Combination anti-HIV antibodies provide sustained virological suppression.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

Immunologic and Virologic Parameters Associated With Human Immunodeficiency Virus (HIV) DNA Reservoir Size in People With HIV Receiving Antiretroviral Therapy.

BACKGROUND: A better understanding of the dynamics of human immunodeficiency virus (HIV) reservoirs in CD4+ T cells of people with HIV (PWH) receiving antiretroviral therapy (ART) is crucial for developing therapies to eradicate the virus. METHODS: We conducted a study involving 28 aviremic PWH receiving ART with high and low levels of HIV DNA. We analyzed immunologic and virologic parameters and their association with the HIV reservoir size. RESULTS: The frequency of CD4+ T cells carrying HIV DNA was associated with higher pre-ART plasma viremia, lower pre-ART CD4+ T-cell counts, and lower pre-ART CD4/CD8 ratios. During ART, the High group maintained elevated levels of intact HIV proviral DNA, cell-associated HIV RNA, and inducible virion-associated HIV RNA. HIV sequence analysis showed no evidence for preferential accumulation of defective proviruses nor higher frequencies of clonal expansion in the High versus Low group. Phenotypic and functional T-cell analyses did not show enhanced immune-mediated virologic control in the Low versus High group. Of considerable interest, pre-ART innate immunity was significantly higher in the Low versus High group. CONCLUSIONS: Our data suggest that innate immunity at the time of ART initiation may play an important role in modulating the dynamics and persistence of viral reservoirs in PWH.

Impact of Monkeypox Virus Infection on Immune Parameters in a Woman With Human Immunodeficiency Virus Receiving Clinically Effective Antiretroviral Therapy.

We describe the immunologic and virologic impact of monkeypox (mpox) infection in a woman with human immunodeficiency virus (HIV) whose plasma HIV viremia was suppressed by clinically effective antiretroviral therapy. Extensive phenotypic analyses of B and T cells in peripheral blood and biomarkers in plasma showed significant immunologic perturbations despite the presence of mild mpox disease. Dramatic shifts were noted in the frequencies of total B cells, plasmablasts, and plasmablast immunoglobulin isotypes. Flow cytometric analyses showed a dramatic increase in the frequency of CD38+HLA-DR+ CD8+ T cells after mpox infection. Our data offer guidance for future studies involving mpox infection in affected populations.

A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings.

BACKGROUND: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls. DESIGN: Cohort study. (ClinicalTrials.gov: NCT04411147). SETTING: National Institutes of Health Clinical Center, Bethesda, Maryland. PARTICIPANTS: Self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of PASC. A control group comprised persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, recruited regardless of their current health status. Both groups were enrolled over the same period and from the same geographic area. MEASUREMENTS: All participants had the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. A subset also underwent exploratory immunologic and virologic evaluations. RESULTS: 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. LIMITATIONS: Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment. CONCLUSION: A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19. PRIMARY FUNDING SOURCE: Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone.

LESSONS LEARNED: Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. BACKGROUND: We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone. METHODS: This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3+3 design. RESULTS: Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. CONCLUSION: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.

Carotid intima-medial thickness in patients with severe hypertriglyceridemia.

Background and aims: Severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) concentration > 10 mmol/L, is relatively uncommon, and its implications for atherosclerotic cardiovascular disease (ASCVD) risk remain somewhat unclear. We evaluated the association between severe HTG and carotid intima-media thickness (IMT), a marker for ASCVD. Methods: We studied three clinical cohorts: 88 patients with severe HTG (mean TG level 20.6 mmol/L), 271 patients with familial hypercholesterolemia (FH) as a contrast group, and 70 normolipidemic controls. Carotid IMT was measured using standardized ultrasound imaging. Statistical analysis was conducted using one-way analysis of variance (ANOVA) to compare mean IMT values, analysis of covariance (ANCOVA) to adjust for confounding variables, specifically age and sex, as well as Spearman pairwise correlation analysis between variables. Results: Unadjusted mean carotid IMT was greater in severe HTG and FH groups compared to controls, however, this was no longer significant for severe HTG after adjustment for age and sex. In contrast, adjusted carotid IMT remained significantly different between the FH and control groups. Conclusions: Our findings suggest that extreme TG elevations in severe HTG patients are not significantly associated with carotid IMT, in contrast to the increased IMT seen in FH patients. These findings add perspective to the complex relationship between severe HTG and ASCVD risk.

Ex vivo sensitivity to broadly neutralizing antibodies and anti-CD4 antibody UB-421 of infectious viral isolates from people living with multidrug-resistant HIV.

