Overcoming the age-dependent SARS-CoV-2 vaccine response through hybrid immunity: analysis of humoral and cellular immunity with mass cytometry profiling.

BACKGROUND: Age-dependent immune responses to coronavirus disease 2019 (COVID-19) vaccinations and breakthrough infections (BIs) in young and middle-aged individuals are unclear. METHODS: This nationwide multicenter prospective cohort study analyzed immune responses in participants of the ChAdOx1 (ChAd)-ChAd-mRNA vaccine group using cytometry by time-of-flight, anti-spike protein antibody (Sab) and anti-nucleocapsid antibody (Nab) titers, plaque reduction neutralization tests (PRNTs), and interferon-gamma (IFN-γ) release assays at various time points. RESULTS: We evaluated 347 participants with an average age of 38.9 ± 9.4 years (range: 21-63). There was a significant inverse correlation between age and Sab levels after the second dose (slope - 14.96, P = 0.032), and this was more pronounced after the third dose (slope - 208.9, P < 0.001). After BIs, older participants showed significantly higher Sab titers (slope 398.8, P = 0.001), reversing the age-related decline observed post-vaccination. This reversal was also observed in PRNTs against wild-type SARS-CoV-2 and the BA.1 and BA.5 variants. IFN-γ responses increased markedly after the third dose and Bis, but showed a weak positive correlation with age, without statistical significance. Immune cell profiling revealed an age-dependent decrease in the proportions of B-cell lineage cells. The proportions of naive CD4+ and CD8+ T cells were inversely correlated with age, whereas the proportions of mature T cell subsets with memory function, including memory CD4+ T, CD8+ TEM, CD8+ TEMRA, and TFH cells, increased with age. CONCLUSIONS: Age-dependent waning of the serologic response to COVID-19 vaccines occurred even in middle-aged individuals, but was reversed after BIs. IFN-γ responses were preserved, compensating for the decrease in naive T cell populations, with an increase in memory T cell populations.

COVID-19's Radiologic, Functional, and Serologic Consequences at 6-Month and 18-Month Follow-up: A Prospective Cohort Study.

BACKGROUND: We evaluated the radiologic, pulmonary functional, and antibody statuses of coronavirus disease 2019 (COVID-19) patients 6 and 18 months after discharge, comparing changes in status and focusing on risk factors for residual computed tomography (CT) abnormalities. METHODS: This prospective cohort study was conducted on COVID-19 patients discharged between April 2020 and January 2021. Chest CT, pulmonary function testing (PFT), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) measurements were performed 6 and 18 months after discharge. We evaluated factors associated with residual CT abnormalities and the correlation between lesion volume in CT (lesionvolume), PFT, and IgG levels. RESULTS: This study included 68 and 42 participants evaluated 6 and 18 months, respectively, after hospitalizations for COVID-19. CT abnormalities were noted in 22 participants (32.4%) at 6 months and 13 participants (31.0%) at 18 months. Lesionvolume was significantly lower at 18 months than 6 months (P < 0.001). Patients with CT abnormalities at 6 months showed lower forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC), and patients with CT abnormalities at 18 months exhibited lower FVC. FVC significantly improved between 6 and 18 months of follow-up (all P < 0.0001). SARS-CoV-2 IgG levels were significantly higher in patients with CT abnormalities at 6 and 18 months (P < 0.001). At 18-month follow-up assessments, age was associated with CT abnormalities (odds ratio, 1.17; 95% confidence interval, 1.03-1.32; P = 0.01), and lesionvolume showed a positive correlation with IgG level (r = 0.643, P < 0.001). CONCLUSION: At 18-month follow-up assessments, 31.0% of participants exhibited residual CT abnormalities. Age and higher SARS-CoV-2 IgG levels were significant predictors, and FVC was related to abnormal CT findings at 18 months. Lesionvolume and FVC improved between 6 and 18 months. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0008573.

Establishment of Safety Monitoring System for Vaccines Not Included in the National Immunization Program in Korea.

