High vaccination coverage and infection rate result in a robust SARS-CoV-2-specific immunity in the majority of liver cirrhosis and transplant patients: A single-center cross-sectional study.

BACKGROUND: In the third year of the SARS-CoV-2 pandemic, little is known about the vaccine- and infection-induced immune response in liver transplant recipients (LTR) and liver cirrhosis patients (LCP). OBJECTIVE: This cross-sectional study assessed the vaccination coverage, infection rate, and the resulting humoral and cellular SARS-CoV-2-specific immune responses in a cohort of LTR and LCP at the University Medical Center Hamburg-Eppendorf, Germany between March and May 2023. METHODS: Clinical and laboratory data from 244 consecutive patients (160 LTR and 84 LCP) were collected via chart review and a patient survey. Immune responses were determined via standard spike(S)- and nucleocapsid-protein serology and a spike-specific Interferon-gamma release assay (IGRA). RESULTS: On average, LTR and LCP were vaccinated 3.7 and 3.3 times, respectively and 59.4% of patients received ≥4 vaccinations. Altogether, 68.1% (109/160) of LTR and 70.2% (59/84) of LCP experienced a SARS-CoV-2 infection. Most infections occurred during the Omicron wave in 2022 after an average of 3.0 vaccinations. Overall, the hospitalization rate was low (<6%) in both groups. An average of 4.3 antigen contacts by vaccination and/or infection resulted in a seroconversion rate of 98.4%. However, 17.5% (28/160) of LTR and 8.3% (7/84) of LCP demonstrated only low anti-S titers (<1000 AU/ml), and 24.6% (16/65) of LTR and 20.4% (10/59) of LCP had negative or low IGRA responses. Patients with hybrid immunity (vaccination plus infection) elicited significantly higher anti-S titers compared with uninfected patients with the same number of spike antigen contacts. A total of 22.2% of patients refused additional booster vaccinations. CONCLUSION: By spring 2023, high vaccination coverage and infection rate have resulted in a robust, mostly hybrid, humoral and cellular immune response in most LTR and LCP. However, booster vaccinations with vaccines covering new variants seem advisable, especially in patients with low immune responses and risk factors for severe disease.

Quantifying sustained pain worsening in knee osteoarthritis.

OBJECTIVE: Recent work suggests that many persons with knee osteoarthritis (OA) experience stable symptoms over time. Whether patients experience periods of symptom exacerbation or flare which interrupt this stable course, and how long such periods last, has received little study. Our objective is to describe the frequency and duration of episodes of pain worsening in persons with knee OA. METHODS: We selected participants from the Osteoarthritis Initiative with radiographic, symptomatic knee OA. We defined a clinically relevant increase in knee pain as an increase in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain of ≥9 points. We defined sustained worsening as maintaining at least 80% of the initial increase. We used Poisson regression to estimate the incidence rate (IR) of episodes of pain worsening. RESULTS: 1093 participants were included in the analysis. Eighty-eight percent had ≥1 increase in WOMAC pain ≥9 points (IR: 26.3 per 100 person years (95% CI: 25.2, 27.4)). Forty-eight percent had ≥1 episode of sustained worsening (IR: 9.7 per 100 person-years (95% CI: 8.9, 10.5)). Elevated pain was maintained an average of 2.4 years after the initial increase. CONCLUSION: Most participants with knee OA reported at least one clinically relevant increase in WOMAC pain, but fewer than half experienced an episode of sustained pain worsening. These individual-level data portray a more nuanced and fluctuating course of OA pain than suggested by trajectory studies. These data could be useful in shared decision-making regarding prognosis and treatment choices in persons affected by symptomatic knee OA.

Treatment of the syndrome of knee pain and meniscal tear in middle-aged and older persons: A narrative review.

