Cytotoxicity of unsaturated fatty acids in fresh human tumor explants: concentration thresholds and implications for clinical efficacy

<p>Abstract</p> <p>Background</p> <p>Unsaturated fatty acids (UFAs) exhibit <it>in vitro </it>cytotoxicity against many malignant cell lines and yield decreased cancer incidence and reduced tumor growth in animal models. But clinical and animal studies to date have achieved response using only localized delivery methods such as intratumoral infusion. To explore possibilities for enhanced clinical efficacy, fresh surgical explants of tumors from 22 patients with five malignancies were exposed to γ-linolenic acid (GLA) and α-linolenic acid (ALA) and analyzed with an <it>in vitro </it>chemosensitivity testing system, the Fluorescent Cytoprint Assay (FCA). A total of 282 micro-organ cultures derived from these malignant tumors were exposed to GLA and ALA at different concentrations.</p> <p>Results</p> <p>GLA and ALA exhibited greater than 90% cytotoxicity at a sharp concentration threshold between 500 μM and 1 mM against all but two malignant micro-organ cultures tested in 5-10% serum. In tests using 30-40% serum, GLA and ALA killed tumor at concentrations of 2 mM and above.</p> <p>Conclusions</p> <p>The concentration threshold of 500 μM to 2 mM exhibited for antitumor activity by GLA and ALA is much higher than that observed in most previously reported cell culture studies but consistent with physiological concentrations found to kill tumor clinically and in animals. A mechanism of antitumor activity by unsaturated fatty acids through selective destabilization of the malignant plasma membrane is considered. An oral regimen is proposed for phase I clinical testing that could push the area under the curve for serum concentration of unbound unsaturated fatty acids over time to much higher levels than previously achieved for systemic administration and into the range that could yield antitumor response.</p

Discrimination and Health: Measurement and Impacts on Ontario’s Transgender Communities

Discrimination may contribute to poorer health outcomes experienced by non-dominant social groups. While discrimination and health research has flourished over the past two decades, little attention has been paid to the assessment of multiple forms of discrimination, nor to the health effects of discrimination for transgender persons in Canada. Therefore, this thesis examines the impacts of discrimination on health behaviours among transgender persons in Ontario and develops a new instrument set for evaluating self-reported discrimination irrespective of attribution, the Intersectional Discrimination Index (InDI). The first four manuscripts draw on data from the Trans PULSE Project, a respondent-driven sampling survey of transgender Ontarians aged 16+ conducted in 2009-2010 (n=433). Analyses were weighted using RDS-II methods, and odds ratios or prevalence ratios were estimated from logistic regression models to identify the impacts of discrimination, social exclusion, and gender transition. The first manuscript investigates correlates of both past-year HIV-related sexual risk and sexual inactivity among transfeminine (male-to-female spectrum) persons. Genital surgery for gender transition was independently associated with lower odds of both outcomes. Discrimination was not associated with sexual risk overall, but sensitivity analyses found that correlates differed by type of sexual risk behaviour. The second manuscript examines HIV-related sexual risk among transmasculine (female-to-male spectrum) persons who are gay, bisexual, or have sex with men. Known correlates of sexual risk among cisgender gay and bisexual men were similarly predictive of risk in this population, including sexual abuse, stimulant use, and depressive symptoms. The third and fourth manuscripts focus on heavy episodic drinking (HED) and illicit drug use, respectively, among all transgender Ontarians. HED, cocaine use, and amphetamine use were more common among transgender Ontarians than expected based on the age-standardized reference population. HED was associated with transmasculine gender and sex work, but not with discrimination. Illicit drug use was associated with anti-transgender violence, homelessness or underhousing, and sex work. The final manuscript describes the development and validation of the InDI, which includes three components measuring anticipated, day-to-day, and major discrimination. The bi-national validity and reliability study found consistent evidence of construct validity and test-retest reliability. Finally, implications and future research directions are discussed

Factors Impacting Transgender Patients’ Discomfort with Their Family Physicians: A Respondent-Driven Sampling Survey

