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Fukazawa et al . report that SIV persists in follicular helper T cells in elite controller macaques, evading clearance by CD8+ T cells Chronic-phase HIV and simian immunodeficiency virus (SIV) replication is reduced by as much as 10,000-fold in elite controllers (ECs) compared with typical progressors (TPs), but sufficient viral replication persists in EC tissues to allow viral sequence evolution and induce excess immune activation. Here we show that productive SIV infection in rhesus monkey ECs, but not TPs, is markedly restricted to CD4 + follicular helper T (T FH ) cells, suggesting that these EC monkeys' highly effective SIV-specific CD8 + T cells can effectively clear productive SIV infection from extrafollicular sites, but their relative exclusion from B cell follicles prevents their elimination of productively infected T FH cells. CD8 + lymphocyte depletion in EC monkeys resulted in a dramatic re-distribution of productive SIV infection to non-T FH cells, with restriction of productive infection to T FH cells resuming upon CD8 + T cell recovery. Thus, B cell follicles constitute 'sanctuaries' for persistent SIV replication in the presence of potent anti-viral CD8 + T cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T cell immunotherapy.

Background Predicting the progression of hip osteoarthritis (OA) remains challenging, and no reliable predictive method has been established. This study aimed to develop an artificial intelligence (AI) model to predict hip OA progression via plain radiographs and patient data and to determine its accuracy. Methods This retrospective study utilized anteroposterior pelvic radiographs of consecutive patients with hip OA who underwent primary unilateral total hip arthroplasty. Radiographs diagnosed with Kellgren–Lawrence (KL) grade 0–2 were extracted from 361 patients and 1697 images. This AI model was developed to predict whether OA would progress from KL grade 0–2 to KL grade ≥ 3 within n years ( n  = 3, 4, 5). A gradient-boosting decision tree approach was utilized according to feature extractions obtained by a convolutional neural network from radiographs and patient data (height, body weight, sex, age, and KL grade given by an orthopedic surgeon) with five-fold cross-validation. The model performance was assessed using accuracy, specificity, sensitivity, and the area under the receiver operating characteristic curve (AUC). Results The mean accuracy, specificity, sensitivity, and AUC of our prediction model were, respectively, 81.8%, 88.0%, 66.7%, and 0.836 for 3 years; 79.8%, 85.0%, 71.6%, and 0.836 for 4 years; and 78.5%, 80.4%, 76.9%, and 0.846 for 5 years. Conclusions The proposed AI model performed adequately in predicting hip OA progression and may be clinically applicable with additional datasets and validation.

Several vaccines have been widely used to counteract the global pandemic caused by SARS-CoV-2. However, due to the rapid emergence of SARS-CoV-2 variants of concern (VOCs), further development of vaccines that confer broad and longer-lasting protection against emerging VOCs are needed. Here, we report the immunological characteristics of a self-amplifying RNA (saRNA) vaccine expressing the SARS-CoV-2 Spike (S) receptor binding domain (RBD), which is membrane-anchored by fusing with an N-terminal signal sequence and a C-terminal transmembrane domain (RBD-TM). Immunization with saRNA RBD-TM delivered in lipid nanoparticles (LNP) efficiently induces T-cell and B-cell responses in non-human primates (NHPs). In addition, immunized hamsters and NHPs are protected against SARS-CoV-2 challenge. Importantly, RBD-specific antibodies against VOCs are maintained for at least 12 months in NHPs. These findings suggest that this saRNA platform expressing RBD-TM will be a useful vaccine candidate inducing durable immunity against emerging SARS-CoV-2 strains. Vaccines with broad and long-lasting protection against variants of concern are still limited. Here, the authors report a self-amplifying RNA (saRNA) vaccine expressing a membrane-anchored SARS-CoV-2 Spike RBD and show that it elicits broad, durable and protective immunity in small animal models and NHPs.