Objective: To summarize the literature investigating management, treatment strategies, short- and longer-term outcomes of treatment for meniscal tear in middle-aged and older adults. Design: We performed a literature search using PubMed to identify relevant articles and selected 15 for a narrative summary on the available evidence. Results: The literature suggests that middle-age and older adults with meniscal tear may benefit from initial physical therapy (PT) potentially followed by arthroscopic partial meniscectomy (APM) for those who do not experience sufficient benefit after PT and in whom other sources of pain are deemed unlikely. There is moderate evidence to suggest that some factors at baseline, such as radiographic OA, meniscal tear type, and pain at baseline may influence outcomes after APM. Over time, APM appears to increase the risk of degenerative changes in cartilage, bone, and other knee structures as evidenced by radiograph and MRI-based assessments. Conclusion: Evidence from research investigating outcomes of treatment for meniscal tear in middle-aged and older adults demonstrates that PT is a reasonable initial treatment. More research is needed to investigate the best treatment for those who do not benefit substantially from initial PT. The evidence also demonstrates that APM may be associated with greater risk of radiographic osteoarthritic changes, though more research and the addition of enhanced quantitative MRI-assessments are needed to further detail any compositional changes in the knee. Focusing on these areas of further study will clarify whether these imaging findings are clinically meaningful.

[Less is more in infectious diseases]. / Weniger ist mehr in der Infektiologie.

BACKGROUND: The increasing development of antimicrobial resistance has been identified as one of the greatest threats to public health and is caused to a relevant extent by falsely indicated antibiotic treatment. OBJECTIVE: The main aim of this article is to identify areas in infectious disease diagnostics and treatment where overuse occurs and to provide recommendations on how to avoid it. MATERIAL AND METHODS: The authors identified current and relevant studies on the topic of medical overuse in infectious diseases via a literature search. In particular, contributions from international "less is more" initiatives were included. The focus was on areas in which a reduction of diagnostic and therapeutic measures leads to an optimization of patient outcomes. RESULTS: In many cases overuse in the context of diagnostics and treatment of infectious diseases not only leads to an unnecessary financial burden on the healthcare system and is not beneficial but can also increase the risk of development of antimicrobial resistance and have adverse consequences for patients. CONCLUSION: Correct indications as well as focused selection and adequate application of antimicrobial agents is crucial to provide the best possible medical care. Diagnostic and antibiotic stewardship measures, which should be implemented in collaboration with infectious disease specialists, can help to identify and reduce areas of overuse and misuse.

[Recurrent vomiting and headaches in a 26-year-old male patient]. / Rezidivierendes Erbrechen und Kopfschmerzen bei einem 26-jährigen Patienten.

This article reports the case of a 26-year-old male patient with recurrent emesis and headache due to central nervous system tuberculosis. The thoracic computed tomography showed bilateral disseminated pulmonary micronodular infiltrates and a cavern connecting to the bronchial system. The cranial magnetic resonance imaging showed multiple supratentorial and infratentorial microabscesses with concomitant meningitis. Mycobacterium tuberculosis was detected in sputum, bronchoalveolar lavage and cerebrospinal fluid. The patient received first-line antituberculous drug treatment, including streptomycin (instead of ethambutol) and adjuvant prednisolone.

Dynamic changes of circulating miRNAs induced by the Ebola virus vaccine VSV-EBOV.

