"To do so in a patient-centred way is not particularly lucrative": The effects of neoliberal health care on PrEP implementation and delivery.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is a highly effective biomedical intervention used by HIV-negative people to prevent HIV acquisition. Despite increased use of PrEP worldwide, several barriers to PrEP implementation have resulted in insufficient uptake, inadequate adherence, and frequent discontinuation. Our objective was to interrogate the social, political, and economic conditions shaping PrEP implementation and delivery among gay, bisexual, queer and other men who have sex with men (GBQM) in Ontario, Canada. METHODS: Six focus groups and three interviews with 20 stakeholders in Ontario (e.g., healthcare professionals, clinicians, community-based organization staff, and government staff) were conducted between July and October 2021. Participants were asked about the personal, workplace, and structural factors shaping PrEP delivery strategies for GBQM. Transcripts were analyzed using reflexive thematic analysis informed by the political economy of PrEP and employed a critique of neoliberalism. RESULTS: Participants critiqued the problematic arrangements of the current healthcare system in Canada. Neoliberal governmentality and policies have resulted in inequitable PrEP care by establishing funding structures prioritizing profit and requiring patients and providers to function as individual entrepreneurs. Consequently, healthcare disparities are compounded for marginalized peoples who lack the resources and capacity to navigate existing healthcare systems. Participants identified several pathways to improve the implementation of PrEP, including greater institutional and governmental supports for PrEP and healthcare, leveraging communities and collaboration, and moving beyond risk-based health frameworks. CONCLUSION: Socio-political-economic changes reflecting post-neoliberal principles are needed to overcome existing barriers to PrEP care, and sexual and reproductive healthcare more broadly.

Gay, bisexual, and queer men's confidence in the Undetectable equals Untransmittable HIV prevention message: longitudinal qualitative analysis of the sexual decision-making of pre-exposure prophylaxis users over time.

BACKGROUND: Our objective was to understand what gay, bisexual, and queer men (GBQM) who had experience using pre-exposure prophylaxis (PrEP) thought about the 'Undetectable equals Untransmittable' (U=U) message and how it informed their sexual decision-making over time. METHODS: We conducted annual longitudinal qualitative interviews (2020-22) with 17 current or former PrEP users as part of a mixed-methods implementation science study examining barriers and facilitators to PrEP awareness, access, and adherence. Over 3years, 47 interviews were conducted with GBQM in Ontario, Canada. Interviews were transcribed verbatim and coded in NVivo following reflexive thematic analysis. RESULTS: Participants' sexual health decision-making was informed by their confidence in biomedical HIV prevention and the person taking medication (i.e. themselves using PrEP versus a real/imagined person living with HIV (PLHIV)). Longitudinal narratives of U=U clustered around four overarching themes: (1) U=U confidence (i.e. increasing trust in U=U irrespective of their PrEP use); (2) PrEP confidence (i.e. accounts of self-reliance and PrEP as sufficient HIV protection); (3) combination confidence (i.e. trusting U=U and PrEP as a package); and (4) partner confidence (i.e. potential 'distrust' of U=U due to uncertainties about partners' medication adherence). Overall, men described increased sex with PLHIV over time, including some participants who, during earlier interviews, said they would 'never be comfortable' with serodifferent sexual partners. CONCLUSIONS: GBQM's use of PrEP shaped how they thought about U=U and sex with PLHIV. Although many GBQM embraced treatment as prevention/U=U as significant to their sexual lives, longitudinal analysis revealed its varied and uneven adoption across participants and time.

Human Papillomavirus Vaccine: The Cancer Prevention Moonshot.

Cervical cancer is the fourth most common cancer in women worldwide with immense associated morbidity and mortality. Although most of the cervical cancer cases are caused by the human papillomavirus (HPV) and can effectively be prevented by HPV vaccination, vaccination unfortunately remains underused on a global scale with vast inequities in distribution. A vaccine as a tool to prevent cancer, cervical and others, is largely unprecedented. Then why do HPV vaccination rates globally remain so low? This article explores the burden of disease, development of the vaccine and its subsequent uptake, cost-effectiveness, and associated equity issues.

Injectable Pre-Exposure Prophylaxis for HIV Prevention: Perspectives on the Benefits and Barriers from Gay, Bisexual, and Queer Men and Health System Stakeholders in Ontario, Canada.

