Shaping immunity against infectious diseases with multivalent DNA vaccines.

Immunization has dramatically transformed human and animal health. Since its earliest days, vaccination has served as a fundamental strategy for infectious disease prevention, providing population-level coverage for childhood diseases and seasonal infections, and serving as a rapid response to pandemic pathogens. Yet, there is continued circulation of endemic, emerging, and reemerging pathogens for which there are no licensed prophylactic measures. The successes of nucleic acid technologies during the COVID-19 pandemic, exemplified in the first two licensed mRNA vaccines [1] and the first DNA vaccine receiving emergency use authorization for human use [2], are reinvigorating vaccine development to tackle this urgent unmet need. The inherent stability of DNA offers advantageous features such as thermostability and extended shelf life. These characteristics are pivotal for transport and storage in resource-constrained environments, like low and middle-income countries. Furthermore, the ability to encode large transgenes and well-established modular assembly pipelines are key attributes of DNA-based platforms. This versatility extends to combination strategies of individual DNA vaccines as a multivalent drug product. Multivalent synthetic DNA vaccines are therefore emerging as part of the exciting nucleic acid-based vaccine landscape as a strategy to induce robust and durable immunity in diverse global populations.

Clonal hematopoiesis in patients with HIV and cancer.

BACKGROUND: Cancer-related deaths for people living with HIV (PWH) are increasing due to longer life expectancies and disparately poor cancer-related outcomes. We hypothesize that advanced biological aging contributes to cancer-related morbidity and mortality for PWH and cancer. We sought to determine the impact of clonal hematopoiesis (CH) on cancer disparities in PWH. METHODS: We conducted a retrospective study to compare the prevalence and clinical outcomes of CH in PWH and people without HIV (PWoH) and cancer. Included in the study were PWH and similar PWoH based on tumor site, age, tumor sequence, and cancer treatment status. Biological aging was also measured using epigenetic methylation clocks. RESULTS: In 136 patients with cancer, PWH had twice the prevalence of CH compared to similar PWoH (23% vs 11%, p=0.07). After adjusting for patient characteristics, PWH were four-times more likely to have CH than PWoH (OR 4.1, 95% CI 1.3-13.9, p=0.02). The effect of CH on survival was most pronounced in PWH, who had a 5-year survival rate of 38% if they had CH (vs 59% if no CH), compared to PWoH who had a 5-year survival rate of 75% if they had CH (vs 83% if no CH). CONCLUSION: This study provides the first evidence that PWH may have a higher prevalence of CH than PWoH with the same cancers. CH may be an independent biological aging risk factor contributing to inferior survival for PWH and cancer.

Interobserver agreement and risk of malignancy using the International Academy of Cytology Yokohama System for reporting breast FNA biopsy in a liquid-based exclusive cohort.

BACKGROUND: Per the College of American Pathologist's National Breast Fine Needle Aspiration Biopsy (FNAB) Practice Survey, ∼40% of laboratories use liquid-based cytology (LBC) for breast FNAB. The reproducibility of the International Academy of Cytology Yokohama System (YS) for reporting breast FNAB on LBC was explored. DESIGN: Breast FNAB specimens submitted as LBC only (all ThinPrep) between January 2017 and January 2021 were retrieved. Cases without histopathologic follow-up were excluded. Clinical and radiologic information was collected. One cytologist and six cytopathologists rendered diagnoses per YS. All reviewers were blinded to the original diagnosis and histopathologic follow-up. The risk of malignancy was calculated. Concordance rates were calculated by a weighted Cohen Kappa score (κ). RESULTS: Review of 110 cases demonstrated substantial to near-perfect agreement between each reviewer (κ = 0.73-0.91) and follow-up histopathology (κ = 0.66-0.85). The agreement was lowest in the inadequate (κ = 0.05) and atypical (κ = 0.04) categories. The lack of concordance in the atypical category was common in cases with low cellularity or incomplete structural features. The risk of malignancy for inadequate, benign, atypical, suspicious for malignancy, and malignant categories were 12.5% (2/16), 3% (2/65), 67%, (8/12) 100% (1/1), and 100% (16/16). CONCLUSION: Interobserver agreement is excellent using the five YS categories in LBC. Lack of cellularity and incomplete architectural features were barriers to perfect agreement. Established pitfalls in the interpretation of LBC were cause for atypical diagnoses. Continuous training and education are recommended to avoid misdiagnosis because of the nonconventional cytomorphologic features of LBC and to improve inadequate and atypical rates within YS.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