VSV-EBOV is a replication-competent Ebola virus (EBOV) vaccine, which was tested in clinical trials as response to the Ebola virus disease (EVD) outbreak 2013-2016. It is the most advanced EBOV candidate currently in the licensure process. The experimental vaccine was again administered as response to outbreaks in the Democratic Republic of Congo. However, underlying molecular mechanisms that convey protection remain incompletely understood. MicroRNAs (miRNAs) are known key regulators that influence gene expression on a post-transcriptional level. The miRNA-mediated control has emerged as a critical regulatory principle in the immune system, which strongly influences the balance of innate and adaptive immune responses by modulation of signaling pathways critical for differentiation of immune cells. We investigated expression levels of circulating miRNAs (c-miRNAs) in plasma from healthy vaccinees, as they may reflect cellular dynamics following VSV-EBOV immunization and additionally may serve as potential biomarkers for vaccine efficacy. As part of the WHO-led VEBCON consortium, we investigated safety and immunogenicity of VSV-EBOV in a phase I trial. A comprehensive analysis of expression levels on c-miRNAs from plasma samples following VSV-EBOV immunization (day 0, 1, 3 post vaccination) was conducted using RT-qPCR assays. Potential biological relevance was assessed using in silico analyses. Additionally, we correlated dynamics of miRNA expressions with our previously reported data on vaccine-induced antibody and cytokine responses and finally evaluated the prognostic power by generating ROC curves. We identified four promising miRNAs (hsa-miR-146a, hsa-miR-126, hsa-miR-199a, hsa-miR-484), showing a strong association with adaptive immune responses, exhibited favourable prognostic performance and are implicated in immunology-related functions. Our results provide evidence that miRNAs may serve as useful biomarkers for prediction of vaccine-induced immunogenicity. Furthermore, our unique data set provides insight into molecular mechanisms that underlie VSV-EBOV-mediated protective immune responses, which may help to decipher VSV-EBOV immune signature and accelerate strategic vaccine design or personalized approaches.

Tropheryma whipplei in children with diarrhoea in rural Ghana.

Tropheryma whipplei has been hypothesized to be able to cause diarrhoea, but data from young children are scarce. In this hospital-based case-control study 534 stool samples of children aged between 2 months and 15 years from rural Ghana were analysed for the presence of T. whipplei. Overall stool prevalence of T. whipplei was high (27.5%). Although there was no difference in T. whipplei carriage overall between cases and controls, cases aged between 0 and 12 months carried T. whipplei in their stool twice as often as controls without diarrhoea. The results from this study may support the hypothesis that T. whipplei can cause diarrhoea in first-time infection.

Comparison of autochthonous and imported cases of hepatitis A or hepatitis E.

BACKGROUND: Hepatitis A and hepatitis E are not limited to tropical countries but are also present in industrialized countries. Both infections share similar clinical features. There is no comparative study evaluating the clinical parameters of autochthonous and imported hepatitis A virus and hepatitis E virus infections. AIMS: The aim of this study was to determine differences between autochthonous and imported hepatitis A virus (HAV) and hepatitis E virus (HEV) infections. METHODS: Medical charts of all patients at our center with acute HAV and HEV infections were analyzed retrospectively (n = 50, study period 01/2009 - 08/2013). RESULTS: Peak bilirubin (median 8.6 vs. 4.4 mg/dL, p = 0.008) and ALT levels (median 2998 vs. 1666 IU/mL, p = 0.04) were higher in patients with hepatitis A compared to hepatitis E. In comparison to autochthones hepatitis E cases, patients with imported infections had significantly higher peak values for AST, ALT, bilirubin and INR (p = 0.009, p = 0.002, p = 0.04 and p = 0.049, respectively). In HAV infection, AST levels tended to be higher in imported infections (p = 0.08). CONCLUSIONS: (i) It is not possible to differentiate certainly between acute HAV and HEV infections by clinical or biochemical parameters, however, HAV infections might be associated with more cholestasis and higher ALT values. (ii) Imported HEV infections are associated with higher transaminases, INR and bilirubin levels compared to autochthonous cases and (iii) imported HAV infections tend to be associated with higher transaminases in comparison to autochthonous cases.

Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers.

