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BACKGROUNDHIV-1-infected CD4+ T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing.METHODSIn this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous CD8+ T cells.RESULTSThe proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous CD8+ T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene.CONCLUSIONSWe provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence.FUNDINGOffice of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research.

Nine dogs with hemophilia A were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9–11.3% of normal FVIII levels. In two of nine dogs, levels of FVIII activity increased gradually starting about 4 years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of the integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A, while emphasizing the importance of long-term monitoring for potential genotoxicity. AAV therapy in dogs leads to clonal expansions of transduced cells.

Introduction. Dual-mobility (DM) implants for total hip arthroplasty (THA) have gained popularity due to their potential to reduce hip instability and dislocation events that may lead to revision surgery. These implants consist of a femoral head articulated within a polyethylene liner, which articulates within an outer acetabular shell, creating a dual-bearing surface. Our study aimed to report our observations on the survivorship of a novel DM implant for primary total hip arthroplasty at two years. Methods. We conducted a retrospective, multicenter study to assess the clinical outcomes of patients undergoing a THA with a novel DM implant (OR3O acetabular system™, Smith & Nephew, Inc., Memphis, TN) from January 2020 to September 2021. Patient demographics, surgical information, and survivorship data were collected from medical records for patients with a minimum of two years of follow-up. Primary outcomes included overall implant survivorship at two years as well as aseptic survivorship, revision rates of the DM acetabular shell, and average time to revision. Patient-reported outcomes were collected in the form of HOOS JR. Results. A total of 250 hips in 245 patients had a minimum two-year follow-up. Primary osteoarthritis (80%) was the most common indication for index THA. The average aseptic survivorship of the DM acetabular components at two years for the cohort was 98.4% and survivorship of the acetabular implants overall was 97.6%. There were a total of four (1.6%) aseptic revisions of the DM acetabular component. Reasons for aseptic acetabular revision included one case of instability, one intraprosthetic dislocation, one periprosthetic acetabular fracture, and one malpositioned acetabular cup resulting in impingement. The mean time of follow-up was 893.9 days. Eighty-seven patients had preoperative and two-year HOOS JR available. HOOS JR improved by an average of 38.5 points. Conclusion. This novel DM acetabular implant demonstrates excellent survivorship at two years follow-up with low rates of instability and intraprosthetic dislocation and no episodes of metal-on-metal corrosion. Use of the DM implant demonstrated clinically relevant improvements in patient-reported outcomes at two years.

Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone's response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells 1 , 2 . We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34 + hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4–1.8 copies per neutrophil) and the persistence of 16–46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients. Initial results from phase I/II lentiviral gene therapy trials provide early evidence supporting its safety and efficacy in treating patients with X-linked chronic granulomatous disease.

After adjustment for all study variables, Spanish (compared with English) primary spoken language was not associated with lower odds of receiving NA (OR 0.97; 95% CI 0.69 to 1.37; p=0.88); however, this was OR 0.54 (95% CI 0.37 to 0.80; p=0.002) for other non-English (vs English) primary spoken language (figure 1).Table 1 Study variables by primary spoken language Primary spoken language English (no. (%)) Non-English (no. (%)) P value Anaesthesia type  Neuraxial anaesthesia 3120 (84.5) 565 (83.7) 0.60  Non-neuraxial anaesthesia 572 (15.5) 110 (16.3) Demographics Sex  Female 2320 (62.8) 519 (76.9) <0.0001  Male 1372 (37.2) 156 (23.1) Median age in years (IQR) 66 (59–73) 66 (64–76) <0.0001 Race  Asian 175 (4.7) 141 (20.9) <0.0001  Black 965 (26.1) 23 (3.4)  White 1741 (47.2) 113 (16.7)  Other 668 (18.1) 375 (55.6)  Unknown 143 (3.9) 23 (3.4) Ethnicity  Hispanic 652 (17.7) 407 (60.3) <0.0001  Non-Hispanic 2686 (72.8) 227 (33.6)  Unknown 354 (9.6) 41 (6.1) Insurance type  Commercial 1422 (38.5) 100 (14.8) <0.0001  Medicaid 364 (9.9) 121 (17.9)  Medicare 1735 (47.0) 428 (63.4)  Self-pay 11 (0.3) 5 (0.7)  Other 160 (4.3) 21 (3.1) Other covariates Procedure type  THA 1515 (41.0) 79 (11.7) <0.0001  TKA 2177 (59.0) 596 (88.3) Median LOS in days (IQR) 2 (2–3) 3 (2–4) <0.0001 ASA status  ASA I 46 (1.2) 2 (0.3) <0.0001  ASA II 2034 (55.1) 333 (49.3)  ASA III 1468 (39.8) 321 (47.6)  ASA IV 63 (1.7) 4 (0.6)  Unknown 81 (2.2) 15 (2.2) Charlson comorbidity index  0 2068 (56.0) 347 (51.4) 0.002  1 944 (25.6) 219 (32.4)  2 393 (10.6) 59 (8.7)  3 287 (7.8) 50 (7.4) Median preoperative VR-12 PCS (IQR) 3.5 (3–4) 4 (3–4) 0.60 Median preoperative VR-12 MCS (IQR) 3 (3–4) 3 (2–4) 0.95 Median HOOS (IQR) 46.7 (36.4–58.9) 46.7 (36.4–56.0) 0.98 Median KOOS (IQR) 42.3 (31.3–52.5) 42.3 (31.3–50.0) 0.09 P values are indicative of comparisons between study variables by primary spoken language (English, non-English) using Mann-Whitney U tests and χ2 tests for continuous and categorical variables, respectively. [...]information on primary spoken language is not routinely available in multi-institutional datasets and thus conclusions must be drawn from single-institutional data that may or may not be generalisable. [...]we found a language-based disparity in terms of NA use in elective orthopedic surgery in a single institution.

Clonal expansion of infected CD[4.sup.+] T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor [beta]-chain (TCR[beta]) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD[4.sup.+] T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCR[beta] repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCR[beta] and integration site analysis showed that infection could occur early or late in the course of a clone's response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes. CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer

Nine hemophilia A dogs were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9%−11.3% of normal FVIII levels. In two of nine dogs, FVIII activity increased gradually starting about four years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of these integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A while emphasizing the importance of long-term monitoring for potential genotoxicity. An AAV gene therapy study in hemophilia A dogs finds clonal expansions of transduced cells.

-The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. -To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. -Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. -The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.