In vivo delivery of engineered synthetic DNA-encoded SARS-CoV-2 monoclonal antibodies for pre-exposure prophylaxis in non-human primates.

COVID-19 remains a major public health concern. Monoclonal antibodies have received emergency use authorization (EUA) for pre-exposure prophylaxis against COVID-19 among high-risk groups for treatment of mild to moderate COVID-19. In addition to recombinant biologics, engineered synthetic DNA-encoded antibodies (DMAb) are an important strategy for direct in vivo delivery of protective mAb. A DMAb cocktail was synthetically engineered to encode the immunoglobulin heavy and light chains of two different two different Fc-engineered anti-SARS-CoV-2 antibodies. The DMAbs were designed to enhance in vivo expression and delivered intramuscularly to cynomolgus and rhesus macaques with a modified in vivo delivery regimen. Serum levels were detected in macaques, along with specific binding to SARS-CoV-2 spike receptor binding domain protein and neutralization of multiple SARS-CoV-2 variants of concern in pseudovirus and authentic live virus assays. Prophylactic administration was protective in rhesus macaques against signs of SARS-CoV-2 (USA-WA1/2020) associated disease in the lungs. Overall, the data support further study of DNA-encoded antibodies as an additional delivery mode for prevention of COVID-19 severe disease. These data have implications for human translation of gene-encoded mAbs for emerging infectious diseases and low dose mAb delivery against COVID-19.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer.

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

Use of the Afirma Xpression Atlas for cytologically indeterminate, Afirma Genomic Sequencing Classifier suspicious thyroid nodules: Clinicopathologic analysis with postoperative molecular testing.

OBJECTIVES: Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules. METHODS: Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available. RESULTS: Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27). CONCLUSIONS: Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test.

JAK2 R683S Mutation Resulting in Dual Diagnoses of Chronic Eosinophilic Leukemia and Myelodysplastic/Myeloproliferative Overlap Syndrome.

A 66-year-old male presented with hypereosinophilia, thrombocytosis, extensive thrombosis refractory to direct oral anticoagulant therapy, and evidence of end-organ damage, including rash, splenic infarcts, and pulmonary infiltrates. Bone marrow biopsy revealed myeloid malignancy consistent with both chronic eosinophilic leukemia and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with SF3B1 mutation and thrombocytosis. Next-generation sequencing of the patient's eosinophils and neutrophil compartments revealed pathologic variants in EZH2 and SF3B1 in addition to a noncanonical JAK2 R683S mutation that has not been previously described in myeloproliferative disorders or other chronic myeloid neoplasms. These mutations were not present in the patient's lymphoid cell fraction, suggesting that the hematopoietic malignancy arose in a myeloid-committed progenitor cell. Based on this case and previous work from our group, we propose that noncanonical JAK2 mutations may permit signal transduction that biases toward eosinophilic differentiation in chronic myeloid neoplasms. Although the patient's blood counts initially responded to ruxolitinib and hydroxyurea, the response was not durable. Early referral for allogenic bone marrow transplant appears necessary to prevent long-term complications and disease progression in myeloid neoplasms with clonal hypereosinophilia driven by noncanonical JAK2 mutations.

Case Series on Autosomal Recessive Non-Syndromic Retinitis Pigmentosa Caused by POMGNT1 Mutations with a Report of a New Variant.

