Indigenous data governance approaches applied in research using routinely collected health data: a scoping review.

Globally, there is a growing acknowledgment of Indigenous Peoples' rights to control data related to their communities. This is seen in the development of Indigenous Data Governance standards. As health data collection increases, it's crucial to apply these standards in research involving Indigenous communities. Our study, therefore, aims to systematically review research using routinely collected health data of Indigenous Peoples, understanding the Indigenous Data Governance approaches and the associated advantages and challenges. We searched electronic databases for studies from 2013 to 2022, resulting in 85 selected articles. Of these, 65 (77%) involved Indigenous Peoples in the research, and 60 (71%) were authored by Indigenous individuals or organisations. While most studies (93%) provided ethical approval details, only 18 (21%) described Indigenous guiding principles, 35 (41%) reported on data sovereignty, and 28 (33%) addressed consent. This highlights the increasing focus on Indigenous Data Governance in utilising health data. Leveraging existing data sources in line with Indigenous data governance principles is vital for better understanding Indigenous health outcomes.

Enhancing the value of digital health tools for mental health help-seeking in Canadian transitional aged youth during the pandemic: Qualitative study.

While the COVID-19 pandemic has greatly exacerbated the mental health challenges of transition-aged youth (TAY) between 17 and 29 years old, it has also led to the rapid adoption of digital tools for mental health help-seeking and treatment. However, to date, there has been limited work focusing on how this shift has impacted perceptions, needs and challenges of this population in using digital tools. The current study aims to understand their perspectives on mental health help-seeking during the pandemic and emerging issues related to digital tools (e.g., digital health equity, inclusivity). A total of 16 TAY were invited from three post-secondary institutions in the Greater Toronto Area. A total of two streams of focus groups were held and participants were invited to share their perceptions, needs and experiences. Five main themes were identified: 1) Helpfulness of a centralized resource encompassing a variety of diverse mental health supports help-seeking; 2) The impact of the shift to online mental health support on the use of informal supports; 3) Digital tool affordability and availability; 4) Importance of inclusivity for digital tools; and 5) Need for additional support for mental health seeking and digital tool navigation. Future work should examine how these needs can be addressed through new and existing digital mental health help-seeking tools for TAY.

Superior antibody and membrane protein-specific T-cell responses to CoronaVac by intradermal versus intramuscular routes in adolescents.

BACKGROUND: Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary. Fractional dosing by intradermal (ID) administration has been shown to be equally immunogenic as intramuscular (IM) administration for several vaccines, but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the full dose is unknown. This study (NCT04800133) investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in adolescents. METHODS: Participants aged 11-17 years received two doses of IM or ID vaccine, followed by the 3rd dose 13-42 days later. Humoral and cellular immunogenicity outcomes were measured post-dose 2 (IM-CC versus ID-CC) and post-dose 3 (IM-CCC versus ID-CCC). Doses 2 and 3 were administered to 173 and 104 adolescents, respectively. RESULTS: Spike protein (S) immunoglobulin G (IgG), S-receptor-binding domain (RBD) IgG, S IgG Fcγ receptor IIIa (FcγRIIIa)-binding, SNM [sum of individual (S), nucleocapsid protein (N), and membrane protein (M) peptide pool]-specific interleukin-2 (IL-2)+CD4+, SNM-specific IL-2+CD8+, S-specific IL-2+CD8+, N-specific IL-2+CD4+, N-specific IL-2+CD8+ and M-specific IL-2+CD4+ responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC, whereas IgG avidity was inferior. For ID-CCC, S-RBD IgG, surrogate virus neutralisation test, 90% plaque reduction neutralisation titre (PRNT90), PRNT50, S IgG avidity, S IgG FcγRIIIa-binding, M-specific IL-2+CD4+, interferon-γ+CD8+ and IL-2+CD8+ responses were superior and non-inferior to IM-CCC. The estimated vaccine efficacies were 49%, 52%, 66% and 79% for IM-CC, ID-CC, IM-CCC and ID-CCC, respectively. The ID groups reported more local, mild adverse reactions. CONCLUSION: This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARS-CoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.

