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Little is known about the stability of HIV-1 cross-neutralizing responses. Taking into account the fact that neutralization breadth has been positively associated with plasma viral load, there is no explanation for the presence of broadly neutralizing responses in a group of patients on treatment with undetectable viremia. In addition, the B-cell profile responsible for broadly cross-neutralizing responses is unknown. Here we studied the evolution of neutralizing responses and the B-cell subpopulation distribution in a group of patients with broadly cross-reactive HIV-1-neutralizing activity. We studied neutralization breadth evolution in a group of six previously identified broadly cross-neutralizing patients and six control patients during a 6-year period with a previously described minipanel of recombinant viruses from five different subtypes. B-cell subpopulation distribution during the study was also determined by multiparametric flow cytometry. Broadly cross-neutralizing activity was transient in four broad cross-neutralizers and stable, up to 4.6 years, in the other two. In four out of five broad cross-neutralizers who initiated treatment, a neutralization breadth loss occurred after viremia had been suppressed for as much as 20 months. B-cell subpopulation analyses revealed a significant increase in the frequency of naive B cells in broadly cross-reactive samples, compared with samples with less neutralization breadth (increased from 44% to 62%). We also observed a significant decrease in tissue-like and activated memory B cells (decreased from 19% to 12% and from 17% to 9%, respectively). Our data suggest that HIV-1 broadly cross-neutralizing activity is variable over time and associated with detectable viremia and partial B-cell restoration. [ABSTRACT FROM AUTHOR]

Little is known about the stability of HIV-1 cross-neutralizing responses. Taking into account the fact that neutralization breadth has been positively associated with plasma viral load, there is no explanation for the presence of broadly neutralizing responses in a group of patients on treatment with undetectable viremia. In addition, the B-cell profile responsible for broadly cross-neutralizing responses is unknown. Here we studied the evolution of neutralizing responses and the B-cell subpopulation distribution in a group of patients with broadly cross-reactive HIV-1-neutralizing activity. We studied neutralization breadth evolution in a group of six previously identified broadly cross-neutralizing patients and six control patients during a 6-year period with a previously described minipanel of recombinant viruses from five different subtypes. B-cell subpopulation distribution during the study was also determined by multiparametric flow cytometry. Broadly cross-neutralizing activity was transient in four broad cross-neutralizers and stable, up to 4.6 years, in the other two. In four out of five broad cross-neutralizers who initiated treatment, a neutralization breadth loss occurred after viremia had been suppressed for as much as 20 months. B-cell subpopulation analyses revealed a significant increase in the frequency of naive B cells in broadly cross-reactive samples, compared with samples with less neutralization breadth (increased from 44% to 62%). We also observed a significant decrease in tissue-like and activated memory B cells (decreased from 19% to 12% and from 17% to 9%, respectively). Our data suggest that HIV-1 broadly cross-neutralizing activity is variable over time and associated with detectable viremia and partial B-cell restoration. [ABSTRACT FROM AUTHOR]

Deals with a study which determined the primary and secondary patency rates after percutaneous mechanical de-clotting. Identification of patient who undergone fistulography; Details of the polytetrafluoroethylene dialysis grafts in the examination; Results of percutaneous de-clotting procedures.

Preventive HIV-1 vaccine strategies rely on the elicitation of broadly neutralizing antibody (bNAb) responses, but their induction in vivo by vaccination remains challenging. Considering that the ability of an epitope to elicit effective humoral immunity depends on its exposure on the virion, we have used a reverse genetics approach to select variants from an HIV-1 AC10_29 randomly mutated envelope library that showed increased affinity for a selected bNAb (4E10 bNAb targeting the HIV-1 MPER region). Isolated envelope sequences were analyzed by deep-sequencing showing a small number of dominant changes, including the loss of four potential N-linked glycosylation sites and disruption of the V1/V2 loop. Accordingly, the dominant variant (LR1-C1), showed not only increased affinity for MPER bNAbs 4E10 and 2F5, but also higher affinity for an additional antibody targeting the V3 loop (447-52D) that could be a consequence of an open conformation tier 1-like Env. Furthermore, the amino acids specific for the selected variant are associated with an increased sensitivity for 4E10 and 2F5 antibodies. In vivo studies showed that sera from mice immunized with LR1-C1 viruses possessed an improved neutralizing activity compared to the wild-type AC10_29 env. While Virus Like Particles (VLPs) carrying this envelope were unable to induce detectable neutralizing activity in immunized rabbits, one animal showed antibody response to the 4E10-proximal region. Our data establish a novel approach that has the potential to yield HIV envelope immunogen sequences that direct antibody responses to specific envelope regions. [ABSTRACT FROM AUTHOR]