Recessive Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) mutations can cause early onset muscle-eye-brain disease but have also more recently been associated with non-syndromic Retinitis Pigmentosa. In this case series, we describe three sisters affected by non-syndromic autosomal recessive POMGNT1 retinopathy with a report of a new variant. The three patients received care at West Virginia University Eye Institute, including full ophthalmic examination with additional fundus imaging, optical coherence tomography (OCT), electroretinogram (ERG), and visual field testing. Diagnostic panel testing of 330 genes was also obtained. The proband was seen for cataract evaluation at age 42, and her fundus examination was suggestive of retinitis pigmentosa. Her oldest sister had been treated for acute anterior uveitis with retinal vasculitis. Another sister was diagnosed with multiple sclerosis (MS) and peripheral retinal degeneration. Posterior subcapsular cataracts were diagnosed between age 42 and 55 in all three sisters, each with constricted fields with preserved central vision. We identified one pathogenic POMGNT1 variant (c.751 + 1G > A) and one likely pathogenic variant (c.1010T > C p.Ile337Thr) in all three sisters. A thorough family history and examination of the siblings with genotyping might have led to an earlier diagnosis of retinal inherited disease and avoidance of immunomodulatory treatment in the oldest sibling.

Leukostasis With Isolated Central Nervous System Involvement in Chronic Phase of Chronic Myelogenous Leukemia.

Chronic myelogenous leukemia (CML) is a hematologic malignancy with unique significance to the field of hematology and oncology, specifically due to the development of tyrosine kinase inhibitors (TKIs). CML often presents with nonspecific symptoms, and the quality of life in patients with CML has drastically improved as a result of TKIs. However, complications of CML including the risk of transforming into life-threatening blast crises continue to exist. Further, as most patients are asymptomatic in the chronic phase, patients often present with serious complications associated with noncompliance to TKIs. For example, central nervous system (CNS) manifestations of CML have been reported, both as the initial presentation of undiagnosed CML and as known complication of uncontrolled CML. Hyperleukocytosis is a manifestation of uncontrolled CML and leukostasis is a complication, occurring in cases of acute myeloid leukemia (AML). Here we present a rare case of leukostasis in a patient with known CML presenting on computed tomography (CT) as intracranial masses in the chronic phase. Our goal is to discuss this rare case of leukostasis in adult CML and describe its management.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

OBJECTIVES: Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. METHODS: Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). RESULTS: The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). CONCLUSION: Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk.

The roles of parenting, resilience, and interpersonal relationships on adolescents' mental health and stress-related growth during COVID-19.

BACKGROUND: The present longitudinal study investigated parenting style as a precursor for Chinese adolescents' stress-related growth and mental health difficulties during the COVID-19 pandemic, as well as the mediating roles of intrapersonal resilience and interpersonal relationships (i.e., peer and parent-adolescent). METHODS: Chinese adolescents in a middle school (7th grade) and their parents in Beijing, China, were invited to complete a survey at two time points (T1: September 2020, T2: June 2021). A total of 206 adolescents (52.9% boys; Mage = 12.90 years, SDage = 0.33) and parents (17.5% fathers, 82.4% mothers; Mage = 43.50 years, SDage = 4.76 years) were included in this study. RESULTS: Results showed that Chinese parents' authoritarian, not authoritative parenting, predicted adolescents' mental health difficulties nine months later. In addition, parent-adolescent relationships, but not peer relationships nor resilience, mediated the relations between parenting style and stress-related growth. Adolescents' resilience predicted fewer mental health difficulties. CONCLUSION: It is important to target multiple ecologies (e.g., family) of adolescents for promoting positive adjustment.

Clinically important change for the FACIT-Fatigue scale in paroxysmal nocturnal hemoglobinuria: a derivation from international PNH registry patient data.

