A Decade of Chronic Norovirus Infection Surveillance at the NIH Clinical Research Center: Clinical Characteristics, Molecular Epidemiology, and Replication.

BACKGROUND: Noroviruses are an important viral cause of chronic diarrhea in immunocompromised individuals. METHOD: We collected norovirus-positive stool samples (n=448) from immunocompromised patients (n=88) at the National Institutes of Health Clinical Research Center, U.S. from 2010-2022. We assessed clinical characteristics of the cohort, norovirus molecular epidemiology, and infectivity of norovirus specimens in human intestinal enteroids (HIEs) monolayers. RESULTS: Thirty-nine of the 88 patients had sequential stool samples that allowed documentation of chronic norovirus infection with shedding levels ranging from 104 to 1011 genome copies/g of stool. The majority with confirmed chronic norovirus infection in this cohort (32/39, 82%) had clinical evidence of an inborn error of immunity (13 identified monogenic diseases), most with combined immunodeficiency (15 of 32) or common variable immunodeficiency (11 of 32). Noroviruses detected in the cohort were genetically diverse: both Genogroup I (GI.2, GI.3, GI.5, and GI.6) and Genogroup II (GII.1-GII.4, GII.6, GII.7, GII.12, GII.14, and GII.17) genotypes were detected, with GII.4 variants (Osaka, Apeldoorn, Den Haag, New Orleans, and Sydney) predominant (51 of 88, 57.9%). Viruses belonging to the GII.4 Sydney variant group that replicated in HIEs (n=9) showed a higher fold-increase in RNA genome copies during infection compared to others that replicated. CONCLUSIONS: Genetically and biologically diverse noroviruses established chronic infection in individuals with both inborn and acquired immunologic defects enrolled in an NIH surveillance study spanning 12 years, demonstrating the unique nature of each virus and host interaction.

Changes in Tablet Color Due to Light Irradiation: Photodegradation of the Coating Polymer, Hypromellose, by Titanium Dioxide.

The color of the tablets and capsules produced by pharmaceutical companies is important from the perspectives of product branding and counterfeiting. According to some studies, light can change tablet color during storage. In this study, tablets comprising amlodipine besylate (AB), a well-known light-sensitive drug, were coated with commonly used coating materials and exposed to light. Compared to the tablets that were not exposed to light, the color of those exposed to light changed over time. In fact, a faster and more pronounced color change was observed in the tablets exposed to light; however, the amount of AB did not decrease significantly in these tablets. The coating materials and their amounts were varied to clarify the materials involved in the color change. Based on the results, titanium dioxide and hypromellose may be involved in the color change process. As titanium dioxide is a photocatalyst, it may induce or promote chemical changes in hypromellose upon light irradiation. Overall, care should be exercised during selection of the coating polymer because titanium dioxide may promote photodegradation of the coatings while protecting the tablet's active ingredient from light.

Foodborne Outbreaks Caused by Human Norovirus GII.P17-GII.17-Contaminated Nori, Japan, 2017.

Seven foodborne norovirus outbreaks attributable to the GII.P17-GII.17 strain were reported across Japan in 2017, causing illness in a total of 2,094 persons. Nori (dried shredded seaweed) was implicated in all outbreaks and tested positive for norovirus. Our data highlight the stability of norovirus in dehydrated food products.

Phylogeny and Immunoreactivity of Norovirus GII.P16-GII.2, Japan, 2016-17.

During the 2016-17 winter season in Japan, human norovirus GII.P16-GII.2 strains (2016 strains) caused large outbreaks of acute gastroenteritis. Phylogenetic analyses suggested that the 2016 strains derived from the GII.2 strains detected during 2010-12. Immunochromatography between 2016 strains and the pre-2016 GII.2 strains showed similar reactivity.

Production and characterization of monoclonal antibodies specific for major capsid VP1 protein of trichodysplasia spinulosa-associated polyomavirus.

