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For over a century, transfusion of convalescent plasma from recovered individuals has been tried as a therapeutic approach when a novel pathogen emerges. As the world awaits SARS-CoV-2 vaccines to be tested and safely deployed, the rapidity with which antiviral monoclonal antibodies can be isolated and engineered offers an attractive alternative option for passive immunization.In this Comment, Jonathan Abraham highlights the potential of passive immunization strategies for COVID-19.

The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently slow, not always accessible and poorly compatible with many antigens. Here, we describe ‘autonomous hypermutation yeast surface display’ (AHEAD), a synthetic recombinant antibody generation technology that imitates somatic hypermutation inside engineered yeast. By encoding antibody fragments on an error-prone orthogonal DNA replication system, surface-displayed antibody repertoires continuously mutate through simple cycles of yeast culturing and enrichment for antigen binding to produce high-affinity clones in as little as two weeks. We applied AHEAD to generate potent nanobodies against the SARS-CoV-2 S glycoprotein, a G-protein-coupled receptor and other targets, offering a template for streamlined antibody generation at large. Autonomous hypermutation yeast surface display (AHEAD) mimics the process of somatic hypermutation in animals to enable the rapid in vitro evolution of antibodies, including nanobodies targeting the RBD of SARS-CoV-2.

ObjectiveCellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development.DesignTo uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment.ResultsWe found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma.ConclusionsThese findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

BackgroundOutpatient primary care experience is vital to internal medicine resident training but may impact quality and equity of care delivered in practices that include resident physicians. Understanding whether quality differences exist among resident and staff primary care physicians (PCPs) may present an opportunity to address health disparities within academic medical centers.ObjectiveTo determine whether there are differences in the quality of primary care provided by resident PCPs compared to staff PCPs.DesignA retrospective cohort study with a propensity-matched analysis.Participants143,274 patients, including 10,870 patients managed by resident PCPs, seen in 16 primary care practices affiliated with an academic medical center.Main MeasuresGuideline-concordant chronic disease management of diabetes (HbA1c, LDL) and coronary artery disease (LDL), preventive breast, cervical, and colorectal cancer screening, and resource utilization measures including emergency department (ED) visits, hospitalizations, high-cost imaging, and patient-reported health experience.Key ResultsAt baseline, there were significant differences in sociodemographic and clinical characteristics between resident and staff physician patients. Resident patients were less likely to achieve chronic disease and preventive cancer screening outcome measures including LDL at goal (adjusted OR [aOR] 0.77 [95% CI 0.65, 0.92]) for patients with coronary artery disease; HbA1c at goal (aOR 0.73 [95% CI 0.62, 0.85]) for patients with diabetes; breast (aOR 0.56 [95% CI 0.49, 0.63]), cervical (aOR 0.66 [95% CI 0.60, 0.74]), and colorectal (aOR 0.72 [95% CI 0.65, 0.79] cancer screening. Additionally, resident patients had higher rates of ED visits and hospitalizations but lower rates of high-cost imaging. Resident patients reported lower rates of satisfaction with certain access to care and communication measures. Similar outcomes were noted in propensity-matched sensitivity analyses.ConclusionAfter controlling for differences in sociodemographic and clinical factors, resident patients were less likely to achieve chronic disease and preventive cancer screening outcomes compared to staff patients. Further efforts to address ambulatory trainee education and primary care quality along with novel approaches to the management of the disproportionately disadvantaged resident patient panels are needed.

Transferrin Receptor (TfR1) is the cell-surface receptor that regulates iron uptake into cells, a process that is fundamental to life. However, TfR1 also facilitates the cellular entry of multiple mammalian viruses. We use evolutionary and functional analyses of TfR1 in the rodent clade, where two families of viruses bind this receptor, to mechanistically dissect how essential housekeeping genes like TFR1 successfully balance the opposing selective pressures exerted by host and virus. We find that while the sequence of rodent TfR1 is generally conserved, a small set of TfR1 residue positions has evolved rapidly over the speciation of rodents. Remarkably, all of these residues correspond to the two virus binding surfaces of TfR1. We show that naturally occurring mutations at these positions block virus entry while simultaneously preserving iron-uptake functionalities, both in rodent and human TfR1. Thus, by constantly replacing the amino acids encoded at just a few residue positions, TFR1 divorces adaptation to ever-changing viruses from preservation of key cellular functions. These dynamics have driven genetic divergence at the TFR1 locus that now enforces species-specific barriers to virus transmission, limiting both the cross-species and zoonotic transmission of these viruses.

Eastern equine encephalitis virus (EEEV) is the most virulent alphavirus that infects humans, and many survivors develop neurological sequelae, including paralysis and intellectual disability. Alphavirus spike proteins comprise trimers of heterodimers of glycoproteins E2 and E1 that mediate binding to cellular receptors and fusion of virus and host cell membranes during entry. We recently identified very-low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as cellular receptors for EEEV and a distantly related alphavirus, Semliki Forest virus (SFV). Here, we use single-particle cryo-electron microscopy (cryo-EM) to determine structures of the EEEV and SFV spike glycoproteins bound to the VLDLR ligand-binding domain and found that EEEV and SFV interact with the same cellular receptor through divergent binding modes. Our studies suggest that the ability of LDLR-related proteins to interact with viral spike proteins through very small footprints with flexible binding modes results in a low evolutionary barrier to the acquisition of LDLR-related proteins as cellular receptors for diverse sets of viruses. Alphaviruses include several important human pathogens with outbreak potential. Here, the authors found that eastern equine encephalitis virus and Semliki Forest virus use distinct surfaces on their spike proteins to bind their shared receptor, VLDLR.