BACKGROUND: Fatigue is the most common symptom associated with paroxysmal nocturnal hemoglobinuria (PNH). The objective of this analysis was to estimate values that would suggest a clinically important change (CIC) for the functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) in patients with PNH. METHODS: Adults with PNH who initiated eculizumab within 28 days of enrollment in the International PNH Registry as of January 2021 with baseline FACIT-Fatigue scores were included in the analysis. Distribution-based estimates of likely difference were calculated using 0.5 × SD and SEM. Anchor-based estimates of CIC considered the European Organization for Research and Treatment of Cancer (EORTC) global health status/quality of life summary score and the EORTC Fatigue Scale score. Changes in anchors and high disease activity (HDA) shift from start of eculizumab treatment to each follow-up visit were then assessed by FACIT-Fatigue score change (≤ 1 CIC, no change, or ≥ 1 CIC). RESULTS: At baseline, 93% of 423 patients had fatigue documented in their medical history. The distribution-based estimates for FACIT-Fatigue were 6.5 using 0.5 × SD and 4.6 using SEM; internal consistency was high (α = 0.87). For anchor-based estimates, the FACIT-Fatigue CIC ranged from 2.5 to 15.5, and generally supported 5 points as a reasonable lower end of the value for meaningful individual change. The percentage of patients who changed from having HDA at baseline to no HDA at eculizumab-treated follow-up visits increased over time. CONCLUSION: These results support the use of 5 points as the CIC for FACIT-Fatigue in patients with PNH, which is within range of the CICs reported in other diseases (3-5 points).

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease that leads to breakdown of the body's red blood cells in the blood vessels (intravascular hemolysis). Many people with PNH have fatigue, which consists of tiredness and weakness. A self-report questionnaire called the FACIT-Fatigue scale that objectively measures how fatigued a patient feels has been validated in clinical trials. Changes in the FACIT-Fatigue score help determine if a treatment is helping patients. The clinically important difference (difference between groups of people) or clinically important change (change within an individual) on the FACIT-Fatigue scale is a value that helps patients and clinicians find out if a drug helps or worsens patient fatigue. There is currently no defined clinically important difference and clinically important change on the FACIT-Fatigue scale for people with PNH. The International PNH Registry is a noninterventional, observational study collecting safety, treatment outcomes, and quality of life data from adults with PNH. This study used data from the International PNH Registry to find a clinically important difference and clinically important change in terms of improvement on the FACIT-Fatigue scale for adults with PNH who started eculizumab treatment. Different approaches were used to determine the amount of change in FACIT-Fatigue that would show that eculizumab has meaningful benefits, meaning patients are less fatigued. The authors demonstrated that a 5-point change on the FACIT-Fatigue is meaningful for people with PNH. This number is similar to the clinically important difference and clinically important change values of 3­5 points determined in other diseases.

Differences in epigenetic age by HIV status among patients with a non-AIDS defining cancer.

OBJECTIVE: People with HIV (PWH) are living longer and experiencing higher numbers of non-AIDS-defining cancers (NADC). Epigenetic aging biomarkers have been linked to cancer risk, and cancer is now a leading cause of death in PWH, but these biomarkers have not been investigated in PWH and cancer. DESIGN: In order to compare epigenetic age by HIV status, HIV-uninfected participants were matched to PWH by reported age, tumor site, tumor sequence number, and cancer treatment status. METHODS: DNA from blood was assayed using Illumina MethylationEPIC BeadChip, and we estimated immune cell composition and aging from three epigenetic clocks: Horvath, GrimAge, and epiTOC2. Age acceleration by clock was computed as the residual from the expected value, calculated using linear regression, for each study participant. Comparisons across HIV status used the Wilcoxon rank sum test. Hazard ratios and 95% confidence intervals for the association between age acceleration and survival in PWH were estimated with Cox regression. RESULTS: Among 65 NADC participants with HIV and 64 without, biological age from epiTOC2 ( P  < 0.0001) and GrimAge ( P  = 0.017) was significantly higher in PWH. Biological age acceleration was significantly higher in PWH using epiTOC2 ( P  < 0.01) and GrimAge ( P  < 0.0001), with the difference in GrimAge remaining statistically significant after adjustment for immune cell composition. Among PWH, GrimAge acceleration was significantly associated with increased risk of death (hazard ratio 1.11; 95% confidence interval (CI) 1.04-1.18). CONCLUSION: We observed a higher epigenetic age in PWH with a NADC diagnosis compared with their HIV-uninfected counterparts, as well as a significant association between this accelerated biological aging and survival for patients diagnosed with a NADC.