Introduction: There is a lack of evidence about the exact deterioration of visual function associated with the age-related natural changes in the lens, particularly in intermediate (stage-2) dysfunctional lens syndrome (DLS). Standard photopic visual acuity and contrast sensitivity tests may not show the visual worsening in daily life activities, such as oncoming vehicle headlights at night. The purpose of this study was to analyze visual function under different conditions and glare sources in stage-2 DLS. Methods: Forty patients over 49 years of age with initial bilateral lens opacification (Lens Opacities Classification System III [LOCS-III] scores up to 3), best-corrected visual acuity of 20/25 or better, and no ocular disease were evaluated. Binocular photopic and mesopic contrast sensitivity (CS) with/without halogen and xenon increasing glare sources were analyzed. Mesopic disability glare (MDG) was calculated as the difference between mesopic CS with/without the glare source. Results: The median logarithmic CS (logCS) values were lower under mesopic conditions (1.05) than under photopic illumination (1.65; P < 0.001). Halogen and xenon glare further decreased mesopic CS (both, median logCS 0.75, P < 0.001). The mean MDG was 0.31 ± 0.10 log units for halogen glare and 0.33 ± 0.09 log units for xenon glare. The mesopic CS and MDG were not associated with any photopic test. The mesopic CS with glare but not photopic CS or mesopic CS was correlated with the LOCS-III scores. The best association was provided by MDG, which showed a pooled correlation with LOCS-III nuclear opalescence (r = 0.411, P < 0.001) and cortical scores (r = 0.226, P = 0.04). Conclusion: The mesopic CS under a glare source is an independent early indicator of visual impairment in stage-2 DLS patients, and appears to be substantial. Furthermore, the MDG is more sensitive than photopic and mesopic CS for evaluating patients with initial phacosclerosis. Surgeons should consider this in the decision-making process of the correct timing for lens surgery. [ABSTRACT FROM AUTHOR]

Longitudinal studies in HIV-1-infected individuals have indicated that 2 to 3 years of infection are required to develop broadly neutralizing antibodies. However, we have previously identified individuals with broadly neutralizing activity (bNA) in early HIV-1 infection, indicating that a vaccine may be capable of bNA induction after short periods of antigen exposure. Here, we describe 5 HIV-1 envelope sequences from individuals who have developed bNA within the first 100 days of infection (early neutralizers) and selected two of them to design immunogens based on HIV-1-Gag virus-like particles (VLPs). These VLPs were homogeneous and incorporated the corresponding envelopes (7 to 9 mg of gp120 in 1010 VLPs). Both envelopes (Envs) bound to well-characterized broadly neutralizing antibodies (bNAbs), including trimer-specific antibodies (PGT145, VRC01, and 35022). For immunogenicity testing, we immunized rabbits with the Env-VLPs or with the corresponding stabilized soluble envelope trimers. A short immunization protocol (105 days) was used to recapitulate the early nAb induction observed after HIV-1 infection in these two individuals. All VLP and trimeric envelope immunogens induced a comparably strong anti-gp120 response despite having immunized rabbits with 30 times less gp120 in the case of the Env-VLPs. In addition, animals immunized with VLP-formulated Envs induced antibodies that cross-recognized the corresponding soluble stabilized trimer and vice versa, even though no neutralizing activity was observed. Nevertheless, our data may provide a new platform of immunogens, based on HIV-1 envelopes from patients with early broadly neutralizing responses, with the potential to generate protective immune responses using vaccination protocols similar to those used in classical preventive vaccines. [ABSTRACT FROM AUTHOR]