One hope surrounding long-acting HIV pre-exposure prophylaxis (PrEP) is reaching new users who could most benefit, as well as improving the experiences of oral PrEP users who may desire to switch modalities. Gay, bisexual, queer, and other men who have sex with men (GBQM) continue to make up over half of new HIV diagnoses in Canada, and oral PrEP uptake has plateaued among this population. Approval of injectable PrEP is anticipated, but there is a paucity of research to inform health promotion and implementation. Between June and October 2021, we conducted 22 in-depth interviews with GBQM oral PrEP users and non-PrEP users living in Ontario, Canada. We also conducted small focus groups or individual interviews with 20 key stakeholders (health care providers, public health officials, community-based organization staff). Interviews were audio recorded, transcribed verbatim, and analyzed in NVivo using thematic analysis. Only about one-third of GBQM had heard of injectable PrEP. Many PrEP users perceived greater convenience, adherence, and confidentiality with injectable PrEP. Some PrEP users did not anticipate switching because of needle discomfort or feeling more "in control" with oral PrEP. None of the non-PrEP users said that injectable PrEP would make them start PrEP. Injectable PrEP may offer additional convenience for GBQM; however, it did not appear to affect participants' PrEP decision-making significantly. Stakeholders noted that injectable PrEP may improve access, support adherence, and benefit marginalized groups. Some clinicians expressed concerns about the time/personnel required to make injectable PrEP available. System-level challenges in implementing injectable PrEP, including cost, must also be addressed.

Evaluation of 5 Fraction Stereotactic Body Radiation Therapy (SBRT) for Osseous Renal Cell Carcinoma Metastases.

OBJECTIVES: The best fractionation for stereotactic body radiotherapy (SBRT) in renal cell carcinoma (RCC) metastases has not been well defined. In addition, the literature on outcomes using 5-fraction SBRT in the setting of osseous metastases has not been well reported. MATERIALS AND METHODS: Thirty-nine patients with 69 RCC osseous metastases were treated using 5-fraction SBRT at a single institution using 2 dose-fractionation schemes. Overall survival and local-control (LC) outcomes of the 2 fractionation schemes were studied using Kaplan-Meier curves. RESULTS: Of the 69 lesions included in the study, 20 were treated with 30 grays (Gy) in 5 fractions and 49 were treated with 40 Gy in 5 fractions. The median age of patients at diagnosis was 58.4 years. The 1-year LC rate for all treated lesions was 85.5% (59/69) with an LC of 90% (18/20) for lesions receiving 30 Gy and 83.7% (41/49) in lesions receiving 40 Gy. There was no statistically significant difference in 1-year LC rate between the 2 fractionation schemes (P-value, 0.553). CONCLUSIONS: Patients with osseous RCC metastases undergoing 5 fractions of SBRT had favorable LC outcomes. There was no difference in survival or LC between the 40 Gy and 30 Gy treatment arms.

"What other choices might I have made?": Sexual Minority Men, the PrEP Cascade and the Shifting Subjective Dimensions of HIV Risk.

The PrEP Cascade is a dominant framework for investigating barriers to HIV pre-exposure prophylaxis (PrEP), an HIV prevention tool. We interviewed 37 PrEP users and 8 non-PrEP users in Ontario and British Columbia, Canada, about their decision-making through the Cascade. Participants were HIV-negative gay, bisexual, and queer men (GBQM). The data were analyzed using thematic analysis. PrEP decision-making was based on pragmatic considerations (logistics, costs, and systemic barriers), biomedical considerations (efficacy, side-effects, and sexually transmitted infections), and subjective considerations (identity, politics, and changing sexual preferences). Affective attachments to established versions of "safer sex" (condoms and serosorting) made some GBQM less likely to try PrEP. Some GBQM expressed increased social expectations to use PrEP, have condomless sex, and serodifferent sex. These findings support offering PrEP at no-cost, offering individualized counseling and community-based opportunities to discuss PrEP use and changing sexual practices, and improving communication on the manageability of PrEP side-effects.

A compendium of kinetic modulatory profiles identifies ferroptosis regulators.

Cell death can be executed by regulated apoptotic and nonapoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using time-lapse imaging and a library of 1,833 bioactive compounds, we assembled a large compendium of kinetic cell death modulatory profiles for inducers of apoptosis and ferroptosis. From this dataset we identify dozens of ferroptosis suppressors, including numerous compounds that appear to act via cryptic off-target antioxidant or iron chelating activities. We show that the FDA-approved drug bazedoxifene acts as a potent radical trapping antioxidant inhibitor of ferroptosis both in vitro and in vivo. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, are on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms that link amino acid metabolism to ferroptosis sensitivity. These results highlight kinetic modulatory profiling as a useful tool to investigate cell death regulation.

