A Causality Assessment Framework for COVID-19 Vaccines and Adverse Events at the COVID-19 Vaccine Safety Research Center.

During the coronavirus disease 2019 (COVID-19) pandemic, conclusively evaluating possible associations between COVID-19 vaccines and potential adverse events was of critical importance. The National Academy of Medicine of Korea established the COVID-19 Vaccine Safety Research Center (CoVaSC) with support from the Korea Disease Control and Prevention Agency to investigate the scientific relationship between COVID-19 vaccines and suspected adverse events. Although determining whether the COVID-19 vaccine was responsible for any suspected adverse event necessitated a systematic approach, traditional causal inference theories, such as Hill's criteria, encountered certain limitations and criticisms. To facilitate a systematic and evidence-based evaluation, the United States Institute of Medicine, at the request of the Centers for Disease Control and Prevention, offered a detailed causality assessment framework in 2012, which was updated in the recent report by the National Academies of Sciences, Engineering, and Medicine (NASEM) in 2024. This framework, based on a weight-of-evidence approach, allows the independent evaluation of both epidemiological and mechanistic evidence, culminating in a comprehensive conclusion about causality. Epidemiological evidence derived from population studies is categorized into four levels-high, moderate, limited, or insufficient-while mechanistic evidence, primarily from biological and clinical studies in animals and individuals, is classified as strong, intermediate, weak, or lacking. The committee then synthesizes these two types of evidence to draw a conclusion about the causal relationship, which can be described as "convincingly supports" ("evidence established" in the 2024 NASEM report), "favors acceptance," "favors rejection," or "inadequate to accept or reject." The CoVaSC has established an independent committee to conduct causality assessments using the weight-of-evidence framework, specifically for evaluating the causality of adverse events associated with COVID-19 vaccines. The aim of this study is to provide an overview of the weight-of-evidence framework and to detail the considerations involved in its practical application in the CoVaSC.

Severe Human Bocavirus-Associated Pneumonia in Adults at a Referral Hospital, Seoul, South Korea.

We report a case series of severe human bocavirus-associated pneumonia in adults in Seoul, South Korea. The virus accounted for 0.5% of all severe pneumonia cases. Structural lung disease and hematologic malignancy were common underlying diseases. Overall death rate was 54.5%. Higher death rates were associated with co-infection (83.3%) and immunocompromise (80.0%).

Comparison of the characteristics of patients with invasive infections and noninvasive infections caused by Trichosporon asahii.

We performed retrospective study to identify the characteristics of invasive Trichosporon asahii infection. A total of 102 patients with T. asahii were identified including 18 (18%) with invasive infection. Invasive infection was associated with indwelling central venous catheter (94% vs 54%, P = .001), prior antifungal agent use (50% vs 18%, P = .01), hematologic malignancy (33% vs 7%, P = .006), and end-stage renal disease (28% vs 7%, P = .02). Patients with invasive infections had higher in-hospital mortality than patients with noninvasive infections (61% vs 27%, P = .006). Those with the above risk factors should be monitored for the development of invasive T. asahii infection. LAY SUMMARY: Patients with indwelling central venous catheter, prior antifungal agent use, hematologic malignancy, and end-stage renal disease were associated with invasive Trichosporon asahii infection. Patients with invasive infections had higher in-hospital mortality than patients without invasive infection.

Epidemiology and Clinical Characteristics of Bloodstream Infection in Patients Under Extracorporeal Membranous Oxygenation.