Trichodysplasia spinulosa-associated polyomavirus (TSPyV), a newly identified polyomavirus, has been implicated as a causative agent of trychodysplasia spinulosa (TS), a rare proliferative skin disease in severely immunocompromised hosts. Diagnosis using mAbs is a promising tool with high specificity towards the specific antigen. However, thus far, no suitable mAbs for diagnosing TS disease have been identified. In this study, mAbs specific for VP1 of TSPyV were developed and characterized. Wheat germ cell-free synthesized VP1 protein of TSPyV was used to immunize BALB/c mice to generate hybridomas. Screening of the resultant hybridoma clones resulted in selection of five strongly positive clones that produce mAbs that react with the TSPyV-VP1 antigen. Epitope mapping and bioinformatic analysis showed that these mAbs recognized epitopes located within highly conserved C-terminal region of all clinical isolates of TSPyV-VP1. Further, all these mAbs were highly effective for immunofluorescence and immunoprecipitation analysis. Three of the five mAbs exhibited no cross-reactivity with VP1 of other related polyomaviruses. In addition, one of our mAbs (#14) provided immunohistochemical staining of skin tissue of TS disease. It can be concluded that three of the mAbs in this panel of anti-VP1 antibodies may provide a useful set of tools for studying TSPyV infection and making the specific diagnosis.

Switching from Inadequate Adjunctive or Combination Treatment Options to Brexpiprazole Adjunctive to Antidepressant: An Open-Label Study on the Effects on Depressive Symptoms and Cognitive and Physical Functioning.

Background: Approximately 50% of patients with major depressive disorder do not respond adequately to their antidepressant treatment, underscoring the need for more effective treatment options. The objective of this study was to investigate the effect of adjunctive brexpiprazole on depressive symptoms in patients with major depressive disorder who were not responding to adjunctive or combination therapy of their current antidepressant treatments with several different classes of agents (NCT02012218). Methods: In this 6-week, open-label, phase 3b study, patients with major depressive disorder who had an inadequate response to ≥1 adjunctive or combination therapy, in addition to history of ≥1 failure to monotherapy antidepressant treatment, were switched to adjunctive brexpiprazole. Efficacy was assessed by change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score. Patient functioning was assessed using the Sheehan Disability Scale and the Cognitive and Physical Functioning Questionnaire. Safety and tolerability were also assessed. Results: A total of 51/61 (83.6%) patients completed 6 weeks of treatment with adjunctive brexpiprazole. Improvements in depressive symptoms were observed (least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score, -17.3 [P < .0001]) as well as improvements in general and cognitive functioning (mean changes from baseline to week 6: Sheehan Disability Scale, -3.1 [P < .0001]; Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire, -9.2 [P < .0001]). The most common adverse event was fatigue (14.8%); akathisia was reported by 8.2% of patients. Conclusions: In patients with major depressive disorder who had switched to open-label adjunctive brexpiprazole following inadequate response to previous adjunctive or combination therapy, improvements were observed in depressive symptoms, general functioning, cognitive function, and energy/alertness.

A method for detecting rash and fever illness-associated viruses using multiplex reverse transcription polymerase chain reaction.

In this study, a new multiplex RT-PCR method for detecting various viral genes in patients with rash and fever illnesses (RFIs) was constructed. New primer sets were designed for detection of herpes simplex viruses 1 and 2 (HSV1 and 2), and Epstein-Barr virus (EBV). The newly designed and previously reported primer sets were used to detect 13 types of RFI-associated viruses by multiplex RT-PCR assay systems. Moreover, to eliminate non-specific PCR products, a double-stranded specific DNase was used to digest double-stranded DNA derived from the templates in clinical specimens. RFI-associated viruses were detected in 77.0% of the patients (97/126 cases) by the presented method, multiple viruses being identified in 27.8% of the described cases (35/126 cases). Detected viruses and clinical diagnoses were compatible in 32.5% of the patients (41/126 cases). Sensitivity limits for these viruses were estimated to be 101 -103 copies/assay. Furthermore, non-specific PCR products were eliminated by a double-stranded specific DNase with no influence on sensitivity. These results suggest that this method can detect various RFI-associated viruses in clinical specimens with high sensitivity and specificity.

Functional Mechanism(s) of the Inhibition of Disease Progression by Combination Treatment with Fingolimod Plus Pathogenic Antigen in a Glucose-6-phosphate Isomerase Peptide-Induced Arthritis Mouse Model.