BACKGROUND: Representing approximately 0.5% of the population, transgender (trans) persons in Canada depend on family physicians for both general and transition-related care. However, physicians receive little to no training on this patient population, and trans patients are often profoundly uncomfortable and may avoid health care. This study examined factors associated with patient discomfort discussing trans health issues with a family physician in Ontario, Canada. METHODS: 433 trans people age 16 and over were surveyed using respondent-driven sampling for the Trans PULSE Project; 356 had a family physician. Weighted logistic regression models were fit to produce prevalence risk ratios (PRRs) via average marginal predictions, for transmasculine (n = 184) and transfeminine (n = 172) trans persons. RESULTS: Among the 83.1% (95% CI = 77.4, 88.9) of trans Ontarians who had a family physician, approximately half reported discomfort discussing trans health issues. 37.2% of transmasculine and 38.1% of transfeminine persons reported at least one trans-specific negative experience. In unadjusted analysis, sociodemographics did not predict discomfort, but those who planned to medically transition sex, but had not begun, were more likely to report discomfort (transmasculine: PRR = 2.62 (95% CI = 1.44, 4.77); transfeminine: PRR = 1.85 (95% CI = 1.08, 3.15)). Adjusted for other factors, greater perceived physician knowledge about trans issues was associated with reduced likelihood of discomfort, and previous trans-specific negative experiences with a family physician with increased discomfort. Transfeminine persons who reported three or more types of negative experiences were 2.26 times as likely, and transmasculine persons 1.61 times as likely, to report discomfort. In adjusted analyses, sociodemographic associations differed by gender, with being previously married or having higher education associated with increased risk of discomfort among transfeminine persons, but decreased risk among transmasculine persons. CONCLUSIONS: Within this transgender population, discomfort in discussing trans health issues with a family physician was common, presenting a barrier to accessing primary care despite having a regular family physician and “universal” health insurance

Guidance and Ethical Considerations for Undertaking Transgender Health Research and Institutional Review Boards Adjudicating this Research

The purpose of this review is to create a set of provisional criteria for Institutional Review Boards (IRBs) to refer to when assessing the ethical orientation of transgender health research proposals. We began by searching for literature on this topic using databases and the reference lists of key articles, resulting in a preliminary set of criteria. We then collaborated to develop the following nine guidelines: (1) Whenever possible, research should be grounded, from inception to dissemination, in a meaningful collaboration with community stakeholders; (2) language and framing of transgender health research should be non-stigmatizing; (3) research should be disseminated back to the community; (4) the diversity of the transgender and gender diverse (TGGD) community should be accurately reflected and sensitively reflected; (5) informed consent must be meaningful, without coercion or undue influence; (6) the protection of participant confidentiality should be paramount; (7) alternative consent procedures should be considered for TGGD minors; (8) research should align with current professional standards that refute conversion, reorientation, or reparative therapy; and (9) IRBs should guard against the temptation to avoid, limit, or delay research on this subject

Securing Safe Supply During COVID-19 and Beyond: Scoping Review and Knowledge Mobilization

Background Safe supply is defined as the legal and regulated provision of drugs with mind and/or body altering properties that have been typically accessible only through the illegal drug market. In response to the coronavirus disease 2019 (COVID-19) pandemic and related social/physical distancing measures, efforts have been made to scale up and increase access to safe supply programs in an effort to reduce overdose and other drug- and drug policy-related risks. However, it remains unclear whether these efforts taken thus far have meaningfully mitigated the barriers to safe supply experienced by People Who Use Drugs (PWUD), both during and beyond the context of COVID-19. We thus undertook a scoping review to identify key concepts, strategies and gaps in evidence with respect to the provision of safe supply during pandemics and other emergencies. Methods We conducted three searches across Scopus, Medline, Embase, CINAHL, and The Cochrane Central Register of Controlled Trials (CENTRAL) for peer-reviewed and grey literature articles to understand barriers/facilitators to both accessing and prescribing legal, pharmaceutical-grade drugs, including opioids, benzodiazepines, and/or stimulants during public health emergencies from January 1 2002 to June 30 2020. We also included opioid agonist therapies (OAT) during emergency conditions. All potential sources underwent title/abstract screening and duplicate full- text review to determine eligibility for inclusion. Three reviewers extracted characteristics and barriers/facilitators to accessing or prescribing drugs for each study, and these were then inductively analyzed to identify common themes. Key stakeholders (PWUD, prescribers, and policymakers/regulators) informed the search strategy and validated findings and interpretations. Input from PWUD and prescribers was gathered through Advisory Committee meetings and one-on-one consultations, respectively. Results We screened 9,839 references and included 169 studies (135 peer-reviewed articles and 36 grey literature reports). From 119 articles, we identified 35 themes related to barriers/facilitators to prescribing safe supply or OAT. Few studies (n=24) focused on emergency or pandemic contexts. Among the most frequently reported barriers were restrictive laws or policies (n= 33; 28%). The most frequently cited facilitator was temporary legal or regulatory exemptions (n= 16; 13%). Further stakeholder consultation identified barriers/facilitators to safe supply absent in the reviewed literature: PWUD reported barriers including lack of access to desired substances, concerns about child apprehension, and a lack of cultural competency within safe supply/OAT programs; prescribers reported barriers including regional differences in service delivery, colleague support, and a lack of, or disagreement between, clinical guidance documents. Conclusion We identified multiple barriers and facilitators to accessing and/or prescribing safe supply or OAT. With few peer-reviewed studies on safe supply models, particularly in the context of emergencies, input from PWUD and other stakeholders offered crucial insights not reflected in the existing literature. To address the overdose epidemic stemming from the criminalization of an unregulated drug supply, prescribers, regulators, and public health authorities should focus on scaling up, and then evaluating, diverse safe supply frameworks that address the facilitators and barriers we have identified