Humoral and Cellular Immunogenicity of 3 Doses of BNT162b2 in Children With Kidney Diseases.

Introduction: Patients with severe kidney diseases are at risk of complications from COVID-19; however, little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. Methods: We investigated the immunogenicity and safety of an accelerated 3-dose primary series of COVID-19 vaccination among 59 pediatric patients with chronic kidney disease (CKD) (mean age 12.9 years; 30 male) with or without immunosuppression, dialysis, or kidney transplant. Dosage was 0.1 ml BNT162b2 to those aged 5 to 11 years, and 0.3 ml BNT162b2 to those aged 11 to 18 years. Results: Three doses of either vaccine type elicited significant antibody responses that included spike receptor-binding domain (S-RBD) IgG (90.5%-93.8% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6%-79.3%). There were notable T cell responses. Weaker neutralization responses were observed among those on immunosuppression, especially those receiving higher number of immunosuppressants or on mycophenolate mofetil. Neutralization was reduced against Omicron BA.1 compared to wild type (WT, i.e., ancestral) (post-dose 3 sVNT% level; 82.7% vs. 27.4%; P < 0.0001). However, the T cell response against Omicron BA.1 was preserved, which likely confers protection against severe COVID-19. Infected patients exhibited hybrid immunity after vaccination, as evidenced by the higher Omicron BA.1 neutralization response among these infected patients who received 2 doses compared with those who were uninfected. Generally mild or moderate adverse reactions following vaccines were reported. Conclusion: An accelerated 3-dose primary series with BNT162b2 is immunogenic and safe in young children and adolescents with kidney diseases.

Antibody and T cell responses against wild-type and Omicron SARS-CoV-2 after third-dose BNT162b2 in adolescents.

The high effectiveness of the third dose of BNT162b2 in healthy adolescents against Omicron BA.1 has been reported in some studies, but immune responses conferring this protection are not yet elucidated. In this analysis, our study (NCT04800133) aims to evaluate the humoral and cellular responses against wild-type and Omicron (BA.1, BA.2 and/or BA.5) SARS-CoV-2 before and after a third dose of BNT162b2 in healthy adolescents. At 5 months after 2 doses, S IgG, S IgG Fc receptor-binding, and neutralising antibody responses waned significantly, yet neutralising antibodies remained detectable in all tested adolescents and S IgG avidity increased from 1 month after 2 doses. The antibody responses and S-specific IFN-γ+ and IL-2+ CD8+ T cell responses were significantly boosted in healthy adolescents after a homologous third dose of BNT162b2. Compared to adults, humoral responses for the third dose were non-inferior or superior in adolescents. The S-specific IFN-γ+ and IL-2+ CD4+ and CD8+ T cell responses in adolescents and adults were comparable or non-inferior. Interestingly, after 3 doses, adolescents had preserved S IgG, S IgG avidity, S IgG FcγRIIIa-binding, against Omicron BA.2, as well as preserved cellular responses against BA.1 S and moderate neutralisation levels against BA.1, BA.2 and BA.5. Sera from 100 and 96% of adolescents tested at 1 and 5 months after two doses could also neutralise BA.1. Our study found high antibody and T cell responses, including potent cross-variant reactivity, after three doses of BNT162b2 vaccine in adolescents in its current formulation, suggesting that current vaccines can be protective against symptomatic Omicron disease.

Safety and immunogenicity of 3 doses of BNT162b2 and CoronaVac in children and adults with inborn errors of immunity.

