Modular synthesis of functional libraries by accelerated SuFEx click chemistry.

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.

Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have the potential to remuscularize infarcted hearts but their arrhythmogenicity remains an obstacle to safe transplantation. Myofibroblasts are the predominant cell-type in the infarcted myocardium but their impact on transplanted hiPSC-CMs remains poorly defined. Here, we investigate the effect of myofibroblasts on hiPSC-CMs electrophysiology and Ca2+ handling using optical mapping of advanced human cell coculture systems mimicking cell-cell interaction modalities. Human myofibroblasts altered the electrophysiology and Ca2+ handling of hiPSC-CMs and downregulated mRNAs encoding voltage channels (KV4.3, KV11.1 and Kir6.2) and SERCA2a calcium pump. Interleukin-6 was elevated in the presence of myofibroblasts and direct stimulation of hiPSC-CMs with exogenous interleukin-6 recapitulated the paracrine effects of myofibroblasts. Blocking interleukin-6 reduced the effects of myofibroblasts only in the absence of physical contact between cell-types. Myofibroblast-specific connexin43 knockdown reduced functional changes in contact cocultures only when combined with interleukin-6 blockade. This provides the first in-depth investigation into how human myofibroblasts modulate hiPSC-CMs function, identifying interleukin-6 and connexin43 as paracrine- and contact-mediators respectively, and highlighting their potential as targets for reducing arrhythmic risk in cardiac cell therapy.

HGF/c-Met/ß1-integrin signalling axis induces tunneling nanotubes in A549 lung adenocarcinoma cells.

Tunneling nanotubes (TNTs) are thin cytoplasmic extensions involved in long-distance intercellular communication and can transport intracellular organelles and signalling molecules. In cancer cells, TNT formation contributes to cell survival, chemoresistance, and malignancy. However, the molecular mechanisms underlying TNT formation are not well defined, especially in different cancers. TNTs are present in non-small cell lung cancer (NSCLC) patients with adenocarcinoma. In NSCLC, hepatocyte growth factor (HGF) and its receptor, c-Met, are mutationally upregulated, causing increased cancer cell growth, survival, and invasion. This study identifies c-Met, ß1-integrin, and paxillin as novel components of TNTs in A549 lung adenocarcinoma cells, with paxillin localised at the protrusion site of TNTs. The HGF-induced TNTs in our study demonstrate the ability to transport lipid vesicles and mitochondria. HGF-induced TNT formation is mediated by c-Met and ß1-integrin in conjunction with paxillin, followed by downstream activation of MAPK and PI3K pathways and the Arp2/3 complex. These findings demonstrate a potential novel approach to inhibit TNT formation through targeting HGF/c-Met receptor and ß1-integrin signalling interactions, which has implications for multi-drug targeting in NSCLC.

Prevalence and Severity Distribution of Type 2 Inflammation-Related Comorbidities Among Patients with Asthma, Chronic Rhinosinusitis with Nasal Polyps, and Atopic Dermatitis.

This observational study assessed the prevalence of co-existing type 2 inflammatory conditions [T2Cs; asthma, atopic dermatitis (AD), allergic rhinitis, and chronic rhinosinusitis with nasal polyps (CRSwNP)] in patients with moderate-to-severe (M/S) type 2 asthma, M/S CRSwNP, or M/S AD, in the real-world setting. Data from 761 physicians in the US and EUR5 were sourced from Adelphi Disease-Specific Programmes covering patients with M/S asthma (n = 899), M/S CRSwNP (n = 683), and M/S AD (n = 1497). At least one T2C was identified in 66%, 69%, and 46% of M/S asthma, M/S CRSwNP, and M/S AD cohorts, respectively, and 24%, 36% and 16% had at least two T2Cs; trends were similar in the US and EUR5. In patients with M/S asthma or M/S CRSwNP, T2Cs commonly presented as mild or moderate. The comorbidity burden suggests that an integrated treatment approach is warranted to address underlying type 2 inflammation in patients with M/S type 2 diseases.

Experiences of a Multiethnic Cohort of Patients Enrolled in a Financial Reimbursement Program for Cancer Clinical Trials.

