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Two studies published in Nature report the structure of apolipoprotein B100 on LDL using high-resolution, artificial intelligence-assisted cryo-electron microscopy and uncover its precise molecular interfaces with the LDL receptor. Dimers of LDL particles connected by a pair of receptors are also visualized for the first time. These studies provide key structural insights into the molecular defects linked to familial hypercholesterolaemia and open exciting avenues for translational research and drug development.

Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) induces the hepatic degradation of the low-density lipoprotein receptor ( LDLR ), thereby increasing the concentration of LDL-cholesterol in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9 , notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the effect of PCSK9 on the peripheral nervous system remains unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy, characterized by reduced thermal and mechanical pain sensations. PCSK9 -deficient mice also presented with skin structural changes, including a reduction in nociceptive Schwann cell number, axonal swelling of Remak fibers, and hypomyelination of small nerve fibers. Interestingly, the peripheral nerves of PCSK9 -deficient mice showed an upregulation of CD36 , a fatty acid transporter, which correlated with increased nerve lipid content, structural mitochondrial abnormalities, and acylcarnitine accumulation. Our findings demonstrate that PCSK9 plays a critical role in peripheral nerves by regulating lipid homeostasis and that its deficiency results in symptoms related to peripheral neuropathy.

Background The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up. Methods In the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110–125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman’s coefficients. Kaplan–Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models. Results During a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA 1c , and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p  = 0.010), apoF (1.22 [1.01; 1.48]; p  = 0.037), apoJ (1.24 [1.03; 1.49]; p  = 0.024), and apoL1 (1.26 [1.05; 1.52]; p  = 0.014) remained significantly associated with the onset of T2D. Kaplan–Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p  = 0.002) compared to the middle and upper thirds. Conclusions The plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations. Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509

Assessment criteria for septic transfusion reactions (STRs) are variable around the world. A scoping review will be carried out to find out, explore and map existing literature on STRs associated criteria. This scoping review will include indexed and grey literatures available in English or French language from January 1, 2000, to December 31, 2021. Literature search will be conducted using four electronic databases (i.e., MEDLINE via PubMed, Web of Science, Science Direct, and Embase via Ovid), and grey literatures accompanying the research questions and objectives. Based on the inclusion criteria, studies will be independently screened by two reviewers for title, abstract, and full text. Extracted data will be presented in tabular form followed by a narrative description of inputs corresponding to research objectives and questions.

ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr −/− mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

The focus on prevention strategies aimed at curbing the HIV epidemic is growing, and therefore screening for HIV has again taken centre stage. Our aim was to establish whether a convenient, non-invasive, HIV test that uses oral fluid was accurate by comparison with the same test with blood-based specimens. We did a systematic review and meta-analysis to compare the diagnostic accuracy of a rapid HIV-antibody-based point-of-care test (Oraquick advance rapid HIV-1/2, OraSure Technologies Inc, PA, USA) when used with oral versus blood-based specimens in adults. We searched five databases of published work and databases of five key HIV conferences. Studies we deemed eligible were those focused on adults at risk of HIV; we excluded studies in children, in co-infected populations, with self-reported inferior reference standards, and with incomplete reporting of key data items. We assessed the diagnostic accuracy of testing with oral and blood-based specimens with bivariate regression analysis. We computed positive predictive values (PPVs) in high-prevalence and low-prevalence settings with Bayesian methods. In a direct head-to-head comparison of studies, we identified a pooled sensitivity about 2% lower in oral (98·03%, 95% CI 95·85–99·08) than in blood-based specimens (99·68%, 97·31–99·96), but similar specificity (oral 99·74%, 99·47–99·88; blood 99·91%, 99·84–99·95). Negative likelihood ratios were small and similar (oral 0·019, 0.009–0·040; blood 0·003, 0·001–0·034), but positive likelihood ratios differed (oral 383·37, 183·87–799·31; blood 1105·16, 633·14–2004·37). Although in high-prevalence settings PPVs were similar (oral 98·65%, 95% credible interval 85·71–99·94; blood 98·50, 93·10–99·79), in low-prevalence settings PPVs were lower for oral (88·55%, 77·31–95·87) than blood (97·65%, 95·48–99·09) specimens. Although Oraquick had a high PPV in high-prevelence settings in oral specimens, the slightly lower sensitivity and PPV in low-prevalence settings in oral specimens should be carefully reviewed when planning worldwide expanded initiatives with this popular test. Canadian Institutes for Health Research (CIHR KRS 102067).