BACKGROUND: Bloodstream infection (BSI) is an important complication of extracorporeal membranous oxygenation (ECMO) and a major cause of mortality. This study evaluated the epidemiological and clinical characteristics of BSI that occur during ECMO application according to microbial etiology. METHODS: Adult patients who underwent ECMO from January 2009 to December 2016 were retrospectively analyzed for BSI episodes at a 2,700-bed, tertiary center. Epidemiological and clinical characteristics and outcomes of BSI were evaluated and were compared for etiologic groups (gram-positive cocci, gram-negative rods, and fungi groups). Risk factors for 14-day mortality were analyzed. RESULTS: A total of 1,100 patients underwent ECMO during the study period, and 65 BSI episodes occurred in 61 patients. The BSI incidence was 8.3 episodes/1,000 ECMO days, which significantly decreased over time (P = 0.03), primarily in gram-positive cocci BSI. Gram-positive cocci, gram-negative rods, and fungi accounted for 38%, 40%, and 22% of the 73 blood isolates, respectively. Baseline characteristics were comparable between groups. Catheter-related infection (CRI) and pneumonia were the most common sources of BSI; 52% of gram-positive cocci BSIs and 79% of fungi BSIs were caused by CRI, and 75% of gram-negative BSIs by pneumonia. Patients with gram-negative rods BSI died more frequently and earlier than those with other BSIs. Independent risk factors for 14-day mortality were older age and gram-negative rods BSI. CONCLUSIONS: The decreased BSI incidence during ECMO was mainly because of the decrease of gram-positive cocci BSI. The high early mortality of gram-negative rods BSI makes prevention and adequate treatment necessary.

Association of herpes zoster with dementia and effect of antiviral therapy on dementia: a population-based cohort study.

We investigated the association between herpes zoster (HZ) and dementia, and the effects of antiviral therapy on the risk of dementia. We used the National Health Insurance Service-National Sample Cohort in South Korea to identify individuals that were followed from January 1, 2002, to December 31, 2013. Occurrences of HZ and dementia were identified using the relevant diagnostic codes. Dementia was defined as the presence of diagnostic codes and history of anti-dementia drug prescription. Propensity score matching (1:1) was carried out among HZ patients according to antiviral therapy. A total of 229,594 individuals aged ≥50 years were analyzed. The incidences of the first-diagnosed HZ and dementia were 16.69 and 4.67 per 1000 person-years (PY), respectively. HZ patients had a higher risk of dementia (incidence rate ratio [IRR], 1.94 [95% CI 1.83-2.06]; adjusted hazard ratio [HR], 1.12 [95% CI 1.05-1.19]). Of the 34,505 patients with HZ, 28,873 (84%) had received antiviral treatment. The crude incidence rates of subsequent dementia in the treated and untreated groups were 7.79 and 12.27 per 1000 PY, respectively, resulting in an IRR of 0.64 (95% CI 0.56-0.72) and covariate-adjusted HR of 0.79 (95% CI 0.69-0.90). After propensity score matching, the treated group showed a significantly lower risk of dementia (HR 0.76; 95% CI 0.65-0.90). In this large population-based cohort study, HZ was associated with a higher risk of dementia. The use of antiviral agents in HZ patients was associated with lower risks of dementia.

A Longitudinal Study of Adult Patients with Staphylococcus aureus Bacteremia over 11 Years in Korea.

BACKGROUND: The temporal changes in the Staphylococcus aureus genotypes causing S. aureus bacteremia (SAB) and the corresponding clinical changes over the last decade in South Korea are rarely investigated. METHODS: A longitudinal study of adult SAB patients was conducted in a large referral hospital in Seoul, South Korea. Adult monomicrobial SAB patients were enrolled between August 2008 and December 2018. Genotyping was performed by multilocus sequence typing (MLST) and staphylococcal protein A (spa) typing. Trends in changes were identified by linear regression analysis. RESULTS: Of 1782 adult SAB patients, the blood isolates of 1,778 (99.8%) and 1,634 (91.7%) were determined to be MLST and spa type, respectively. ST5 (-2.626%/year) and ST239 (-0.354%/year) decreased during the study period (P < 0.001 for both), but ST72 (2.009%/yr)-and ST8 (0.567%/yr) increased (P < 0.001 for both). The most common genotype was changed from ST5 in 2008 (44.9%) to ST72 in 2018 (36.3%). Panton-Valentine leukocidin-positive spa-t008-MRSA (USA300) was found in 28.6%. Central venous catheter (CVC)-related SAB (-2.440%/yr) and persistent SAB (-1.016%/yr) decreased, but mortality and recurrence rates were unchanged. CONCLUSION: Over the last decade, the hospital clones ST5 and ST239 have been replaced by community genotype ST72. This was associated with decreased CVC-related and persistent SAB. Increased USA300 was observed in community and hospital settings. Further research is required to identify the reasons for the ST72 epidemic and predict the impending epidemic of ST8 strains, including USA300.