In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds

Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of ivermectin and 14 related compounds, by which the infectivity and morbidity of the SARS-CoV-2 virus may be limited. Binding affinity computations were performed for these agents on several docking sites each for models of (1) the spike glycoprotein of the virus, (2) the CD147 receptor, which has been identified as a secondary attachment point for the virus, and (3) the alpha-7 nicotinic acetylcholine receptor (&alpha;7nAChr), an indicated point of viral penetration of neuronal tissue as well as an activation site for the cholinergic anti-inflammatory pathway controlled by the vagus nerve. Binding affinities were calculated for these multiple docking sites and binding modes of each compound. Our results indicate the high affinity of ivermectin, and even higher affinities for some of the other compounds evaluated, for all three of these molecular targets. These results suggest biological mechanisms by which ivermectin may limit the infectivity and morbidity of the SARS-CoV-2 virus and stimulate an &alpha;7nAChr-mediated anti-inflammatory pathway that could limit cytokine production by immune cells

Characterizing Men Who Have Sex with Men and Use Injection Drugs in Vancouver, Canada

We examined factors associated with reporting sex with men among men who inject drugs in Vancouver, Canada. Data were drawn from three open prospective cohorts of people who use drugs between 2005 and 2014. Generalized estimating equations were used to identify factors associated with reporting non-transactional sex with men (MSM) in the previous six months. Of 1663 men who used injection drugs, 225 (13.5%) were MSM over the study period. Sex with men was independently associated with younger age (Adjusted Odds Ratio [AOR]=0.96), childhood sexual abuse (AOR=2.65), sex work (AOR=3.33), crystal methamphetamine use (AOR=1.30), borrowing used syringes (AOR=1.39), inconsistent condom use (AOR=1.76), and HIV seropositivity (AOR=3.82). MSM were less likely to be Hepatitis C-positive (AOR=0.43) and to have accessed addiction treatment in the previous six months (AOR=0.83) (all p&lt;0.05). Findings highlight vulnerabilities and resiliencies among MSM-PWID and indicate a need for trauma-informed and affirming harm reduction and substance use treatment services for MSM-PWID

Beyond a Zero-Sum Game: How Does the Impact of COVID-19 Vary by Gender?

Epidemics and pandemics, like COVID-19, are not gender neutral. Much of the current work on gender, sex, and COVID-19, however, has seemed implicitly or explicitly to be attempting to demonstrate that either men or women have been hardest hit, treating differences between women and men as though it is not important to understand how each group is affected by the virus. This approach often leaves out the effect on gender and sexual minorities entirely. Believing that a more nuanced approach is needed now and for the future, we brought together a group of gender experts to answer the question: how are people of different genders impacted by COVID-19 and why? Individuals working in women's, men's, and LGBTQ health and wellbeing wrote sections to lay out the different ways that women, men, and gender and sexual minorities are affected by COVID-19. We demonstrate that there is not one group "most affected," but that many groups are affected, and we need to move beyond a zero-sum game and engage in ways to mutually identify and support marginalized groups