BACKGROUND: In Korea, there are no surveillance programs for vaccines that are not included in the national immunization program (NIP), and vaccine safety monitoring in the adult population is inadequate. This study aimed to establish a safety monitoring system for non-NIP vaccines in adults. METHODS: Frequently administered non-NIP vaccines were selected. Individuals were included if they received at least one of the selected vaccines at a participating institution and provided informed consent. Solicited and unsolicited adverse events were monitored using questionnaires sent through text messages on days 1, 3, 7, 28, and 90 post-vaccination. Selected adverse events of special interest (AESIs) were monitored monthly by retrospective review of electronic medical records. Causality was assessed according to the Korea Disease Control and Prevention Agency guidelines. RESULTS: Four vaccines (tetanus-diphtheria-pertussis [Tdap], pneumococcal conjugate 13-valent [PCV13], live zoster vaccine [ZVL], and recombinant zoster vaccine [RZV]) were selected, and their safety profiles were monitored at four tertiary hospitals and 10 primary care clinics. The response rates of the questionnaires on post-vaccination days 1, 7, 28, and 90 were 99.2%, 93.6%, 81.0%, and 48.7%, respectively. Of 555 AESI identified over 10 months, 10 cases received one of the selected non-NIP vaccines within 90 days of the event. CONCLUSION: We are establishing the first safety monitoring system for selected non-NIP vaccines in Korea since September 2022 and report its progress as of July 2023. However, continuous government support is essential for its maintenance and improvement.

Interim Estimates of 2023-2024 Seasonal Influenza Vaccine Effectiveness Among Adults in Korea.

In the 2023-2024 season, the influenza epidemic in South Korea peaked earlier than in recent years. In this study, we aimed to estimate the interim vaccine effectiveness (VE) of the influenza vaccination to prevent influenza during the early season. From November 1, 2023, to December 31, 2023, we enrolled 2,632 subjects with influenza-like illness from eight hospitals participating in hospital-based influenza morbidity and mortality surveillance. A retrospective test-negative case-control study was conducted to estimate the VE. The results showed an adjusted VE of 22.5% (95% confidence interval [CI], 6.6 to 35.8) for the total population. The adjusted VE was 22.3% (95% CI, 6.1 to 35.7) for influenza A and 9.4% (95% CI, -51.3 to 45.7) for influenza A/H1N1. Full results of the analysis will be reported.

Effectiveness of Bivalent mRNA Booster Vaccine Against COVID-19 in Korea.

BACKGROUND: Bivalent booster mRNA vaccines containing the omicron-variant strains have been introduced worldwide in the autumn of 2022. Nevertheless, the omicron subvariants evoked another large coronavirus disease 2019 (COVID-19) pandemic wave in late 2022 and early 2023. METHODS: A retrospective, test-negative, case-control study was conducted to estimate the vaccine effectiveness (VE) of bivalent COVID-19 vaccines in 8 university hospitals between January and February 2023. The case and control groups were divided based on nasopharyngeal COVID-19 real-time polymerase chain reaction results and matched based on age, sex, hospital, and date (week) of the test performed. The VE of the BA.1- or BA.4/BA.5-based mRNA vaccines were estimated. VE was calculated using the 1-adjusted odds ratio from multivariable logistic regression. RESULTS: In total, 949 patients and 947 controls were enrolled in this study. VE for the BA.4/BA.5-based bivalent mRNA vaccine was 43% (95% confidence interval [CI], 17, 61%). In subgroup analysis based on age and underlying medical conditions, BA.4/BA.5-based bivalent mRNA vaccine was effective against old adults aged ≥ 65-years (VE, 55%; 95% CI, 23, 73%) and individuals with comorbidities (VE, 54%; 95% CI, 23, 73%). In comparison, the BA.1-based bivalent mRNA vaccine did not demonstrate statistically significant effectiveness (VE, 25%; 95% CI, -8, 49%). CONCLUSION: The BA.4/BA.5-based bivalent mRNA booster vaccine provided significant protection against COVID-19 in the Korean adults, especially in the older adults aged ≥ 65 years and in individuals with underlying medical conditions.

Clinical utility of quantitative immunoassays and surrogate virus neutralization tests for predicting neutralizing activity against the SARS-CoV-2 Omicron BA.1 and BA.5 variants.

