Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis

Background: Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have not been identified. We aimed to assess how the dose and timing of administration affect treatment outcome. Methods: In this systematic review and meta-analysis, we extracted data from published studies of passive antibody treatment from Jan 1, 2019, to Jan 31, 2023, that were identified by searching multiple databases, including MEDLINE, PubMed, and ClinicalTrials.gov. We included only randomised controlled trials of passive antibody administration for the prevention or treatment of COVID-19. To compare administered antibody dose between different treatments, we used data on in-vitro neutralisation titres to normalise dose by antibody potency. We used mixed-effects regression and model fitting to analyse the relationship between timing, dose and efficacy. Findings: We found 58 randomised controlled trials that investigated passive antibody therapies for the treatment or prevention of COVID-19. Earlier clinical stage at treatment initiation was highly predictive of the efficacy of both monoclonal antibodies (p<0·0001) and convalescent plasma therapy (p=0·030) in preventing progression to subsequent stages, with either prophylaxis or treatment in outpatients showing the greatest effects. For the treatment of outpatients with COVID-19, we found a significant association between the dose administered and efficacy in preventing hospitalisation (relative risk 0·77; p<0·0001). Using this relationship, we predicted that no approved monoclonal antibody was expected to provide more than 30% efficacy against some omicron (B.1.1.529) subvariants, such as BQ.1.1. Interpretation: Early administration before hospitalisation and sufficient doses of passive antibody therapy are crucial to achieving high efficacy in preventing clinical progression. The relationship between dose and efficacy provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. Funding: The Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council, the University of New South Wales, Monash University, Haematology Society of Australia and New Zealand, Leukaemia Foundation, and the Victorian Government

Patient perspectives on molecular tumor profiling: "why wouldn't you?"

© 2019 The Author(s). Aim: This study explored the attitudes of patients with advanced cancer towards MTP and return of results, prior to undergoing genomic testing within a research program. Methods: Participants were recruited as part of the longitudinal PiGeOn (Psychosocial Issues in Genomics in Oncology) study involving patients with advanced/metastatic solid cancer who had exhausted therapeutic options and who were offered MTP in order to identify cognate therapies. Twenty patients, selected by purposive sampling, were interviewed around the time they gave consent to MTP. Interviews were audio recorded, transcribed and analysed using thematic analysis. Themes identified in the transcripts were cross-validated via qualitative responses to the PiGeOn study survey (n = 569; 63%). Results: All interviewed participants gave consent to MTP without reservation. Three themes were identified and further supported via the survey responses: (1) Obvious agreement to participate, primarily because of desire for new treatments and altruism. (2) The black box - while participant knowledge of genomics was generally poor, faith in their oncologists and the scientific process encouraged them to proceed with testing; and (3) Survival is the priority - receiving treatment to prolong life was the priority for all participants, and other issues such as identification of a germline variant were generally seen as ancillary. Conclusion: Having advanced cancer seemed to abrogate any potential concerns about MTP. Participants valued the research for varied reasons, but this was secondary to their priority to survive. While no negative attitudes toward MTP emerged, limitations in understanding of genomics were evident

Identifying recombination hotspots in the HIV-1 genome

HIV-1 infection is characterised by the rapid generation of genetic diversity that facilitates viral escape from immune selection and antiretroviral therapy. Despite recombination's crucial role in viral diversity and evolution, little is known about the genomic factors that influence recombination between highly similar genomes. In this study, we use a minimally modified full length HIV-1 genome and high throughput sequence analysis to study recombination in gag and pol in T cells. We find that recombination is favoured at a number of recombination hotspots, where recombination occurs six times more frequently than at corresponding coldspots. Interestingly, these hotspots occur near important features of the HIV-1 genome, but do not occur at sites immediately around protease inhibitor or reverse transcriptase inhibitor drug resistance mutations. We show that the recombination hot and cold spots are consistent across five blood donors and are independent of co-receptor mediated entry. Finally, we check common experimental confounders and find that these are not driving the location of recombination hotspots. This is the first study to identify the location of recombination hotspots, between two similar viral genomes with great statistical power and under conditions that closely reflect natural recombination events amongst HIV-1 quasispecies

