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BACKGROUND The extent to which treatment recommendations in the orthopedic setting contribute to well-established racial disparities in the utilization of total joint replacement (TJR) in the treatment of advanced knee/hip osteoarthritis has not been explored. OBJECTIVE To examine whether orthopedic surgeons are less likely to recommend TJR to African-American patients compared to white patients with similar clinical indications, and whether there are racial differences in the receipt of TJR within six months of study enrollment. DESIGN Prospective, observational study. PARTICIPANTS African-American (AA; n = 120) and white (n = 337) patients seeking treatment for knee or hip osteoarthritis in Veterans Affairs orthopedic clinics. MAIN MEASURES Patients completed surveys that assessed socio-demographic and clinical variables that could influence osteoarthritis treatment. Orthopedic surgeons’ notes were reviewed to determine whether patients had been recommended for TJR and whether they underwent the procedure within 6 months of study enrollment. RESULTS Rate of TJR recommendation was 19.5%. Odds of receiving a TJR recommendation were lower for AA than white patients of similar age and disease severity (OR = 0.46, 95% CI = 0.26–0.83; P = 0.01). However, this difference was not significant after adjusting for patient preference for TJR (OR = 0.69, 95% CI = 0.36–1.31, P = 0.25). Overall, 10.3% of patients underwent TJR within 6 months. TJR was less likely for AA patients than for white patients of similar age and disease severity (OR = 0.41, 95% CI = 0.16–1.05, P = 0.06), but this difference was reduced after adjusting for whether patients had received a recommendation for the procedure at the index visit (OR = 0.57, 95% CI = 0.21–1.54, P = 0.27). CONCLUSIONS In this study, race differences in patient preferences for TJR appeared to underlie race differences in TJR recommendations, which led to race differences in utilization of the procedure. Our findings suggest that patient treatment preferences play an important role in racial disparities in TJR utilization in the orthopedic setting.

Materials whose luminescence can be switched by optical stimulation drive technologies ranging from superresolution imaging 1 – 4 , nanophotonics 5 , and optical data storage 6 , 7 , to targeted pharmacology, optogenetics, and chemical reactivity 8 . These photoswitchable probes, including organic fluorophores and proteins, can be prone to photodegradation and often operate in the ultraviolet or visible spectral regions. Colloidal inorganic nanoparticles 6 , 9 can offer improved stability, but the ability to switch emission bidirectionally, particularly with near-infrared (NIR) light, has not, to our knowledge, been reported in such systems. Here, we present two-way, NIR photoswitching of avalanching nanoparticles (ANPs), showing full optical control of upconverted emission using phototriggers in the NIR-I and NIR-II spectral regions useful for subsurface imaging. Employing single-step photodarkening 10 – 13 and photobrightening 12 , 14 – 16 , we demonstrate indefinite photoswitching of individual nanoparticles (more than 1,000 cycles over 7 h) in ambient or aqueous conditions without measurable photodegradation. Critical steps of the photoswitching mechanism are elucidated by modelling and by measuring the photon avalanche properties of single ANPs in both bright and dark states. Unlimited, reversible photoswitching of ANPs enables indefinitely rewritable two-dimensional and three-dimensional multilevel optical patterning of ANPs, as well as optical nanoscopy with sub-Å localization superresolution that allows us to distinguish individual ANPs within tightly packed clusters. This study reports unlimited near-infrared photoswitching in inorganic avalanching nanoparticles via a discrete shift of threshold intensity mediated by internal defect-based colour centres.

Piezoelectrics made simple Application of mechanical force to a piezo­electric material generates a voltage; conversely, apply a voltage and you get a force. This combination of properties has many applications, primarily in the generation of ultrasound. The largest electromechanical responses tend to occur in highly complex materials, and the desired properties tend to be maximum when associated with a 'morphotropic' phase transition — an abrupt structural change usually linked to changes in composition. Muhtar Ahart et al . show that a similar phase transition can occur in a simple, pure compound, under high pressure. The compound is the prototypical ferroelectric, lead titanate, and it produces an electro-mechanical response larger than any known. It may be possible to chemically tune these effects to ambient pressures, which would potentially reduce the costs and enhance the utility of high-performance piezoelectric materials. This paper shows that even a pure compound, in this case lead titanate, can display a morphotropic phase boundary under pressure. The results are consistent with first principles theoretical predictions, but show a richer phase diagram than anticipated; moreover, the predicted electromechanical coupling at the transition is larger than any known. A piezoelectric material is one that generates a voltage in response to a mechanical strain (and vice versa). The most useful piezoelectric materials display a transition region in their composition phase diagrams, known as a morphotropic phase boundary 1 , 2 , where the crystal structure changes abruptly and the electromechanical properties are maximal. As a result, modern piezoelectric materials for technological applications are usually complex, engineered, solid solutions, which complicates their manufacture as well as introducing complexity in the study of the microscopic origins of their properties. Here we show that even a pure compound, in this case lead titanate, can display a morphotropic phase boundary under pressure. The results are consistent with first-principles theoretical predictions 3 , but show a richer phase diagram than anticipated; moreover, the predicted electromechanical coupling at the transition is larger than any known. Our results show that the high electromechanical coupling in solid solutions with lead titanate is due to tuning of the high-pressure morphotropic phase boundary in pure lead titanate to ambient pressure. We also find that complex microstructures or compositions are not necessary to obtain strong piezoelectricity. This opens the door to the possible discovery of high-performance, pure-compound electromechanical materials, which could greatly decrease costs and expand the utility of piezoelectric materials.

