Pregnancy enables antibody protection against intracellular infection.

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.

Design and Implementation of a Didactic Curriculum in a Large Neonatal-Perinatal Medicine Fellowship Program: A Single-center Experience.

OBJECTIVE: Although the Accreditation Council for Graduate Medical Education and American Board of Pediatrics (ABP) provide regulations and guidance on fellowship didactic education, each program establishes their own didactic schedules to address these learning needs. Wide variation exists in content, educators, amount of protected educational time, and the format for didactic lectures. This inconsistency can contribute to fellow dissatisfaction, a perceived poor learning experience, and poor attendance. Our objective was to create a Neonatal-Perinatal Medicine (NPM) fellow curriculum based on adult learning theory utilizing fellow input to improve the perceived fellow experience. STUDY DESIGN: A needs assessment of current NPM fellows at Cincinnati Children's Hospital was conducted to guide the development of a new curriculum. Fellow perception of educational experience and board preparedness before and after introduction of the new curriculum was collected. Study period was from October 2018 to July 2021. RESULTS: One hundred percent of the fellows responded to the needs assessment survey. A response rate of 100 and 87.5% were noted on mid-curriculum survey and postcurriculum survey, respectively. Key themes identified and incorporated into the curriculum included schedule structure, content, and delivery mode. A new didactic curriculum implementing a consistent schedule of shorter lectures grouped by organ system targeting ABP core content was created. After curriculum implementation, fellows had higher self-perception of board preparedness, and overall improved satisfaction. CONCLUSION: Our positive experience in implementing this curriculum provides a framework for individual programs to implement similar curricula, and could be utilized to aid in development of national NPM curricula. KEY POINTS: · Fellowship didactic education varies significantly resulting in learner dissatisfaction and poor attendance.. · Widespread need to restructure didactic curricula exists.. · Our study provides a framework for future curricula..

Driving adoption of new technologies in biopharmaceutical manufacturing.

The challenge of introducing new technologies into established industries is not a problem unique to the biopharmaceutical industry. However, it may be critical to the long-term competitiveness of individual manufacturers and, more importantly, the ability to deliver therapies to patients. This is especially true for new treatment modalities including cell and gene therapies. We review several barriers to technology adoption which have been identified in various public forums including business, regulatory, technology, and people-driven concerns. We also summarize suitable enablers addressing one or more of these barriers along with suggestions for developing synergies or connections between innovation in product discovery and manufacturing or across the supplier, discovery, manufacturing, and regulatory arms of the holistic innovation engine.

Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection.

BACKGROUND: Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses. RESULTS: Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1-/- recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7- TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection. CONCLUSIONS: This study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.

Designing fast and efficient electrically driven phase change photonics using foundry compatible waveguide-integrated microheaters.

Phase change chalcogenides such as Ge2Sb2Te5 (GST) have recently enabled advanced optical devices for applications such as in-memory computing, reflective displays, tunable metasurfaces, and reconfigurable photonics. However, designing phase change optical devices with reliable and efficient electrical control is challenging due to the requirements of both high amorphization temperatures and extremely fast quenching rates for reversible switching. Here, we use a Multiphysics simulation framework to model three waveguide-integrated microheaters designed to switch optical phase change materials. We explore the effects of geometry, doping, and electrical pulse parameters to optimize the switching speed and minimize energy consumption in these optical devices.

Biomanufacturing readiness levels [BRL]-A shared vocabulary for biopharmaceutical technology development and commercialization.

The Manufacturing Readiness Levels (MRLs) developed by the Department of Defense are well-established tools for describing the maturity of new technologies resulting from government-sponsored Research and Development programs, from the concept phase to commercial deployment. While MRLs are generally applicable to a wide range of industries and technologies, there is significant value in offering an industry-specific view on how the basic principles may be applied to biomanufacturing. This paper describes Biomanufacturing Readiness Levels (BRLs) developed by the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), a public/private partnership that is part of the Manufacturing USA network. NIIMBL brings together private, federal, nonprofit, and academic stakeholders to accelerate the deployment of innovative technologies for biopharmaceutical production and to educate and train a world-leading biomanufacturing workforce. We anticipate that these BRLs will lay the groundwork for a shared vocabulary for assessment of technology maturity and readiness for commercial biomanufacturing that effectively meets the needs of this critical, specialized, and highly regulated industry.

Persistent Zika Virus Clinical Susceptibility despite Reduced Viral Burden in Mice with Expanded Virus-Specific CD8+ T Cells Primed by Recombinant Listeria monocytogenes.