Invasive Pulmonary Aspergillosis in Patients With Severe Fever With Thrombocytopenia Syndrome.

Sixteen of 45 patients with severe fever with thrombocytopenia (36%) were admitted to an intensive care unit; 9 (56%) developed invasive pulmonary aspergillosis (IPA) within a median of 8 days (range, 2-11). Mortality was higher in the IPA vs non-IPA patients and in those without vs with antifungal therapy.

Treatment of Latent Tuberculosis Infection Based on the Interferon-γ Release Assay in Allogeneic Stem Cell Transplant Recipients.

In hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-γ release assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative or indeterminate IGRA (1.15/100 person-years; P = .01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years; P = .09). The number needed to treat was 22 (95% confidence interval, 12-99) with positive IGRA results.

Decreased Incidence of Methicillin-Resistant Staphylococcus aureus Bacteremia in Intensive Care Units: a 10-Year Clinical, Microbiological, and Genotypic Analysis in a Tertiary Hospital.

There are limited long-term data on the trends in incidence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB) in intensive care units (ICUs) in which infection control measures have been adopted. We evaluated the trend of incidence and changes in characteristics of MRSA bacteremia in ICUs at a tertiary-care hospital over 10 years using prospective cohort data. ICU-acquired bacteremia was defined as S. aureus bacteremia (SAB) that occurred 48 h or more after ICU admission. MRSA isolates were collected and subjected to microbiological and genotypic analyses. A total of 529 SAB episodes were identified among 367,175 ICU patients. Of these episodes, 288 (54.4%) were ICU acquired, 238 (82.6%) of which were MRSAB. The incidence density of ICU-acquired MRSAB decreased from 1.32 per 1,000 patient-days to 0.19 per 1,000 patient-days (a decrease of 20% annually; P < 0.001 for trend), whereas that of non-ICU-acquired MRSAB fluctuated and did not decrease significantly. The decline in ICU-acquired MRSAB was due to lower catheter-related infection and less pneumonia. Rates of persistent bacteremia and 12-week mortality also fell significantly. A total of 183 isolates were collected from 238 ICU-acquired MRSAB cases. There were no significant changes in the geometric means of vancomycin MICs, vancomycin heteroresistance, or the sequence types of MRSA isolates over time. Chlorhexidine MICs decreased (P < 0.001 for trend) in association with a decline in frequency of the qacA or qacB gene that was related to reductions in specific spa types. The incidence of MRSAB in ICUs has decreased dramatically over time, but most of the microbiological and genotypic characteristics of MRSA isolates have not changed.

Antagonistic Effect of Colistin on Vancomycin Activity against Methicillin-Resistant Staphylococcus aureus in In Vitro and In Vivo Studies.