Extramedullary disease (EMD), an aggressive form of multiple myeloma (MM), may require a multi-targeted treatment approach rather than standard MM therapies. While precise EMD treatment outcome estimates remain challenging given small clinical trial patient numbers, pooled estimates across studies may increase outcome precision. Meta-regression analyses used Bayesian multilevel, random-effects modeling of patients with and without EMD across nine historical clinical studies of standard treatment regimens, including daratumumab, for relapsed/refractory multiple myeloma (RRMM) from 2013 to 2019. EMD was defined as soft tissue plasmacytomas noncontiguous with bone (“true” EMD). Adjustments were performed to account for differences in baseline age, number of prior lines of therapy (LOT), and International Staging System (ISS) stage. Outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). In patients with EMD ( n  = 158) versus without EMD ( n  = 2706), pooled ORR (95% credible interval) was 20.7% (11.7–33.9) versus 66.2% (53.0–77.4) with an odds ratio of 0.13 (0.09–0.20), pooled median PFS was 6.3 (4.2–9.5) versus 12.9 (8.8–18.8) months with a hazard ratio of 1.95 (1.63–2.32), and pooled median OS was 21.0 (15.9–27.9) versus 39.0 (31.0–48.5) months with a hazard ratio of 1.87 (1.53–2.26). Poorer outcomes in patients with versus without EMD were consistent following adjustment for age, number of prior LOT, and ISS stage. These results in patients with RRMM treated with standard treatment regimens confirmed notably worse outcomes in patients with versus without EMD, emphasizing continued unmet clinical need in this patient population.

Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination. Longitudinal sampling is used to map the evolution of an HIV-1 virus from the time of infection, and the co-evolution of a broadly neutralizing antibody in the same infected patient; the findings have important implications for HIV vaccine development. Pattern of HIV growth and antibody formation Hua-Xin Liao et al . followed the evolution of an HIV-1 virus, and the concurrent co-evolution of a CD4-binding-site broadly neutralizing antibody (BnAb), from the time of infection of a single African patient for a period of more than 3 years. The neutralizing antibody, of CH103 lineage, is a new type of BnAb that binds in a completely loop-based manner that differs from that of VRC01 class monoclonal antibodies — the CH103 lineage is less mutated, with fewer unusual macromutations and may be easier to induce. This work has implications for HIV vaccine development, suggesting viral strains that might generate broadly neutralizing antibodies within the host.

Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3–4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0–1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0–1 (23 [28%] vs three [4%], difference 24% [95% CI 13–34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29–55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. Sanofi and Regeneron Pharmaceuticals

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ–induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti–PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

Among previously untreated patients with HCV genotype 1 infection, three new antiviral agents, with or without ribavirin, resulted in high rates of sustained virologic response. Omission of ribavirin resulted in reduced response in genotype 1a infection but not in genotype 1b infection. Hepatitis C virus (HCV) infection is a worldwide health issue, with 3 million to 4 million new infections yearly and infection rates as high as 5% in some countries. 1 Chronic infection leads to liver disease, cirrhosis, or liver cancer in a large proportion of infected persons, and hepatitis C accounts for 25% of all liver cancers, representing the leading indication for liver transplantation. 1 – 3 Genotype 1 is the most common HCV genotype worldwide and includes 11 subgenotypes, of which 1a and 1b are responsible for the vast majority of infections. 4 Genotype 1b infection is the most prevalent form worldwide, particularly . . .

HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses. A phase 1-2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%-22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%-24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%-22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%-36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%-35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%-35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%-76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%-33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%-37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%-38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain. In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination. ClinicalTrials.gov NCT02404311. South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

Background Photocopiers emit nanoparticles with complex chemical composition. Short-term exposures to modest nanoparticle concentrations triggered upper airway inflammation and oxidative stress in healthy human volunteers in a recent study. To further understand the toxicological properties of copier-emitted nanoparticles, we studied in-vitro their ability to induce cytotoxicity, pro-inflammatory cytokine release, DNA damage, and apoptosis in relevant human cell lines. Methods Three cell types were used: THP-1, primary human nasal- and small airway epithelial cells. Following collection in a large volume photocopy center, nanoparticles were extracted, dispersed and characterized in the cell culture medium. Cells were doped at 30, 100 and 300 μg/mL administered doses for up to 24 hrs. Estimated dose delivered to cells, was ~10% and 22% of the administered dose at 6 and 24 hrs, respectively. Gene expression analysis of key biomarkers was performed using real time quantitative PCR (RT-qPCR) in THP-1 cells at 5 μg nanoparticles/mL for 6-hr exposure for confirmation purposes. Results Multiple cytokines, GM-CSF, IL-1β, IL-6, IL-8, IFNγ, MCP-1, TNF-α and VEGF, were significantly elevated in THP-1 cells in a dose-dependent manner. Gene expression analysis confirmed up-regulation of the TNF-α gene in THP-1 cells, consistent with cytokine findings. In both primary epithelial cells, cytokines IL-8, VEGF, EGF, IL-1α, TNF-α, IL-6 and GM-CSF were significantly elevated. Apoptosis was induced in all cell lines in a dose-dependent manner, consistent with the significant up-regulation of key apoptosis-regulating genes P53 and Casp8 in THP-1 cells. No significant DNA damage was found at any concentration with the comet assay. Up-regulation of key DNA damage and repair genes, Ku70 and Rad51, were also observed in THP-1 cells, albeit not statistically significant. Significant up-regulation of the key gene HO1 for oxidative stress, implicates oxidative stress induced by nanoparticles. Conclusions Copier-emitted nanoparticles induced the release of pro-inflammatory cytokines, apoptosis and modest cytotoxicity but no DNA damage in all three-human cell lines. Taken together with gene expression data in THP-1 cells, we conclude that these nanoparticles are directly responsible for inflammation observed in human volunteers. Further toxicological evaluations of these nanoparticles, including across different toner formulations, are warranted.