BACKGROUND: People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking. METHODS: We examined levels of immune activation and exhaustion markers on CD8+ T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay. FINDINGS: The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38+/HLA-DR+ (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421. INTERPRETATION: Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials. FUNDING: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Investigating the Market Value of Brumbies (Equus caballus) in the Australian Riding Horse Market.

Feral horses, also known as brumbies, are widely distributed across Australia with some populations being managed largely by human intervention. Rehoming of suitable feral horses following passive trapping has wide community acceptance as a management tool. However, there is little information about the number and relative economic value of feral horses compared with cohorts in the riding horse market. We examined 15,404 advertisements of horses for sale in 53 editions of Horse Deals, published from February 2017 to July 2022. Despite the considerable media attention and public scrutiny surrounding feral horse management, rehomed feral horses represented only a tiny fraction of the horse market in the current study. Of the 15,404 advertisements examined, only 128 (0.0083%) were for feral horses. We recorded phrases used to describe behavioural characteristics and other variables. The following variables were found to be not independent: Ridden Status, Height, Age, Sex, Colour, and Warning terms/more work. Using descriptive statistics to describe basic features of the data, the average price for feral horses ($1408) was lower than that for domestic horses ($1790) with the maximum price for a domestic horse being nearly twice the maximum for a feral horse. Univariate analysis showed feral horses were over-represented among "Unbroken" horses and underrepresented among "Ridden", "Broodmare" and "Harness" horses compared with domestic bred horses (p < 0.001). Feral horses appeared over-represented at shorter heights, among younger age groups (3 years or younger and 3.1 to 6 years) (p < 0.001) and in the dilute colour category (p = 0.008). The multivariable mixed model on price revealed that for domestic horses, the highest estimated marginal mean price averaged across the colour categories was for ridden horses aged 6.1-10-year-old at $1657.04 (95% CI $1320.56-$2074.66). In contrast, for feral horses, the multivariable mixed model demonstrated the similar highest estimated marginal mean averaged was for green broken 3-6-year-old horses that have undergone foundation training under saddle at $2526.97 (95% CI $1505.63-$4208.27). Australian feral horses were valued differently tfromsimilar domestic horses in the recreational riding horse market and further research is warranted to determine appropriate target markets and boost the sustainability of rehoming as a feral horse management tool.

In Situ Provisioning Wildlife with Food, Water, or Shelter after Bushfires: Using a One Welfare Framework to Guide Responses.

Australia's 2019-2020 bushfires had a devastating impact on animals, humans, and ecosystems. They also demonstrated the lack of evidence or guidance for wildlife provisioning in response to severe fire events when volunteers and wildlife organisations rose to respond. In addition, the unprecedented scale and intensity of the fires and an absence of institutional support for wildlife provisioning meant that well-intentioned interventions were largely uncoordinated and lacked clear short-term, mid-term, and long-term objectives. Fundamentally, a lack of consensus was revealed on whether any such interventions are advisable. Given the strong evidence indicating that future bushfire seasons will become longer and more intense in Australia and elsewhere, the welfare and survival of millions of wild animals are at risk every year. Understanding the impacts of supplementary resource interventions and contributing to the development of best practice information is crucial to inform the response to the next major fire event. Here, we contextualize the arguments for and against provisioning within a 'One Welfare' framework that recognizes that animal welfare, biodiversity, and the environment are intertwined with human welfare and community resilience. We propose that the One Welfare approach can facilitate appropriate consideration of the extant scientific and lay literature; local legislation; views of stakeholders; emerging data; and modelling from historic fire events. As a further step, we see merit in engaging with wildlife provisioners and the broader conservation community to build an evidence base for future wildlife provisioning activities. From an informed position, we can encourage beneficial interventions and reduce the risk of negative outcomes. Finally, we propose controlled experiments (e.g., using hazard reduction burns), ongoing data collection using emergent technology, and longitudinal analysis to address shifting research priorities as the climate changes. We conclude that the ordered collection of the necessary evidence relevant to each of the three stakeholder groups in the One Welfare framework has the greatest potential to support an informed policy platform on wildlife provisioning across Australia that is feasible, legal, and sustainable.

Spatial and Temporal Movements of Free-Roaming Cats and Wildlife in Two Local Government Areas in Greater Sydney, Australia.