ClinicNet: machine learning for personalized clinical order set recommendations.

OBJECTIVE: This study assesses whether neural networks trained on electronic health record (EHR) data can anticipate what individual clinical orders and existing institutional order set templates clinicians will use more accurately than existing decision support tools. MATERIALS AND METHODS: We process 57 624 patients worth of clinical event EHR data from 2008 to 2014. We train a feed-forward neural network (ClinicNet) and logistic regression applied to the traditional problem structure of predicting individual clinical items as well as our proposed workflow of predicting existing institutional order set template usage. RESULTS: ClinicNet predicts individual clinical orders (precision = 0.32, recall = 0.47) better than existing institutional order sets (precision = 0.15, recall = 0.46). The ClinicNet model predicts clinician usage of existing institutional order sets (avg. precision = 0.31) with higher average precision than a baseline of order set usage frequencies (avg. precision = 0.20) or a logistic regression model (avg. precision = 0.12). DISCUSSION: Machine learning methods can predict clinical decision-making patterns with greater accuracy and less manual effort than existing static order set templates. This can streamline existing clinical workflows, but may not fit if historical clinical ordering practices are incorrect. For this reason, manually authored content such as order set templates remain valuable for the purposeful design of care pathways. ClinicNet's capability of predicting such personalized order set templates illustrates the potential of combining both top-down and bottom-up approaches to delivering clinical decision support content. CONCLUSION: ClinicNet illustrates the capability for machine learning methods applied to the EHR to anticipate both individual clinical orders and existing order set templates, which has the potential to improve upon current standards of practice in clinical order entry.

Ranking of non-coding pathogenic variants and putative essential regions of the human genome.

A gene is considered essential if loss of function results in loss of viability, fitness or in disease. This concept is well established for coding genes; however, non-coding regions are thought less likely to be determinants of critical functions. Here we train a machine learning model using functional, mutational and structural features, including new genome essentiality metrics, 3D genome organization and enhancer reporter data to identify deleterious variants in non-coding regions. We assess the model for functional correlates by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements in over 3 Mb of genome sequence. Finally, we explore two user cases that involve indels and the disruption of enhancers associated with a developmental disease. We rank variants in the non-coding genome according to their predicted deleteriousness. The model prioritizes non-coding regions associated with regulation of important genes and with cell viability, an in vitro surrogate of essentiality.

Neural Networks for Clinical Order Decision Support.

Consistent and high quality medical decisions are difficult as the amount of literature, data, and treatment options grow. We developed a model to provide automated physician order decision support suggestions for inpatient care through a feed-forward neural network. Given a patient's current status based on information data-mined and extracted from the Electronic Health Record (EHR), our model predicts clinical orders a physician enters for a patient within 24 hours. As a reference benchmark of real-world standard-of-care clinical decision support, existing manually-curated order sets implemented in the hospital demonstrate precision: 0.21, recall: 0.48, AUROC: 0.75 relative to what clinicians actually order within 24 hours. Our feed-forward model provides an automated, scalable, and robust system that achieves precision: 0.41, recall: 0.61, AUROC: 0.80.

Systematic Quantification of Population Cell Death Kinetics in Mammalian Cells.

Cytotoxic compounds are important drugs and research tools. Here, we introduce a method, scalable time-lapse analysis of cell death kinetics (STACK), to quantify the kinetics of compound-induced cell death in mammalian cells at the population level. STACK uses live and dead cell markers, high-throughput time-lapse imaging, and mathematical modeling to determine the kinetics of population cell death over time. We used STACK to profile the effects of over 1,800 bioactive compounds on cell death in two human cancer cell lines, resulting in a large and freely available dataset. 79 potent lethal compounds common to both cell lines caused cell death with widely divergent kinetics. 13 compounds triggered cell death within hours, including the metallophore zinc pyrithione. Mechanistic studies demonstrated that this rapid onset lethal phenotype was caused in human cancer cells by metabolic disruption and ATP depletion. These results provide the first comprehensive survey of cell death kinetics and analysis of rapid-onset lethal compounds.