Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors

In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications

Impaired platelet aggregation and rebalanced hemostasis in patients with chronic hepatitis C virus infection

Increased risk of both cardiovascular disease (CVD) and bleeding has been found in patients with chronic hepatitis C (CHC) infection, and a re-balanced hemostasis has been proposed. The aim of this study was to investigate functional whole blood coagulation and platelet function in CHC infection. The prospective study included 82 patients with CHC infection (39 with advanced liver fibrosis and 43 with no or mild liver fibrosis) and 39 healthy controls. A total of 33 patients were treated for CHC infection and achieved sustained virological response (SVR). Baseline and post-treatment blood samples were collected. Hemostasis was assessed by both standard coagulation tests and functional whole blood hemostatic assays (thromboelastograhy (TEG), and platelet aggregation (Multiplate). Patients with CHC and advanced fibrosis had impaired platelet aggregation both compared to patients with no or mild fibrosis and to healthy controls. Patients with CHC and advanced fibrosis also had lower antithrombin, platelet count, and coagulation factors II-VII-X compared to healthy controls. In contrast, TEG did not differ between groups. In treated patients achieving SVR, post-treatment platelet count was higher than pre-treatment counts (p = 0.033) and ADPtest, ASPItest, and RISTOhightest all increased post treatment (all p < 0.05). All Multiplate tests values, however, remained below those in the healthy controls. CHC-infected patients displayed evidence of rebalanced hemostasis with only partly hemostatic normalization in patients achieving SVR. The implications of rebalanced hemostasis and especially the impact on risk of CVD and bleeding warrants further studies

Incomplete Immune Recovery in HIV Infection: Mechanisms, Relevance for Clinical Care, and Possible Solutions

Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) usually results in diminished viral replication, increasing CD4+ cell counts, a reversal of most immunological disturbances, and a reduction in risk of morbidity and mortality. However, approximately 20% of all HIV-infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution. Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution in HIV infection, including mechanisms, relevance for clinical care, and possible solutions

Impact of calcium on salivary α-amylase activity, starch paste apparent viscosity and thickness perception

Thickness perception of starch-thickened products during eating has been linked to starch viscosity and salivary amylase activity. Calcium is an essential cofactor for α-amylase and there is anecdotal evidence that adding extra calcium affects amylase activity in processes like mashing of beer. The aims of this paper were to (1) investigate the role of salivary calcium on α-amylase activity and (2) to measure the effect of calcium concentration on apparent viscosity and thickness perception when interacting with salivary α-amylase in starch-based samples. α-Amylase activity in saliva samples from 28 people was assessed using a typical starch pasting cycle (up to 95 °C). The activity of the enzyme (as measured by the change in starch apparent viscosity) was maintained by the presence of calcium, probably by protecting the enzyme from heat denaturation. Enhancement of α-amylase activity by calcium at 37 °C was also observed although to a smaller extent. Sensory analysis showed a general trend of decreased thickness perception in the presence of calcium, but the result was only significant for one pair of samples, suggesting a limited impact of calcium enhanced enzyme activity on perceived thickness

The Endo-Lysosomal System of Brain Endothelial Cells Is Influenced by Astrocytes In Vitro

Receptor- and adsorptive-mediated transport through brain endothelial cells (BEC) of the blood-brain barrier (BBB) involves a complex array of subcellular vesicular structures, the endo-lysosomal system. It consists of several types of vesicles, such as early, recycling, and late endosomes, retromer-positive structures, and lysosomes. Since this system is important for receptor-mediated transcytosis of drugs across brain capillaries, our aim was to characterise the endo-lysosomal system in BEC with emphasis on their interactions with astrocytes. We used primary porcine BEC in monoculture and in co-culture with primary rat astrocytes. The presence of astrocytes changed the intraendothelial vesicular network and significantly impacted vesicular number, morphology, and distribution. Additionally, gene set enrichment analysis revealedthat 60 genes associated with vesicular trafficking showed altered expression in co-cultured BEC. Cytosolic proteins involved in subcellular trafficking were investigated to mark transport routes, such as RAB25 for transcytosis. Strikingly, the adaptor protein called AP1-1B, important for basolateral sorting in epithelial cells, was not expressed in BEC. Altogether, our data pin-point unique features of BEC trafficking network, essentially mapping the endo-lysosomal system of in vitro BBB models. Consequently, our findings constitute a valuable basis for planning the optimal route across the BBB when advancing drug delivery to the brain.Peer reviewe

Clinical Course of Postoperative Atrial Fibrillation After Cardiac Surgery and Long-term Outcome