Our study (NCT04800133) aimed to determine the safety and immunogenicity in patients with IEIs receiving a 3-dose primary series of mRNA vaccine BNT162b2 (age 12+) or inactivated whole-virion vaccine CoronaVac (age 3+) in Hong Kong, including Omicron BA.1 neutralization, in a nonrandomized manner. Intradermal vaccination was also studied. Thirty-nine patients were vaccinated, including 16 with homologous intramuscular 0.3ml BNT162b2 and 17 with homologous intramuscular 0.5ml CoronaVac. Two patients received 3 doses of intradermal 0.5ml CoronaVac, and 4 patients received 2 doses of intramuscular BNT162b2 and the third dose with intradermal BNT162b2. No safety concerns were identified. Inadequate S-RBD IgG and surrogate virus neutralization responses were found after 2 doses in patients with humoral immunodeficiencies and especially so against BA.1. Dose 3 of either vaccine increased S-RBD IgG response. T cell responses against SARS-CoV-2 antigens were detected in vaccinated IEI patients by intracellular cytokine staining on flow cytometry. Intradermal third dose vaccine led to high antibody response in 4 patients. The primary vaccination series of BNT162b2 and CoronaVac in adults and children with IEIs should include 3 doses for optimal immunogenicity.

The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain.

Introduction: Bortezomib has been reported to favourably impact the outcomes of t(4;14) and del(17p) in multiple myeloma (MM), but its impact on gain 1q (+1q) is unknown. Methods: To address this, 250 patients treated with bortezomib-based induction were analysed. All myeloma samples had fluorescence in situ hybridization (FISH) performed on CD138-sorted bone marrow aspirate, and plasma cells were analysed using DNA probes specific for the following chromosomal aberrations: del(13q14), del(17p), t(14;16), t(4;14), and +1q. Presence of +1q was defined as the presence of at least three copies of 1q21 at the cut off level of 20% of bone marrow plasma cells. Results: +1q identified in 167 (66.8%) and associated with t(4;14) and high lactate dehydrogenase (LDH). +1q was not associated with response rate but shorter event-free survival (EFS) (median EFS 35 vs 55 months, p = 0.05) and overall survival (OS) (median OS 74 vs 168 months, p = 0.00025). Copy number and clone size did not impact survival. Multivariate analysis showed +1q was an independent adverse factor for OS together with International Staging System (ISS)3, high LDH, del(17p) and t(4;14). When a risk score of 1 was assigned to each independent adverse factor, OS was shortened incrementally by a risk score from 0 to 4. Post-relapse/progression survival was inferior in those with +1q (median 60 vs 118 months, p = 0.000316). Autologous stem cell transplantation (ASCT) improved OS for those with +1q (median OS 96 vs 49 months, p = 0.000069). Conclusion: +1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM.

Assessing the usability and user engagement of Thought Spot - A digital mental health help-seeking solution for transition-aged youth.

OBJECTIVE: To evaluate the perceived usability of and user engagement with a digital platform (Thought Spot) designed to enhance mental health and wellness help-seeking among transition-aged youth (TAY; 17-29-years old). MATERIALS AND METHODS: Survey responses and usage patterns were collected as part of a randomized controlled trial evaluating the efficacy of Thought Spot. Participants given Thought Spot completed an adapted Usefulness, Satisfaction, and Ease of Use (USE) Questionnaire to measure perceived usability of the platform. User engagement patterns on Thought Spot were examined using analytics data collected throughout the study (March 2018-June 2019). RESULTS: A total of 131 transition-aged participants completed the USE questionnaire and logged on to Thought Spot at least once. Ease of learning scored higher than ease of use, usefulness and satisfaction. Participants identified numerous strengths and challenges related to usability, visual appeal, functionality and usefulness of the content. In terms of user engagement, most participants stopped using the platform after 3 weeks. Participants searched and were interested in a variety of resources, including mental health, counselling and social services. DISCUSSION: Participants reported mixed experiences while using Thought Spot and exhibited low levels of long-term user engagement. User satisfaction, the willingness to recommend Thought Spot to others, and the willingness for future use appeared to be influenced by content relevance, ease of learning, available features, and other contextual factors. Analysis of the types of resources viewed and searches conducted by TAY end-users provided insight into their behaviour and needs. CONCLUSION: Users had mixed perceptions about the usability of Thought Spot, which may have contributed to the high attrition rate. User satisfaction and engagement appears to be influenced by content relevance, ease of learning, and the types of features available. Further investigation to understand the contextual factors that affect TAYs' adoption and engagement with digital mental health tools is required.

