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Context.--In 2018 the College of American Pathologists Diagnostic Immunology and Flow Cytometry Committee designed and implemented a new plasma cell neoplasia flow cytometry proficiency testing program--PCNEO--to allow clinical flow cytometry laboratories to monitor and assess their performance compared with a peer group. Objective.--To report the results from the first 4 years of the PCNEO program. Design.--Program participants were sent 2 sets of challenges per year, each including 1 wet challenge and 2 dry challenges, with associated clinical and laboratory findings. The wet challenges were composed of myeloma cell line specimens (with or without dilution in preserved whole blood) for flow cytometric analysis. The dry (paper) challenges were composed of clinical case summaries and images of flow cytometric test results from various flow cytometry laboratories of committee members. Results.--A total of 116 to 145 laboratories from 17 countries enrolled in the proficiency testing program. For the wet challenges, almost all participants (97%--100%; cumulative, 98.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of undiluted myeloma cell lines. Slightly fewer participants (89.0%--97.4%; cumulative, 95.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of diluted myeloma cell lines (10% or 50% dilutions into peripheral blood) intended to better represent a typical clinical sample. There was generally agreement among 80% or more of participants for positive or negative staining for CD38, CD138, CD19, CD20, and surface and cytoplasmic K and λ light chains. Similarly, 84% to 100% of participants were able to correctly identify the presence of neoplastic plasma cell populations in paper challenges, including the presence of small, neoplastic plasma cell populations (0.01%--5.0% clonal plasma cells) and the presence of nonneoplastic plasma cell populations (correctly identified by 91%--96% of participants). Conclusions.--Participant performance in the new proficiency testing program was excellent overall, with the vast majority of participants able to perform flow cytometric analysis and identify neoplastic plasma cell populations and to identify small plasma cell clones or expanded populations of reactive plasma cells in dry challenge flow cytometry results. This program will allow laboratories to verify the accuracy of their testing program and test interpretations for the assessment of patients suspected of having a plasma cell neoplasm. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths in the United States due to its late-stage diagnosis. Currently, there are no early diagnostic tests. The best treatment for PDAC is surgery, but by then, the cancer has already spread, making it difficult to perform. This study aims to address the potential of targeting neoantigens, unique cancer-specific proteins that trigger an immune response, as potential immunotherapy targets. However, PDAC develops characteristics such as immune cell avoidance, creating an environment suppressing immune cells, and converting cells to become unstable. Targeting neoantigens could revolutionize PDAC therapy, offering better survival rates. Though trials are still in the early stages, they do offer a greater understanding and potential for fighting cancer. This article hopes to shed light and pave the way for innovative treatments to improve the prognosis of PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death by 2030. The diagnosis at a late stage is the underlying cause for higher mortality and poor prognosis after surgery. Treatment resistance to chemotherapy and immunotherapy results in recurrence after surgery and poor prognosis. Neoantigen burden and CD8+ T-cell infiltration are associated with clinical outcomes in PDAC and paucity of neoantigen-reactive tumor-infiltrating lymphocytes may be the underlying cause for treatment resistance for immunotherapy. This suggests a need to identify additional neoantigens and therapies targeting these neoantigens to improve clinical outcomes in PDAC. In this review, we focus on describing the pathophysiology, current treatment strategies, and treatment resistance in PDAC followed by the need to target neoantigens in PDAC. [ABSTRACT FROM AUTHOR]

Background: Pancreas transplantation is the most effective treatment to improve quality of life and overcome complications in patients with end‐stage renal disease and diabetes mellitus. One of the main approaches for concurrent renal disease and diabetes mellitus which has been underutilized during the past decade is a pancreas transplant after kidney transplantation. Our study aimed to quantify outcomes following pancreas after kidney transplants (PAKs) in the United States from 2001 to 2020 with an emphasis on graft and patient survival. Methods and Materials: A retrospective registry analysis was performed by accessing the OPTN/UNOS database for PAKs that were performed in the United States from January 2001 to April 2020. The study population was divided into two subgroups: patients receiving a pancreas transplant between 2001 and 2010 and those receiving a pancreas transplant between 2011 and 2020. Results: The study examined a total number of 3706 PAK recipients; patients who received a PAK from January 2001 through December 2010 (n = 2892) and those who received a PAK from January 2011 to April 2020 (n = 814). The selection process of transplant recipients did not drastically change throughout the 2001–2010 and 2011–2020 periods. Length of stay at the hospital after the transplantation improved significantly in the 2011–2020 group relative to the 2001–2010 group (8.48 vs. 10.08 days, mean, p < 0.01). Additionally, more transplantation with 4–6 human leukocyte antigen mismatch occurred in the 2011–2020 group than in the 2001–2010 group (80.6% vs. 71.4%, p < 0.01). The pancreas preservation time of 13.35 h in the 2001–2010 group decreased significantly to 11.17 h in the 2011–2020 group (p < 0.001). The mean donor's amylase and lipase also decreased significantly in the 2011–2020 cohort. Significant graft survival improvement was observed in the 2011–2020 group compared to the 2001–2010 group after a long‐term follow‐up (p < 0.001). The mean Calculated Pancreas Donor Risk Index was 1.08 for the 2001–2010 group and 0.99 for the 2011–2020 group with a significant difference (p < 0.001). Conclusion: The beneficial results and improved outcomes observed in PAK patients demonstrate the effectiveness of the operation for individuals in need of a pancreas transplant. PAKs can prove to be a meaningful solution to overcome long waiting times, decrease the donor‐recipient imbalance, expand the donor pool, and overcome the current underutilization in order to improve the short‐ and long‐term quality of life in the groups of interest. [ABSTRACT FROM AUTHOR]

The loss of RAB25 expression—RAS superfamily of GTPase characteristic of numerous breast cancers—corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Current therapies are often insufficiently effective in patients with acute myeloid leukemia (AML), prompting ongoing interest in developing new drugs for this aggressive type of blood cancer. Many efforts focus on drugs that target CD33, a cell surface protein that is widely expressed on AML cells. Gemtuzumab ozogamicin (GO), which consists of a CD33 antibody linked to a small molecule toxin, benefits some AML patients but not many others, leaving room for other CD33-targeted therapeutics. Here, we examined CC-96191, a "TriNKET" protein drug that binds CD33 on AML cells at the same time it binds two different proteins, CD16a and NKG2D, on natural killer (NK) cells, thereby activating these immune cells and engaging them to kill AML cells. In preclinical studies, we found CC-96191 to be broadly active against human AML cells that express CD33. CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a protein drug that binds CD33 and CD3 on T cells. Moreover, CC-96191 eliminated AML cells but not normal CD33+ monocytes, suggesting selectivity toward leukemic cells. Together, these findings support the clinical exploration of CC-96191 as is currently ongoing. Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655. [ABSTRACT FROM AUTHOR]

The article comments on the development of a standardized, laboratory result-based hepatitis C virus (HCV) clearance cascade for public health jurisdictions. It identifies elements for constructing a population-level HCV cascade, as well as the important data-to-share opportunities measured by a laboratory result-based HCV cascade. It informs about the funding to support health departments to implement laboratory result-based HCV cascades and cites limitations of HCV cascade.