PURPOSE: Financial reimbursement programs (FRPs) offset out-of-pocket (OOP) expenses from therapeutic clinical trial (TCT) participation. The study explores patients' experience in TCTs after enrollment in a FRP at two academic medical centers, including barriers and opportunities to improve trial participation. METHODS: From May 2019 to January 2020, adults diagnosed with cancer and eligible for TCTs and FRP were recruited from the Improving Patient Access to Cancer Clinical Trials randomized trial at the University of California San Francisco and University of Southern California. Patients with income ≤ 700% of national poverty guidelines were eligible. Semistructured interviews were conducted in patients' preferred language. Qualitative analysis was performed by site and preferred language by two independent coders. RESULTS: Of 65 trial patients, 53 participated (38%, University of California San Francisco; 62%, USC). The median age was 59 (IQR, 46-65) years, and 58% were female. Nearly half (49%) identified as Latinx/Hispanic compared with 32% non-Hispanic White, 10% Asian, 4% Black, 1% Native American, and 4% Others. A third were non-English speakers, 42% had college education or more, and 55% were retired/unemployed. Most common malignancies were gastrointestinal (42%), breast (19%), and genitourinary (13%), and 66% had metastatic disease. Patients experienced long travel time (1-4.5 hours) among 57% and financial toxicity from OOP costs (68%). High acceptability of the FRP was reported (81%). Although 30% of patients reported willingness to discuss finances of cancer treatment/trial with physicians, majority (87%) preferred discussion with social workers or TCT staff. Proposed modifications to TCTs included decentralization, recruitment strategies, voucher structure, and established rates for OOP expenses. CONCLUSION: Patients' experience with TCTs reveal financial and logistical stressors that may be lessened by the Improving Patient Access to Cancer Clinical Trial reimbursement program. FRPs may address inequities in clinical trial access among low-income and diverse populations.

NIVOLUMAB-INDUCED HARADA-LIKE UVEITIS WITH BACILLARY DETACHMENT MIMICKING CHOROIDAL METASTASIS.

PURPOSE: To describe a patient with metastatic clear cell renal cell carcinoma in remission on maintenance nivolumab therapy who developed late-onset ocular toxicity manifesting as creamy chorioretinal lesions with exudative retinal detachment concerning for choroidal metastasis. METHOD: Case report. Main outcome measures include ophthalmoscopic examination, fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and B-scan ultrasonography. RESULTS: A 49-year-old woman with a medical history of metastatic clear cell renal cell carcinoma in remission for two years after immunotherapy with four cycles of ipilimumab and nivolumab followed by maintenance nivolumab infusions developed lesions concerning for choroidal metastases in her right eye. Optical coherence tomography of the lesions revealed a bacillary layer detachment containing possible fibrinous exudate organized into layers and underlying choroidal thickening with chorioretinal folds. Later, choroidal thickening and chorioretinal folds also occurred in the left eye. Given that pan imaging detected no metastasis and the posterior segment abnormalities resolved after cessation of nivolumab and treatment with systemic corticosteroids, the patient was diagnosed with nivolumab-induced Vogt-Koyanagi-Harada-like uveitis. CONCLUSION: This case expands on the clinical spectrum of nivolumab-induced Vogt-Koyanagi-Harada-like uveitis, a condition that can also present with bacillary layer detachment mimicking an early choroidal metastasis, manifest asymmetrically in each eye, and develop after long-standing treatment.

A 48-YEAR-OLD CAUCASIAN MAN WITH UNILATERAL "SMUDGE" IN INFERIOR VISUAL FIELD.

PURPOSE: To report an increasingly prevalent fundoscopic manifestation of syphilitic uveitis. METHODS: Case report of a patient with acute retinal necrosis secondary to syphilis. RESULTS: A 48-year-old man presented with decreased vision, anterior segment inflammation, and a wedge-shaped retinal lesion in the superior periphery, with a diaphanous leading edge extending down toward the superior arcade. The patient was HIV+ and poorly compliant with therapy. The top three differential diagnoses were herpetic necrotizing retinitis, syphilis, and lymphoma. An extensive lab workup was positive for syphilis. The patient was treated with IV penicillin G and demonstrated improvement in visual acuity and examination. CONCLUSION: There have been an increasing number of reports of syphilis patients, especially in the population of men who have sex with men, who present with fundus findings similar to acute retinal necrosis. These findings include a characteristic ground glass, translucent appearance of unifocal or multifocal lesions, primarily affecting the inner retina and sometimes associated with co-localizing occlusive vasculitis. Treatment with IV penicillin G is warranted and has demonstrated good visual recovery.

Adjuvanted recombinant zoster vaccine decreases herpes zoster-associated pain and the use of pain medication across 3 randomized, placebo-controlled trials.