Postsecondary Student Engagement With a Mental Health App and Online Platform (Thought Spot): Qualitative Study of User Experience.

BACKGROUND: There is growing interest in using mobile apps and online tools to support postsecondary student mental health, but most of these solutions have suboptimal user engagement in real-world settings. Poor engagement can limit long-term effectiveness and usefulness of these tools. Previous literature has proposed several theories that link factors such as low usability and poor user-centered design to app disengagement. However, few studies provide direct evidence showing what factors contribute to suboptimal user engagement in the context of mobile mental health apps for postsecondary students. OBJECTIVE: This study focuses on understanding postsecondary students' attitudes and behaviors when using Thought Spot, a co-designed mental health app and online platform, to understand factors related to engagement and user experience. METHODS: Students who were given access to Thought Spot for 6 months during a randomized trial of the intervention were invited to participate in one-on-one semistructured interviews. The interviews explored participants' overall experiences and perceptions of the app, along with factors that affected their usage of various features. All interviews were recorded, and template analysis was used to analyze transcripts. RESULTS: User satisfaction was mixed among users of Thought Spot. The degree of engagement with the app appeared to be affected by factors that can be grouped into 5 themes: (1) Students valued detailed, inclusive, and relevant content; (2) Technical glitches and a lack of integration with other apps affected the overall user experience and satisfaction with the app; (3) Using the app to support peers or family can increase engagement; (4) Crowdsourced information from peers about mental health resources drove user engagement, but was difficult to obtain; and (5) Users often turned to the app when they had an immediate need for mental health information, rather than using it to track mental health information over time. CONCLUSIONS: Content, user experience, user-centeredness, and peer support are important determinants of user engagement with mobile mental health apps among postsecondary students. In this study, participants disengaged when the app did not meet their expectations on these determinants. Future studies on user engagement should further explore the effectiveness of different features and the relative importance of various criteria for high-quality apps. Further focus on these issues may inform the creation of interventions that increase student engagement and align with their mental health needs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03412461; https://clinicaltrials.gov/ct2/show/NCT03412461. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.6446.

Effects of a Mobile and Web App (Thought Spot) on Mental Health Help-Seeking Among College and University Students: Randomized Controlled Trial.

BACKGROUND: Mental health disorders are the most prevalent health issues among postsecondary students, yet few solutions to this emerging crisis exist. While mobile health technologies are touted as promising solutions for the unmet mental health needs of these students, the efficacy of these tools remains unclear. In response to these gaps, this study evaluates Thought Spot, a mobile and web app created through participatory design research. OBJECTIVE: The goal of the research is to examine the impact of Thought Spot on mental health and wellness help-seeking intentions, behaviors, attitudes, self-stigma, and self-efficacy among postsecondary students in Canada. METHODS: A 2-armed randomized controlled trial involving students from three postsecondary institutions was conducted. Students were eligible if they were aged 17 to 29 years, enrolled in full-time or part-time studies, functionally competent in English, and had access to a compatible digital device. The usual care group received a mental health services information pamphlet. The intervention group received the Thought Spot app on their digital device. Thought Spot is a standalone app that allows users to add, review, and search crowdsourced information about nearby mental health and wellness services. Users can also track their mood on the app. Outcomes were self-assessed through questionnaires collected at baseline and 3 and 6 months. The primary outcome was change in formal help-seeking intentions from baseline to 6 months, measured by the General Help-Seeking Questionnaire. A mixed-effects model was used to compare the impact of usual care and intervention on the primary outcome (formal help-seeking intentions). Secondary outcomes included changes in informal help-seeking intentions and help-seeking behaviors, help-seeking attitudes, self-stigma, and self-efficacy. RESULTS: A total of 481 students were randomized into two groups: 240 to usual care, and 241 to the intervention group. There were no significant differences in help-seeking intentions between the usual care and intervention groups over 6 months (F2,877=0.85; P=.43, f=0.04). Both groups demonstrated similar increases in formal help-seeking intentions at 3 and 6 months (F2,877=23.52; P<.001, f=0.21). Compared with males, females sought more help from formal resources (OR 1.86; 95% CI 1.22 to 2.83, P=.001). Females were less likely to seek help from informal sources than males (OR 0.80; 95% CI 0.22 to 0.73, P<.001). CONCLUSIONS: Prompting postsecondary students about mental health and help-seeking appears to increase help-seeking intentions. mHealth interventions may be as effective as information pamphlets in increasing formal help-seeking but may confer a small advantage in driving help-seeking from informal sources. Although there is enthusiasm, developers and health policy experts should exercise caution and thoroughly evaluate these types of digital tools. Future studies should explore the cost-effectiveness of digital interventions and develop strategies for improving their efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03412461; https://clinicaltrials.gov/ct2/show/NCT03412461. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.6446.