Propolis is a resinous substance collected by bees (Apis mellifera). It is used for its biological properties. This natural product is available as a safe therapeutic option. Herein, we report the antiviral effects of brown propolis extract from Mexico and green and red propolis extracts from Brazil, as well as their phenolic compounds (quercetin, caffeic acid, and rutin) in preventing infection of MRC-5 cells by HCoV-229E. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. All samples studied showed antiviral activity. Green and brown propolis extracts, and quercetin exhibited the best EC50 values with values of 19.080, 11.240, and 77.208 µg/mL against HCoV-229E, respectively, and with TC50 of 62.19, 29.192, and 298 µg/mL on MRC-5 cells, respectively. These results are the first in vitro study of the effects of propolis on HCoV-229E and provide the basis for the development of natural formulations against other coronavirus strains. [ABSTRACT FROM AUTHOR]

Pozelimab (pozelimab-bbfg; VEOPOZ™) is a fully human immunoglobulin (Ig) G4P (i.e. IgG4 with a proline substitution to promote stabilization of the disulfide bonds between the two heavy chains) monoclonal antibody developed by Regeneron Pharmaceuticals Inc., to block the activity of complement factor 5 (C5) and prevent diseases mediated by the complement pathway. In August 2023, pozelimab received its first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease, in the USA. It is the first US FDA-approved treatment for this disease. In the USA, pozelimab has been granted orphan drug designations for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) [both as a monotherapy and in combination with cemdisiran] and for the treatment of myasthenia gravis (in combination with cemdisiran). Pozelimab is also undergoing clinical development in several other countries worldwide for the treatment of CD55-deficient PLE, PNH and myasthenia gravis. This article summarizes the milestones in the development of pozelimab leading to this first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient PLE, also known as CHAPLE disease, in the USA. [ABSTRACT FROM AUTHOR]

The number of heart transplants performed annually in the United States and worldwide continues to increase, but there has been little change in graft longevity and patient survival over the past 2 decades. The reference standard for diagnosis of acute cellular and antibody-mediated rejection includes histologic and immunofluorescence evaluation of endomyocardial biopsy samples, despite invasiveness and high interrater variability for grading histologic rejection. Circulating biomarkers and molecular diagnostics have shown substantial predictive value in rejection monitoring, and emerging data support their use in diagnosing other posttransplant complications. The use of genomic (cell-free DNA), transcriptomic (mRNA and microRNA profiling), and proteomic (protein expression quantitation) methodologies in diagnosis of these posttransplant outcomes has been evaluated with varying levels of evidence. In parallel, growing knowledge about the genetically mediated immune response leading to rejection (immunogenetics) has enhanced understanding of antibody-mediated rejection, associated graft dysfunction, and death. Antibodies to donor human leukocyte antigens and the technology available to evaluate these antibodies continues to evolve. This review aims to provide an overview of biomarker and immunologic tests used to diagnose posttransplant complications. This includes a discussion of pediatric heart transplantation and the disparate rates of rejection and death experienced by Black patients receiving a heart transplant. This review describes diagnostic modalities that are available and used after transplant and the landscape of future investigations needed to enhance patient outcomes after heart transplantation. [ABSTRACT FROM AUTHOR]

Patient: Male, 38-year-old Final Diagnosis: Acute IRIS-HBV flare Symptoms: Arthralgias * fatigue * loose stools Clinical Procedure: CT guided liver biopsy Specialty: Gastroenterology and Hepatology * Immunology * Infectious Diseases Objective: Unknown etiology Background: Immune reconstitution inflammatory syndrome (IRIS) is a well-recognized complication after antiretroviral therapy (ART) initiation among patients with HIV. Acute HBV flares after starting antiretroviral therapy have been reported in 20% to 25% of coinfected patients, among whom only 1% to 5% develop clinical hepatitis. Liver biopsy and serological evaluation help in diagnosis. Case Report: A 24-year-old man with history of HIV diagnosed in 2018 developed severe IRIS-related HBV flare after initiation of ART. He was taking ART since 2018 until his immigration to the United States in 2021. He came to establish care and was started on bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF). Three weeks later, he presented to the Emergency Department with polyarthralgia and loose stools; transaminases showed an increasing trend on follow-up. He was admitted for closer monitoring. Workup was remarkable for reactive HBsAg, HBeAg, and HBcIgM antibodies, with HBV viral load of 295 304 copies/mL. Abdominal imaging was unremarkable. ART was switched to rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF), considering the hypothetical risk of hepatotoxicity from BIC/F/TAF. Despite therapy, transaminases were up-trending. He underwent computerized tomography-guided liver biopsy, showing moderate to severe acute hepatitis, compatible with IRIS. He received steroids, and ART was continued. Transaminases resolved, HBV load reduced significantly, HIV load became undetectable at 9 weeks, and he developed HBeAb (seroconversion) at 4 months after initiating ART. Conclusions: Our case highlights the importance of early recognition and management of IRIS-HBV flares after initiation of ART among coinfected patients. Liver biopsy is indicated for definitive diagnosis. ART directed against both viruses should be continued. [ABSTRACT FROM AUTHOR]

Virtual crossmatch (VXM) is used as an alternative to or in conjunction with a cell-based physical crossmatch (PXM) for assessing HLA (human leukocyte antigen) compatibility prior to deceased donor kidney transplantation (DDKT). Data on practice patterns and perceptions regarding VXM use in the US are limited. We performed a survey of US HLA directors and transplant surgeons regarding HLA testing and crossmatch strategies. 53 (56 %) HLA directors and 68 surgeons (representing ∼ 23 % of US transplant centers) completed the survey. Both groups agreed that VXM could reduce cold ischemia time (CIT), costs and improve allocation efficiency. VXM use increased following the 2021 kidney allocation change. Reducing CIT was the primary reason for favoring VXM over PXM. Preference for VXM reduced as candidates' panel reactive antibodies increased. Regulations, program policies and limitations of HLA technology were cited as important reasons for preferring PXM over VXM. Surgeons reported similar perceptions, but findings are limited by the low response rate. Finally, half the labs reported lacking specific protocols for VXM use. In conclusion, improved HLA technology and protocols along with changes to institutional procedures and policy regulations are needed for safer expansion of VXM in DDKT. [ABSTRACT FROM AUTHOR]

Background Despite high vaccination rates, the United States has experienced a resurgence in reported cases of pertussis after switching to the acellular pertussis vaccine, indicating a need for improved vaccines that enhance infection control. Methods Bordetella pertussis antigens recognized by convalescent-baboon serum and nasopharyngeal wash were identified by immunoproteomics and their subcellular localization predicted. Genes essential or important for persistence in the baboon airway were identified by transposon-directed insertion-site sequencing (TraDIS) analysis. Results In total, 314 B. pertussis antigens were identified by convalescent baboon serum and 748 by nasopharyngeal wash. Thirteen antigens were identified as immunogenic in baboons, essential for persistence in the airway by TraDIS, and membrane-localized: BP0840 (OmpP), Pal, OmpA2, BP1485, BamA, Pcp, MlaA, YfgL, BP2197, BP1569, MlaD, ComL, and BP0183. Conclusions The B. pertussis antigens identified as immunogenic, essential for persistence in the airway, and membrane-localized warrant further investigation for inclusion in vaccines designed to reduce or prevent carriage of bacteria in the airway of vaccinated individuals. [ABSTRACT FROM AUTHOR]

Renal transplantation is the treatment of choice for patients suffering from chronic renal disease, one of the leading causes of death worldwide. Among the biological barriers that may increase the risk of acute renal graft rejection is the presence of human leukocyte antigen (HLA) incompatibilities between donor and recipient. This work presents a comparative study of the influence of HLA incompatibilities on renal transplantation survival in the Andalusian (South of Spain) and United States (US) population. The main objective is to analyse the extent to which results about the influence of different factors on renal graft survival can be generalised to different populations. The Kaplan–Meier estimator and the Cox model have been used to identify and quantify the impact on the survival probability of HLA incompatibilities, both in isolation and in conjunction with other factors associated with the donor and recipient. According to the results obtained, HLA incompatibilities considered in isolation have negligible impact on renal survival in the Andalusian population and a moderate impact in the US population. Grouping by HLA score presents some similarities for both populations, while the sum of all HLA scores (aHLA) only has an impact on the US population. Finally, the graft survival probability of the two populations differs when aHLA is considered in conjunction with blood type. The results suggest that the disparities in the renal graft survival probability between the two populations under study are due not only to biological and transplantation-associated factors, but also to social–health factors and ethnic heterogeneity between populations. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of death worldwide, placing a significant burden on healthcare systems as well as the global economy. Rare cancers comprise a group of about 200 cancers that individually occur at extremely low frequencies. In the United States (US), their frequency is approximately 15 cases per 100,000 people, and it is even lower in Europe with approximately 6 cases per 100,000 people. However, combined their frequency of occurrence is much higher than any singular cancer. Cancer treatment and management has tremendously improved in the last decade, particularly with the administration of immune-based therapies. The four most prevalent immune-based therapies are (1) the use of immune-checkpoint inhibitors, (2) macrophage therapy, (3) Chimeric Antigen Receptor (CAR) T cell therapy, and (4) neoantigen-based therapies. In our review, we discuss these various aproaches and their implementation in the treatment of a variety of rare cancers. Furthermore, we discuss their limitations and potential strategies to overcome them to enhance the therapeutic efficacy of these approaches. Finally, our article presents the future directions and other additional immune therapies that may be incorporated into the treatment of rare cancers. [ABSTRACT FROM AUTHOR]