Developing new antibody assays for emerging SARS-CoV-2 variants is challenging. SARS-CoV-2 surrogate virus neutralization tests (sVNT) targeting Omicron BA.1 and BA.5 have been devised, but their performance needs to be validated in comparison with quantitative immunoassays. First, using 1749 PRNT-positive sera, we noticed that log-transformed optical density (OD) ratio of wild-type (WT) sVNT exhibited better titer-correlation with plaque reduction neutralization test (PRNT) than % inhibition value. Second, we tried 798 dilutional titration tests with 103 sera, but nonlinear correlation between OD ratio and antibody concentration limited titration of sVNT. Third, the titer-correlations of two sVNT kits for BA.1 and two quantitative immunoassays for WT were evaluated with BA.1 and BA.5 PRNT. All tested kits exhibited a linear correlation with PRNT titers, but the sVNT kits exhibited high false-negative rates (cPass-BA.1 kit, 45.4% for BA.1 and 44.2% for BA.5; STANDARD F-BA.1 kit, 1.9% for BA.1 and 2.2% for BA.5), while quantitative immunoassays showed 100% sensitivity. Linear mixed-effects model suggested superior titer-correlation with PRNT for quantitative immunoassays compared to sVNT kits. Taken together, the use of quantitative immunoassays for WT, rather than rapid development of new kits, would be practical for predicting neutralizing activities against emerging new variants.

Concomitant Use of Sodium-Glucose Cotransporter 2 Inhibitors and Overactive Bladder Drugs and the Risk of Urinary Tract Infection.

Concomitant use of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and overactive bladder (OAB) drugs potentially poses a risk of urinary tract infections (UTIs) due to the urinary retention of highly concentrated glucose in the urine. Thus, this study aimed to investigate the risk of UTIs among patients who initiated SGLT-2i treatment while taking OAB drugs. This population-based cohort study included new-users of SGLT-2i or comparator antidiabetics (dipeptidyl peptidase-4 inhibitor (DPP-4i); glucagon-like peptide-1 receptor agonist (GLP-1RA)) with OAB drugs between 2014 and 2020 using claim data from Korea. Primary outcome was a composite UTI event composite end point comprising pyelonephritis, cystitis, and urethritis, using both inpatient and outpatient diagnoses. Propensity score fine stratification was used to adjust for potential confounding factors. Weighted hazard ratios (HR) were calculated using the Cox proportional hazards model. In the first cohort, 796 and 9,181 new-users of SGLT-2i and DPP-4i with OAB drugs were identified, respectively. This study found a similar risk of UTIs in concomitant users of SGLT-2i and DPP-4i (weighted HR 1.08, 95% confidence interval: 0.88-1.32) with OAB drugs. In the second cohort, 2,387 and 280 new-users of SGLT-2i and GLP-1RA with OAB drugs were identified, respectively. Initiation of SGLT-2i while on OAB treatment was not associated with increased risk of UTI (0.89, 0.50-1.60), compared with initiation of GLP-1RA. These results show that the concomitant use of SGLT-2i with OAB drugs was not associated with an increased risk of UTI compared with the concomitant use of DPP-4i or GLP-1RA with OAB drugs.

COVID-19 Vaccination Strategies in the Endemic Period: Lessons from Influenza.

Coronavirus disease 2019 (COVID-19) is a highly contagious zoonotic respiratory disease with many similarities to influenza. Effective vaccines are available for both; however, rapid viral evolution and waning immunity make them virtually impossible to eradicate with vaccines. Thus, the practical goal of vaccination is to reduce the incidence of serious illnesses and death. Three years after the introduction of COVID-19 vaccines, the optimal vaccination strategy in the endemic period remains elusive, and health authorities worldwide have begun to adopt various approaches. Herein, we propose a COVID-19 vaccination strategy based on the data available until early 2024 and discuss aspects that require further clarification for better decision making. Drawing from comparisons between COVID-19 and influenza vaccination strategies, our proposed COVID-19 vaccination strategy prioritizes high-risk groups, emphasizes seasonal administration aligned with influenza vaccination campaigns, and advocates the co-administration with influenza vaccines to increase coverage.

Comparative safety analysis of mRNA and adenoviral vector COVID-19 vaccines: a nationwide cohort study using an emulated target trial approach.