COX2 is induced in the ovarian epithelium during ovulatory wound repair and promotes cell survival†.

The ovarian surface epithelium (OSE) is a monolayer of cells surrounding the ovary that is ruptured during ovulation. After ovulation, the wound is repaired, however, this process is poorly understood. In epithelial tissues, wound repair is mediated by an epithelial-to-mesenchymal transition (EMT). Transforming Growth Factor Beta-1 (TGFß1) is a cytokine commonly known to induce an EMT and is present throughout the ovarian microenvironment. We, therefore, hypothesized that TGFß1 induces an EMT in OSE cells and activates signaling pathways important for wound repair. Treating primary cultures of mouse OSE cells with TGFß1 induced an EMT mediated by TGFßRI signaling. The transcription factor Snail was the only EMT-associated transcription factor increased by TGFß1 and, when overexpressed, was shown to increase OSE cell migration. A polymerase chain reaction array of TGFß signaling targets determined Cyclooxygenase-2 (Cox2) to be most highly induced by TGFß1. Constitutive Cox2 expression modestly increased migration and robustly enhanced cell survival, under stress conditions similar to those observed during wound repair. The increase in Snail and Cox2 expression with TGFß1 was reproduced in human OSE cultures, suggesting these responses are conserved between mouse and human. Finally, the induction of Cox2 expression in OSE cells during ovulatory wound repair was shown in vivo, suggesting TGFß1 increases Cox2 to promote wound repair by enhancing cell survival. These data support that TGFß1 promotes ovulatory wound repair by induction of an EMT and activation of a COX2-mediated pro-survival pathway. Understanding ovulatory wound repair may give insight into why ovulation is the primary non-hereditary risk factor for ovarian cancer.

Evaluating the Use of an Electronic Death Registration System for Mortality Surveillance During and After Hurricane Sandy: New York City, 2012.

OBJECTIVES: We evaluated the use of New York City's (NYC's) electronic death registration system (EDRS) to conduct mortality surveillance during and after Hurricane Sandy. METHODS: We used Centers for Disease Control and Prevention guidelines for surveillance system evaluation to gather evidence on usefulness, flexibility, stability, timeliness, and quality. We assessed system components, interviewed NYC Health Department staff, and analyzed 2010 to 2012 death records. RESULTS: Despite widespread disruptions, NYC's EDRS was stable and collected timely mortality data that were adapted to provide storm surveillance with minimal additional resources. Direct-injury fatalities and trends in excess all-cause mortality were rapidly identified, providing useful information for response; however, the time and burden of establishing reports, adapting the system, and identifying indirect deaths limited surveillance. CONCLUSIONS: The NYC Health Department successfully adapted its EDRS for near real-time disaster-related mortality surveillance. Retrospective assessment of deaths, advanced methods for case identification and analysis, standardized reports, and system enhancements will further improve surveillance. Local, state, and federal partners would benefit from partnering with vital records to develop EDRSs for surveillance and to promote ongoing evaluation.

Genomic compartmentalization of gene families encoding core components of metazoan signaling systems.