Background: Turmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic, and human leukocyte antigen (HLA) associations of turmeric-associated liver injury cases enrolled the in US Drug-Induced Liver Injury Network (DILIN).Methods: All adjudicated cases enrolled in DILIN between 2004 and 2022 in which turmeric was an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing.Results: Ten cases of turmeric-associated liver injury were found, all enrolled since 2011, and 6 since 2017. Of the 10 cases, 8 were women, 9 were White, and median age was 56 years (range 35-71). Liver injury was hepatocellular in 9 patients and mixed in 1. Liver biopsies in 4 patients showed acute hepatitis or mixed cholestatic-hepatic injury with eosinophils. Five patients were hospitalized, and 1 patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products tested; 3 also contained piperine (black pepper). HLA typing demonstrated that 7 patients carried HLA-B*35:01, 2 of whom were homozygous, yielding an allele frequency of 0.450 compared with population controls of 0.056-0.069.Conclusion: Liver injury due to turmeric appears to be increasing in the United States, perhaps reflecting usage patterns or increased combination with black pepper. Turmeric causes potentially severe liver injury that is typically hepatocellular, with a latency of 1 to 4 months and strong linkage to HLA-B*35:01. [ABSTRACT FROM AUTHOR]

Background The Centers for Disease Control and Prevention recommends serial rapid antigen assay collection within congregate facilities. Although modeling and observational studies from communities and long-term care facilities have shown serial collection provides adequate sensitivity and specificity, the accuracy within correctional facilities remains unknown. Methods Using Connecticut Department of Correction data from 21 November 2020 to 15 June 2021, we estimated the accuracy of a rapid assay, BinaxNOW (Abbott), under 3 collection strategies: single test collection and serial collection of 2 and 3 tests separated by 1–4 days. The sensitivity and specificity of the first (including single), second, and third serially collected BinaxNOW tests were estimated relative to RT-PCRs collected ≤1 day of the BinaxNOW test. The accuracy metrics of the testing strategies were then estimated as the sum (sensitivity) and product (specificity) of tests in each strategy. Results Of the 13 112 residents who contributed ≥1 BinaxNOW test during the study period, 3825 contributed ≥1 RT-PCR paired BinaxNOW test. In relation to RT-PCR, the 3-rapid-antigen-test strategy had a sensitivity of 95.9% (95% CI: 93.6–97.5%) and specificity of 98.3% (95% CI: 96.7–99.1%). The sensitivities of the 2- and 1-rapid-antigen-test strategies were 88.8% and 66.8%, and the specificities were 98.5% and 99.4%, respectively. The sensitivity was higher among symptomatic residents and when RT-PCRs were collected before BinaxNOW tests. Conclusions We found serial antigen test collection resulted in high diagnostic accuracy. These findings support serial collection for outbreak investigation, screening, and when rapid detection is required (such as intakes or transfers). [ABSTRACT FROM AUTHOR]

We summarize studies of varicella vaccine's effectiveness for prevention of varicella and lessons learned during the first 25 years of the varicella vaccination program in the United States. One dose of varicella vaccine provided moderate protection (82%-85%) against varicella of any severity and high protection (100%) against severe varicella, with some waning of protection over time. The 1-dose program (1995-2006) had a substantial impact on the incidence both of varicella and of severe outcomes (71%-90% decrease) although it did not prevent low-level community transmission and some outbreaks continued to occur in highly vaccinated populations. Two doses of varicella vaccine improved the vaccine's effectiveness by at least 10% against varicella of any severity, with further declines in the incidence both of varicella and of severe outcomes as well as in both number and size of outbreaks. There is no evidence for waning of the effectiveness of 2 doses of the vaccine. [ABSTRACT FROM AUTHOR]

Background Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). Methods Plasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n = 36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n = 53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre–COVID-19 (n = 67) or within 24 hours of negative RT-PCR (n = 43). Results Specificities of N and S assays were 95–97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤ 35 were 93%/63%. Antigen concentrations ranged from 1.28–3844 pg/mL (N) and 1.65–1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. Conclusions Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis. [ABSTRACT FROM AUTHOR]

Background Cryptococcosis is a serious opportunistic fungal disease, and the proportion of cases among patients with immunosuppressive conditions other than HIV or organ transplant has increased. Understanding laboratory testing patterns for cryptococcosis is useful for estimating its true burden and developing testing guidance. Methods We identified cryptococcosis tests (cryptococcal antigen [CrAg], cryptococcal antibody, and fungal cultures) performed at a major national commercial laboratory ordered during March 1, 2019–October 1, 2021, and analyzed test results, patient and provider features, reasons for testing, geography, and temporal trends. Results Among 29 180 serum CrAg tests, 4422 (15.2%) were positive, and among 10 724 cerebrospinal fluid (CSF) CrAg tests, 492 (4.6%) were positive. Frequent reasons for serum CrAg testing in nonhospital settings (10 882 tests) were HIV (44.6%) and cryptococcosis (17.0%); other underlying conditions were uncommonly listed (<10% total). Serum CrAg positivity declined from 25.6% in October 2019 to 11.3% in September 2021. The South had the highest positivity for serum CrAg tests (16.6%), CSF CrAg tests (4.7%), and fungal cultures (0.15%). Among 5009 cryptococcal antibody tests, 5 (0.1%) were positive. Conclusions Few outpatient serum CrAg tests were performed for patients with immunocompromising conditions other than HIV, suggesting potential missed opportunities for early detection. Given the high positive predictive value of CrAg testing, research is needed to improve early diagnosis, particularly in patients without HIV. Conversely, the low yield of antibody testing suggests that it may be of low value. The decline in CrAg positivity during the COVID-19 pandemic warrants further investigation. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) is associated with tumor aggressiveness, drug resistance, and poor survival in non-small cell lung cancer (NSCLC) and other cancers. The identification of immune-checkpoint ligands (ICPLs) associated with NSCLCs that display a mesenchymal phenotype (mNSCLC) could help to define subgroups of patients who may benefit from treatment strategies using immunotherapy. We evaluated ICPL expression in silico in 130 NSCLC cell lines. In vitro , CRISPR/Cas9-mediated knockdown and lentiviral expression were used to assess the impact of ZEB1 expression on CD70. Gene expression profiles of lung cancer samples from the TCGA (n = 1018) and a dataset from MD Anderson Cancer Center (n = 275) were analyzed. Independent validation was performed by immunohistochemistry and targeted-RNA sequencing in 154 NSCLC whole sections, including a large cohort of pulmonary sarcomatoid carcinomas (SC, n = 55). We uncover that the expression of CD70, a regulatory ligand from the tumor necrosis factor ligand family, is enriched in mNSCLC in vitro models. Mechanistically, the EMT-inducer ZEB1 impacted CD70 expression and fostered increased activity of the CD70 promoter. CD70 overexpression was also evidenced in mNSCLC patient tumor samples and was particularly enriched in SC, a lung cancer subtype associated with poor prognosis. In these tumors, CD70 expression was associated with decreased CD3+ and CD8+ T-cell infiltration and increased T-cell exhaustion markers. Our results provide evidence on the pivotal roles of CD70 and ZEB1 in immune escape in mNSCLC, suggesting that EMT might promote cancer progression and metastasis by not only increasing cancer cell plasticity but also reprogramming the immune response in the local tumor microenvironment. • The EMT-inducer ZEB1 modulates the expression of CD70, a ligand from the TNF family. • CD70 expression is enriched in pulmonary sarcomatoid carcinomas (SC). • In SC, CD70 expression is associated with features of an immunosuppressive environment. [ABSTRACT FROM AUTHOR]