Vaccines against Zika virus (ZIKV) infection that target CD8+ T cells are of considerable interest because Abs may enhance infection susceptibility. However, whether CD8+ T cells are protective or promote susceptibility to clinical infection symptoms remains uncertain. To more precisely investigate ZIKV-specific CD8+ T cells in isolation, we engineered a Listeria monocytogenes-based vector to express a single MHC class I-restricted immune dominant peptide, E294-302, from ZIKV envelope protein. We show accumulation of activated ZIKV-specific CD8+ T cells primed by recombinant L. monocytogenes is associated with reductions in circulating virus levels after ZIKV challenge in type I IFN receptor-deficient mice and wildtype mice administered neutralizing Abs against type I IFN receptor. Interestingly, susceptibility to ZIKV clinical infection including weight loss and mortality each persists and is neither significantly improved nor worsened compared with isogenic L. monocytogenes-primed control mice. These data demonstrating persistent ZIKV clinical susceptibility despite reduced viral burden in mice with expanded virus-specific CD8+ T cells highlights the need for targeting other adaptive immune components in developing vaccines against ZIKV infection.

Bioindustrial manufacturing readiness levels (BioMRLs) as a shared framework for measuring and communicating the maturity of bioproduct manufacturing processes.

Readiness level (RL) frameworks such as technology readiness levels and manufacturing readiness levels describe the status of a technology/manufacturing process on its journey from initial conception to commercial deployment. More importantly, they provide a roadmap to guide technology development and scale-up from a ''totality of system'' approach. Commercialization risks associated with too narrowly focused R&D efforts are mitigated. RLs are defined abstractly so that they can apply to diverse industries and technology sectors. However, differences between technology sectors make necessary the definition of sector specific RL frameworks. Here, we describe bioindustrial manufacturing readiness levels (BioMRLs), a classification system specific to bioindustrial manufacturing. BioMRLs will give program managers, investors, scientists, and engineers a shared vocabulary for prioritizing goals and assessing risks in the development and commercialization of a bioindustrial manufacturing process.

End-to-end collaboration to transform biopharmaceutical development and manufacturing.

An ambitious 10-year collaborative program is described to invent, design, demonstrate, and support commercialization of integrated biopharmaceutical manufacturing technology intended to transform the industry. Our goal is to enable improved control, robustness, and security of supply, dramatically reduced capital and operating cost, flexibility to supply an extremely diverse and changing portfolio of products in the face of uncertainty and changing demand, and faster product development and supply chain velocity, with sustainable raw materials, components, and energy use. The program is organized into workstreams focused on end-to-end control strategy, equipment flexibility, next generation technology, sustainability, and a physical test bed to evaluate and demonstrate the technologies that are developed. The elements of the program are synergistic. For example, process intensification results in cost reduction as well as increased sustainability. Improved robustness leads to less inventory, which improves costs and supply chain velocity. Flexibility allows more products to be consolidated into fewer factories, reduces the need for new facilities, simplifies the acquisition of additional capacity if needed, and reduces changeover time, which improves cost and velocity. The program incorporates both drug substance and drug product manufacturing, but this paper will focus on the drug substance elements of the program.

Roadmap on emerging hardware and technology for machine learning.

Recent progress in artificial intelligence is largely attributed to the rapid development of machine learning, especially in the algorithm and neural network models. However, it is the performance of the hardware, in particular the energy efficiency of a computing system that sets the fundamental limit of the capability of machine learning. Data-centric computing requires a revolution in hardware systems, since traditional digital computers based on transistors and the von Neumann architecture were not purposely designed for neuromorphic computing. A hardware platform based on emerging devices and new architecture is the hope for future computing with dramatically improved throughput and energy efficiency. Building such a system, nevertheless, faces a number of challenges, ranging from materials selection, device optimization, circuit fabrication and system integration, to name a few. The aim of this Roadmap is to present a snapshot of emerging hardware technologies that are potentially beneficial for machine learning, providing the Nanotechnology readers with a perspective of challenges and opportunities in this burgeoning field.

Tacrolimus exposure windows responsible for Listeria monocytogenes infection susceptibility.

Tacrolimus is widely used to prevent graft rejection after allogeneic transplantation by suppressing T cells in a non-antigen-specific fashion. Global T-cell suppression makes transplant recipients more susceptible to infection, especially infection by opportunistic intracellular pathogens. Infection followed by secondary challenge with the opportunistic intracellular bacterial pathogen, Listeria monocytogenes, was used to probe when tacrolimus most significantly impacts antimicrobial host defense. Tacrolimus-treated mice showed no difference in innate susceptibility following primary infection, whereas susceptibility to secondary challenge was significantly increased. Modifying the timing of tacrolimus initiation with respect to primary infection compared with secondary challenge showed significantly reduced susceptibility in tacrolimus-treated mice where tacrolimus was discontinued prior to secondary challenge. Thus, tacrolimus overrides protection against secondary infection primed by primary infection (and presumably live attenuated vaccines), with the most critical window for tacrolimus-induced infection susceptibility being exposure immediately prior to secondary challenge. These results have important implications for strategies designed to boost antimicrobial T-cell-mediated immunity in transplant recipients.