BACKGROUND. Human immunodeficiency virus (HIV) elite controllers are able to control infection with HIV-1 spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although low frequencies of HIV-infected peripheral CD4(+) T cells have been reported in this group, it remains unclear to what extent these are due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. METHODS. We assessed proviral DNA levels, autologous viral growth from and infectability of in vitro activated, CD8(+) T cell-depleted CD4(+) T cells from HIV elite controllers (mean viral load, <50 copies/mL), viremic controllers (mean viral load, <2000 copies/mL), chronic progressors, and individuals receiving highly active antiretroviral therapy. RESULTS. Although we successfully detected autologous virus production in ex vivo activated CD4(+) T cells from all chronic progressors and from most of the viremic controllers, we were able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4(+) T cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to those in CD4(+) T cells from HIV-uninfected subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contribute to difficulty in isolation of virus. CONCLUSIONS. These data indicate that elite control is not due to inability of activated CD4(+) T cells to support HIV infection, but the relative contributions of host and viral factors that account for maintenance of low-level infection remain to be determined.

Observation intervention: time for an overview.

This paper aims to illustrate the nature and extent of research and development work related to observation practice over the last 28 years. It aims to show both local Scottish work and the National picture, how there is still a lack of research evidence despite all the work that has taken place and what needs to be performed to explore observation practice for the future. It is not intended to be a literature review in the traditional sense. Observation has not been studied enough to know the continuing ever-changing picture of what goes on in the reality of practice. There are now studies examining observation but none of these are 'gold standard' randomized controlled trials; some are quantitative and some are qualitative audit or guidelines all based at a lower level in research evidence terms. The time has come to take the evidence base to the next level through evaluative research.

Knowledge of dental trauma first aid (DTFA): the example of avulsed incisors in casualty departments and schools in London.

OBJECTIVE: To investigate awareness and practices of dental trauma first aid (DTFA) in hospital emergency settings and in primary and secondary schools in London. DESIGN: A cross-sectional study using self-administered questionnaires and semi-structured interviews. SETTING: Primary and secondary schools and casualty/emergency and walk-in casualty centres in London in 2005. SUBJECTS AND METHODS: A randomly selected sample of 125 schools and a total of 31 walk-in casualty centres, providing services for five randomly selected London boroughs. A person responsible for emergency care of children represented each of these study sites. RESULTS: Response rates of 81.6% and 87% were achieved for schools and casualty/emergency centres respectively. The school respondents who had previously received advice on DTFA were three times more likely to be willing to replant an avulsed tooth compared to those who had not. A third of casualty personnel showed gaps in knowledge in DTFA. Results from schools showed an unwillingness to start emergency action mainly due to perceived inadequacy in knowledge/skills and also for legal reasons. CONCLUSION: There is the need for further studies focused on the barriers resulting in unwillingness to provide DTFA among school personnel and clarification regarding issues of responsibility and acceptable levels of competence of professionals other than dentists.

Regulatory and accessory HIV-1 proteins: potential targets for HIV-1 vaccines?

The HIV-1 regulatory proteins Tat and Rev and the accessory proteins Vpr, Vpu and Vif are essential for efficient viral replication, and their cytoplasmic production suggests that they should be processed for recognition by cytotoxic T lymphocytes. However, only limited data is available, evaluating the role of immune responses directed against these proteins in natural HIV-1 infection. Recent advances in the methods used for the characterization of HIV-1-specific cellular immune responses, including quantification of antigen-specific IFN-gamma production by ELISpot assay and flow-cytometry-based intracellular cytokine quantification, have allowed for a much more comprehensive assessment of virus-specific immune responses. Emerging data show that the regulatory and accessory proteins serve as important targets for HIV-1-specific T cell responses, and multiple CTL epitopes have been identified in functionally important regions of these proteins. Moreover, the use of autologous peptides have allowed for the detection of significantly stronger HIV-1-specific T cell responses in the more variable regulatory and accessory HIV-1 proteins Tat and Vpr. These data indicate that despite the small size of these proteins, regulatory and accessory proteins are targeted by cellular immune responses in natural HIV-1 infection and contribute importantly to the total HIV-1-specific CD8+ T cell response. A multi-component vaccine, with the inclusion of these proteins plus structural proteins remains the most promising choice for an effective AIDS vaccine.

