Abstract
The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the ...heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-
pol
and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients’ hurdle towards a cure.
Abstract
Aims
We report the collective European experience of percutaneous left atrial appendage (LAA) suture ligation using the recent generation LARIAT+ suture delivery device.
Methods and results
...A total of 141 patients with non-valvular atrial fibrillation and contraindication to oral anticoagulation (OAC), thrombo-embolic events despite OAC or electrical LAA isolation were enrolled at seven European hospitals to undergo LAA ligation. Patients were followed up by clinical visits and transoesophageal echocardiography (TOE) following LAA closure. Left atrial appendage ligation was completed in 138/141 patients (97.8%). Three patients did not undergo attempted deployment of the LARIAT device due to pericardial adhesion after previous epicardial ventricular tachycardia ablation (n = 1), a pericardial access-related complication (n = 1), and multiple posterior LAA lobes (n = 1). Serious 30-day procedural adverse events occurred in 4/141 patients (2.8%). There were two device-related LAA perforations (1.4%) not resulting in any corrective intervention as the LAA was completely sealed with the LARIAT. Minor adverse events occurred in 19 patients (13.5%), including two pericardial effusions due to procedure-related pericarditis requiring pericardiocentesis. Transoesophageal echocardiography was performed after LAA ligation in 103/138 patients (74.6%) after a mean of 181 ± 72 days. Complete LAA closure was documented in 100 patients (97.1%). Two patients (1.8% of patients with follow-up) experienced a transient ischaemic attack at 4 and 7 months follow-up, although there was no leak observed with TOE. There were two deaths during long-term follow-up which were both not device related.
Conclusion
Initial experience with the LARIAT+ device demonstrates feasibility of LAA exclusion. Further larger prospective studies with longer follow-up are warranted.
Abstract Introduction rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of ...haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII. Materials and Methods Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate® ) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl3 -induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200–250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice. Results rVIII-SingleChain displayed a high affinity for von Willebrand factor (KD = 44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl3 -induced arterial occlusion model. Conclusions rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.
Background. Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants (MVs) are present in some antiretroviral therapy (ART)-naive patients. They may result from de novo ...mutagenesis or transmission. To date, the latter has not been proven. Methods. MVs were quantified by allele-specific polymerase chain reaction in 204 acute or recent seroconverters from the Zurich Primary HIV Infection study and 382 ART-naive, chronically infected patients. Phylogenetic analyses identified transmission clusters. Results. Three lines of evidence were observed in support of transmission of MVs. First, potential transmitters were identified for 12 of 16 acute or recent seroconverters harboring M184V MVs. These variants were also detected in plasma and/or peripheral blood mononudear cells at the estimated time of transmission in 3 of 4 potential transmitters who experienced virological failure accompanied by the selection of the M184V mutation before transmission. Second, prevalence between MVs harboring the frequent mutation M184V and the particularly uncommon integrase mutation N155H differed highly significantly in acute or recent seroconverters (8.2% vs 0.5%; P < .001). Third, the prevalence of less-fit M184V MVs is significantly higher in acutely or recently than in chronically HIV-1-infected patients (8.2% vs 2.5%; P = .004). Conclusions. Drug-resistant HIV-1 MVs can be transmitted. To what extent the origin—transmission vs sporadic appearance—of these variants determines their impact on ART needs to be further explored.
...within this category, Li et al. in “Effects of cholinergic neuromodulation on thalamocortical rhythms during NREM sleep: a model study,” study a new model of the thalamo-cortical network with ...cholinergic modulation that exhibits the hallmarks of NREM sleep and allows formulating hypotheses for the role of this important neuromodulator in generating these hallmarks. ...Ludl and Soriano, in “Impact of physical obstacles on the structural and effective connectivity of in silico neuronal circuits,” take us all the way to cultured brain circuits and find that in their simulations physical obstacles placed into the path of neurons growing on silicon substrates lead to the formation of local effective microcircuits. Thomas Nowotny1*, Sacha J. van Albada2,3, Jean-Marc Fellous4, Julie S. Haas5, Renaud B. Jolivet6, Christoph Metzner7,8,9 and Tatyana Sharpee10,11 * 1School of Engineering and Informatics, University of Sussex, Brighton, United Kingdom * 2Jülich Research Centre, Institute of Neuroscience and Medicine (INM-6) and Institute for Advanced Simulation (IAS-6) and JARA-Institute Brain Structure-Function Relationships (INM-10), Jülich, Germany * 3Department of Biology, Faculty of Mathematics and Natural Sciences, Institute of Zoology, University of Cologne, Cologne, Germany * 4Departments of Psychology and Biomedical Engineering, University of Arizona, Tucson, AZ, United States * 5Department of Biological Sciences, Lehigh University, Bethlehem, PA, United States * 6Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands * 7Department of Electrical Engineering and Computer Science, Institute of Software Engineering and Theoretical Computer Science, Technische Universität Berlin, Berlin, Germany * 8Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany * 9School of Physics, Engineering and Computer Science, University of Hertfordshire, Hatfield, United Kingdom * 10Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, United States * 11Department of Physics, University of California, San Diego, La Jolla, CA, United States
Perioperative visual loss, a rare but dreaded complication of spinal fusion surgery, is most commonly caused by ischemic optic neuropathy (ION). The authors sought to determine risk factors for ION ...in this setting.