We previously reported that combination treatment with fingolimod (FTY720) plus antigenic peptide of glucose-6-phosphate isomerase (residues 325-339) (GPI325-339) from the onset of symptoms significantly inhibited disease progression in a mouse model of GPI325-339-induced arthritis. In this study, we investigated the mechanism(s) involved. The model mice were treated from arthritis onset with FTY720 alone, GPI325-339 alone, or the combination of FTY720 plus GPI325-339. At the end of treatment, inguinal lymph nodes (LNs) were excised and examined histologically and in flow cytometry. Levels of apoptotic cells, programmed death-1-expressing CD4(+)forkhead box P3(-) nonregulatory T cells (non-Tregs), and cytotoxic T-lymphocyte antigen 4-expressing non-Tregs in inguinal LNs were markedly increased in the combination treatment group mice. Regulatory T cells (Tregs) were also increased. These results indicate that combination treatment with FTY720 plus GPI325-339 inhibits the progression of arthritis by inducing clonal deletion and anergy of pathogenic T cells and also by immune suppression via Tregs.

Evaluation of new immunochromatographic assay kit for adenovirus detection in throat swab: comparison with culture and real-time PCR results.

A new immunochromatographic (IC) assay kit, BD Veritor System Adeno was evaluated to comparing with commercial available kit, BD Adeno Examan, cell culture, and real-time PCR using throat swab samples. Specimens were collected from 146 pediatric patients between July 2011 and January 2012. Mean age of patients was 4 years (8 months-15 years old). Patients were diagnosed with pharyngitis (n = 67), tonsillitis (n = 45), pharyngoconjunctival fever (n = 26), upper respiratory tract infection (n = 6), conjunctivitis (n = 1), or bronchitis (n = 1). Thirty-one of the patients (21.2%) had more than one disease. Among all samples, 61 (41.8%) were positive for adenovirus with BD Veritor System Adeno; 68 (46.6%) with BD Adeno Examan; 63 (43.2%) with real-time PCR; and 65 (44.5%) with cell culture. Serotype 3 (n = 41; 63.1%) was predominant among the 65 adenovirus isolates, followed by serotype 2 (n = 12; 18.5%), 1 (n = 6; 9.2%), 5 (n = 4; 6.2%), and 4 (n = 2; 3.1%). Relative sensitivity and specificity of BD Veritor System Adeno, BD Adeno Examan, and real-time PCR were 93.8% and 98.7%, 96.9% and 93.8%, and 96.9% and 100%, respectively. Positive predictive and negative predictive values for these methods were 98.4% and 95.1%, 92.6% and 97.4%, and 100% and 97.6%, respectively. The sensitivity and specificity of real-time PCR was greater than that of IC assay kits. However, IC assay kits also showed high sensitivity and specificity appropriate for clinical use.

Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system.

Acute lung injury (ALI) is a devastating disease with an overall mortality rate of 30 to 40%. The coagulation/fibrinolysis system is implicated in the pathogenesis of ALI. Thrombin-activatable fibronolysis inhibitor (TAFI) is an important component of the fibrinolysis system. Recent studies have shown that the active form of TAFI can also regulate inflammatory responses by its ability to inhibit complement C3a, C5a, and osteopontin. We hypothesized that TAFI might have a protective role in ALI. To demonstrate this hypothesis, the development of ALI was compared between wild-type (WT) and TAFI-deficient mice. ALI was induced by intratracheal instillation of LPS. Control mice were treated with saline. Animals were killed 24 hours after LPS. The number of inflammatory cells and the concentration of total protein and inflammatory cytokines were significantly increased in bronchoalveolar lavage fluid from LPS-treated, TAFI-deficient mice compared with their WT counterparts. Significantly higher concentrations of C5a were found in bronchoalveolar lavage fluid and plasma in LPS-treated TAFI knockout mice compared with WT mice. Pretreatment with inhaled C5a receptor antagonist blocked the detrimental effects of TAFI deficiency to levels found in WT mice. Our results show that TAFI protects against ALI, at least in part, by inhibiting the complement system.

Genome sequence of an unusual human G10P[8] rotavirus detected in Vietnam.

A rare human G10P[8] rotavirus with a reassortment between bovine and human viruses was detected from a patient with acute gastroenteritis in Vietnam. Genetic analysis using complete coding sequences of all segments showed a genomic constellation of this virus of G10-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. Its VP7 region was genetically related to that of a bovine rotavirus derived from Australia (strain VICG10.01), whereas all other genes were identical to those of a human rotavirus derived from Australia (strain Victoria/CK00047). These results indicate a possibility that the reassortment of the rotavirus was caused by immune escape in Australia and the rotavirus was carried to Vietnam. Additionally, this finding will help further understanding the evolution of rotaviruses circulating in Vietnam.