An Inexpensive Workplace Initiative to Motivate High-Risk Individual Health Improvement

Unhealthy lifestyles cost businesses, governmental organizations, and the U.S. military billions of dollars every year, not to mention intangible costs associated with increased mortality. This study implemented a low-cost cognitive-behavioral motivational intervention to effect behavioral change in high-risk civilian employees working for a U.S. military organization, with accompanying improvement in certain health indicators after 120 days compared with a control group. Our analysis of these results led to two conclusions: first, low-cost cognitive-behavioral motivational treatments can improve both behavior and health, and second, tentative results indicate a fully mediated relationship may exist among the cognitive variables of locus of control and self-efficacy, vice the predicted parallel relationship. Overall, we assert that effective implementation of an intervention like the one used in this study might lower the U.S. Air Force\u27s health care bill by as much as $40 million, improve employee efficiency and mission capability, enable healthier lives, and prevent premature death

Validation of the multidimensional impact of Cancer Risk Assessment Questionnaire to assess impact of waiting for genome sequencing results.

OBJECTIVE: To determine whether the existing Multidimensional Impact of Cancer Risk Assessment (MICRA) scale, which assesses impact of receiving genetic test results on individuals being assessed for cancer risk, can be successfully adapted to cancer patients experiencing prolonged waiting for results of germline genome sequencing (GS). METHODS: Patients previously diagnosed with likely hereditary cancer (n = 250) who were waiting for germline GS results completed questionnaires 3 months after baseline. We adapted the MICRA to measure anxiety associated with waiting for results, and assessed factor structure, internal consistency, test-retest reliability and construct validation. RESULTS: Factor analysis revealed four factors: distress, positive experience, family support and uncertainty. Internal consistency for each sub-scale was high with the values of Cronbach's alpha for the distress, positive experiences, family support and uncertainty sub-scales 0.92, 0.88, 0.92 and 0.87, respectively. Test-retest reliability was poor, with intra-class correlations of 0.53, 0.13, 0.33 and 0.52 for the four factors, respectively. Construct validation showed large correlations between the MICRA distress and uncertainty sub-scale scores and the Impact of Events score intrusion (0.42 and 0.62, respectively) and IES avoidant thinking sub-scales (0.40 and 0.58, respectively) but not the Hospital Anxiety and Depression Scale sub-scales. CONCLUSIONS: The adapted MICRA identified test-related anxiety and uncertainty in a population of cancer patients waiting for germline GS results. Results suggest that the distress and uncertainty sub-scales of the adapted measure are most useful in this context

Fear of cancer recurrence in patients undergoing germline genome sequencing

Purpose: Fear of cancer recurrence/occurrence (FCR/O) is prevalent and associated with poorer psychological outcomes but can also motivate individuals to pursue genomic information about cancer risk. Guided by Protection Motivation Theory, this study investigated FCR/O prevalence and associated factors among probands previously diagnosed with a cancer of likely heritable origin, and their relatives, who had agreed to have germline genome sequencing. Methods: Three hundred and forty-eight probands and 167 relatives completed the Concerns about Recurrence Questionnaire (adapted for occurrence for some relatives) within 1 month of agreeing to undertake genome sequencing. Linear regressions investigated demographic, disease, attitude and behavioral associations with FCR/O. Results: Probands demonstrated greater FCR compared to relatives. In probands, greater FCR was associated with being female, non-English speaking at home, less time since diagnosis, greater intention to change behavior if gene variant found, lower perceived ability to cope with results, higher perceived susceptibility to having a recurrence, and more negative attitudes towards uncertainty. For relatives with cancer, greater FCR was associated with being male, greater intention to change behavior if a gene variant found, and higher perceived susceptibility to recurrence. In relatives without cancer, greater FCO was associated with not having had genetic testing prior to this study, lower perceived ability to cope with results, and higher perceived susceptibility to developing cancer. Conclusion: Current findings on FCR/O prevalence and associated demographic and attitudinal variables in those who pursue genomic risk information might be used to target interventions that can prevent adverse psychological outcomes in vulnerable patients