Free-roaming cats pose a risk to their own health and welfare, as well as to the health and welfare of wildlife and humans. This study aimed to monitor and quantify area-specific free-roaming cat movement. Two local government areas (LGAs) in Greater Sydney were included, Campbelltown (CT) and the Blue Mountains (BM). Motion-capture cameras were installed on 100 volunteer properties (50 per LGA) to indirectly capture animal movements over two months. Transect drives were completed eight times (four per LGA) to directly observe roaming cats in residential areas. The cameras and transects both identified higher free-roaming cat numbers in CT (density of 0.31 cats per ha, resulting in an estimated abundance of 361 cats in the 1604 ha of residential area) than the BM (density of 0.21 cats per ha, resulting in an estimated abundance of 3365 cats in the 10,000 ha of residential area). More wildlife events were captured in the BM (total = 5580) than CT (total = 2697). However, there was no significant difference between CT and the BM for cat events (p = 0.11) or wildlife events (p = 0.32) observed via the cameras. Temporally, cats were observed via the cameras throughout the entire day with peaks at 9:30 am and 8:00 pm in the BM, and 7:00 am and 12:00 pm in CT. Overlaps in activity times were recorded for free-roaming cats with bandicoots (BM), possums (BM), and small mammals (BM and CT). This study demonstrates that camera monitoring on private property and transect drives are useful methods to quantify free-roaming cat abundance to inform cat management interventions.

An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.

OBJECTIVE: Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. METHODS AND RESULTS: First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. CONCLUSIONS: HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.

Treatment of Homozygous Familial Hypercholesterolemia With Evinacumab.

Patients with homozygous familial hypercholesterolemia (HoFH) have extremely elevated levels of low-density lipoprotein cholesterol (LDL-C), with premature atherosclerosis and aortic valve disease. Available drug treatments are inadequate, and even with serial apheresis, HoFH patients rarely achieve acceptable LDL-C levels. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 that lowers LDL-C via a novel receptor-independent mechanism. We describe an Ontario patient with HoFH who for 17 months has been treated with monthly infusions of evinacumab added to pre-existing statin, ezetimibe, and evolocumab therapy. Evinacumab in this HoFH patient was associated with markedly improved LDL-C levels and decreased frequency of apheresis.

Les patients atteints d'hypercholestérolémie familiale homozygote (HFH) présentent des taux extrêmement élevés de cholestérol à li-poprotéines de faible densité (C-LDL) avec une athérosclérose prématurée et une valvulopathie aortique. Les traitements médicamenteux disponibles sont inadéquats et, même avec un traitement par aphérèses en série, on obtient rarement des taux acceptables de C-LDL chez les patients atteints d'HFH. L'évinacumab, un anticorps monoclonal dirigé contre la protéine 3 de type angiopoïétine, réduit le taux de C-LDL par un nouveau mécanisme indépendant du récepteur. Nous décrivons le cas d'un patient ontarien atteint d'HFH traité par l'évinacumab pendant 17 mois à raison d'une perfusion mensuelle administrée en complément d'un traitement préexistant par une statine, l'ézétimibe et l'évolocumab. L'évinacumab a été associé chez ce patient à une amélioration marquée des taux de C-LDL et à une diminution de la fréquence des aphérèses.

Ethical Treatment of Invasive and Native Fauna in Australia: Perspectives through the One Welfare Lens.

The One Welfare concept is proposed to guide humans in the ethical treatment of non-human animals, each other and the environment. One Welfare was conceptualized for veterinarians but could be a foundational concept through which to promote the ethical treatment of animals that are outside of direct human care and responsibility. However, wild-living animals raise additional ethical conundrums because of their multifarious values and roles, and relationships that humans have with them. At an open facilitated forum, the 2018 Robert Dixon Memorial Animal Welfare Symposium, a panel of five experts from different fields shared their perspectives on "loving and hating animals in the wild" and responded to unscripted questions from the audience. The Symposium's objectives were to elucidate views on the ethical treatment of the native and invasive animals of Australia and to identify some of the resultant dilemmas facing conservationists, educators, veterinarians and society. Here, we document the presented views and case studies and synthesize common themes in a One Welfare framework. Additionally, we identified points of contention that can guide further discourse. With this guide in place, the identification and discussion of those disparate views was a first step toward practical resolutions on how to manage wild-living Australian fauna ethically. We concluded that there was great utility in the One Welfare approach for any discourse about wild animal welfare. It requires attention to each element of the triple bottom line and ensures that advocacy for one party does not vanquish the voices from other sectors. We argue that, by facilitating a focus on the ecology in the context of wild animal issues, One Welfare is more useful in this context than the veterinary context for which it was originally developed.

Effect of aging on immune cells in male HIV-infected and -uninfected healthy individuals.