What is known and objectives: The optimal strategy for maintenance therapy in patients with metastatic colorectal cancer (mCRC) remains controversial. Considering that, beyond progression, co‐therapy with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate. We aimed to investigate the differences in efficacy and safety between bevacizumab combined with capecitabine maintenance therapy and capecitabine monotherapy for RAS‐mutant mCRC （as defined by mutations in KRAS and NRAS exons 2–4）controlled by bevacizumab plus FOLFIRI chemotherapy for at least 12 weeks. Methods: We retrospectively analysed patients with RAS‐mutant mCRC admitted to the Department of Oncology, Huizhou Municipal Central Hospital from December, 2015 to December, 2020. All patients were first treated with bevacizumab combined with FOLFIRI for at least 12 weeks of induction therapy. 154 patients whose disease was brought under control then continued maintenance therapy. 78 patients were in the observation group (bevacizumab plus capecitabine) and 76 patients were in the control group (capecitabine alone). The efficacy and adverse effects of maintenance treatment were compared between the two groups. The clinicopathological characteristics such as sex, age, performance status (PS) score, primary tumour site, degree of pathological differentiation, baseline carcinoembryonic antigen (CEA) level, microsatellite instability (MSI) status, number of metastatic tumour sites and efficacy of induction treatment were compared in terms of prognosis. Results and discussion: The median progression‐free survival (mPFS)of patients was 9.0 months (95% CI 8.0–10.0) in the observation group and 7.2 months (95% CI 6.0–8.4) in the control group, with a statistically significant difference (p < 0.05). The baseline CEA level was an independent prognostic factor. Both groups tolerated the toxic side effects. What is new and conclusion: Bevacizumab combined with capecitabine was well tolerated and contributed to a longer PFS time than capecitabine alone, and it is worthy of popularization in clinical practice. [ABSTRACT FROM AUTHOR]

Persons with isolated antibody to hepatits B virus (HBV) core antigen (IAHBc) may have occult HBV infection (OBI), which is associated with reactivation and potential risk for hepatocellular carcinoma and HBV transmission. We used National Health and Nutrition Examination Survey data to estimate US IAHBc prevalence and published studies of IAHBc-associated OBI prevalence to estimate OBI burden. During 2001-2018, the prevalence of IAHBc was 0.8% (approximately 2.1 million persons), and the OBI burden range was 35 500-83 600 persons. These data support the need for more robust estimates of IAHBc-associated OBI prevalence in the general US population. [ABSTRACT FROM AUTHOR]

Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus. [ABSTRACT FROM AUTHOR]

Context.--Coronavirus disease 2019 (COVID-19) rapid antigen tests generate intrinsically fast, inherently spatial, and immediately actionable results. They quickly confirm COVID-19, but weakly rule out infection. Test performance depends on prevalence and testing protocol. Both affect predictive values. Objectives.--To use original mathematics and visual logistics for interpreting COVID-19 rapid antigen test performance patterns, gauge the influence of prevalence, and evaluate repeated testing. Design.--Mathematica and open access software helped graph relationships, perform recursive computations, and compare performance patterns. PubMed retrieved articles addressing endemic COVID-19 were reviewed. Results.--Tiered sensitivity/specificity comprise the following: T1 (90%/95%), T2 (95%/97.5%), and T3 (100%/≥99%). Performance of self-tests and home antigen tests with US Food and Drug Administration Emergency Use Authorization peaks in low prevalence. Fall-off in performance appears with increasing prevalence because sub-optimal sensitivity creates false negatives. The rate of false omissions limits clinical use because of prevalence boundaries based on tolerance for risk. Mathematical analysis supports testing twice to improve predictive values and extend prevalence boundaries nearly to levels of herd immunity. Conclusions.--COVID-19 is quickly becoming endemic. Suboptimal sensitivity of rapid antigen tests limits performance in high prevalence. Risk of contagion in packed spaces (eg, airplanes) might be avoided with dual testing 36 hours apart, allowing time for viral load to increase. Awareness of community prevalence and proof of improved performance with repeated testing will help manage COVID-19 risk, while meeting rapid decision-making needs for highly contagious and new variants (eg, Delta). New COVID-19 variants call for high-quality, low cost, readily accessible, fast, user friendly, and ubiquitous point-of-care testing. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Safety studies assessing the association between the entire recommended childhood immunization schedule and autoimmune diseases, such as type 1 diabetes mellitus (T1DM), are lacking. To examine the association between the recommended immunization schedule and T1DM, we conducted a retrospective cohort study of children born between 2004 and 2014 in 8 US health care organizations that participate in the Vaccine Safety Datalink. METHODS: Three measures of the immunization schedule were assessed: average days undervaccinated (ADU), cumulative antigen exposure, and cumulative aluminum exposure. T1DM incidence was identified by International Classification of Disease codes. Cox proportional hazards models were used to analyze associations between the 3 exposure measures and T1DM incidence. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated. Models were adjusted for sex, race and ethnicity, birth year, mother's age, birth weight, gestational age, number of well-child visits, and study site. RESULTS: In a cohort of 584171 children, the mean ADU was 38 days, the mean cumulative antigen exposure was 263 antigens (SD = 54), and the mean cumulative aluminum exposure was 4.11 mg (SD = 0.73). There were 1132 incident cases of T1DM. ADU (aHR = 1.01; 95% CI, 0.99-1.02) and cumulative antigen exposure (aHR = 0.98; 95% CI, 0.97-1.00) were not associated with T1DM. Cumulative aluminum exposure >3.00 mg was inversely associated with T1DM (aHR = 0.77; 95% CI, 0.60-0.99). CONCLUSIONS: The recommended schedule is not positively associated with the incidence of T1DM in children. These results support the safety of the recommended childhood immunization schedule. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B (CHB) infection causes most liver-related morbidity and mortality worldwide. Numerous Chinese-Americans remain unscreened, and many HBV infected individuals are not accessing adequate care. We evaluated the prevalence of chronic HBV infection, patient awareness of infection, and linkage-to-care among Chinese-Americans in northern New Jersey. Screening 898 Chinese Americans revealed 5.5% hepatitis B virus (HBV) infected, 62.7% immune, and 31.8% non-immune. Our study suggests that HBV prevalence among Chinese-American adults may be lower than previously thought, but a large percentage of the population is still at risk for infection. Thirty-one of 49 hepatitis B surface antigen (HBsAg) seropositive subjects knew of their infections, but only 5 had accessed care. Within 6–20 months after screening education, 25 participants were accessing care. These results demonstrate a need to address possibly inadequate education and other important barriers preventing linkage to care (LTC). [ABSTRACT FROM AUTHOR]

Objectives: General gynecologists are often the first to face a newly diagnosed adnexal mass. Bothering mass symptoms, fertility issues, and the effect of a possible surgical intervention on fertility in term of mechanical factor and ovarian follicular reserve are all considerations that should be accounted for. This study summarizes and compares five different adnexal mass management guidelines, enabling clinicians to peruse consensus and controversy issues, thus choosing the optimal management method.Design: We retrieved, reviewed and compared the most recent national guidelines of adnexal mass management from the national societies of the United States (American College of Obstetricians and Gynecologists), England (the Royal College of Obstetricians and Gynecologists), Canada (the Society of Obstetricians and Gynaecologists of Canada), Australia (the Royal Australian College of General Practitioners), and France (French College of Gynaecologists and Obstetricians).Results: There is a broad consensus regarding the role of transvaginal ultrasound as part of the initial evaluation of an adnexal mass and the radiological characteristics suggesting it being malignant. The role of transabdominal ultrasound or doppler mode is controversial. The use of MRI in cases of indeterminate adnexal masses is widely accepted. Ultrasound-guided aspiration is generally not recommended. There is a broad consensus that CA-125 should not be used as an ovarian cancer disease screening tool, though its role in the initial evaluation of adnexal masses is controversial. Risk prediction models are generally accepted, particularly the 'International Ovarian Tumor Analysis simple rules' and the 'Risk of Malignancy Index'.Conclusion: Adnexal mass management national guidelines, though similar, had noticeable variations in the content, references cited, and recommendations made. While this variation might raise a concern as to the reproducibility of synthesizing literature, it can help practitioners present all spectra of recommendations and available data. [ABSTRACT FROM AUTHOR]