OBJECTIVE: This nationwide cohort study compared the incidence of adverse events of special interest (AESIs) between adenoviral vector-based (ChAdOx1) and mRNA-based (BNT162b2 or mRNA-1273) coronavirus disease 2019 (COVID-19) vaccines. METHODS: A targeted trial emulation study was conducted using data from the National Health Insurance Service database. Vaccinees aged 18-85 years who had received at least one dose of ChAdOx1 or an mRNA-based vaccine were identified. The 42-day risks of AESIs were calculated. RESULTS: A total of 1 767 539 ChAdOx1 vaccinees were matched exactly with mRNA vaccinees according to their risk factors. The 42-day risks of adverse events were low (∼0 to 176 events per 100 000 persons in both vaccine groups), and the incidence rates of AESIs were comparable between the two platforms, except for a higher occurrence of acute cardiac injury (incidence rate ratio [IRR], 1.22; 95% CI, 1.10-1.35), myocarditis or pericarditis (IRR, 2.14; 95% CI, 1.14-4.04), and arrhythmia (IRR, 1.46; 95% CI, 1.24-1.71) in mRNA vaccinees. The incidence of Guillain-Barré syndrome (IRR, 0.20; 95% CI, 0.06-0.69), vasovagal syncope (IRR, 0.77; 95% CI, 0.62-0.97), radiculopathy (IRR = 0.59, 95% CI, 0.41-0.84), and aseptic arthritis (IRR, 0.81; 95% CI, 0.70-0.93) was significantly lower in mRNA-based vaccinees compared with ChAdOx1 vaccinees. DISCUSSION: A remarkable platform-dependent difference was observed in the safety profiles of COVID-19 vaccines, particularly for myocarditis or pericarditis and Guillain-Barré syndrome. However, the overall risk of AESIs was low for both vaccine platforms.

Mammalian adaptation risk in HPAI H5N8: a comprehensive model bridging experimental data with mathematical insights.

Understanding the mammalian pathogenesis and interspecies transmission of HPAI H5N8 virus hinges on mapping its adaptive markers. We used deep sequencing to track these markers over five passages in murine lung tissue. Subsequently, we evaluated the growth, selection, and RNA load of eight recombinant viruses with mammalian adaptive markers. By leveraging an integrated non-linear regression model, we quantitatively determined the influence of these markers on growth, adaptation, and RNA expression in mammalian hosts. Furthermore, our findings revealed that the interplay of these markers can lead to synergistic, additive, or antagonistic effects when combined. The elucidation distance method then transformed these results into distinct values, facilitating the derivation of a risk score for each marker. In vivo tests affirmed the accuracy of scores. As more mutations were incorporated, the overall risk score of virus heightened, and the optimal interplay between markers became essential for risk augmentation. Our study provides a robust model to assess risk from adaptive markers of HPAI H5N8, guiding strategies against future influenza threats.

Spatiotemporal variations in migratory bird diversity and abundance along the coast of Gochang getbol.

Tidal flats provide critical habitat for migratory waterbird species; however, populations of migratory waterbirds have significantly declined due to tidal flat loss and degradation caused by human activities, particularly in Asia. Gochang getbol is one of tidal flats located on the southwest coast of South Korea and a center of clam production. Using bird monitoring data collected at five zones (zone1 to zone5) established across Gochang getbol and near coastal area, we examined distribution patterns of migratory bird diversity and conservation-related species along the coast of Gochang getbol. The intensity of human activity ‒ mudflat culture (mostly bivalve) and aquaculture was relatively high at zone2 and zone3, occupying > 30% of 2km circular area surrounding most sample points of these zones. Zone1 and particularly zone4 contained more natural/semi-natural habitats (less disturbed mudflats and wetlands) and zone5 had smallest mudflat than others. Shannon diversity, species richness, and abundance of migratory birds differed between zones (Anova test, P ≤ 0.02) except Shannon diversity in winter. In fall, all values were higher at zone4 than zone3 and zone5. In winter, zone1 showed greatest species richness and higher abundance than zone2, zone3, and zone5. In spring, while most differences were found between zone4 and zone5, abundance at zone4 was somewhat higher than zone2. The results from the fourth corner analysis indicated that abundance of species foraging at mudflat level was positively associated with zone1 (winter) but negatively with zone3 (fall). Sandpipers were positively associated with zone4. Abundance distribution maps of conservation-related species, created by inverse distance-weighted interpolation modeling, also showed high abundance of most conservation-related species at zone4 and 1. The findings of our study suggest the importance of natural/semi-natural habitat, and the possible link between human activity and distribution patterns of migratory birds in Gochang getbol. While we need further investigation on direct response of migratory birds to human activity, areas with low human activity with more natural/semi-natural habitat, e.g., zone4 and zone1 may be crucial for the conservation of migratory birds.