Funding Information: The study was supported by the Swedish Heart-Lung Foundation (grant 20180560 to AJ), the Swedish state (ALFGBG-725131 to AJ) under the agreement between the Swedish government and the county councils concerning economic support of research and education of doctors (ALF agreement), Region Västra Götaland (grant VGFOUREG-847811 to AJ and grant VGFOUREG-648981 to AT), and Wilhelm and Martina Lundgrens Foundation (grant 2019-3110 to AT). The authors had full freedom of investigation and full control of the design of the study, analysis of data, and production of the written report. Dr Jeppsson discloses a financial relationship with Boehringer-Ingelheim, XVIVO, Portola, Baxter, and LFB; Dr Taha with Bayer; Dr Bergfeldt with Bayer, Boehringer Ingelheim, and Sanofi. Funding Information: The study was supported by the Swedish Heart-Lung Foundation (grant 20180560 to AJ), the Swedish state (ALFGBG-725131 to AJ) under the agreement between the Swedish government and the county councils concerning economic support of research and education of doctors (ALF agreement), Region Västra Götaland (grant VGFOUREG-847811 to AJ and grant VGFOUREG-648981 to AT), and Wilhelm and Martina Lundgrens Foundation (grant 2019-3110 to AT). The authors had full freedom of investigation and full control of the design of the study, analysis of data, and production of the written report. Publisher Copyright: © 2022 The Society of Thoracic SurgeonsBackground: New-onset postoperative atrial fibrillation (POAF) after cardiac surgery is associated with worse short- and long-term outcomes. Although the clinical presentation of POAF varies substantially, almost all studies model it with a dichotomous yes or no variable. We explored potential associations between the clinical course of POAF and long-term outcome. Methods: This retrospective, observational, single-center study included 6435 coronary artery bypass grafting and/or valve patients between 2010 and 2018. POAF patients were grouped into spontaneous/pharmacologic conversion to sinus rhythm, sinus rhythm after electrical cardioversion, and sustained AF at discharge. Multivariable Cox regression models adjusted for age, sex, type of surgery, comorbidities, and early-initiated oral anticoagulation were used to study associations between the clinical course of POAF and long-term risk for mortality, ischemic stroke, thromboembolic events, heart failure hospitalization, and major bleeding. Median follow-up time was 3.8 years (range, 0-8.3). Results: POAF occurred in 2172 patients (33.8%), 94.9% of whom converted to sinus rhythm before discharge. Of these, 73.6% converted spontaneously or with pharmacologic treatment and 26.4% after electrical cardioversion. Both sustained AF and electrical cardioversion were independently associated with an increased long-term risk for heart failure (adjusted hazard ratio for sustained AF at discharge, 2.55 [95% confidence interval, 1.65-3.93; P < .001]; adjusted hazard ratio for electrical cardioversion, 1.28 [95% confidence interval, 1.00-1.65; P = .049]) but not with increased long-term risk for death, thromboembolic complications, or bleeding. Conclusions: A more complicated POAF course is associated with increased long-term risk for heart failure hospitalization but not for all-cause mortality or thromboembolic complications.Peer reviewe

Associations between new-onset postoperative atrial fibrillation and long-term outcome in patients undergoing surgical aortic valve replacement

© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.OBJECTIVES: Data on prognostic implications of new-onset postoperative atrial fibrillation (POAF) after surgical aortic valve replacement (SAVR) is limited. We sought to explore associations between POAF, early initiated oral anticoagulation (OAC) and long-term outcome after SAVR and combined SAVR + coronary artery bypass grafting (CABG). METHODS: This is a retrospective, population-based study including all isolated SAVR (n = 7038) and combined SAVR and CABG patients (n = 3854) without a history of preoperative atrial fibrillation (AF) in Sweden 2007-2017. Individual patient data were merged from 4 nationwide registries. Inverse probability of treatment weighting-adjusted Cox regression models were employed separately in SAVR and SAVR + CABG patients. The median follow-up time was 4.7 years (range 0-10 years). RESULTS: POAF occurred in 44.5% and 50.7% of SAVR and SAVR + CABG patients, respectively. In SAVR patients, POAF was associated with increased long-term risk of death [adjusted hazard ratio (aHR) 1.21 (95% confidence interval 1.06-1.37)], ischaemic stroke [aHR 1.32 (1.08-1.59)], any thromboembolism, heart failure hospitalization and recurrent AF. In SAVR + CABG, POAF was associated with death [aHR 1.31 (1.14-1.51)], recurrent AF and heart failure, but not with ischaemic stroke [aHR 1.04 (0.84-1.29)] or thromboembolism. OAC was dispensed within 30 days after discharge to 67.0% and 65.9%, respectively, of SAVR and SAVR + CABG patients with POAF. Early initiated OAC was not associated with reduced risk of death, ischaemic stroke or thromboembolism in any group of patients. CONCLUSIONS: POAF after SAVR is associated with an increased risk of long-term mortality and morbidity. Further studies are warranted to clarify the role of OAC in SAVR patients with POAF.Peer reviewe