ABSTRACT: Herpes zoster (HZ) and HZ-associated pain greatly affect patients' quality of life, particularly in older and immunocompromised adults, for whom comorbidities and polypharmacy are often reported. Three phase III, randomized, placebo-controlled clinical trials have reported the adjuvanted recombinant zoster vaccine (RZV) as highly efficacious in preventing HZ and reducing pain severity in healthy adults ≥50 years old (Zoster Efficacy Study [ZOE]-50 study, NCT01165177) and ≥70 years old (ZOE-70; NCT01165229) and in immunocompromised adults ≥18 years old undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414). Here, we investigated efficacy of RZV in reducing (i) the duration of clinically significant pain (Zoster Brief Pain Inventory pain score ≥3) and (ii) HZ-associated pain medication use and duration of use in participants with confirmed HZ ("breakthrough cases") from the 3 studies. Recombinant zoster vaccine effectively reduced the duration of clinically significant HZ-associated pain during HZ episodes by 38.5% ( P -value: 0.010) in the ZOE-HSCT study. Although a similar trend was observed in the ZOE-50 and ZOE-70 studies, the results were not statistically significant because of the high vaccine efficacy (VE) against HZ resulting in rare breakthrough cases. VE in reducing pain medication use (39.6%; P -value: 0.008) and duration of medication use (49.3%, P -value: 0.040) was reported in the ZOE-70 study; corresponding positive VE estimates were observed in the ZOE-50 and ZOE-HSCT studies but were not statistically significant. Data reported here demonstrate efficacy of RZV in reducing HZ-associated pain duration and pain medication use in breakthrough cases, thereby improving quality of life of those with HZ.

A highly photostable and versatile two-photon fluorescent probe for the detection of a wide range of intracellular nitric oxide concentrations in macrophages and endothelial cells.

Nitric oxide (NO) is involved in many biological processes affecting the cardiovascular, nervous and immune systems. Intracellular NO can be monitored using fluorescent probes in combination with fluorescence imaging techniques. Most of the currently available NO fluorescent molecular probes are excited via one-photon excitation using UV or Vis light, which results in poor penetration and high photodamage to living tissues. Here, we report a two-photon fluorescent molecular probe, DANPY-NO, able to detect NO in live cells. The probe consists of an o-phenylenediamine linked to a naphthalimide core; and operates via photoinduced electron transfer. DANPY-NO exhibits good sensitivity (LOD of 77.8 nM) and high selectivity towards NO, and is stable over a broad range of pHs. The probe targeted acidic organelles within macrophages and endothelial cells, and demonstrated enhanced photostability over a commercially available NO probe. DANPY-NO was used to selectively detect endogenous NO in RAW264.7ϒ NO- macrophages, THP-1 human leukemic cells, primary mouse (bone marrow-derived) macrophages and endothelial cells. The probe was also able to detect exogenous NO in endothelial cells and distinguish between increasing concentrations of NO. The NO detection was evidenced using confocal laser scanning and two-photon microscopies, and flow cytometry. Further evidence was obtained by recording the changes in the intracellular fluorescence emission spectrum of the probe. Importantly, the probe displayed negligible toxicity to the analysed biological samples. The excellent sensitivity, selectivity, stability and versatility of DANPY-NO confirm its potential for in vitro and in vivo imaging of NO.

Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis.

BACKGROUND: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials. OBJECTIVE: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis. METHODS: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/µL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented. RESULTS: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/µL; week 4: 515-578 cells/µL), CRSwNP (baseline: 440-448 cells/µL; week 16: 595 cells/µL), and atopic dermatitis (baseline: 434-600 cells/µL; week 4: 410-710 cells/µL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/µL; week 4: 230 cells/µL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy. CONCLUSIONS: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms.

Comparative accuracy and resolution assessment of two prototype proton computed tomography scanners.

BACKGROUND: Improving the accuracy of relative stopping power (RSP) in proton therapy may allow reducing range margins. Proton computed tomography (pCT) has been shown to provide state-of-the-art RSP accuracy estimation, and various scanner prototypes have recently been built. The different approaches used in scanner design are expected to impact spatial resolution and RSP accuracy. PURPOSE: The goal of this study was to perform the first direct comparison, in terms of spatial resolution and RSP accuracy, of two pCT prototype scanners installed at the same facility and by using the same image reconstruction algorithm. METHODS: A phantom containing cylindrical inserts of known RSP was scanned at the phase-II pCT prototype of the U.S. pCT collaboration and at the commercially oriented ProtonVDA scanner. Following distance-driven binning filtered backprojection reconstruction, the radial edge spread function of high-density inserts was used to estimate the spatial resolution. RSP accuracy was evaluated by the mean absolute percent error (MAPE) over the inserts. No direct imaging dose estimation was possible, which prevented a comparison of the two scanners in terms of RSP noise. RESULTS: In terms of RSP accuracy, both scanners achieved the same MAPE of 0.72% when excluding the porous sinus insert from the evaluation. The ProtonVDA scanner reached a better overall MAPE when all inserts and the body of the phantom were accounted for (0.81%), compared to the phase-II scanner (1.14%). The spatial resolution with the phase-II scanner was found to be 0.61 lp/mm, while for the ProtonVDA scanner somewhat lower at 0.46 lp/mm. CONCLUSIONS: The comparison between two prototype pCT scanners operated in the same clinical facility showed that they both fulfill the requirement of an RSP accuracy of about 1%. Their spatial resolution performance reflects the different design choices of either a scanner with full tracking capabilities (phase-II) or of a more compact tracker system, which only provides the positions of protons but not their directions (ProtonVDA).