Clinical and radiologic outcomes of eccentric glenosphere versus concentric glenosphere in reverse shoulder arthroplasty.

BACKGROUND: The use of an eccentric glenosphere (EG) has been proposed as a way to prevent scapular notching in reverse shoulder arthroplasty (RSA). The purpose of this study was to investigate whether the use of an EG decreases scapular notching compared with matched standard concentric glenosphere (CG) controls. METHODS: A retrospective analysis was performed. This study included 49 RSAs with an EG and 49 paired RSAs with a CG with a minimum 60 months of both clinical and radiographic follow-up. Clinical and radiologic outcomes of the EG and CG groups were compared at inclusion and at the last follow-up using the paired Student t test for quantitative data and the χ2 test for qualitative data. Scapular notching was graded according to the Sirveaux classification. Statistical significance was set at P < .05. RESULTS: Notching was observed 2.7 times (95% confidence interval, 1.0-6.8 times) more often in the CG group (P = .037). The difference in notching severity between the groups was not statistically relevant; however, there was a trend toward more severe notching in the CG group (P = .059). Compared with a CG, an EG did not increase the percentage of radiolucent lines around the screws (3% vs. 1.5%, P = .62), around the post (3% vs. 1.5%, P = .62), or below the baseplate (15% vs. 7.5%, P = .18). CONCLUSION: EGs are associated with less notching than CGs. This finding confirms that RSA with an EG is an effective procedure without specific complications at a minimum follow-up of 5 years.

The Problem of Fairness in Synthetic Healthcare Data.

Access to healthcare data such as electronic health records (EHR) is often restricted by laws established to protect patient privacy. These restrictions hinder the reproducibility of existing results based on private healthcare data and also limit new research. Synthetically-generated healthcare data solve this problem by preserving privacy and enabling researchers and policymakers to drive decisions and methods based on realistic data. Healthcare data can include information about multiple in- and out- patient visits of patients, making it a time-series dataset which is often influenced by protected attributes like age, gender, race etc. The COVID-19 pandemic has exacerbated health inequities, with certain subgroups experiencing poorer outcomes and less access to healthcare. To combat these inequities, synthetic data must "fairly" represent diverse minority subgroups such that the conclusions drawn on synthetic data are correct and the results can be generalized to real data. In this article, we develop two fairness metrics for synthetic data, and analyze all subgroups defined by protected attributes to analyze the bias in three published synthetic research datasets. These covariate-level disparity metrics revealed that synthetic data may not be representative at the univariate and multivariate subgroup-levels and thus, fairness should be addressed when developing data generation methods. We discuss the need for measuring fairness in synthetic healthcare data to enable the development of robust machine learning models to create more equitable synthetic healthcare datasets.

Midterm clinical and radiologic results of reverse shoulder arthroplasty with an eccentric glenosphere.

BACKGROUND: An eccentric glenosphere (EG) has been proposed as a way of preventing scapular notching after reverse shoulder arthroplasty (RSA). Our aim was to report the midterm clinical and radiographic results of EG after RSA. A number of the patients described here were included in a previous study with short-term follow-up. The current retrospective study gave us the opportunity to follow many of these patients for a longer period of time. METHODS: A retrospective analysis of prospectively collected data was conducted. Statistical significance was set at P < .001. Forty-nine RSAs with an EG and at least 60 months of follow-up were included. Range of motion (ROM), Constant scores (CSs), and Subjective Shoulder Value (SSV) were assessed. Scapular notching was graded according to the Sirveaux classification. RESULTS: At the last follow-up, the mean improvement in active elevation (ROM) was 46° and the mean CS increased by nearly 31 points (both groups P < .001). The final SSV was 70%. Twenty-one patients (43%) had scapular notching, but in two-thirds of patients it was low-grade. CONCLUSION: The use of an EG provided excellent clinical outcomes that persisted with midterm follow-up. The rate of notching was lower than in other studies with EGs, but further studies are required to confirm this. An EG was safe and there were no issues with baseplate loosening or failure.

Failure of Adjustably Aligned Modular Radial Head Arthroplasty With Head-Neck Dissociation and Metallosis.