New HIV infections occur annually in Canada, highlighting the need for pre- and postexposure prophylaxis (PrEP and PEP). Through the Canadian Institutes of Health Research (CIHR) Pan-Canadian Network for HIV/AIDS and STBBI (sexually transmitted and blood-borne infections) Clinical Trials Research, we have updated the 2017 guideline on clinical indications and drug regimens for PrEP and PEP in Canada. Drawing on meetings with community-based organizations representing key populations affected by HIV in Canada, along with evidence from 3 systematic reviews on PrEP, PEP, and HIV risk assessment tools (searches to June 2024), our diverse panel of 19 experts formulated recommendations on PrEP and PEP. We used a formal evidence-to-decision-making framework and the Grading of Recommendations, Assessment, Development, and Evaluation system. We followed the Guidelines International Network principles for managing competing interests. Our guideline development and reporting adhere with Appraisal of Guidelines for Research and Evaluation II. This guideline contains 31 recommendations and 10 good practice statements. Although it is appropriate to prescribe PrEP to adults and adolescents who request it, clinicians are also encouraged to assess HIV risk during routine health visits to identify people who would benefit from PrEP. Clinicians should elicit information about patients’ anatomy and sexual partners in a culturally sensitive and affirming manner to determine which PrEP regimens — daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), on-demand TDF/FTC, daily oral tenofovir alafenamide/emtricitabine, or long-acting injectable cabotegravir — are suitable options. When assessing whether PEP is needed, clinicians should consider the likelihood that the source person has transmissible HIV, as well as the biological risk of HIV transmission based on exposure type. Preferred PEP regimens are dolutegravir plus TDF/FTC, or bictegravir/tenofovir alafenamide/emtricitabine. Multiple safe, effective PrEP and PEP regimens are now available in Canada, making it increasingly possible to find suitable options for all who could benefit. Implementation of this guideline should expand access to biomedical HIV prevention interventions for those at risk and decrease the incidence of HIV in Canada.

Background Men who have sex with men (MSM) are not eligible to donate blood or plasma in Canada if they have had sex with another man in the last 3 months. This time-based deferment has reduced since 2013; from an initial lifetime ban, to five-years, one-year, and now three-months. Our previous research revealed that gay, bisexual, queer, and other MSM (GBM) supported making blood donation policies gender-neutral and behaviour-based. In this analysis, we explored the willingness of Canadian GBM to donate plasma, even if they were not eligible to donate blood. Methods We conducted in-depth interviews with 39 HIV-negative GBM in Vancouver ( n  = 15), Toronto ( n  = 13), and Montreal ( n  = 11), recruited from a large respondent-driven sampling study called Engage. Men received some basic information on plasma donation prior to answering questions. Transcripts were coded in NVivo following inductive thematic analysis. Results Many GBM expressed a general willingness to donate plasma if they became eligible; like with whole blood donation, GBM conveyed a strong desire to help others in need. However, this willingness was complicated by the fact that most participants had limited knowledge of plasma donation and were unsure of its medical importance. Participants’ perspectives on a policy that enabled MSM to donate plasma varied, with some viewing this change as a “stepping stone” to a reformed blood donation policy and others regarding it as insufficient and constructing GBM as “second-class” donors. When discussing plasma, many men reflected on the legacy of blood donor policy-related discrimination. Our data reveal a significant plasma policy disjuncture— a gulf between the critical importance of plasma donation from the perspective of Canada’s blood operators and patients and the feelings of many GBM who understood this form of donation as less important. Conclusions Plasma donor policies must be considered in relation to MSM blood donation policies to understand how donor eligibility practices are made meaningful by GBM in the context of historical disenfranchisement. Successful establishment of a MSM plasma donor policy will require extensive education, explicit communication of how this new policy contributes to continued/stepwise reform of blood donor policies, and considerable reconciliation with diverse GBM communities.