Early treatment (i.e., soon after the onset of Covid-19 symptoms) with monoclonal antibodies that target the SARS-CoV-2 spike protein reduces the risks of Covid-19–related hospitalization and death. 1-3 Yet, despite the success of these interventions, in response to continued pressure from human immune responses, the SARS-CoV-2 spike protein has evolved to evade almost all available monoclonal antibody–based drugs. 4 In this issue of the Journal , Levin et al. 5 report on the use of AZD7442 (tixagevimab–cilgavimab) for the prevention of Covid-19. Tixagevimab and cilgavimab are monoclonal antibodies that target the SARS-CoV-2 spike protein. Both were derived from B cells obtained from persons infected . . .

Optimal clinical outcomes in cancer treatments could be achieved through the development of reliable, precise ex vivo tumor models that function as drug screening platforms for patient-targeted therapies. Microfluidic tumor-on-chip technology is emerging as a preferred tool since it enables the complex set-ups and recapitulation of the physiologically relevant physical microenvironment of tumors. In order to overcome the common hindrances encountered while using this technology, a fully 3D-printed device was developed that sustains patient-derived multicellular spheroids long enough to conduct multiple drug screening tests. This tool is both cost effective and possesses four necessary characteristics of effective microfluidic devices: transparency, biocompatibility, versatility, and sample accessibility. Compelling correlations which demonstrate a clinical proof of concept were found after testing and comparing different chemotherapies on tumor spheroids, derived from ten patients, to their clinical outcomes. This platform offers a potential solution for personalized medicine by functioning as a predictive drug-performance tool. A unique 3D-printed device made of sustainable materials was developed to produce 3D spheroids from primary cells and perform drug screening assays in a biomimetic environment.

Objective To assess patients’ compliance with post-operative rehabilitation protocols following orthopaedic lower limb surgeries, and to identify clinical, demographic, and socioeconomic factors leading to variability in compliance within and across different types of surgeries performed. Methods This was a prospective study conducted in a tertiary healthcare hospital in South India. 240 patients who underwent orthopaedic lower limb surgery under the same unit, aged above 18 years, with cognitive capability to comprehend rehabilitation protocols, were included in the study. Patient compliance was assessed according to five parameters: adherence to appointments, weight-bearing activities, exercises, use of walking aids, and intake of medications. Patients’ compliance is scored dichotomously for a total score of five, followed by statistical evaluation (binary and multivariate regression analysis) to identify factors leading to variability in compliance. Results 53.7% patients were compliant (5/5). The highest compliance was with the intake of medications (91.7%), and the lowest was weight-bearing advice (75.4%). Statistical significance observed for compliance with the appointment date and exercises advised. Males (58.2%) and married individuals (58.3%) with (p value = 0.041 and 0.022, respectively) demonstrated higher compliance. 70.5% of patients in the government scheme in arthroscopy surgeries demonstrated non-compliance. 76.2% married individuals were compliant in the subgroup of other surgeries. 70% females who underwent arthroplasty demonstrated non-compliance. However, no independent predictor was statistically significant in the regression analysis. Conclusion Understanding the factors leading to variation in compliance and tailoring the rehabilitation plan is essential to balance the intervention demands and the patient’s needs.

Background Giant inguinal hernia (GIH) is a rare condition in the developed world, and the literature is scarce. Case reports describe different techniques in an attempt to prevent abdominal compartment syndrome (ACS). We aimed to review our experience with GIH repair. Method A retrospective review of the medical records of all consecutive patients who underwent a tension-free mesh GIH repair using a transverse inguinal incision between 2014 and 2021 at a tertiary university referral center. In brief, the technique included head-down positioning, maximal pre-incision reduction of hernia contents, and repair with mesh. Follow-up was conducted in outpatient clinic. We compared the results to a time-based open standard inguinal hernia repair group (control group). Results During the study period, 58 patients underwent an open GIH repair with mesh without abdominal preparation. 232 patients were included in the control group. The mean surgery duration was 125.5 min in the GIH group and 84 min in the control group (p < 0.001). Bowel resection was not necessary in any case. In-hospital complication rates were 13.8% vs. 5.6% in the GIH and control groups, respectively (p = 0.045). Early complication rates (up to 30 days post-operatively) were 62.1% vs. 14.7% in the GIH and control groups, respectively (p < 0.001). Late complications rate was similar (p = 0.476). ACS and mortality were not reported. No recurrence event was reported in the GIH group. Conclusion Tension-free mesh repair for GIH using a standard transverse inguinal incision is feasible and safe and there is no need for abdominal cavity preparation. Early complications are more common than in the control group, but there were no higher rate of late or severe complications and no recurrence event.