Background While fear of movement is an important predictor of pain and disability in osteoarthritis (OA), its impact on patients with hip OA remains uncertain. This study aimed to determine whether fear of movement, evaluated by the Tampa Scale for Kinesiophobia (TSK)-11, and pain catastrophizing, evaluated by the Pain Catastrophizing Scale (PCS), were associated with quality of life (QOL) in patients with hip OA. Methods This cross-sectional study was conducted between November 2017 and December 2018. Ninety-one consecutively enrolled patients with severe hip OA were scheduled for primary unilateral total hip arthroplasty. The EuroQOL-5 Dimensions questionnaire was used to measure general QOL. The Japanese Orthopedic Association Hip Disease Evaluation Questionnaire was used to assess disease-specific QOL. The covariates included age, sex, body mass index (BMI), pain intensity, high pain catastrophizing (PCS ≥ 30), and high kinesiophobia (TSK-11 ≥ 25). Variables were subjected to multivariate analysis using each QOL scale. Results In multiple regression analysis, pain intensity, high pain catastrophizing, and BMI were independently correlated with the disease-specific QOL scale. High pain catastrophizing, pain intensity, and high kinesiophobia were independently correlated with the general QOL scale. Conclusions High pain catastrophizing (PCS ≥ 30) was independently associated with disease and general QOL scales. High kinesiophobia (TSK-11 ≥ 25) was independently associated with the general QOL scale in preoperative patients with severe hip OA.

Background Implant impingement and soft tissue tension are factors involved in dislocation after total hip arthroplasty (THA). Combined anteversion (CA) has been used as an indicator for implant placement. However, optimal implant placement remains a challenge. Moreover, the effect of changes in offset on dislocation is still unclear. In this study, we aimed to clarify the effects of postoperative CA and pre- and postoperative changes in offset on dislocation. Methods Included were patients who underwent primary cementless THA between 2013 and 2020. The mean values of CA and offset in the dislocation and non-dislocation groups were compared. The CA values within ± 10% of the recommended values were defined as good CA, and those outside the range were rated as poor CA. The dislocation rates were compared between the good and poor CA groups and between the groups with and without increased offset. Results A total of 283 hips were included. The mean values of CA in the dislocation and non-dislocation groups were significantly different ( P  < 0.05). The dislocation rate was significantly lower in the good CA group ( P  < 0.05). The dislocation rates in the groups with and without increased total offset were 0.5% and 4.3%, respectively ( P  = 0.004). There were no dislocations in patients with good CA and increased offset. Conclusions The dislocation rate was significantly lower when implants were placed within ± 10% of the recommended CA value. Our results suggest that dislocation can be avoided by placing the implant in the good CA range and considering the increase in total offset on the operative side.

HIV-1 Env glycoprotein (Env) immunogenicity is limited in part by structural instability and extensive glycan shielding and is likely the greatest obstacle to an HIV-1 vaccine. Stabilized Env trimers can elicit serum neutralizing antibodies, but the response is short-lived. Here we use Newcastle Disease Virus-like particle (NDV-VLP) platform to present stabilized versions of HIV-1 Env at high valency and in the context of varied conformational stability, adjuvants, dose, and antigen persistence. Influenza virus hemagglutinin, or SARS-CoV2 Spike-bearing VLPs rapidly induce neutralizing antibodies, in contrast, they were not induced by those bearing Env. A replicating adenovirus type 4 expressing Env rapidly induces autologous neutralizing antibodies. However, durable neutralizing antibodies are induced only when multiple features of a replicating virus infection are combined, with the largest impact from dose and escalating dose. In summary, we show here immunogenicity of HIV-1 Env could be improved by reproducing features of virus infection. Vaccination efficiency in HIV infection is hampered by the low immunogenicity of HIV-1 Env glycoprotein (Env). Here authors optimise the neutralising antibody response to Env by stabilizing the Env trimers in the context of expressing them in a Newcastle Disease Virus-like particle and providing conditions that mimics replicating virus infection.