Background The secondary impacts of the COVID-19 pandemic may disproportionately affect gay, bisexual, and other men who have sex with men (GBM), particularly related to HIV prevention and treatment outcomes. We applied syndemic theory to examine PrEP disruptions during the during the height of the COVID-19 pandemic in Vancouver, Canada. Methods Sexually-active GBM, aged 16 + years, were enrolled through respondent-driven sampling (RDS) from February 2017 to August 2019. Participants completed a Computer-Assisted Self-Interview every six months and data were linked to the BC PrEP Program (program responsible for publicly funded PrEP in the province) to directly measure PrEP disruptions. The analysis period for this study was from March 2018-April 2021. We used univariable generalized linear mixed models to examine (1) six-month trends for syndemic conditions: the prevalence of moderate/severe depressive or anxiety symptoms, polysubstance use, harmful alcohol consumption, intimate partner violence, and (2) six-month trends for PrEP interruptions among HIV-negative/unknown GBM. We also applied 3-level mixed-effects logistic regression with RDS clustering to examine whether syndemic factors were associated with PrEP interruptions. Results Our study included 766 participants, with 593 participants who had at least one follow-up visit. The proportion of respondents with abnormal depressive symptoms increased over the study period (OR = 1.35; 95%CI = 1.17, 1.56), but we found decreased prevalence for polysubstance use (OR = 0.89; 95%CI = 0.82, 0.97) and binge drinking (OR = 0.74; 95%CI = 0.67, 0.81). We also found an increase in PrEP interruptions (OR = 2.33; 95%CI = 1.85, 2.94). GBM with moderate/severe depressive symptoms had higher odds (aOR = 4.80; 95%CI = 1.43, 16.16) of PrEP interruptions, while GBM with experiences of IPV had lower odds (aOR = 0.38; 95%CI = 0.15, 0.95) of PrEP interruptions. GBM who met clinical eligibility for PrEP had lower odds of experiencing PrEP interruptions (aOR = 0.25; 95%CI = 0.11, 0.60). Conclusion There were increasing PrEP interruptions since March 2020. However, those most at risk for HIV were less likely to have interruptions. Additional mental health services and targeted follow-up for PrEP continuation may help to mitigate the impacts of the COVID-19 pandemic on GBM.

Background Gay, bisexual, and other men who have sex with men (gbMSM) experience disproportionate risks of HIV acquisition and transmission. In 2017, Montréal became the first Canadian Fast-Track City, setting the 2030 goal of zero new HIV infections. To inform local elimination efforts, we estimate the evolving role of prevention and sexual behaviours on HIV transmission dynamics among gbMSM in Montréal between 1975 and 2019. Methods Data from local bio-behavioural surveys were analyzed to develop, parameterize, and calibrate an agent-based model of sexual HIV transmission. Partnership dynamics, HIV’s natural history, and treatment and prevention strategies were considered. The model simulations were analyzed to estimate the fraction of HIV acquisitions and transmissions attributable to specific groups, with a focus on age, sexual partnering level, and gaps in the HIV care-continuum. Results The model-estimated HIV incidence peaked in 1985 (2.3 per 100 person years (PY); 90% CrI: 1.4–2.9 per 100 PY) and decreased to 0.1 per 100 PY (90% CrI: 0.04–0.3 per 100 PY) in 2019. Between 2000–2017, the majority of HIV acquisitions and transmissions occurred among men aged 25–44 years, and men aged 35–44 thereafter. The unmet prevention needs of men with > 10 annual anal sex partners contributed 90–93% of transmissions and 67–73% of acquisitions annually. The primary stage of HIV played an increasing role over time, contributing to 11–22% of annual transmissions over 2000–2019. In 2019, approximately 70% of transmission events occurred from men who had discontinued, or never initiated antiretroviral therapy. Conclusions The evolving HIV landscape has contributed to the declining HIV incidence among gbMSM in Montréal. The shifting dynamics identified in this study highlight the need for continued population-level surveillance to identify gaps in the HIV care continuum and core groups on which to prioritize elimination efforts.