Knowledge, attitude, and practice toward herpes zoster (HZ) and HZ vaccination: Concept elicitation findings from a multi-country study in the Asia Pacific.

Herpes zoster (HZ) is a prevalent disease characterized by a painful rash. A multi­country study was conducted to elicit public and physician knowledge, attitude, and practice (KAP) toward HZ disease and vaccination for the assessment of local factors influencing HZ vaccine perceptions in four Asian-Pacific countries/territories One-to-one qualitative interviews were conducted in 2022, among the public (people aged ≥ 50 years, adults with parents aged ≥ 50 years, zoster vaccine live-vaccinated individuals aged ≥ 50 years in Republic of Korea, and HZ patients; n = 78) and physicians (general practitioners and specialists; n = 24). Themes surrounding KAP toward HZ and HZ vaccination were summarized using a thematic analysis. A substantial knowledge gap related to HZ was observed among the public, including its causes, long-term impacts, and the at-risk population. There was a low perceived risk of HZ and low general awareness of HZ vaccine availability, although country/territory-specific differences existed. Fear of HZ-associated pain contributed toward vaccination intent among HZ patients and adults with parents aged ≥ 50 years. HZ-naïve adults who were encouraged to receive the vaccine by others were not motivated to do so due to optimism bias. Physicians were perceived to be a reliable source of information. However, physicians did not always proactively discuss HZ vaccination due to time constraints and a perceived need to prioritize other vaccinations including influenza and pneumococcal vaccines. Initiatives are needed to improve public awareness of HZ and its complications, in terms of overall impact on individuals and society, and highlight the important role of physicians in recommending vaccination.

Effectiveness of COVID-19 XBB.1.5 monovalent mRNA vaccine in Korea: interim analysis.

As coronavirus disease-2019 (COVID-19) becomes an endemic disease, the virus continues to evolve and become immunologically distinct from previous strains. Immune imprinting has raised concerns about bivalent mRNA vaccines containing both ancestral virus and Omicron variant. To increase efficacy against the predominant strains as of the second half of 2023, the updated vaccine formulation contained only the mRNA of XBB.1.5 sublineage. We conducted a multicenter, test-negative, case-control study to estimate XBB.1.5 monovalent vaccine effectiveness (VE) and present the results of an interim analysis with data collected in November 2023. Patients who underwent COVID-19 testing at eight university hospitals were included and matched based on age (19-49, 50-64, and ≥65 years) and sex in a 1:1 ratio. VE was calculated using the adjusted odds ratio derived from multivariable logistic regression. Of the 992 patients included, 49 (5.3%) received the XBB.1.5 monovalent vaccine at least 7 days before COVID-19 testing. Patients with COVID-19 (cases) were less likely to have received the XBB.1.5 monovalent vaccine (case 3.5% vs. control 7.2%, p=0.019) and to have a history of COVID-19 within 6 months (2.2% vs. 4.6%, p=0.068). In contrast, patients with COVID-19 were more likely to be healthcare workers (8.2% vs. 3.0%, p=0.001) and to have chronic neurological diseases (16.7% vs. 11.9%, p=0.048). The adjusted VE of the XBB.1.5 monovalent mRNA vaccine was 56.8% (95% confidence interval: 18.7-77.9%). XBB.1.5 monovalent mRNA vaccine provided significant protection against COVID-19 in the first one to two months after vaccination.

Recommendations for Adult Immunization by the Korean Society of Infectious Diseases, 2023: Minor Revisions to the 3rd Edition.

The Korean Society of Infectious Diseases has been regularly developing guidelines for adult immunization since 2007. In 2023, the guidelines for the following seven vaccines were revised: influenza, herpes zoster, pneumococcal, tetanus-diphtheria-pertussis (Tdap), human papillomavirus (HPV), meningococcal, and rabies vaccines. For the influenza vaccine, a recommendation for enhanced vaccines for the elderly was added. For the herpes zoster vaccine, a recommendation for the recombinant zoster vaccine was added. For the pneumococcal vaccine, the current status of the 15-valent pneumococcal conjugate vaccine and 20-valent PCV was described. For the Tdap vaccine, the possibility of using Tdap instead of tetanus-diphtheria vaccine was described. For the HPV vaccine, the expansion of the eligible age for vaccination was described. For the meningococcal vaccine, a recommendation for the meningococcal B vaccine was added. For the rabies vaccine, the number of pre-exposure prophylaxis doses was changed. This manuscript documents the summary and rationale of the revisions for the seven vaccines. For the vaccines not mentioned in this manuscript, the recommendations in the 3rd edition of the Vaccinations for Adults textbook shall remain in effect.