Radial head arthroplasty was introduced in 1941 and the literature supports satisfactory overall midterm patient outcomes and acceptable complication profiles with several models. There are several previously described mechanisms by which radial head complications typically occur. We present the case of a rarely described mechanism of radial head implant failure: elbow synovitis and pain from partial dissociation and metallosis in an adjustably aligned, modular, monopolar, mixed metal, press-fit radial head arthroplasty.

Grammont Award 2018: Scapular fractures in reverse shoulder arthroplasty (Grammont style): prevalence, functional, and radiographic results with minimum 5-year follow-up.

BACKGROUND: Scapular fractures after reverse shoulder arthroplasty (RSA) are an increasingly reported complication. Information is missing regarding midterm to long-term follow-up consequences. The aim of this study was to determine the rate of scapular fracture (acromial base and spine) after Grammont-style RSA and to report functional and radiographic results of patients with a minimum 5-year follow-up. MATERIALS AND METHODS: We retrospectively reviewed 1953 Grammont-style RSAs in 1745 patients in a multicenter study. Of these, 953 patients (1035 RSAs) had minimum 5-year follow-up for functional and radiographic assessment (anteroposterior and scapular Y views. RESULTS: Twenty-six patients (1.3%) had sustained a scapular fracture; of these, 19 (10 acromial base and 9 spine fractures) had minimum 5-year follow-up and were reviewed at a mean follow-up of 97 months. Three patients (15.8%) were diagnosed at the last follow-up after an undiagnosed fracture. There were 3 traumatic cases (15.8%) and 13 (68.4%) without antecedent trauma. These 16 patients underwent nonoperative treatment. The fracture was healed in 8 (4 acromion and 4 spine). The average active forward elevation was 109° (range, 50°-170°), and the Constant score was 47.0 points (range, 8-81 points). CONCLUSIONS: Scapular fractures after Grammont-style RSAs are rare (1.3%) but remain a concern. These fractures occur mainly in the early postoperative 6 months. Immobilization with an abduction splint frequently resulted in nonunion or malunion. Final functional outcomes are poor regardless of acromial or spine fracture compared with primary RSA without fracture.

Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.

Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8(+) T cell (TCD8) functional impairment during acute viral LRI, but the role of TCD8 impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus infection induces virus-specific lung TCD8 that fail to produce effector cytokines or degranulate late postinfection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung TCD8 upregulated multiple inhibitory receptors, including PD-1, lymphocyte activation gene 3 (LAG-3), T cell Ig mucin 3, and 2B4. Moreover, coexpression of these receptors continued to increase even after viral clearance, with most virus-specific lung TCD8 expressing three or more inhibitory receptors on day 14 postinfection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and APCs, further establishing an inhibitory environment. In vitro Ab blockade revealed that multiple inhibitory receptors contribute to TCD8 impairment induced by either human metapneumovirus or influenza virus infection. In vivo blockade of T cell Ig mucin 3 signaling failed to enhance TCD8 function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored TCD8 effector functions but increased lung pathology, indicating that LAG-3 mediates lung TCD8 impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung TCD8 functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung TCD8 impairment may prevent immunopathology but also contributes to recurrent lung infections.

Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype.

Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag-induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.

Evaluation of Fixation Techniques for Metatarsocuneiform Arthrodesis.

First metatarsocuneiform joint arthrodesis has been used in foot and ankle surgery for the treatment of hallux abductovalgus deformity, among other pedal pathologic entities. The goal of the present retrospective study was to compare the fusion rates and complications of an intraplate compression screw fixation, crossing solid core screw fixation, and a single interfragmentary screw with a simple locking plate. All procedures were performed by a single surgeon, and all patients received an identical postoperative protocol. A medical record review was performed of 147 evenly distributed surgical methods. All patients were non-weightbearing by protocol for 4 weeks. The patient covariates included sex, age, nicotine status, osteoporosis, and diabetes. These variables were balanced among the treatment groups and were noncontributory, with the exception of sex. Male patients had a 6 times greater odds of experiencing nonunion. The overall nonunion rate was 6.7%, with 4% symptomatic and requiring revision. The individual nonunion rates for each method were 2% for intraplate compression screw fixation, 5% for single interfragmentary screw with locking plate fixation, and 9% for crossing solid core screw fixation. None of the differences reached statistical significance. The corresponding hardware removal rates were 12%, 11%, and 0%.

Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication.

UNLABELLED: Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR(-/-)) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells of IFNAR(-/-) mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8(+) T cells of IFNAR(-/-) mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1(low) dendritic cells (DCs), but not PD-L1(high) alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8(+) T cell impairment. IMPORTANCE: Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8(+) T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8(+) T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8(+) T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8(+) T cell impairment.