughout the thymus, but levels were approximately twofold higher in the cortex than in the medulla. PNMT activity was barely detectable in the spleen, and only a few cells expressing PNMT mRNA were located in the marginal zone of the white pulp. These findings suggest that cells in the thymus of young mice have the ability to synthesize epinephrine.