A disproportionate incidence of death has occurred in African Americans (Blacks) in the United States due to COVID-19. The reason for this disparity is likely to be multi-factorial and may involve genetic predisposition. The association of human leukocyte antigens (HLA) with severe COVID-19 was examined in a hospitalized population (89% Black, n = 36) and compared to HLA typed non-hospitalized individuals (20% Black, n = 40) who had recovered from mild disease. For additional comparison, HLA typing data was available from kidney transplant recipients and deceased donors. Hospitalized patients were followed for 45 days after admission to our medical center with death as the primary end-point. One HLA allele, B53, appeared to be more prevalent in the hospitalized COVID-19 patients (percent of positive subjects, 30.5) compared to national data in US Black populations (percent of positive subjects, 24.5). The percent B53 positive in non-hospitalized COVID-19 patients was 2.6, significantly less than the percent positive in the hospitalized COVID-19 patients (p = 0.001, Fisher's exact test) and less than the 8 percent positive listed in national data bases for US Caucasian populations. Significantly greater deaths (73 percent) were observed in HLA B53 positive hospitalized COVID-19 patients compared to hospitalized COVID-19 patients who were B53 negative (40 percent). Multi-variate analysis indicated that HLA B53 positive Black hospitalized COVID-19 patients were at a 7.4 fold greater risk of death than Black COVID-19 patients who were B53 negative. Consideration for accelerated vaccination and treatment should be given to HLA B53 positive Black COVID19 patients. [ABSTRACT FROM AUTHOR]

Background Streptococcus pneumoniae is a causative agent of community-acquired pneumonia (CAP). The 13-valent pneumococcal conjugate vaccine (PCV13) has significantly decreased the burden of PCV13-serotype pneumococcal disease; however, disease from nonvaccine serotypes remains substantial. A recent study documented the persistence of PCV13 serotypes among US adults hospitalized with radiographically confirmed CAP. The current analysis used a recently developed urinary antigen detection (UAD) assay (UAD2) to extend these results to additional serotypes included in an investigational PCV20 vaccine. Methods This prospective study enrolled adults aged ≥18 years hospitalized with radiographically confirmed CAP between October 2013 and September 2016. Presence of S pneumoniae was determined by blood and respiratory sample culture, BinaxNOW urine testing, and UAD. In addition to Quellung on cultured isolates when available, serotypes were identified from urine specimens using UAD1 for PCV13 serotypes and UAD2 for 7 PCV20-unique serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) and 4 additional serotypes (2, 9N, 17F, and 20). Results Among 12 055 subjects with radiographically confirmed CAP, 1482 were positive for S pneumoniae. PCV13- and PCV20-unique serotypes were associated with 37.7% (n = 559) and 27.0% (n = 400) of cases, respectively; 288 subjects were exclusively diagnosed as positive for S pneumoniae by UAD2. Demographic and clinical disease characteristics were similar between subjects with CAP caused by PCV13 and PCV20-unique serotypes. Conclusions The current analysis using UAD2 identified a sizeable proportion of hospitalized adult CAP associated with PCV20-unique serotypes. PCV20 may therefore address the burden of CAP caused by the additional serotypes present in the vaccine. [ABSTRACT FROM AUTHOR]

Although indications for immune checkpoint inhibitors (ICIs) have dramatically increased in the past decade, ICIs have been associated with autoinflammatory immune-related adverse events, which can resemble autoimmune diseases (ADs). Little is known about the impact of baseline AD on mortality in cancer patients treated with ICIs. Here, we identified 17 497 patients with preexisting autoimmune diagnoses prior to treatment with antiprogrammed cell death receptor-1 or antiprogrammed cell death ligand-1 therapy and 17 497 matched controls through the TriNetX Diamond network of more than 200 million patients across the United States and Europe. Using a Cox proportional hazards model, we found that patients with history of AD were not at higher risk of mortality than non-AD patients (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 1 to 1.07; P = .05). Additionally, history of Hashimoto disease (HR = 0.75, 95% CI = 0.62 to 0.90; P = .002) and vitiligo (HR = 0.52, 95% CI = 0.34 to 0.81; P = .003) were statistically significantly associated with decreased mortality. This suggests that underlying AD need not be a contraindication to inclusion in clinical trials and administration of ICI for treatment of cancer. [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus (HIV)–exposed, uninfected (HEU) infants experience higher rates of morbidity and mortality than HIV-unexposed, uninfected (HUU) infants. Few studies have examined whether particular infections and/or immune responses are associated with hospitalization among HEU infants born in the United States. Methods We evaluated a subset of HEU infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1025 and/or Pediatric HIV/AIDS Cohort Study Surveillance Monitoring for ART Toxicities studies. We determined seroconversion to 6 respiratory viruses and measured antibody concentrations to 9 vaccine antigens using quantitative ELISA or electrochemiluminescence. Multivariable modified Poisson regression models were fit to evaluate associations of seroconversion to each respiratory virus/family and antibody concentrations to vaccine antigens with risk of hospitalization in the first year of life. Antibody concentrations to vaccine antigens were compared between HEU infants and HUU infants from a single site using multivariable linear regression models. Results Among 556 HEU infants, seroconversion to respiratory syncytial virus (RSV) and parainfluenza was associated with hospitalization (adjusted risk ratio, 1.95 [95% CI, 1.21–3.15] and 2.30 [1.42–3.73], respectively). Antibody concentrations to tetanus toxoid, pertussis, and pneumococcal vaccine antigens were higher among 525 HEU compared with 100 HUU infants. No associations were observed between antibody concentrations with any vaccine and hospitalization among HEU infants. Conclusions RSV and parainfluenza contribute to hospitalization among HEU infants in the first year of life. HEU infants demonstrate robust antibody responses to vaccine antigens; therefore, humoral immune defects likely do not explain the increased susceptibility to infection observed in this population. [ABSTRACT FROM AUTHOR]

Background: After decades of decline, US acute hepatitis B incidence flattened since 2011. In persons aged ≥40 years and in jurisdictions affected by the opioid crisis, there is an increase in new cases. Data suggest new infections are occurring among US-born persons.Methods: We used National Health and Nutrition Examination Survey data during 2001-2018 to examine changes in total antibody to hepatitis B virus core antigen (anti-HBc) prevalence in US-born persons. During 2013-2018, the distribution of characteristics was examined.Results: During 2001-2006, 2007-2012, and 2013-2018, anti-HBc prevalence was 3.5%, 2.5%, and 2.6% among US-born persons, respectively. This corresponded to 5.7 (range, 4.8-6.6) million US-born persons with resolved or current HBV infection during 2013-2018, including 344 600 persons aged 6-29 years. The largest increase and highest prevalence was among persons who reported injection drug use (IDU), which increased from 35.3% during 2001-2006 to 58.4% during 2013-2018 (P = .07).Conclusions: Anti-HBc prevalence among US-born persons remained flat during the most recent period, coinciding with a doubling of prevalence among persons reporting IDU. These data are consistent with acute hepatitis B surveillance trends, showing increasing incidence in subpopulations where prevention could be strengthened.Anti-HBc prevalence among US-born persons decreased from 2001-2006 to 2007-2012 and remained flat during 2013-2018, coinciding with a near doubling of prevalence among US-born persons reporting a history of injection drug use. [ABSTRACT FROM AUTHOR]