Electro-stimulation of tofu wastewater for the production of single cell protein from various microorganisms.

Tofu wastewater can be utilized as a substrate for microorganisms that produce single-cell proteins (SCPs). Because different microorganisms have different cellular components, the composition of SCPs varies. Electro-stimulation has the potential to speed up fermentation and increase product yield. The goal of this study was to find the best way to produce SCPs from Aspergillus awamori, Rhizopus oryzae, and Saccharomyces cerevisiae in the tofu wastewater substrate using electro-stimulation. The experimental method was used in the study, the data were analyzed using independent t-test statistical analysis, and the best treatment was identified using the effective index method. This treatment consisted of producing SCP with electro-stimulation of -1.5 V and without electro-stimulation for 72 h for the yeast and 96 h for the mold at 25 °C in tofu wastewater that had already been conditioned to a pH of 5. The parameters measured included measurement of population of microorganism, change in pH, dry biomass weight, carbohydrate content, and protein content. Electro-stimulation reduced the optimum fermentation time of A. awamori SCP from 56 to 32 h, resulting in 0.0406 g/50 mL of dry biomass, 30.09% carbohydrate content, and 6.86% protein content. Meanwhile, the optimal fermentation time on R. oryzae and S. cerevisiae were not accelerated by electro-stimulation. The best treatment was A. awamori without electro-stimulation, which produced 0.0931 g/50 mL of dry biomass, 20.29% carbohydrate, and 7.55% protein.

Evolving Coronary Stent Technologies - A Glimpse Into the Future.

One of the most widely accepted forms of treatment for coronary artery disease (CAD) is the implementation of stents into the vessel. This area of research is constantly evolving, ranging from bare-metal stents through drug-eluting stents and, more recently, approaching bioresorbable stents and polymer-free stents. This article reviews the evolution of all these devices and emphasizes how they might be further evolved to provide an optimal coronary stent and overcome unsolved challenges in stent development. We thoroughly evaluated a number of published studies in order to advance coronary stent technologies. Additionally, we looked for various literature that highlighted the inadequacies of the coronary stents that are currently available and how they might be modified to create the optimum coronary stent. Coronary stents have significantly improved clinical outcomes in interventional cardiology, but there are still a number of drawbacks, including an persisted risk of thrombosis due to endothelial injury and in-stent restenosis. Gene eluting stents (GES) and customized coronary stents with self-reporting stent sensors are appealing alternatives to existing stent approaches. Considering the adequacy of these gene eluting stents (GES), customized coronary stents produced by novel 4D printing technologies and integrated self-reporting stent sensors should be assumed for anticipating future advancements to optimal coronary stent devices; however, more interventional evidence is required to determine the future prospects of these stent innovations.

Rhinogenic Optic Neuropathy with No Light Perception Secondary to Onodi Cell Mucocele with Visual Recovery after Optic Nerve Decompression.

Rhinogenic optic neuropathy (RON) results from ethmoid or sphenoid sinus inflammation or infection causing optic nerve impairment.1 Treatment often requires endoscopic surgery and vision restoration occurs in select cases. There is no clear evidence for the benefit of optic nerve decompression (OND) in these situations. We present a unique case of RON caused by an Onodi cell mucocele for which isolated endoscopic mucocele drainage was not enough and further OND was needed to improve vision.