Multimodal imaging of soccer ball-related ocular posterior segment injuries.

PURPOSE: To investigate the clinical and anatomic characteristics of soccer ball-induced posterior segment injuries in the era of modern multi-modal imaging. METHODS: Retrospective case series of patients with soccer ball injury and diagnostic imaging from 2007 to 2020 at a single vitreoretinal practice. RESULTS: Eight patients met inclusion criteria. Fundus photographs (FP) and optical coherence tomography (OCT) were obtained in eight patients, fundus autofluorescence (FAF) in five patients, fluorescein angiography (FA) in three patients, and en-face OCT and OCT-Angiography (OCT-A) were obtained in two patients each. FA and FAF identified traumatic pigment epitheliopathy secondary to commotio. Increased hypo-autofluorescence was associated with shallow, peripheral retinal detachment on FAF. OCT of the macula displayed outer retinal changes associated with commotio, and offered insight into the acute and subacute changes of traumatic macular hole formation. A patient displayed foveal hyper-reflectivity in the shape of an hourglass with retinal cyst at the level of the external limiting membrane (ELM) as seen on OCT and En-face OCT. A patient with commotio involving the macula lacked microvascular changes on OCT-A. CONCLUSION: OCT, FA, and FAF imaging may aid in the work-up and management of the soccer ball-related posterior segment injuries.

Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2.

The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half1 ( https://www.who.org/ ). Individuals with SARS-CoV-2 infection typically develop mild-to-severe flu-like symptoms, whereas infection of a subset of individuals leads to severe-to-fatal clinical outcomes2. Although vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics, which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs. Here we screened approximately 18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validated 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Among these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2, suggesting a clinical path forward.

Implementation of a Multisite Financial Reimbursement Program in Cancer Clinical Trials Integrated With Patient Navigation: A Pilot Randomized Clinical Trial.

PURPOSE: Cancer clinical trial participants face considerable indirect costs associated with participation, such as travel and lodging, which may contribute to poor enrollment. Here, we report the findings in IMproving Patient Access to Cancer clinical Trials, a pilot feasibility study investigating the efficacy of offering a financial reimbursement program (FRP) during a therapeutic clinical trial discussion with or without additional outreach in improving patient enrollment. METHODS: Study participants for this study were recruited at two National Cancer Institute-designated comprehensive cancer centers (CCCs) from April 8, 2019, to September 19, 2019. Eligible participants were adults with a cancer diagnosis being approached to consider enrollment in a clinical trial. Participants were randomly assigned 1:1 to receive no follow-up (usual care) or a follow-up telephone call to facilitate FRP utilization stratified by study site. The target enrollment was 132 patients, with 66 patients in each study arm. The primary outcome was the consent rate to the multisite interventional study on the FRP among participants enrolling in clinical trials. RESULTS: The study had a 78% consent rate and enrolled a total of 132 participants, of whom 51% were non-White compared with 28% of CCC treatment clinical trial participants in 2019. No difference in enrollment in clinical trials between the two study arms was observed as the proportion of enrollment was 70% for both study arms. The most common reason for not enrolling in a clinical trial was due to ineligibility determined through screening procedures (75%). CONCLUSION: The current study observed that implementation of FRP at CCCs is feasible and serves a diverse patient population. Future studies will measure the impact of programs on overall clinical trial accrual and among racial/ethnic minorities.

The role of Monte Carlo simulation in understanding the performance of proton computed tomography.

Proton computed tomography (pCT) is a promising tomographic imaging modality allowing direct reconstruction of proton relative stopping power (RSP) required for proton therapy dose calculation. In this review article, we aim at highlighting the role of Monte Carlo (MC) simulation in pCT studies. After describing the requirements for performing proton computed tomography and the various pCT scanners actively used in recent research projects, we present an overview of available MC simulation platforms. The use of MC simulations in the scope of investigations of image reconstruction, and for the evaluation of optimal RSP accuracy, precision and spatial resolution omitting detector effects is then described. In the final sections of the review article, we present specific applications of realistic MC simulations of an existing pCT scanner prototype, which we describe in detail.