Background: The seroprotection rate (SPR) of hepatitis B vaccination in adults is suboptimal. The aim of this study was to compare the SPR of a tri-antigenic hepatitis B vaccine (TAV), with a mono-antigenic vaccine (MAV) in adults of all ages.Methods: This was a multicentre, double-blind, phase 3, randomised controlled trial (PROTECT) comparing the immunogenicity and safety of TAV with MAV in 28 community and hospital sites in the USA, Finland, Canada, and Belgium. Adults (aged ≥18 years) seronegative for hepatitis B virus (HBV), including those with well-controlled common chronic conditions, were randomly assigned (1:1) and stratified by study centre and age according to a web-based permuted blocked randomisation. Participants received either TAV or MAV which were administered as an intramuscular dose (1 mL) of TAV (10 μg; Sci-B-Vac, VBI Vaccines [SciVac, Rehovot, Israel]) or MAV (20 μg; Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium]) on days 0, 28, and 168 with six study visits and 24 weeks of follow-up after the third vaccination. Participants, investigators, and those assessing outcomes were masked to group assignment. The co-primary outcomes were to show non-inferiority of the SPRs 4 weeks after the third vaccination with TAV versus MAV in adults aged 18 years and older, as well as superiority in adults aged 45 years and older. SPR was defined as the percentage of participants attaining anti-HBs titres of 10 mIU/mL or higher. Non-inferiority of TAV to MAV was concluded if the lower limit of the 95% CI for the between-group difference was greater than -5%. Non-inferiority was assessed in the per-protocol set of participants (aged ≥18 years) and superiority was assessed in all participants (aged ≥45 years) who received at least one vaccination and had at least one evaluable immunogenicity sample after baseline (full analysis set). Safety analyses were a secondary outcome and included all participants who received at least one injection. This trial is registered at Clinicaltrials.gov (NCT03393754) and EudraCT (2017-001819-36) and is closed to new participants.Findings: Between Dec 13, 2017, and April 8, 2019, 1607 participants (796 allocated to TAV and 811 allocated to MAV) were randomly assigned and distributed across age cohorts of 18-44 years (299 of 1607; 18·6%), 45-64 years (716 of 1607; 44·6%), and 65 years and older (592 of 1607; 36·8%). In participants aged 18 years and older, SPR was 91·4% (656 of 718) in the TAV group versus 76·5% (553 of 723) in the MAV group (difference 14·9%, 95% CI 11·2-18·6), showing non-inferiority in the per-protocol set. In participants aged 45 years and older, SPR was 89·4% (559 of 625) in the TAV group versus 73·1% (458 of 627) in the MAV group (difference 16·4%, 95% CI 12·2-20·7), showing superiority in the full analysis set. TAV was associated with higher rates of mild or moderate injection site pain (63·2% [503 of 796] in TAV vs 36·3% [294 of 811] in MAV), tenderness (60·8% [484 of 796] in TAV vs 34·8% [282 of 811] in MAV), and myalgia (34·7% [276 of 796] vs 24·3% [197 of 811] in MAV). Otherwise, the safety profile of TAV was similar to that of MAV.Interpretation: The safety and efficacy of TAV shows its usefulness for the prevention of HBV infection in adults, including those with stable and controlled chronic conditions.Funding: VBI Vaccines. [ABSTRACT FROM AUTHOR]

Background: Chronic hypersensitivity pneumonitis (CHP) is an interstitial lung disease (ILD) caused by long term exposure to an offending antigen. Antigen avoidance is associated with improved outcomes. We are unable to identify the antigen source in approximately half of patients. When an antigen is successfully identified, patients have difficulty with avoidance.Methods: We conducted three structured group discussions with US based ILD specialists utilizing the nominal group technique (NGT). Participants listed barriers to antigen detection and avoidance in CHP. Each participant ranked what they perceived to be the top three barriers in the list in terms of importance. The master list of barriers was consolidated across the three groups into themes that were prioritized based on receiving the highest rankings by participants.Results: Twenty-five physicians participated; 56% had experience caring for CHP patients for ≥ 16 years. Sixty barriers to antigen detection were categorized into seven themes of which the top three were: 1. unclear significance of identified exposures; 2. gaps in clinical knowledge and testing capabilities; 3. there are many unknown and undiscovered antigens. Twenty-eight barriers to antigen avoidance were categorized into five themes of which the top three were: 1. patient limitations, financial barriers and lack of resources; 2. individual patient beliefs, emotions and attachments to the antigen source; and 3. gaps in clinical knowledge and testing capabilities.Conclusions: This study uncovered challenges at the individual patient, organizational, and societal levels and ranked them in terms of level of importance. These findings provide information to guide development and validation of multidisciplinary support and interventions geared towards antigen identification and avoidance in CHP. [ABSTRACT FROM AUTHOR]

Whooping cough is resurging in the United States despite high vaccine coverage. The rapid rise of Bordetella pertussis isolates lacking pertactin (PRN), a key vaccine antigen, has led to concerns about vaccine-driven evolution. Previous studies showed that pertactin can mediate binding to mammalian cells in vitro and act as an immunomodulatory factor in resisting neutrophil-mediated clearance. To further investigate the role of PRN in vivo, we examined the functions of pertactin in the context of a more naturally low dose inoculation experimental system using C3H/HeJ mice that is more sensitive to effects on colonization, growth and spread within the respiratory tract, as well as an experimental approach to measure shedding and transmission between hosts. A B. bronchiseptica pertactin deletion mutant was found to behave similarly to its wild-type (WT) parental strain in colonization of the nasal cavity, trachea, and lungs of mice. However, the pertactin-deficient strain was shed from the nares of mice in much lower numbers, resulting in a significantly lower rate of transmission between hosts. Histological examination of respiratory epithelia revealed that pertactin-deficient bacteria induced substantially less inflammation and mucus accumulation than the WT strain and in vitro assays verified the effect of PRN on the induction of TNF-α by murine macrophages. Interestingly, only WT B. bronchiseptica could be recovered from the spleen of infected mice and were further observed to be intracellular among isolated splenocytes, indicating that pertactin contributes to systemic dissemination involving intracellular survival. These results suggest that pertactin can mediate interactions with immune cells and augments inflammation that contributes to bacterial shedding and transmission between hosts. Understanding the relative contributions of various factors to inflammation, mucus production, shedding and transmission will guide novel strategies to interfere with the reemergence of pertussis. Author summary: B. pertussis strains lacking pertactin have been rising in prevalence especially in countries using acellular vaccines containing pertactin as a key, membrane-associated surface antigen. Previous in vivo studies revealed immunomodulatory properties of pertactin in conventional B. pertussis infection models in which roughly one million bacteria are delivered into lungs, leading to severe pneumonic disease and a strong immune response. However, natural infections begin in the nasopharyngeal region, progress slowly during a prolonged catarrhal stage, only later reaching the trachea and rarely involve the lungs. In this study, a more natural experimental system takes advantage of the ability of B. bronchiseptica, a closely related species, to naturally colonize mice with inocula as low as 5 colony forming units (CFU). In this system B. bronchiseptica can be observed to efficiently colonize, grow, spread within the respiratory tract, is shed from the nares, and transmits between hosts, allowing each of these steps to be measured and studied. Under these conditions, an isogenic pertactin deletion strain was indistinguishable from its parental strain in its abilities to colonize, grow in numbers and spread within the respiratory tract. However, the pertactin-deficient mutant was shed from these mice in lower numbers than wild type, and was defective in transmission between mice. These assays reveal novel roles of pertactin in the induction of inflammation, mucus production, shedding and transmission. [ABSTRACT FROM AUTHOR]

Objectives: For men with intermediate prostate-specific antigen (PSA) levels (4-10 ng/mL), urine-based biomarkers and multiparametric magnetic resonance imaging (MRI) are increasingly used as reflex tests before prostate biopsy. We assessed the cost effectiveness of these reflex tests in the United States.Methods: We used an existing microsimulation model of prostate cancer (PCa) progression and survival to predict lifetime outcomes for a hypothetical cohort of 55-year-old men with intermediate PSA levels. Urine-based biomarkers-PCa antigen (PCA3), TMPRSS2:ERG gene fusion (T2:ERG), and the MyProstateScore (MPS) for any PCa and for high-grade (Gleason score ≥7) PCa (MPShg)-were generated using biomarker data from 1112 men presenting for biopsy at 10 United States institutions. MRI results were based on published sensitivity and specificity for high-grade PCa. Costs and utilities were sourced from literature and Medicare reimbursement schedules. Outcome measures included life years, quality-adjusted life years (QALYs), and lifetime medical costs per patient. Incremental cost-effectiveness ratios were empirically calculated on the basis of simulated life histories under different reflex testing strategies.Results: Biopsying all men provided the most life years and QALYs, followed by reflex testing using MPShg, MPS, MRI, T2:ERG, PCA3, and biopsying no men (QALY range across strategies 15.98-16.09). Accounting for costs, MRI and MPShg were dominated by other strategies. PCA3, T2:ERG, and MPS were likely to be the most cost-effective strategy at willingness-to-pay thresholds of $100 000/QALY, $125 000/QALY, and $150 000/QALY, respectively.Conclusions: Using PCA3, T2:ERG, or MPS as reflex tests has greater economic value than MRI, biopsying all men, or biopsying no men with intermediate PSA levels. [ABSTRACT FROM AUTHOR]