Adenosine deaminase augments SARS-CoV-2 specific cellular and humoral responses in aged mouse models of immunization and challenge.

Despite numerous clinically available vaccines and therapeutics, aged patients remain at increased risk for COVID-19 morbidity. Furthermore, various patient populations, including the aged can have suboptimal responses to SARS-CoV-2 vaccine antigens. Here, we characterized vaccine-induced responses to SARS-CoV-2 synthetic DNA vaccine antigens in aged mice. Aged mice exhibited altered cellular responses, including decreased IFNγ secretion and increased TNFα and IL-4 secretion suggestive of TH2-skewed responses. Aged mice exhibited decreased total binding and neutralizing antibodies in their serum but significantly increased TH2-type antigen-specific IgG1 antibody compared to their young counterparts. Strategies to enhance vaccine-induced immune responses are important, especially in aged patient populations. We observed that co-immunization with plasmid-encoded adenosine deaminase (pADA)enhanced immune responses in young animals. Ageing is associated with decreases in ADA function and expression. Here, we report that co-immunization with pADA enhanced IFNγ secretion while decreasing TNFα and IL-4 secretion. pADA expanded the breadth and affinity SARS-CoV-2 spike-specific antibodies while supporting TH1-type humoral responses in aged mice. scRNAseq analysis of aged lymph nodes revealed that pADA co-immunization supported a TH1 gene profile and decreased FoxP3 gene expression. Upon challenge, pADA co-immunization decreased viral loads in aged mice. These data support the use of mice as a model for age-associated decreased vaccine immunogenicity and infection-mediated morbidity and mortality in the context of SARS-CoV-2 vaccines and provide support for the use of adenosine deaminase as a molecular adjuvant in immune-challenged populations.

Diabetic retinopathy screenings in West Virginia: an assessment of teleophthalmology implementation.

BACKGROUND: The prevalence of diabetes in the state of West Virginia (WV) is amongst the highest in the United States, making diabetic retinopathy (DR) and diabetic macular edema (DME) a major epidemiological concern within the state. Several challenges exist regarding access to eye care specialists for DR screening in this rural population. A statewide teleophthalmology program has been implemented. We analyzed real-world data acquired via these systems to explore the concordance between image findings and subsequent comprehensive eye exams and explore the impact of age on image gradeability and patient distance from the West Virginia University (WVU) Eye Institute on follow-up. METHODS: Nonmydriatic fundus images of diabetic eyes acquired at primary care clinics throughout WV were reviewed by retina specialists at the WVU Eye Institute. Analysis included the concordance between image interpretations and dilated examination findings, hemoglobin A1c (HbA1c) levels and DR presence, image gradeability and patient age, and distance from the WVU Eye Institute and follow-up compliance. RESULTS: From the 5,512 fundus images attempted, we found that 4,267 (77.41%) were deemed gradable.  Out of the 289 patients whose image results suggested DR, 152 patients (52.6%) followed up with comprehensive eye exams-finding 101 of these patients to truly have DR/DME and allowing us to determine a positive predictive value of 66.4%. Patients within the HbA1c range of 9.1-14.0% demonstrated significantly greater prevalence of DR/DME (p < 0.01).  We also found a statistically significant decrease in image gradeability with increased age.  When considering distance from the WVU Eye Institute, it was found that patients who resided within 25 miles demonstrated significantly greater compliance to follow-up (60% versus 43%, p < 0.01). CONCLUSIONS: The statewide implementation of a telemedicine program intended to tackle the growing burden of DR in WV appears to successfully bring concerning patient cases to the forefront of provider attention.  Teleophthalmology addresses the unique rural challenges of WV, but there is suboptimal compliance to essential follow-up with comprehensive eye exams. Obstacles remain to be addressed if these systems are to effectively improve outcomes in DR/DME patients and diabetic patients at risk of developing these sight-threatening pathologies.