To investigate the role of gene localization and genome organization in cell-cell signalling and regulation, we mapped the distribution pattern of gene families that comprise core components of intercellular communication networks. Our study is centered on the distinct evolutionarily conserved metazoan signalling pathways that employ proteins in the receptor tyrosine kinase, WNT, hedgehog, NOTCH, Janus kinase/STAT, transforming growth factor beta, and nuclear hormone receptor protein families. Aberrant activity of these signalling pathways is closely associated with the promotion and maintenance of human cancers. The cataloguing and mapping of genes encoding these signalling proteins and comparisons across species has led us to propose that the genome can be subdivided into six genome-wide primary linkage groups (PLGs). PLGs are composed of assemblages of gene families that are often mutually exclusive, raising the possibility of unique functional identities for each group. Examination of the localization patterns of genes with distinct functions in signal transduction demonstrates dichotomous segregation patterns. For example, gene families of cell-surface receptors localize to genomic compartments that are distinct from the locations of their cognate ligand gene families. Additionally, genes encoding negative-acting components of signalling pathways (inhibitors and antagonists) are topologically separated from their positive regulators and other signal transducer genes. We, therefore, propose the existence of conserved genomic territories that encode key proteins required for the proper activity of metazoan signaling and regulatory systems. Disruption in this pattern of topologic genomic organization may contribute to aberrant regulation in hereditary or acquired diseases such as cancer. We further propose that long-range looping genomic regulatory interactions may provide a mechanism favouring the remarkable retention of these conserved gene clusters during chordate evolution.

Lipase maturation factor 1 is required for endothelial lipase activity.

Lipase maturation factor 1 (Lmf1) is an endoplasmic reticulum (ER) membrane protein involved in the posttranslational folding and/or assembly of lipoprotein lipase (LPL) and hepatic lipase (HL) into active enzymes. Mutations in Lmf1 are associated with diminished LPL and HL activities ("combined lipase deficiency") and result in severe hypertriglyceridemia in mice as well as in human subjects. Here, we investigate whether endothelial lipase (EL) also requires Lmf1 to attain enzymatic activity. We demonstrate that cells harboring a (cld) loss-of-function mutation in the Lmf1 gene are unable to generate active EL, but they regain this capacity after reconstitution with the Lmf1 wild type. Furthermore, we show that cellular EL copurifies with Lmf1, indicating their physical interaction in the ER. Finally, we determined that post-heparin phospholipase activity in a patient with the LMF1(W464X) mutation is reduced by more than 95% compared with that in controls. Thus, our study indicates that EL is critically dependent on Lmf1 for its maturation in the ER and demonstrates that Lmf1 is a required factor for all three vascular lipases, LPL, HL, and EL.

Mouse hepatic lipase alleles with variable effects on lipoprotein composition and size.

The structural features responsible for the activities of hepatic lipase (HL) can be clarified by in vivo comparisons of naturally occurring variants. The coding sequence of HL from C57BL/6J (B6) and SPRET/EiJ (SPRET) mice differs by four amino acids (S106N, A156V, L416V, S480T); however, these changes are not predicted to influence HL function. To test for allelic effects, we generated SPRET-HL transgenics with physiological levels of HL mRNA and HL activity that was parallel in female transgenics and about 70% higher in male transgenics, toward tri-[3H]oleate, compared with B6 controls. We found no correlation between activity levels and plasma lipids. However, significant allelic effects on plasma lipids were observed. Compared with B6-HL, SPRET-HL mediated reductions in total cholesterol (TC) and VLDL-, LDL- and HDL-cholesterol and HDL-triglyceride (TG) in fed males, and SPRET-HL decreased total TG and VLDL- and HDL-TG levels in fasted males. Fasted female transgenics had reduced TC compared with controls. We also found allele and sex effects on lipoprotein particle size. Male transgenic mice had increased VLDL and decreased LDL size, and female transgenic mice had decreased HDL size compared with control animals. These findings demonstrate highly divergent effects of naturally occurring HL coding sequence variants on lipid and lipoprotein metabolism.