Using a Participatory Approach to Develop Research Priorities for Future Leaders in Cancer-Related Precision Public Health

Precision public health is an emerging discipline combining principles and frameworks of precision health with the goal of improving population health. The development of research priorities drawing on the strengths of precision and public health is critical to facilitate the growth of the discipline to improve health outcomes. We held an interactive workshop during a virtual conference bringing together early-career researchers across public health disciplines to identify research priorities in precision public health. The workshop participants discussed and voted to identify three priority areas for future research and capacity building including 1) enhancing equity and access to precision public health research and resources, 2) improving tools and metrics for evaluation and 3) applying principles of implementation science to support sustainable practices. Participants also developed future objectives for achieving each priority. Future efforts by working groups will continue the process of identifying, revising, and advancing critical research priorities to grow the impact of precision public health

Identification of SOX3 as an XX male sex reversal gene in mice and humans

Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.Edwina Sutton, James Hughes... Nicholas Rogers... Dale McAninch... Paul Thomas, et al

Recommendations for effective documentation in regional anesthesia: an expert panel Delphi consensus project

Background and objectives: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. Results: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Parental decision making about clinical trial enrollment: A survey of parents of children with Fragile X syndrome.

OBJECTIVE:Opportunities for patients to enroll in clinical trials for neurodevelopmental conditions are increasing. We studied what factors are associated with parents' decisional process to enroll their child in a clinical trial for a genetic neurodevelopmental condition (Fragile X syndrome). METHOD:Parents (n = 354; mostly biological mothers of a child with Fragile X syndrome) were recruited through Fragile X syndrome advocacy groups. Parents reported attitudes about children in research, trust in child's doctor, threat resources (self-affirmation and dispositional optimism), and demographic and clinical characteristics in an online questionnaire. Three outcome measures assessed associations with these factors at different stages of the decision-making process. The three outcomes were (a) awareness about clinical trial opportunities, (b) enrollment decisions, and (c) decisional regret. RESULTS:Parents who were positive about involving children in research were more aware of clinical trial opportunities (OR = 3.27, 95% CI [2.11, 5.07]), were more likely to have enrolled their child in a clinical trial (OR = 1.69, 95% CI [1.12, 2.56]), and reported lower levels of decisional regret (β = -8.95, 95% CI [-16.38, -1.52]). Parents with higher threat resources had considered enrolling their child in a clinical trial (OR = 1.51, 95% CI [1.02, 2.23]) and reported lower levels of decisional regret (β = -8.73, 95% CI [-17.36, -0.11]). Among parents with lower levels of trust in their child's doctor, higher threat resources were associated with higher enrollment (β = 0.60, 95% CI [0.12, 1.08]). CONCLUSIONS:It may be possible to intervene on the factors (attitudes about children in research and threat resources) associated with clinical trial decision making to boost trial enrollment and promote informed decision making. (PsycInfo Database Record (c) 2020 APA, all rights reserved)

Production of Definitive Data from Indonesian Geomagnetic Observatories

Measurement of the geomagnetic field in Indonesia is undertaken by the Meteorological, Climatological, and Geophysical Agency (BMKG). Routine activities at each observatory include the determination of declination, inclination, and total field using absolute and variation measurements. The oldest observatory is Tangerang (TNG), started in 1957, followed by Tuntungan (TUN) in 1980, Tondano (TND) in 1990, Pelabuhan Ratu (PLR) and Kupang (KPG) in 2000, and Jayapura (JAY) in 2012. One of the main obligations of a geomagnetic observatory is to produce final versions of data, released as definitive data, for each year and make them widely available both for scientific and non-scientific purposes, for example to the World Data Centre of Geomagnetism (WDC-G). Unfortunately, some Indonesian geomagnetic observatories do not share their data with the WDC-G and often have difficulty in producing definitive data. In addition, some more basic problems still exist, such as low-quality data due to anthropogenic or instrumental noise, a lack of data-processing knowledge, and limited observer training. In this study, we report on the production of definitive data from Indonesian observatories, and some recommendations are provided about how to improve the data quality. These methods and approaches are applicable to other institutes seeking to enhance their data quality and scientific utility, for example in main field modelling or space weather monitoring. The definitive data from the years 2010 to 2018 are now available in the WDC-G