Using a multicenter case-control design, the authors compared 80 adult patients with ION from the American Society of Anesthesiologists Postoperative Visual Loss Registry with 315 adult control subjects without ION after spinal fusion surgery, randomly selected from 17 institutions, and matched by year of surgery. Preexisting medical conditions and perioperative factors were compared between patients and control subjects using stepwise multivariate analysis to assess factors that might predict ION.
After multivariate analysis, risk factors for ION after spinal fusion surgery included male sex (odds ratio OR 2.53, 95% CI 1.35-4.91, P = 0.005), obesity (OR 2.83, 95% CI 1.52-5.39, P = 0.001), Wilson frame use (OR 4.30, 95% CI 2.13-8.75, P < 0.001), anesthesia duration (OR per 1 h = 1.39, 95% CI 1.22-1.58, P < 0.001), estimated blood loss (OR per 1 l = 1.34, 95% CI 1.13-1.61, P = 0.001), and colloid as percent of nonblood replacement (OR per 5% = 0.67, 95% CI 0.52-0.82, P < 0.001). After cross-validation, area under the curve = 0.85, sensitivity = 0.79, and specificity = 0.82.
This is the first study to assess ION risk factors in a large, multicenter case-control fashion with detailed perioperative data. Obesity, male sex, Wilson frame use, longer anesthetic duration, greater estimated blood loss, and decreased percent colloid administration were significantly and independently associated with ION after spinal fusion surgery.
BACKGROUND:The primary hurdle for the eradication of HIV-1 is the establishment of a latent viral reservoir early after primary infection. Here, we investigated the potential influence of human ...genetic variation on the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment.
SETTING:Genome-wide association study and exome sequencing study to look for host genetic determinants of HIV-1 reservoir measurements in patients enrolled in the Swiss HIV Cohort Study, a nation-wide prospective observational study.
METHODS:We measured total HIV-1 DNA in peripheral blood mononuclear cells from study participants, as a proxy for the reservoir size at 3 time points over a median of 5.4 years, and searched for associations between human genetic variation and 2 phenotypic readoutsthe reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants.
RESULTS:Genome-wide and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive antiretroviral treatment.
CONCLUSIONS:Our results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.
Abstract Background Mortality among people with human immunodeficiency virus (HIV) declined with the introduction of combination antiretroviral therapy. We investigated trends in mortality in people ...with HIV from 1999 through 2020. Methods Data were collected from the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort between January 1999 through January 2015 and the International Cohort Consortium of Infectious Disease (RESPOND) from October 2017 through December 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV, were calculated. Poisson models were used to assess mortality over time. Results Among 55 716 participants followed for median 6 years (interquartile range, 3–11), 5263 died (mortality rate MR, 13.7/1000 person-years of follow-up PYFU; 95% confidence interval CI, 13.4–14.1). Changing mortality was observed: AIDS mortality was most common between 1999–2009 (n = 952; MR, 4.2/1000 PYFU; 95% CI, 4.0–4.5) and non-AIDS–defining malignancy (NADM) between 2010–2020 (n = 444; MR, 2.8/1000 PYFU; 95% CI, 2.5–3.1). In multivariable analysis, all-cause mortality declined (adjusted mortality rate ratio aMRR, 0.97 per year; 95% CI, .96–.98), mostly 1999–2010 (aMRR, 0.96 per year; 95% CI, .95–.97) but was stable 2011–2020 (aMRR, 1.00 per year; 95% CI, .96–1.05). Mortality due to all known causes except NADM also declined. Conclusions Mortality among people with HIV in the D:A:D and/or RESPOND cohorts declined between 1999–2009 and was stable over the period 2010–2020. This decline in mortality was not fully explained by improvements in immunologic–virologic status or other risk factors.
Efficient antiretroviral therapy (ART) of HIV-1 infection reduces the viral load to undetectable levels and restores the immune system. However, therapy failure appears in a substantial fraction of ...patients and is mostly associated with the appearance of drug-resistant viruses. It is still not clear when the drug pressure leads to the earliest selection and appearance of drug-resistant HIV-1 populations. In this study, we wanted to determine whether drug-resistant viruses are already selected during viral decline within the first months of ART.
Fifteen mostly chronically HIV-1 infected patients were included. None had received ART prior to this study. The selection of three key resistance mutations, L90M (protease), K103N and M184V (reverse transcriptase), were measured by allele-specific real-time PCR allowing us to track minority quasispecies with a discriminative power of 0.01-0.2%.
Drug-resistant HIV-1 variants were found in 7/15 patients (46.7%) prior to ART. Rapid selection of drug resistance was detected in six patients (40%) independent of the presence of drug-resistant HIV-1 prior to ART. The risk for the selection of drug resistant viruses was correlated with the time until viral load became undetectable (P = 0.02). Besides the proportional increment of drug-resistant viruses, we observed in two patients a quantitative increase of this virus population while the total viral load decreased.
Drug-resistant viruses can be selected and replicate even in the first weeks of suppressive ART, thus, intensification of ART during the initial treatment period should be considered and further evaluated in clinical studies.
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