Background: A risk assessment model for predicting the risk of haemolytic disease of the fetus and newborn (HDFN) in future pregnancies following the transfusion of Rh(D)‐positive red blood cell (RBC)‐containing products to females of childbearing potential (FCP) was developed, accounting for the age that the FCP is transfused in various countries. Methods: The HDFN risk prediction model included the following inputs: risk of FCP death in trauma, Rh(D) alloimmunization rate following Rh(D)‐positive RBC transfusion, expected number of live births following resuscitation, probability of carrying an Rh(D)‐positive fetus, the probability of HDFN in an Rh(D)‐positive fetus carried by an alloimmunized mother. The model was implemented in Microsoft R Open, and one million FCPs of each age between 18 and 49 years old were simulated. Published data from eight countries, including the United States, were utilized to generate country‐specific HDFN risk estimates. Results: The risk predictions showed similar characteristics for each country in that the overall risk of having a pregnancy affected by HDFN was higher if the FCP was younger when she received her Rh(D)‐positive transfusion than if she was older. In the United States, the overall risk of HDFN if the FCP was transfused at age 18 was 3·4% (mild: 1·20%, moderate: 0·45%; severe: 1·15%; IUFD: 0·57%); the risk was approximately 0% if the FCP was 43 years or older at the time of transfusion. Conclusion: This model can be used to predict HDFN outcomes when establishing transfusion policies as it relates to the administration of Rh(D)‐positive products for massively bleeding FCPs. [ABSTRACT FROM AUTHOR]

Recent reemergence of pertussis (whooping cough) in highly vaccinated populations and rapid expansion of Bordetella pertussis strains lacking pertactin (PRN), a common acellular vaccine antigen, have raised the specter of vaccine-driven evolution and potential return of what was once the major killer of children. The discovery that most circulating B. pertussis strains in the United States have acquired new and independent disruptive mutations in PRN is compelling evidence of strong selective pressure. However, the other 4 antigens included in acellular vaccines do not appear to be selected against so rapidly. We consider 3 aspects of PRN that distinguish it from other vaccine antigens, which might, individually or collectively, explain why only this antigen is being precipitously eliminated. An understanding of the increase in PRN-deficient strains should provide useful information for the current search for new protective antigens and provide broader lessons for the design of improved subunit vaccines. [ABSTRACT FROM AUTHOR]

Background Echinococcus multilocularis is one of the most severe and lethal parasitic diseases of humans, most often reported in Europe and Asia. Only 1 previous case has been documented in the contiguous United States from Minnesota in 1977. European haplotypes have been identified in carnivores and domestic dogs as well as recently in patients in western and central Canada. Methods We used immunohistochemical testing with the monoclonal antibody Em2G11 and a species-specific enzyme-linked immunosorbent assay affinity-purified antigen Em2, as well as COX1 gene sequencing. Results Using pathology, immunohistochemical staining, specific immunodiagnostic testing, and COX1 gene sequencing, we were able to definitively identify E. multilocularis as the causative agent of our patient's liver and lung lesions, which clustered most closely with the European haplotype. Conclusions We have identified the first case of a European haplotype E. multilocularis in the United States and the first case of this parasitic infection east of the Mississippi River. Given the identification of this haplotype in Canada, this appears to be an emerging infectious disease in North America. [ABSTRACT FROM AUTHOR]

Purpose: Although evidence suggests an inverse association between yogurt consumption and the risk of disorders, such as type 2 diabetes and certain cancers, the mechanisms remain poorly understood. We aimed to examine the association between yogurt consumption and concentrations of plasma soluble CD14, a marker of gut barrier dysfunction. Methods: We analyzed cross-sectional data from 632 women in the Nurses' Health Study (1989–1990) and 444 men in the Health Professionals Follow-up Study (1993–1994) with soluble CD14 concentrations. We estimated yogurt consumption from food frequency questionnaires. We used multivariable-adjusted linear regression models to estimate the percentage difference (95% CI) of soluble CD14 concentrations by yogurt consumption. Results: Among men, higher consumption was associated with a lower soluble CD14 concentration (at least 2 cups/week vs. non-consumers; unadjusted % difference: − 7.6%; 95% CI − 13.0%, − 2.1%; Ptrend = 0.003). The inverse association was slightly attenuated following multivariable adjustment (% difference: − 5.8%; 95% CI − 11.0%, − 0.1%; Ptrend = 0.01). For the same comparison, yogurt consumption was inverse, but not statistically significant associated with soluble CD14 concentration in women (% difference: − 1.2%; 95% CI − 5.6%, 3.5%; Ptrend = 0.64). In stratified analyses, the inverse association between yogurt consumption and the concentrations of soluble CD14 was slightly stronger in men who consumed alcohol at least 20 g/day. Conclusions: Higher yogurt consumption was associated with lower soluble CD14 concentrations, especially in men. Our findings suggest the strengthening of gut barrier function as a plausible mechanism for the observed inverse associations of yogurt consumption with gastrointestinal diseases and disorders involving other systems. [ABSTRACT FROM AUTHOR]

Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70 years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1‐year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immunoreactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under‐ and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long‐term outcomes during the next era of immunosuppression, which will move from universal protocols to patient‐specific optimization. [ABSTRACT FROM AUTHOR]

Importance: An estimated 862 000 persons in the US are living with chronic infection with hepatitis B virus (HBV). Persons born in regions with a prevalence of HBV infection of 2% or greater, such as countries in Africa and Asia, the Pacific Islands, and parts of South America, often become infected at birth and account for up to 95% of newly reported chronic infections in the US. Other high-prevalence populations include persons who inject drugs; men who have sex with men; persons with HIV infection; and sex partners, needle-sharing contacts, and household contacts of persons with chronic HBV infection. Up to 60% of HBV-infected persons are unaware of their infection, and many remain asymptomatic until onset of cirrhosis or end-stage liver disease.Objective: To update its 2014 recommendation, the USPSTF commissioned a review of new randomized clinical trials and cohort studies published from 2014 to August 2019 that evaluated the benefits and harms of screening and antiviral therapy for preventing intermediate outcomes or health outcomes and the association between improvements in intermediate outcomes and health outcomes. New key questions focused on the yield of alternative HBV screening strategies and the accuracy of tools to identify persons at increased risk.Population: This recommendation statement applies to asymptomatic, nonpregnant adolescents and adults at increased risk for HBV infection, including those who were vaccinated before being screened for HBV infection.Evidence Assessment: The USPSTF concludes with moderate certainty that screening for HBV infection in adolescents and adults at increased risk for infection has moderate net benefit.Recommendation: The USPSTF recommends screening for HBV infection in adolescents and adults at increased risk for infection. (B recommendation). [ABSTRACT FROM AUTHOR]

Background The Infectious Diseases Society of America recommends pneumococcal urinary antigen testing (UAT) when identifying pneumococcal infection would allow for antibiotic de-escalation. However, the frequencies of UAT and subsequent antibiotic de-escalation are unknown. Methods We conducted a retrospective cohort study of adult patients admitted with community-acquired or healthcare-associated pneumonia to 170 US hospitals in the Premier database from 2010 to 2015, to describe variation in UAT use, associations of UAT results with antibiotic de-escalation, and associations of de-escalation with outcomes. Results Among 159 894 eligible admissions, 24 757 (15.5%) included UAT performed (18.4% of intensive care unit [ICU] and 15.3% of non-ICU patients). Among hospitals with ≥100 eligible patients, UAT proportions ranged from 0% to 69%. Compared to patients with negative UAT, 7.2% with positive UAT more often had a positive Streptococcus pneumoniae culture (25.4% vs 1.9%, P <.001) and less often had resistant bacteria (5.2% vs 6.8%, P <.05). Of patients initially treated with broad-spectrum antibiotics, most were still receiving broad-spectrum therapy 3 days later, but UAT-positive patients more often had coverage narrowed (38.4% vs 17.0% UAT-negative and 14.6% untested patients, P <.001). Hospital rate of UAT was strongly correlated with de-escalation following a positive test. Only 3 patients de-escalated after a positive UAT result were subsequently admitted to ICU. Conclusions UAT is not ordered routinely in pneumonia, even in ICU. A positive UAT result was associated with less frequent resistant organisms, but usually did not lead to antibiotic de-escalation. Increasing UAT and narrowing therapy after a positive UAT result are opportunities for improved antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is the leading cause of childhood acquired heart disease in developed nations and can result in coronary artery aneurysms and death. Clinical and epidemiologic features implicate an infectious cause but specific antigenic targets of the disease are unknown. Peripheral blood plasmablasts are normally highly clonally diverse but the antibodies they encode are approximately 70% antigen-specific 1-2 weeks after infection.Methods: We isolated single peripheral blood plasmablasts from children with KD 1-3 weeks after onset and prepared 60 monoclonal antibodies (mAbs). We used the mAbs to identify their target antigens and assessed serologic response among KD patients and controls to specific antigen.Results: Thirty-two mAbs from 9 of 11 patients recognize antigen within intracytoplasmic inclusion bodies in ciliated bronchial epithelial cells of fatal cases. Five of these mAbs, from 3 patients with coronary aneurysms, recognize a specific peptide, which blocks binding to inclusion bodies. Sera from 5/8 KD patients day ≥ 8 after illness onset, compared with 0/17 infant controls (P < .01), recognized the KD peptide antigen.Conclusions: These results identify a protein epitope targeted by the antibody response to KD and provide a means to elucidate the pathogenesis of this important worldwide pediatric problem. [ABSTRACT FROM AUTHOR]