As concerns arise that the vancomycin MIC of methicillin-resistant Staphylococcus aureus (MRSA) could be increased by concurrent colistin administration, we evaluated the effect of colistin on vancomycin efficacy against MRSA via in vitro and in vivo studies. Among MRSA blood isolates collected in a tertiary-care hospital, we selected representative strains from community-associated MRSA strains (CA-MRSA; ST72-MRSA-SCCmec IV) and hospital-acquired MRSA strains (HA-MRSA; ST5-MRSA-SCCmec II). USA CA-MRSA (USA300), HA-MRSA (USA100), N315 (New York/Japan clone), and a MRSA standard strain (ATCC 43300) were used for comparison. We performed checkerboard assays to identify changes in the vancomycin MIC of MRSA following colistin exposure and evaluated the effect of a vancomycin-colistin combination using time-kill assays. We also assessed the in vivo antagonistic effect by administering vancomycin, colistin, and a combination of these two in a neutropenic murine thigh infection model. In the checkerboard assays, vancomycin MICs of all MRSA strains except N315 were increased by from 0.25 to 0.75 µg/ml following colistin exposure. However, the time-kill assays indicated antagonism only against ST5-MRSA and USA100, when the vancomycin concentration was twice the MIC. In the murine thigh infection model with ST5-MRSA and USA100, vancomycin monotherapy reduced the number of CFU/muscle >1 log10 compared to a combination treatment after 24 h in ST5-MRSA, indicating an antagonistic effect of colistin on vancomycin treatment. This study suggests that exposure to colistin may reduce the susceptibility to vancomycin of certain MRSA strains. Combination therapy with vancomycin and colistin for multidrug-resistant pathogens might result in treatment failure for concurrent MRSA infection.

Immunodeficiency risk score for prediction of mortality by parainfluenza virus infection in patients with hematologic malignancy.

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0-2), moderate (3-5), and high risk (6-8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p < 0.005, Harrell's C-index = 0.84). PIV infection can result in substantial mortality in patients with hematologic malignancy if it progresses to LRTI. The immunodeficiency risk score presented here may be useful for distinguishing moderate and high risk groups that might benefit from antiviral therapy.

Clinical characteristics and prognostic factors of extraintestinal infection caused by Clostridioides difficile: analysis of 60 consecutive cases.

Data regarding extraintestinal Clostridioides difficile infections (ECDIs) remain scarce and anecdotal. We conducted a retrospective cohort study to investigate characteristics and prognostic factors in patients with ECDI. From January 1997 through December 2018, 60 patients were enrolled and divided into three groups as follows: group A (gastrointestinal [GI] disruption caused by malignancy, n = 13); group B (GI disruption from causes other than malignancy, n = 25); group C (no GI disruption, n = 22). GI disruption was defined as compromised integrity of the GI tract caused by abdominal surgery, perforation, malignancy, enterocolitis, or bleeding. The incidence of ECDI was 2.53 per 100,000 admissions. The most common specimens yielded C. difficile were blood (36.7%), peritoneal fluid (20.0%), and abscesses (16.7%). Six patients (10.0%) had confirmed C. difficile enterocolitis, and 36 patients (60.0%) had a polymicrobial infection. C. difficile bacteremia was significantly more common in group A patients than those in groups B or C (53.8% vs. 48.0% vs. 13.6%, p = 0.02), as was the 30-day mortality rate (69.2% vs. 12.0% vs. 18.2%, respectively; p < 0.001). In multivariate analysis, group A (adjusted odds ratio [aOR], 17.32; 95% confidence interval [CI], 2.96-101.21; p = 0.002) and an age of > 65 years (aOR, 7.09; 95% CI, 1.31-38.45; p = 0.02) were independent risk factors for 30-day mortality. ECDI was uncommonly associated with C. difficile enterocolitis. Two factors, GI disruption caused by malignancy, and old age, were associated with significantly poorer short-term outcomes.

Clinical characteristics and outcomes of Staphylococcus aureus bacteremia from a biliary source.