Efficacy of combination treatment with fingolimod (FTY720) plus pathogenic autoantigen in a glucose-6-phosphate isomerase peptide (GPI325-339)-induced arthritis mouse model.

Fingolimod (FTY720) is known to have a significant therapeutic effect in various autoimmune disease models. Here, we examined FTY720 in a model of rheumatoid arthritis, induced by immunizing DBA/1 mice with a peptide consisting of residues 325 through 339 of glucose-6-phosphate isomerase (GPI325-339). The efficacy was evaluated in terms of macroscopic findings, inflammatory cell infiltration and autoantibody level. Prophylactic administration of FTY720 from the day of immunization significantly suppressed the development of paw swelling, but therapeutic administration of FTY720 from onset of symptoms on day 8-9 was less effective. Interestingly, however, combination treatment with FTY720 plus GPI325-339 for 5 d after onset of symptoms significantly reduced the severity of symptoms in all mice, and no relapse occurred after booster immunization. Taking into account the reported mechanism of action of FTY720, these results indicate that combination treatment with FTY720 plus pathogenic autoantigen might efficiently induce immune tolerance by sequestering circulating autoantigen-specific lymphocytes from blood and peripheral tissues to the secondary lymphoid tissues. Combination treatment with FTY720 plus pathogenic autoantigen may become a breakthrough treatment for remission-induction in patients with autoimmune diseases including rheumatoid arthritis.

Norovirus evolves as one or more distinct clonal populations in immunocompromised hosts.

Noroviruses are a major cause of acute gastroenteritis worldwide and can establish chronic infection in immunocompromised individuals. To investigate the mechanisms of norovirus evolution during chronic infection, we selected seven representative patients from a National Institutes of Health study cohort who sustained norovirus infection for periods ranging from 73 to 1,492 days. Six patients shed viruses belonging to a single genotype (GII.2[PNA], GII.4 New Orleans[P4], GII.4 Den Haag[P4], GII.3[P21], GII.6[P7], or GII.14[P7]) over the period examined, while one patient sequentially shed two genotypes (GII.6[P7] followed by GII.4 Sydney[P31]). Norovirus genomes from consecutive stool samples were sequenced at high resolution (>3,300 reads/nucleotide position) using the Illumina platform and subjected to bioinformatics analysis. Norovirus sequences could be resolved into one or more discrete clonal RNA genomes that persisted within these patients over time. Phylogenetic analyses inferred that clonal populations originated from a single founder virus and not by reinfection with community strains. Estimated evolutionary rates of clonal populations during persistent infection were similar to those of noroviruses from acute infection in the global database, suggesting that inherently higher RNA-dependent polymerase error rates were not associated with the ability to persist. The high-resolution analysis of norovirus diversity and evolution at the population level described here should allow a better understanding of adaptive mutations sustained during chronic infection. IMPORTANCE Noroviruses are an important cause of chronic diarrhea in patients with compromised immune systems. Presently, there are no effective therapies to clear the virus, which can persist for years in the intestinal tract. The goal of our study was to develop a better understanding of the norovirus strains that are associated with these long-term infections. With the remarkable diversity of norovirus strains detected in the immunocompromised patient cohort we studied, it appears that most, if not all, noroviruses circulating in nature may have the capacity to establish a chronic infection when a person is unable to mount an effective immune response. Our work is the most comprehensive genetic data set generated to date in which near full-length genomes from noroviruses associated with chronic infection were analyzed by high-resolution next-generation sequencing. Analysis of this data set led to our discovery that certain patients in our cohort were shedding noroviruses that could be subdivided into distinct haplotypes or populations of viruses that were co-evolving independently. The ability to track haplotypes of noroviruses during chronic infection will allow us to fine-tune our understanding of how the virus adapts and maintains itself in the human host, and how selective pressures such as antiviral drugs can affect these distinct populations.

Molecular Evolutionary Analyses of the RNA-Dependent RNA Polymerase (RdRp) Region and VP1 Gene in Human Norovirus Genotypes GII.P6-GII.6 and GII.P7-GII.6.