OBJECTIVE: HIV induces immunologic dysfunction in T cells of infected individuals. However, the impact of aging on T cell phenotypes in HIV-infected individuals receiving antiretroviral therapy (ART) has not been fully delineated. We evaluated the relationship between aging and the expression of immune activation and exhaustion markers on CD8 + T cells of age-matched HIV-infected and -uninfected male participants. DESIGN: Levels of immune activation and exhaustion markers on peripheral blood CD8 + T cells of HIV-infected and -uninfected participants were examined. METHODS: 110 HIV-infected aviremic male participants receiving ART and 146 HIV-uninfected male participants were studied. The levels of TIGIT, PD-1, CD38, and CD226 on CD8 + T cells of the study participants were determined by flow cytometry. RESULTS: The level of TIGIT on CD8 + T cells was higher in aviremic HIV-infected compared to uninfected participants ( P  < 0.0001). In contrast, no significant differences were found in the levels of PD-1 and CD38 on CD8 + T cells between the two groups. Statistically significant correlations were observed between age and the levels of TIGIT + and CD38 + CD8 + T cells in both groups; however, no correlation was found between age and the level of PD-1 + CD8 + T cells in HIV-infected participants. Age-stratification of HIV-infected and -uninfected groups did not show any significant differences in the level of PD-1 expression on CD8 + T cells. CONCLUSIONS: The findings of our study highlight the role of aging in the expression of immune markers on CD8 + T cells and have important implications for therapies that target immune checkpoints in HIV-infected individuals.

Effect of Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Booster on Human Immunodeficiency Virus Reservoirs and Immune Markers.

We investigated effects of the severe acute respiratory syndrome coronavirus 2 (SARV-CoV-2) booster vaccination on human immunodeficiency virus (HIV) reservoir size, immune markers, and host immune responses in people with HIV receiving antiretroviral therapy. Our data suggest that the SARS-CoV-2 booster vaccine is not likely to replenish the persistent HIV reservoir nor provide an immunologic environment to facilitate active HIV expression/replication.

Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry.

BACKGROUND: Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. METHODS: A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. RESULTS: There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2 = 2.3%; P = 0.0001). CONCLUSION: The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.

A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia.

Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism--'hyperlipoproteinemia' (HLP)--it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie--to an apparently even greater degree--susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples.

Causal Loop Analysis Can Identify Solutions to Complex Dog Management Problems in Remote Australian Aboriginal Communities.

Companion animal management in Australian remote Aboriginal communities (rAcs) is a complex problem with multiple stakeholders involved, with differing needs, knowledge, power and resources. The Comm4Unity (Cycle of Multiple Methods for Unity-For Community) approach was designed to address such problems. This study represents the second step of the Comm4Unity framework, where a causal loop analysis (CLA) was adapted and tested as a tool to address the issue of dog overpopulation in Wurrumiyanga, and in particular the systemic causes of the problem and necessary transformational management solutions. Ten focus group discussions (FGDs) were held amongst three of the four stakeholder groups identified during the first step in the analysis. The CLA identified 13 positive feedback loops, which drive vicious cycles and perpetuate the dog overpopulation issue. All three groups agreed and developed 22 solutions to address the causes of dog overpopulation. Despite the differences in the framings of the three groups, "training" and "education" were both the top priority solutions for all three groups. The majority of the solutions discussed by the groups were not only transformational but also social, requiring collaboration. This study was successful in so far as transformational actions were co-developed by all FGDs, which may have also built capacity and agency amongst the local community to implement them as a cohesive group.

Frame Analysis: An Inclusive Stakeholder Analysis Tool for Companion Animal Management in Remote Aboriginal Communities.

Companion animal management in Australian remote Aboriginal communities (rAcs) is a complex problem, with multiple stakeholders involved with differing needs, knowledge, power and resources. We present our CoMM4Unity approach, a participatory systemic action research process designed to address such problems. In the first step, frame analysis is used to analyse stakeholders' perspectives, knowledge types and power dynamics to determine their relative roles in animal management. Twenty individuals were interviewed from stakeholder groups involved in animal management in the remote, island rAc of Wurrumiyanga, Tiwi Islands. Frame analysis indicated that stakeholders aligned into four groups with distinct identity frames, knowledge types and power frames: Indigenous Locals, Indigenous Rangers, Non-Indigenous Locals and Animal Managers. All four groups shared overlapping perceptions about companion animals in Wurrumiyanga, and agreed that dog overpopulation was the primary issue. However, the groups differed in their strength of opinions about how dogs should be managed. Therefore, the situation is not one of diametrically opposing frames but more a misalignment of goals and values. Our application showed that frame analysis can reveal subtle variations in stakeholder groups' identities, goals and values, and hence how they prioritise management measures.