Staphylococcus aureus is a virulent gram-positive organism, which rarely involves the biliary tract. This study aimed to analyze the clinical characteristics and outcomes of S. aureus bacteremia (SAB) originating from the biliary tract by comparing them with those of catheter-related SAB and biliary Klebsiella pneumoniae bacteremia. A matched case-control study within a prospective observational cohort of patients with SAB was conducted. Biliary SAB was defined as the isolation of S. aureus from blood cultures with symptoms and signs of biliary infection. Biliary SAB patients were matched (1:3) with the control groups: patients with catheter-related SAB and biliary Klebsiella pneumoniae bacteremia. Out of 1818 patients with SAB enrolled in the cohort, 42 (2%) had biliary SAB. Majority of these patients had solid tumors involving the pancreaticobiliary tract or liver, biliary drainage stent, and/or recent broad-spectrum antibiotic exposure. Patients with biliary SAB were more likely to have community-onset SAB, solid tumors, and lower APACHE II score than those with catheter-related SAB. They were less likely to have community-acquired infection and solid tumors and more likely to have lower Charlson comorbidity index and higher APACHE II score as compared with biliary K. pneumoniae bacteremia. The 12-week mortality in the biliary SAB group was higher than those in other control groups (60% vs. 20% and 14%). After adjusting for confounding factors, biliary SAB was independently associated with higher mortality. Biliary SAB is relatively rare. When it is clinically suspected, early aggressive treatment should be considered due to high mortality.

Management and outcomes of Burkholderia cepacia complex bacteremia in patients without cystic fibrosis: a retrospective observational study.

Burkholderia cepacia complex (BCC) is an emerging pathogen of nosocomial infection in chronic or critically ill patients without cystic fibrosis (CF). The objective was to evaluate the management and outcomes of BCC bacteremia in patients without CF. We conducted a retrospective study of non-CF adult patients with BCC bacteremia between January 1997 and December 2016 at 4 tertiary hospitals in South Korea. A total of 216 non-CF patients with BCC bacteremia were identified. Most cases were hospital-acquired (79.2%), and the most common source was a central venous catheter (CVC) (42.1%). The rates of susceptibility to trimethoprim-sulfamethoxazole and piperacillin-tazobactam of BCC isolates were high as 92.8% and 90.3%, respectively. The rates of susceptibility to ceftazidime, meropenem, and levofloxacin were 75.5%, 72.3%, and 64.1%, respectively. The 14-day, 30-day, and in-hospital mortality rate was 19.4%, 23.1%, and 31.0%, respectively. Female (OR = 3.1; 95% CI, 1.4-6.8), liver cirrhosis (OR = 6.2; 95% CI, 1.6-16.6), septic shock (OR = 11.2; 95% CI, 5.1-24.8), and catheter-related infection (OR = 2.6, 95% CI, 1.2-5.8) were the independent risk factors for 30-day mortality. The outcome did not differ according to type of antibiotics used. Among 91 patients with CVC-related BCC bacteremia, delayed CVC removal (> 3 days) had a higher rate of persistent bacteremia (54.5 vs. 26.1%; P = 0.03) and lower rate of clinical response (49.0 vs. 71.9%; P = 0.04), compared with early CVC removal (within 3 days). BCC bacteremia occurring in non-CF patients was mostly hospital-acquired and CVC-related. Early removal of the catheter is crucial in treatment of CVC-related BCC bacteremia.

Impact of neutropenia on the clinical outcomes of Staphylococcus aureus bacteremia in patients with hematologic malignancies: a 10-year experience in a tertiary care hospital.

Staphylococcus aureus bacteremia is one of the most serious bacterial infections and may lead to worse clinical outcomes in patients with prolonged severe neutropenia. However, clinical data on S. aureus bacteremia in neutropenic patients with hematologic malignancies are limited. We conducted two case-control studies using a 10-year prospective cohort of patients with S. aureus bacteremia. Neutropenic and non-neutropenic hematologic malignancy patients were compared on clinical characteristics and treatment outcomes. An additional matched case-control study using solid tumor patients was conducted. Risk factors for 12-week mortality were analyzed. Of 1643 patients with S. aureus bacteremia, 64 (3.9%) neutropenic and 108 (6.6%) non-neutropenic patients with hematologic malignancies were included in the study. There were no significant differences in the incidence of metastatic infection between the two groups (17.2% vs. 17.6%, p = 0.95), in contrast with a previous study that observed no metastatic infection in neutropenic patients. Twelve-week mortality in neutropenic patients with hematologic malignancies tended to be lower than in non-neutropenic patients with hematologic malignancies (15.6% vs. 26.9%, p = 0.09) and was significantly lower than in neutropenic patients with solid tumors (15.6% vs. 45.8%, p = 0.003). Independent risk factors for mortality in hematologic malignancy patients with S. aureus bacteremia were high Charlson comorbidity score, high APACHE II score, and skin and soft tissue infection. Neutropenia was not independently associated with mortality. Our findings suggest that neutropenia in hematologic malignancies may not affect the incidence of metastatic infection or 12-week mortality of S. aureus bacteremia.