To understand the evolution of GII.P6-GII.6 and GII.P7-GII.6 strains, the prevalent human norovirus genotypes, we analysed both the RdRp region and VP1 gene in globally collected strains using authentic bioinformatics technologies. A common ancestor of the P6- and P7-type RdRp region emerged approximately 50 years ago and a common ancestor of the P6- and P7-type VP1 gene emerged approximately 110 years ago. Subsequently, the RdRp region and VP1 gene evolved. Moreover, the evolutionary rates were significantly faster for the P6-type RdRp region and VP1 gene than for the P7-type RdRp region and VP1 genes. Large genetic divergence was observed in the P7-type RdRp region and VP1 gene compared with the P6-type RdRp region and VP1 gene. The phylodynamics of the RdRp region and VP1 gene fluctuated after the year 2000. Positive selection sites in VP1 proteins were located in the antigenicity-related protruding 2 domain, and these sites overlapped with conformational epitopes. These results suggest that the GII.6 VP1 gene and VP1 proteins evolved uniquely due to recombination between the P6- and P7-type RdRp regions in the HuNoV GII.P6-GII.6 and GII.P7-GII.6 virus strains.

Novel human adenovirus strain, Bangladesh.

We report a novel human adenovirus D (HAdV-65) isolated from feces of 4 children in Bangladesh who had acute gastroenteritis. Corresponding genes of HAdV-65 were related to a hexon gene of HAdV-10, penton base genes of HAdV-37 and HAdV-58, and a fiber gene of HAdV-9. This novel virus may be a serious threat to public health.

Transient proliferation of proanthocyanidin-accumulating cells on the epidermal apex contributes to highly aluminum-resistant root elongation in camphor tree.

Aluminum (Al) is a harmful element that rapidly inhibits the elongation of plant roots in acidic soils. The release of organic anions explains Al resistance in annual crops, but the mechanisms that are responsible for superior Al resistance in some woody plants remain unclear. We examined cell properties at the surface layer of the root apex in the camphor tree (Cinnamomum camphora) to understand its high Al resistance mechanism. Exposure to 500 µm Al for 8 d, more than 20-fold higher concentration and longer duration than what soybean (Glycine max) can tolerate, only reduced root elongation in the camphor tree to 64% of the control despite the slight induction of citrate release. In addition, Al content in the root apices was maintained at low levels. Histochemical profiling revealed that proanthocyanidin (PA)-accumulating cells were present at the adjacent outer layer of epidermis cells at the root apex, having distinctive zones for cell division and the early phase of cell expansion. Then the PA cells were gradually detached off the root, leaving thin debris behind, and the root surface was replaced with the elongating epidermis cells at the 3- to 4-mm region behind the tip. Al did not affect the proliferation of PA cells or epidermis cells, except for the delay in the start of expansion and the accelerated detachment of the former. In soybean roots, the innermost lateral root cap cells were absent in both PA accumulation and active cell division and failed to protect the epidermal cell expansion at 25 µm Al. These results suggest that transient proliferation and detachment of PA cells may facilitate the expansion of epidermis cells away from Al during root elongation in camphor tree.

Role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma.

BACKGROUND: Bronchial asthma is an inflammatory disease of the airways. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that besides inhibiting fibrinolysis, also regulates inflammatory processes. The only validated substrate known for TAFI is fibrin. In the present study we evaluated the role of TAFI in bronchial asthma by comparing the development of allergic bronchial asthma between wild-type (WT) and TAFI-deficient mice (KO). METHODS: Asthmatic inflammation was induced by sensitization and challenge with ovalbumin in WT (WT/OVA) and TAFI KO (KO/OVA) mice. WT mice (WT/SAL) and TAFI KO (KO/SAL) were used as controls. Cytokines, markers of inflammation, and coagulation were measured in bronchoalveolar lavage fluid (BALF). RESULTS: Airway hyperresponsiveness was worse in KO/OVA mice than in WT/OVA mice or control mice. Markers of lung injury were significantly increased in BALF from KO/OVA mice compared to WT/OVA mice. Airway hyperresponsiveness and the BALF concentrations of IL-5 and osteopontin were significantly increased in KO/OVA mice compared to WT/OVA mice. Treatment of WT/OVA and KO/OVA mice with a C5a receptor antagonist significantly decreased hyperresponsiveness along with the BALF concentrations of total protein and C5a compared to untreated asthmatic mice. CONCLUSION: The results of this study suggest that TAFI plays a protective role in the pathogenesis of allergic inflammation probably by inhibiting the complement system.