Objective: Single vehicle run-off crashes in urban areas constitute a growing problem that deserves more attention from authorities and researchers. This study aims to detect geometric road design risk factors characterizing places where urban run-off crashes might happen. Methods: A case-control study was performed in the urban area of Valladolid (Spain) with data corresponding to a four-year period. Logistic regression models were used to analyze data, considering different variables related to design parameters in the models: type of intersection, radius of curvature, width of the pavement, width of the traffic lane, number of lanes for traffic in the same direction, direction of the traffic, length of the previous straight section, distance to the previous traffic light, slope, and finally, priority regulation. Two different scenarios were investigated: intersections and curves. Results: The Adjusted Odds-Ratio of a run-off crash was five times higher in double direction roads with median strip than in one-way urban roads, for both curves and intersections, and almost nine times higher on road sections with previous straight lengths greater than 500 meters. Specific risk factors for intersections are "number of lanes for traffic in the same direction" (the odds of a run-off crash are more than five times higher on a road with two or more lanes), "length of preceding straight section" (the odds on road sections with lengths greater than 500 meters are more than nine times that of road sections with a length of less than 150 meters). For curves, specific factors are "width of the traffic lane" (the odds of a run-off crash on curves with lanes wider than 3.75m are more than six times higher) and "priority regulation" (the odds of a run-off crash increases more than twelve times on road sections with traffic light regulation over those without any regulation). Conclusions: The current study identifies urban road configurations that might require redesigning with the aim of decreasing the odds of a run-off crash, or the implementation of passive protective systems to mitigate their consequences. Specifically, intersections in two direction roads with median strip, more than two lanes per direction and a long preceding straight section, as well as curves with wide lanes and traffic light regulation, are the places that require attention. [ABSTRACT FROM AUTHOR]

Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (<20 copies/106 CD4+ T-cells) without evidence of replication-competent viruses (<0.025 IUPM), consistent with high levels of defective genomes, strong cellular HIV-1-specific immune response, and a high poly-functionality index (>0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (<0.01 s/n) in env gene than other EC. We postulate that these EEC represent cases of spontaneous functional HIV-1 cure. A non-functional and non-genetically evolving viral reservoir along with an HIV-1-specific immune response seems to be key for the spontaneous functional cure. [ABSTRACT FROM AUTHOR]

This study evaluated the neutralization breadth in dually infected (DI) HIV-1 long-term non-progressor elite controller patients (LTNP-EC) using a representative minipanel of 6 viruses from 5 different subtypes. Our results showed an improved neutralization breadth in DI LTNP-EC patients when compared with matched LTNP single-infected patients. The role of viral diversity in neutralization was estimated with the Shannon Entropy and the p-distance in viral quasispecies. We found a positive correlation between neutralization breadth and diversity within the viral quasispecies. This correlation could explain why a group of LTNP-EC patients developed a broad neutralizing response despite having undetectable levels of viremia. [ABSTRACT FROM AUTHOR]

Abstract: Powered two-wheelers (PTWs – mopeds, motorcycles, and scooters) remain the most dangerous form of travel on today''s roads. This study used hospital discharge data from eight European countries to examine the frequencies and patterns of injury among PTW users (age≥14 years), the predicted incidence of the loss of functional ability, and the mechanisms of the head injuries observed (all in light of increased helmet use). Of 977,557 injured patients discharged in 2004, 12,994 were identified as having been injured in PTW collisions. Lower extremity injuries accounted for 26% (25.6–26.7, 95% C.I.) of the total injuries, followed by upper extremity injuries (20.7%: 20.3–21.2), traumatic brain injuries (TBI) (18.5%: 18–19), and thoracic injuries (8.2%: 7.8–8.5). Approximately 80% of the lower extremity injury cases were expected to exhibit some functional disability one year following discharge (predicted Functional Capacity Index, pFCI-AIS98<100), compared to 47% of the upper extremity injury cases and 24% of the TBI cases. Although it occurred less frequently, patients that were expected to experience some functional limitation from TBI were predicted to fair worse on average (lose more functional ability) than patients expected to have functional limitations from extremity injuries. Cerebral concussion was the most common head injury observed (occurring in 56% of head injury cases), with most concussion cases (78%) exhibiting no other head injury. Among the AIS3+ head injuries that could be mapped to an injury mechanism, 48% of these were associated with a translational-impact mechanism, and 37% were associated with a rotational mechanism. The observation of high rates of expected long-term disability suggests that future efforts aim to mitigate lower and upper extremity injuries among PTW users. Likewise, the high rates of concussion and head injuries associated with a rotational mechanism provide goals for the next phase of PTW user head protection. [Copyright &y& Elsevier]