Long-term methicillin-resistant Staphylococcus aureus bacteremia persisting for more than 2 weeks: risk factors and outcomes.

The clinical significance of long-term methicillin-resistant Staphylococcus aureus (MRSA) bacteremia remains unclear. We evaluated the clinical, microbiological characteristics, and clinical outcomes of long-term MRSA bacteremia. A nested case-control study was conducted in a prospective cohort of adult patients with MRSA bacteremia at a tertiary hospital between August 2008 and December 2017. Patients with long-term MRSA bacteremia (≥ 14 days) were compared with control patients, defined as having bacteremia that resolved in less than 3 days. The following variables were documented: heteroresistance phenotype, genotypes, agr dysfunction, and the presence of 41 virulence genes in isolates. Of the total 890 patients studied, 69 patients (7.8%) exhibited long-term MRSA bacteremia and 599 (67.3%) exhibited resolving bacteremia. The most common sources of long-term bacteremia were central venous catheter-related infection (39%) and osteomyelitis (19%). Independent risk factors for long-term MRSA bacteremia included male sex (adjusted odds ratio [aOR] = 2.43), community-acquired bacteremia (aOR = 2.93), the presence of a prosthetic device (aOR = 3.40), and osteomyelitis (aOR = 7.98). Metastatic infections developed more frequently in patients with long-term bacteremia than in those with resolving bacteremia (56.5% vs. 8.0%; P < 0.001). Although there were no significant differences in 30-day, 12-week, or in-hospital mortality rates between the two groups, infection-attributable mortality was higher in the long-term bacteremia group (23.2% vs. 11.5%; P = 0.01). Microbiological characteristics did not differ significantly between the two groups. Clinical factors, including community-acquired bacteremia, the presence of a prosthetic device, and osteomyelitis, appear to contribute to long-term MRSA bacteremia more than microbiological factors.

Diagnostic usefulness of differential time to positivity in neutropenic cancer patients with suspected catheter-related candidemia.

Methods for distinguishing catheter-related candidemia (CRC) from non-CRC before catheter removal remain limited. We thus evaluated the diagnostic performance of differential time to positivity (DTP) to diagnose CRC in neutropenic cancer patients with suspected CRC. Of the 35 patients enrolled, 15 (43%) with CRC (six definite and nine probable) and 17 (49%) with non-CRC were finally analyzed. Based on the receiver operating characteristic curve, the optimal cutoff value of DTP for diagnosing CRC was ≥1.45 hours with the sensitivity 80% (95% confidence interval [CI], 51-95) and specificity 100% (95% CI, 80-100), respectively.

Candida auris colonization or infection of the ear: A single-center study in South Korea from 2016 to 2018.

Candida auris was first identified in Japan from specimens obtained from the ear, but most reports since have reported invasive infections or non-ear based cases. We reviewed all the microbiology records from a single center in South Korea from February 2016 to July 2018. One hundred eleven isolates were positive for C. auris from 79 patients. All 79 patients positive for C. auris had positive ear discharge samples. All but one of the patients with C. auris had been to the otorhinolaryngology clinic. Symptom-driven ear culture was done for all but one patient, whose culture was performed for surveillance. Ear discharges were mostly purulent (60%) or serous (34%). We performed the environmental cultures at the otorhinolaryngology outpatient clinic to evaluate the environmental contamination of C. auris, but C. auris was not isolated from medical equipment and environmental surfaces.

Epstein-Barr virus-encoded miR-BART5-5p upregulates PD-L1 through PIAS3/pSTAT3 modulation, worsening clinical outcomes of PD-L1-positive gastric carcinomas.