OCULAR INJURIES ASSOCIATED WITH ELASTIC EXERCISE BANDS.

PURPOSE: To discuss the mechanism of injury and characterize the clinical features of ocular trauma associated with elastic cord exercise equipment band injuries in a consecutive series of patients seen at a single vitreoretinal surgery practice. METHODS: We performed a retrospective review of all patients who were treated for blunt trauma from 2013 to 2020 at a single vitreoretinal practice. RESULTS: Thirteen eyes from 11 patients met the inclusion criteria of possessing ocular trauma secondary to recoil from exercise bands. Presenting visual acuity ranged from 20/16 to HM (median: 20/32). The most frequently observed anterior segment pathologies were traumatic iritis (54%) and angle recession (31%). The most common posterior segment findings were vitreous hemorrhage (54%) and peripheral commotio retinae (54%). Three eyes (23%) required surgical intervention. Follow-up intervals ranged from 0 to 10 months (median: 1.75 months). Visual acuity at last examination ranged from 20/13 to 20/400 (median: 20/40). CONCLUSION: A wide spectrum of serious ocular injuries requiring medical and surgical intervention can result from this form of blunt ocular trauma. The frequency of this event would be decreased by the use of sports goggles and careful inspection of equipment for wear and over use.

Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis.

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known coreceptors for VEGFRs, core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathologic angiogenesis. Here we demonstrate, using NRP1 ECKO , NRP2 ECKO , and NRP1/NRP2 ECKO mouse models, that maximum inhibition of primary tumor development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2 ECKO animals. Mechanistic studies revealed that codepleting NRP1 and NRP2 in mouse-microvascular endothelial cells stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumor angiogenesis. Significance: The findings presented in this study demonstrate that tumor angiogenesis and growth can be arrested completely by cotargeting endothelial NRP1 and NRP2. We provide new insight into the mechanisms of action regulating NRP-dependent tumor angiogenesis and signpost a novel approach to halt tumor progression.

An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice.

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.

Incidence of anterior tibial spine fracture among skiers does not differ with age.

PURPOSE: Injury to the anterior cruciate ligament (ACL) is common in alpine skiing in the form of either an intra-substance ACL tear or anterior tibial spine fracture (ATSF). Anterior tibial spine fractures are typically reported in children. However, several case reports describe these injuries in adults while skiing. The purpose of this study is to describe the sport specific incidence of ATSF in alpine skiing. METHODS: The study was conducted over a 22-year period. Skiers who suffered an ATSF were identified and radiographs were reviewed to confirm the diagnosis. Additionally, control data from intra-substance ACL injury groups were collected. The incidence of these injuries in children, adolescents, and adults (grouped as ages 0-10, 11-16, and 17 + years old, respectively) was evaluated and the risk factors for ATSF versus ACL tear were determined. RESULTS: There were 1688 intra-substance ACL and 51 ATSF injuries. The incidence of intra-substance ACL injury was greater in adults (40.0 per 100,000 skier days) compared to the adolescent (15.4 per 100,000) and child (1.1 per 100,000) age groups. In contrast, the incidence of ATSF was similar in the adult (0.9 per 100,000), adolescent (1.9 per 100,000), and child (1.9 per 100,000) age groups. Loose ski boot fit was identified as a risk factor for ATSF. CONCLUSION: The incidence of ATSF in alpine skiers is similar among all age groups. However, the incidence of intra-substance ACL injuries is far greater in adult skiers compared to adolescents and children. Risk factors for ATSF relate to compliance between the foot/ankle and the ski boot. LEVEL OF EVIDENCE: III.

Vitreoretinal lymphoma following primary testicular lymphoma: Report of two cases and review of the literature.

PURPOSE: To report two cases of vitreoretinal lymphoma that developed following primary testicular lymphoma and review the literature. OBSERVATIONS: Two men, one age 66 and the other age 77, both with a history of diffuse large B-cell testicular lymphoma, diagnosed one and three years previously, respectively, presented with vitritis and yellow-white subretinal infiltrates. Diagnostic vitrectomy in both cases revealed diffuse large B-cell lymphoma. Systemic work up in both cases showed no evidence of disease relapse elsewhere. Each were treated with intravitreal methotrexate injections. CONCLUSIONS: Vitreoretinal lymphoma can occur following primary testicular lymphoma, and may mimic primary vitreoretinal lymphoma. Monitoring of patients with a history of testicular lymphoma with regular dilated fundus examinations should be considered.