Persistent differences in the immunogenicity of the two COVID-19 primary vaccines series, modulated by booster mRNA vaccination and breakthrough infection.

INTRODUCTION: The long-term impact of initial immunogenicity induced by different primary COVID-19 vaccine series remains unclear. METHODS: A prospective cohort study was conducted at 10 tertiary hospitals in Korea from March 2021 to September 2022. Immunogenicity assessments included anti-spike protein antibody (Sab), SARS-CoV-2-specific interferon-gamma releasing assay (IGRA), and multiplex cytokine assays for spike protein-stimulated plasma. Spike proteins derived from wild-type SARS-CoV-2 and alpha variant (Spike1) and beta and gamma variant (Spike2) were utilized. RESULTS: A total of 235 healthcare workers who had received a two-dose primary vaccine series of either ChAdOx1 or BNT162b2, followed by a third booster dose of BNT162b2 (166 in the ChAdOx1/ChAdOx1/BNT162b2 (CCB) group and 69 in the BNT162b2/BNT162b2/BNT162b2 (BBB) group, based on the vaccine series) were included. Following the primary vaccine series, the BBB group exhibited significantly higher increases in Sab levels, IGRA responses, and multiple cytokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1ß, interleukin (IL)-1ra, IFN-γ, IL-2, IL-4, and IL-10) compared to the CCB group (all P < 0.05). One month after the third BNT162b2 booster, the CCB group showed Sab levels comparable to those of the BBB group, and both groups exhibited lower levels after six months without breakthrough infections (BIs). However, among those who experienced BA.1/2 BIs after the third booster, Sab levels increased significantly more in the BBB group than in the CCB group (P < 0.001). IGRA responses to both Spike1 and Spike2 proteins were significantly stronger in the BBB group than the CCB group after the third booster, while only the Spike2 response were higher after BIs (P = 0.007). The BBB group exhibited stronger enhancement of T-cell cytokines (IL-2, IL-4, and IL-17A) after BIs than in the CCB group (P < 0.05). CONCLUSION: Differences in immunogenicity induced by the two primary vaccine series persisted, modulated by subsequent booster vaccinations and BIs.

Clinical utility of prostate-specific antigen mass ratio for prediction of prostate cancer detection on a repeated prostate biopsy

Purpose To assess the clinical utility of the prostate-specific antigen mass ratio (PSA-MR), a newly developed PSA derivative, simply defined as the (i) PSA density (PSA-D) multiplied by the plasma volume or (ii) total PSA amount in circulation per prostate volume, for predicting prostate cancer (PCa) among men undergoing repeated prostate biopsy (PBx). Materials and Methods Patients (n = 286), who underwent a repeated PBx, were analyzed. The various parameters associated with PCa detection were noted in each patient. PSA-MR was also calculated. Results PCa was detected in 63 (22.0%) of 286 patients. PSA-MR was the independent predictor in the univariate- and multivariate logistic regression analyses (OR = 3.448, p = 0.001 and OR = 13.430, p = 0.033, respectively). A nomogram that incorporated PSA-MR was considered a useful tool (predictive accuracy: 79.2%, 95% CI: 0.726-0.858, p < 0.001). Furthermore, a nomogram that incorporated PSA-MR would have avoided 59.6% of unnecessary repeated PBx. The predictive accuracy of PSA-MR was also superior to that of PSA or PSA-D (p = 0.013 and 0.009, respectively). Conclusions PSA-MR was an independent predictor, and its consideration would have avoided 59.6% of unnecessary repeated PBx for PCa detection. PSA-MR was also superior than PSA or PSA-D. Our results support the use of PSA-MR to facilitate counseling with patients after a negative initial PBx, and use of PSA-MR might reduce further unnecessary biopsies. .