Genomic characterization of a novel human adenovirus type 31 recombinant in the hexon gene.

A novel human recombinant adenovirus of species A (HAdV-A31 MZ) was isolated from a patient with acute gastroenteritis in Japan. The complete genome of HAdV-A31 strain MZ contains 33 776 bp. Analysis of the hexon gene of HAdV-A31 MZ indicated that its hexon sequence is the result of a genetic recombination between those of HAdV-A31 and a close relative to HAdV-A12. The recombination sites were found around the border of hypervariable loops 1 and 2 in the hexon gene, which are the most important determinants for virus neutralization. Loops 1 and 2 of this virus were genetically related to HAdV-A12, whereas all other parts of the genome were highly similar to HAdV-A31. In order to understand the evolution of adenoviruses correctly and to avoid misidentification of HAdV types, we recommend characterizing not only the hexon gene, but also the penton base and fiber genes.

Implication of dopaminergic projection from the ventral tegmental area to the anterior cingulate cortex in µ-opioid-induced place preference.

Despite the importance of prefrontal cortical dopamine in modulating reward, little is known about the implication of the specific subregion of prefrontal cortex in opioid reward. We investigated the role of neurons projecting from the ventral tegmental area (VTA) to the anterior cingulate cortex (ACG) in opioid reward. Microinjection of the retrograde tracer fluorogold (FG) into the ACG revealed several retrogradely labelled cells in the VTA. The FG-positive reactions were noted in both tyrosine hydroxylase (TH)-positive and -negative VTA neurons. The released levels of dopamine and its major metabolites in the ACG were increased by either the electrical stimulation of VTA neurons or microinjection of a selective µ-opioid receptor (MOR) agonist, (D-Ala²,N-MePhe4,Gly-ol5) enkephalin (DAMGO), into the VTA. MOR-like immunoreactivity was seen in both TH-positive and -negative VTA neurons projecting to the ACG. The conditioned place preference induced by intra-VTA injection of DAMGO was significantly attenuated by chemical lesion of dopaminergic terminals in the ACG. The depletion of dopamine in the ACG induced early extinction of µ-opioid-induced place preference. The levels of phosphorylated DARPP32 (Thr34) and phosphorylated CREB (Ser133) were increased in the ACG of rats that had maintained the morphine-induced place preference, whereas the increases of these levels induced by morphine were blocked by pre-treatment of a selective dopamine D1 receptor antagonist SCH23390. These findings suggest that VTA-ACG transmission may play a crucial role in the acquisition and maintenance of µ-opioid-induced place preference. The activation of DARPP32 and CREB through dopamine D1 receptors in the ACG could be implicated in the maintenance of µ-opioid-induced place preference.

Influence diagnostics and outlier detection for meta-analysis of diagnostic test accuracy.

Meta-analyses of diagnostic test accuracy (DTA) studies have been gaining prominence in research in clinical epidemiology and health technology development. In these DTA meta-analyses, some studies may have markedly different characteristics from the others and potentially be inappropriate to include. The inclusion of these "outlying" studies might lead to biases, yielding misleading results. In addition, there might be influential studies that have notable impacts on the results. In this article, we propose Bayesian methods for detecting outlying studies and their influence diagnostics in DTA meta-analyses. Synthetic influence measures based on the bivariate hierarchical Bayesian random effects models are developed because the overall influences of individual studies should be simultaneously assessed by the two outcome variables and their correlation information. We propose four synthetic measures for influence analyses: (a) relative distance, (b) standardized residual, (c) Bayesian p-value, and (d) influence statistic on the area under the summary receiver operating characteristic curve. We also show that conventional univariate Bayesian influential measures can be applied to the bivariate random effects models, which can be used as marginal influential measures. Most of these methods can be similarly applied to the frequentist framework. We illustrate the effectiveness of the proposed methods by applying them to a DTA meta-analysis of ultrasound in screening for vesicoureteral reflux among children with urinary tract infections.