Background Hepatitis B virus (HBV) can transmit through needle sharing. The national HBV infection prevalence in persons who inject drugs remains ill-defined. We estimated the prevalence of total HBV core antibody (anti-HBc) positivity, indicating a previous or ongoing HBV infection, among adults aged 20–59 years with an injection drug use (IDU) history. We compared select characteristics by anti-HBc status. Methods Using 2001–2016 National Health and Nutrition Examination Survey data, we calculated the anti-HBc positivity prevalence among adults with IDU histories and among the general US population. For adults with IDU histories, we compared sex, age group, birth cohort, race/ethnicity, health insurance coverage, and hepatitis A immunity by anti-HBc status. Using marginal structural models, we calculated model-adjusted prevalence rates and ratios to determine the characteristics associated with anti-HBc positivity among adults with IDU histories. Results From 2001–2016, the anti-HBc positivity prevalence was 19.7% (95% confidence interval [CI] 16.0–24.0%) among those with IDU histories, compared with 4.6% (95% CI 4.3–5.0%) in the general population. The HBV surface antigen positivity prevalence was 0.4% (95% CI 0.3–0.5%) in the general population. Among adults with IDU histories, 19.8% reported prior-year IDU and 28.5% had a hepatitis A immunity. Conclusions One-fifth of adults with IDU histories had a previous or ongoing HBV infection: a rate over 4 times higher than the prevalence in the general population. One-fifth of adults with IDU histories reported prior-year use. Programs promoting safe IDU practices, drug treatment, and hepatitis A and B vaccinations should be key components of viral hepatitis prevention. [ABSTRACT FROM AUTHOR]

Occult HBV infection (OBI) is defined as the presence of detectable hepatitis B virus (HBV) DNA in HBV surface antigen (HBsAg) negative individuals. Rarely, OBI is attributed to mutant HBV that cannot be detected by commercial assays, but most cases occur in the setting of chronic hepatitis B, particularly infection with wild-type viruses associated with strong HBV suppression. OBI is a high-risk diagnosis as it is associated with multiple complications: HBV reactivation in immunocompromised states, transmission of HBV, progression of liver disease, and hepatocellular carcinoma. The diagnosis is also easy to overlook, as the negative HBsAg in such cases can be falsely reassuring. This case series describes four male patients (mean age 51) who were diagnosed with OBI in the same military treatment facility between February 2018 and October 2018. Two of the four patients were active duty service members at the time of diagnosis. These patients had variable clinical presentations and outcomes. This case series illustrates the clinical significance of OBI and the importance of screening for OBI in HBsAg negative patients with signs of chronic or severe hepatic inflammation. It also prompts an intriguing question regarding the prevalence of both HBV and OBI in the United States military and whether or not routine screening for HBV should be implemented in this population. Further study is warranted to determine if adding HBV core antibody to a universally employed screening regimen would be beneficial. [ABSTRACT FROM AUTHOR]

Background Hepatitis B virus (HBV) infection can be prevented through vaccination. However, previous data show that only about 24%–45% of US adults at high risk of HBV infection are protected. Our aims were to assess prevalence and trends in protective levels of hepatitis B surface antibody (anti-HBs) from 2003 to 2014 and explore factors associated with protection among adults at high risk. Methods Data were taken from the 2003–2014 National Health and Nutrition Examination surveys. Our sample included adults aged 18-49 years who were tested for HBV and reported at least 1 of the following infection risks: history of sexually transmitted disease, sex with men (for men), infection with human immunodeficiency virus, and injection drug use. We calculated the prevalence of anti-HBs (≥10 mIU/mL), indicative of immunity from vaccination, among respondents for three 4-year time intervals (2003–2006, 2007–2010, and 2011–2014) and applied the Cochran-Mantel-Haenszel test to assess trends. Using multivariable logistic regression, we examined factors associated with positive anti-HBs serology. Results The prevalence of positive anti-HBs serology was 23.4%. Prevalence increased from 2003–2006 (16.3%) to 2007–2010 (27.3%), but no change occurred from 2007–2010 (27.3%) to 2011–2014 (28.1%). Among factors predicting positive anti-HBs serology were young age and higher education. Conclusions By 2014, less than one-third of adults aged 18-49 years at risk of infection exhibited protective antibodies ≥10 mIU/mL. Because these adults account for a majority of unprotected adults, targeted intervention strategies are essential to achieve the hepatitis B elimination goal. [ABSTRACT FROM AUTHOR]

The consequences of prolonging cold ischemia time (CIT) to facilitate HLA matching in kidney transplantation are not known. Patients with a history of kidney transplant in the United States (2000-2016) with 0 HLA mismatch (MM) were categorized based on CIT (< 10; 10 to < 15; 15 to < 20; 20 to < 25; 25 to < 30; and ≥ 30 hours). Time to graft loss was compared for each CIT category to a reference group of individuals with > 0 HLA MM and short CIT (< 10 hours) using a multivariable Cox proportional hazards model. The adjusted risk of graft failure was significantly lower for 0 HLA MM with the shortest CIT compared to the reference group (hazard ratio, 0.82; 95% confidence interval, 0.72-0.94), and this survival advantage persisted to a threshold of < 20 hours of CIT. No survival advantage was observed for the 0 HLA MM group once CIT was > 20 hours. This trend persisted after excluding highly sensitized recipients (panel reactive antibody > 98%) where shipping of organs occurs to achieve more equitable access to organs rather than optimize HLA match. CIT > 20 hours offsets the benefit of 0 HLA MM in kidney transplantation. This may have implications in organ shipping to facilitate immunologic match. [ABSTRACT FROM AUTHOR]

Cervical, ovarian, and endometrial cancers are common in the female reproductive system. Cervical cancer starts from the cervix, while ovarian cancer develops when abnormal cells grow in the ovary. Endometrial or uterine cancer starts from the lining of the womb in the endometrium. Approximately 12,000 women are affected every year by cervical cancer in the United States. Squamous cell carcinoma antigen (SCC-Ag) is a well-established biomarker in serum for diagnosing gynecological cancers, and its levels were observed to be elevated in cervical, ovarian, and endometrial cancer patients. Moreover, SCC-Ag was used to identify the tumor size and progression stages. Various biosensing systems have been proposed to identify SCC-Ag; herein, enhanced interdigitated electrode sensing is presented with the use of gold nanoparticles (GNPs) to conjugate an antigen/antibody. It was proved that the limit of detection is 62.5 fM in the case of antibody-GNP, which is 2-fold higher than that by SCC-Ag-GNP. Furthermore, the antibody-GNP-modified surface displays greater current increases with concomitant dose-dependent SCC-Ag levels. High analytical performance was shown by the discrimination against α-fetoprotein and CYFRA 21-1 at 1 pM. An enhanced sensing system is established for gynecological tumors, representing an advance from the earlier detection methods. [ABSTRACT FROM AUTHOR]