Epidemiological aspects of oral tori in a Ghanaian community.

AIM: To determine the prevalence of oral tori, commonly found among Ghanaians, and compare with that in other regions. METHOD: Dental examination records of all 926 patients seen from January 1998 to April 2000 in a dental outpatient clinic in Accra, Ghana, were studied. The existence of a torus had systematically and routinely been ascertained by visual inspection and palpation. RESULTS: Frequency distribution and cross-tabulation analysis showed an overall prevalence of 14.6% with a female: male ratio of 1.1: 1. The most prevalent variety was the bilateral mandibular torus (12.1%) and the midpalatal torus of the maxillary tori (4.3 %). Females had 2.2 times the probability of having midpalatal torus compared to men (Odds Ratio (OR) = 2.2; Confidence Interval: 1.05, 4.70). There was a very strong concurrent relationship between mandibular and maxillary tori (OR = 16; CI = 7.8, 32.5). CONCLUSION: Comparisons indicated a strong similarity between torus prevalence in Ghana and the Caribbean regions. This should help in further discussions on the epidemiology of this bony anomaly.

Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities.

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection.

CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/ micro l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.

Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load.

Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/10(6) PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

Cytotoxic T-lymphocyte (CTL) responses directed against regulatory and accessory proteins in HIV-1 infection.

The HIV-1 regulatory proteins Tat and Rev and the accessory proteins Vpr, Vpu, and Vif are essential for viral replication, and their cytoplasmic production suggests that they should be processed for recognition by cytotoxic T lymphocytes. However, only limited data is available evaluating to which extent these proteins are targeted in natural infection and optimal cytotoxic T lymphocyte (CTL) epitopes within these proteins have not been defined. In this study, CTL responses against HIV-1 Tat, Rev, Vpr, Vpu, and Vif were analyzed in 70 HIV-1 infected individuals and 10 HIV-1 negative controls using overlapping peptides spanning the entire proteins. Peptide-specific interferon-gamma (IFN-gamma) production was measured by Elispot assay and flow-based intracellular cytokine quantification. HLA class I restriction and cytotoxic activity were confirmed after isolation of peptide-specific CD8+ T-cell lines. All regulatory and accessory proteins served as targets for HIV-1- specific CTL and multiple CTL epitopes were identified in functionally important regions of these proteins. In certain individuals HIV-1-specific CD8+ T-cell responses to these accessory and regulatory proteins contributed up to a third to the magnitude of the total HIV-1-specific CTL response. These data indicate that despite the small size of these proteins regulatory and accessory proteins are targeted by CTL in natural HIV-1 infection, and contribute importantly to the total HIV-1-specific CD8+ T-cell responses. These findings are relevant for the evaluation of the specificity and breadth of immune responses during acute and chronic#10; infection, and will be useful for the design and testing of candidate human immunodeficiency virus (HIV) vaccines.

Cellular immune responses in transplantation-associated chronic viral infections.

Viral pathogens are important causes of morbidity following transplantation. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections represent two major viral complications in transplant recipients. Recent advances in methodology have led to a better understanding of host immune responses directed against chronic viral infections. We review the nature of antiviral immunity involved in control of CMV and EBV. Viral mechanisms of immune evasion and immunotherapeutic strategies in the transplantation setting will also be addressed.

1,2,4-triazolo[3,4-a]pyridine as a novel, constrained template for fibrinogen receptor (GPIIb/IIIa) antagonists.

Conformationally constrained analogues of the GPIIb/IIIa antagonist elarofiban (RWJ-53308) have been synthesized and biologically evaluated. The 1,2,4-triazolo[3,4-a]pyridine scaffold provided potent antagonists with favorable pharmacodynamic and pharmacokinetic attributes in dogs. Compounds 12a and 13a exhibited enhancements in oral bioavailability, t(1/2), and ex vivo duration of action (inhibition of ADP-induced platelet aggregation) relative to elarofiban.