Background Obtaining a larger theoretical range of motion (ROM) is crucial to avoid prosthetic impingement after total hip arthroplasty (THA); however, no reports have examined the permissible range values of combined anteversion (CA) satisfying targeted ROM without prosthetic impingement. This retrospective study aimed to evaluate the possible postoperative CA extent that would allow meeting target ROM criteria according to Yoshimine’s theory using computed tomography (CT)-based three-dimensional motion analysis after THA. Methods This study included 114 patients (133 hips) who underwent cementless primary THA using a CT-based navigation system and implants (oscillation angle ≥ 135°). Implant positions were determined using Yoshimine's CA formula. Postoperative evaluation was conducted using a three-dimensional templating software for CT data. The postoperative Yoshimine’s and Widmer’s CA was calculated, and the difference between the target and postoperative values was defined as the error of Yoshimine’s CA and Widmer’s CA. Prosthetic ROM was assessed by Yoshimine’s stringent criteria for activities of daily living. Based on fulfilling these criteria, all patients were divided into the ROM (+) and ROM (−) groups. Evaluation items were compared between the two groups. Results There were 111 and 22 hips in the ROM (+) and ROM (−) groups, respectively. A significant difference was noted in the absolute error of Yoshimine’s and Widmer’s CA between the two groups. Using receiver operating characteristic analysis, threshold values of 6.0 (higher values indicate greater disability; sensitivity 90.9%, specificity 72.1%) for the absolute Yoshimine’s CA difference (area under the curve [AUC] 0.87, P  < 0.01) and 6.9 (higher values indicate greater disability; sensitivity 68.2%, specificity 88.3%) for the absolute Widmer’s CA difference (AUC 0.83, P  < 0.01) were predictors in the ROM (−) group. Conclusions The target range of Yoshimine’s CA (90.8° ± 6.0°) and Widmer’s CA values (37.3° ± 6.9°) was crucial in implant orientation for obtaining theoretical ROM without prosthetic impingement after THA.

Background Hip arthroplasty using acrylic prosthesis was once conducted; however, it has now been abandoned because of early breakages and wear of material. Therefore, complications or revision surgeries due to the use of acrylic prostheses are becoming rare. Case presentation A 76-year-old woman presented with a sudden onset of severe pain in her left femur while walking. Radiographs revealed severe osteolysis and periprosthetic femoral fracture 45 years after the initial hemiarthroplasty using an acrylic prosthesis. We performed a Girdlestone resection arthroplasty by removing the prosthesis and fixing the fracture site using an intramedullary nail and metal plate. The patient was pain-free in her hip and leg 2 years and 9 months after the surgery. Although she walked with a cane or crutches, no postoperative complications were observed. Conclusions The combined use of an intramedullary nail and plate fixation with resection arthroplasty could offer acceptable results for patients with severe osteolysis and periprosthetic fracture after femoral head replacement using an acrylic prosthesis. Our report seems relevant because it not only reminds us of the significant steps made in the development of modern total hip arthroplasty; it also highlights one of the surgical options for severe osteolysis and periprosthetic fracture of the hip.

Despite effective control of plasma viremia with the use of combination antiretroviral therapies (cART), minor cognitive and motor disorders (MCMD) persist as a significant clinical problem in HIV-infected patients. Non-human primate models are therefore required to study mechanisms of disease progression in the central nervous system (CNS). We isolated a strain of simian immunodeficiency virus (SIV), SIVsm804E, which induces neuroAIDS in a high proportion of rhesus macaques and identified enhanced antagonism of the host innate factor BST-2 as an important factor in the macrophage tropism and initial neuro-invasion of this isolate. In the present study, we further developed this model by deriving a molecular clone SIVsm804E-CL757 (CL757). This clone induced neurological disorders in high frequencies but without rapid disease progression and thus is more reflective of the tempo of neuroAIDS in HIV-infection. NeuroAIDS was also induced in macaques co-inoculated with CL757 and the parental AIDS-inducing, but non-neurovirulent SIVsmE543-3 (E543-3). Molecular analysis of macaques infected with CL757 revealed compartmentalization of virus populations between the CNS and the periphery. CL757 exclusively targeted the CNS whereas E543-3 was restricted to the periphery consistent with a role for viral determinants in the mechanisms of neuroinvasion. CL757 would be a useful model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.

While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4 + T cells harbor replication-competent SIV DNA; however, only brain CD4 + T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS. Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4 + T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4 + memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain. IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4 + T cells harbor replication-competent SIV DNA; however, only brain CD4 + T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.