BACKGROUND: Epstein-Barr virus (EBV) is etiologically associated with ~ 10% of all gastric carcinomas. However, the molecular mechanisms and roles of EBV miRNAs in gastric carcinoma oncogenesis are yet to be elucidated. METHODS: MicroRNA microarray and TaqMan quantitative real-time RT-PCR were conducted. RT-PCR and luciferase reporter assay for PIAS3, western blotting for 20 proteins, immunofluorescence for STAT3, transfection with miRBART5-5p-plasmid, STAT3-plasmid, miRBART5-5p mimic, or PIAS3-siRNA, and in vitro assays for biological effects of PD-L1 were implemented. In situ hybridization for EBV-encoded small RNAs and immunohistochemistry were performed on gastric carcinoma tissues. RESULTS: Transfecting miR-BART5-5p into EBV(-) gastric carcinoma cell lines caused a decrease in PIAS3 3'-UTR reporter activity, PIAS3 downregulation, and subsequent STAT3 activation followed by PIAS3/pSTAT3-dependent PD-L1 upregulation. Interestingly, due to PD-L1 knockdown, apoptosis was increased, while the rate of cell proliferation, invasion capacity, and migration were decreased in miR-BART5-5p-transfected cells. In EBV(+) gastric carcinoma cells, anti-miR-BART5-5p reduced PD-L1 levels through PIAS3/pSTAT3 control. Among 103 patients with EBV-associated gastric carcinomas, overall survival was significantly shortened for those with PD-L1(+) tumors compared to those with PD-L1(-) tumors (P = 0.049). CONCLUSIONS: Our findings imply that miR-BART5-5p directly targets PIAS3 and augments PD-L1 through miR-BART5/PIAS3/pSTAT3/PD-L1 axis control. This contributes to antiapoptosis, tumor cell proliferation, invasion and migration, as well as immune escape, furthering gastric carcinoma progression and worsening the clinical outcome, especially in the PD-L1(+) group of patients with EBV-associated gastric carcinomas. miR-BART5-5p may, therefore, be amenable to PD-1/PD-L1 immune checkpoint inhibitor therapy.

Epidemiology and risk factors associated with Pneumocystis jirovecii pneumonia in kidney transplant recipients after 6-month trimethoprim-sulfamethoxazole prophylaxis: A case-control study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity and mortality in kidney transplant recipients (KTRs), and prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended. The aim of this study was to investigate incidence and risk factors for PCP in KTRs after 6-month TMP-SMX prophylaxis. METHODS: We conducted a case-control study of patients with PCP who received 6-month PCP prophylaxis with TMP-SMX after kidney transplantation (KT). In cases of rejection, PCP prophylaxis was provided for six additional months after anti-rejection therapy. Cytomegalovirus (CMV) infection was not considered an indication for PCP prophylaxis due to concerns of nephrotoxicity associated with TMP-SMX. RESULTS: Among 3941 kidney or pancreas-kidney transplant recipients, 67 (1.7%) developed PCP after discontinuing TMP-SMX. A total of 47 patients with KT PCP and 94 controls were included. Duration of PCP prophylaxis was similar between cases and controls (median 6 months, P = .53). In multivariate analysis, rejection (OR 3.9; 95% CI 1.4-11.1) and CMV infection (OR 2.4; 95% CI 1.0-5.8) were independently associated with PCP development after TMP-SMX. Rejection or CMV infection was observed in 70% of patients with PCP. Time to PCP development after rejection (median [IQR] 6 [5-19] months) was slightly shorter than after CMV infection (median [IQR] 9 [5-12] months; P = .18). CONCLUSION: Post-prophylaxis PCP occurred in <2% of KTRs, and about two-thirds of these experienced rejection or CMV infection. These data suggest that at least 6 to 9-month additional chemoprophylaxis may be needed to prevent PCP in KTRs with transplant rejection or CMV infection.