An optimized hepatocellular carcinoma prediction model for chronic hepatitis B with well-controlled viremia.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) substantially decreased in the era of potent antiviral therapy. We developed an optimized HCC risk prediction model for CHB with well-controlled viremia by nucelos(t)ide analogs (NUCs). METHOD: We analysed those who achieved virological response (VR; serum HBV-DNA < 2000 IU/mL on two consecutive assessments) by NUCs. Liver stiffness by transient elastography, ultrasonography and laboratory tests was performed at the time of confirmed VR. Patients with decompensated cirrhosis or HCC at baseline were excluded. Multivariate Cox-regression analysis was used to determine key variables to construct a novel risk-scoring model. RESULTS: Among 1511 patients, 9.5% developed HCC. Cirrhosis on ultrasonography (adjusted HR [aHR] 2.47), age (aHR 1.04), male (aHR 1.90), platelet count <135 000/uL (aHR 1.57), albumin <4.5 g/dL (aHR 1.77) and liver stiffness ≥11 kPa (aHR 6.09) were independently associated with HCC. Using these, CAMPAS model was developed with c-index of 0.874. The predicted and observed HCC probabilities were calibrated with a reliable agreement. Such results were reproduced from internal validation and external validation among the independent cohort (n = 252). The intermediate-risk (CAMPAS model score 75 ~ 161) and high-risk (score >161) groups were more likely to develop HCC compared with the low-risk group (score ≤75) with statistical significances (HRs; 4.43 and 47.693 respectively; both P < .001). CONCLUSION: CAMPAS model derived through comprehensive clinical evaluation of liver disease allowed the more delicate HCC prediction for CHB patients with well-controlled viremia by NUCs.

Microsatellite Instability and Programmed Cell Death-Ligand 1 Expression in Stage II/III Gastric Cancer: Post Hoc Analysis of the CLASSIC Randomized Controlled study.

OBJECTIVE: We investigated microsatellite instability (MSI) status and programed cell death ligand 1 (PD-L1) expression as predictors of prognosis and responsiveness to chemotherapy for stage II/III gastric cancer. BACKGROUND: The clinical implications of MSI status and PD-L1 expression in gastric cancer have not been well-elucidated. METHODS: Tumor specimens and clinical information were collected from patients enrolled in the CLASSIC trial-a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. Five quasi-monomorphic mononucleotide markers were used to assess tumor MSI status. PD-L1 expressions of tumor and stromal immune cells were evaluated using immunohistochemistry. RESULTS: Of 592 patients, 40 (6.8%) had MSI-high (MSI-H) tumors. Among 582 patients available for immunohistochemistry evaluation, PD-L1 was positive in tumor cells (tPD-L1) of 16 patients (2.7%) and stromal immune cells (sPD-L1) of 165 patients (28.4%). Multivariable analysis of disease-free survival (DFS) showed that MSI-H and sPD-L1-positivity were independent prognostic factors [hazard ratio 0.301 (0.123-0.736), 0.714 (0.514-0.991); P = 0.008, 0.044), as were receiving chemotherapy, age, tumor grade, and TNM stage. Although adjuvant chemotherapy improved DFS in the microsatellite-stable (MSS) group (5-year DFS: 66.8% vs 54.1%; P = 0.002); no benefit was observed in the MSI-H group (5-year DFS: 83.9% vs 85.7%; P = 0.931). In the MSS group, sPD-L1-negative patients, but not sPD-L1-positive patients, had significant survival benefit from adjuvant chemotherapy compared with surgery only (5-year DFS: 66.1% vs 50.7%; P = 0.001). CONCLUSION: MSI status and PD-L1 expression are clinically actionable biomarkers for stratifying patients and predicting benefit from adjuvant chemotherapy after D2 gastrectomy for stage II/III gastric cancer.

Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis.

BACKGROUND: Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer. METHODS: In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival. FINDINGS: We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2-92·0), 74·8% (69·9-80·1), and 66·0% (60·1-72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5-87·1] vs 64·5% [56·8-73·3]; univariate hazard ratio 0·47 [95% CI 0·30-0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5-79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8-79·9] in patients who only had surgery; 0·93 [0·62-1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (pinteraction=0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort. INTERPRETATION: The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted. FUNDING: Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.

High and low sodium intakes are associated with incident chronic kidney disease in patients with normal renal function and hypertension.

The association between salt intake and renal outcome in subjects with preserved kidney function remains unclear. Here we evaluated the effect of sodium intake on the development of chronic kidney disease (CKD) in a prospective cohort of people with normal renal function. Data were obtained from the Korean Genome and Epidemiology Study, a prospective community-based cohort study while sodium intake was estimated by a 24-hour dietary recall Food Frequency Questionnaire. A total of 3,106 individuals with and 4,871 patients without hypertension were analyzed with a primary end point of CKD development [a composite of estimated glomerular filtration rate (eGFR) under 60 mL/min/1.73 m2 and/or development of proteinuria during follow-up]. The median ages were 55 and 47 years, the proportions of males 50.9% and 46.3%, and the median eGFR 92 and 96 mL/min/1.73 m2 in individuals with and without hypertension, respectively. During a median follow-up of 123 months in individuals with hypertension and 140 months in those without hypertension, CKD developed in 27.8% and 16.5%, respectively. After adjusting for confounders, multiple Cox models indicated that the risk of CKD development was significantly higher in people with hypertension who consumed less than 2.08 g/day or over 4.03 g/day sodium than in those who consumed between 2.93-4.03 g/day sodium. However, there was no significant difference in the incident CKD risk among each quartile of people without hypertension. Thus, both high and low sodium intakes were associated with increased risk for CKD, but this relationship was only observed in people with hypertension.

Effectiveness of the polysaccharide hemostatic powder in non-variceal upper gastrointestinal bleeding: Using propensity score matching.

BACKGROUND AND AIM: Recently, the application of hemostatic powder to the bleeding site has been used to treat active upper gastrointestinal bleeding (UGIB). We aimed to assess the effectiveness of the polysaccharide hemostatic powder (PHP) in patients with non-variceal UGIB. METHODS: We reviewed prospectively collected 40 patients with UGIB treated with PHP therapy between April 2016 and January 2017 (PHP group) and 303 patients with UGIB treated with conventional therapy between April 2012 and October 2014 (conventional therapy group). We compared the rate of successful hemostasis and the rebleeding between the two groups after as well as before propensity score matching using the Glasgow-Blatchford score and Forrest classification. RESULTS: Thirty patients treated with the PHP and 60 patients treated with conventional therapy were included in the matched groups. Baseline patient characteristics including comorbidities, vital signs, and bleeding scores were similar in the matched groups. The rate of immediate hemostasis and 7-day and 30-day rebleeding were also similar in the two groups before and after matching. In the subgroup analysis, no significant differences in immediate hemostasis or rebleeding rate were noted between PHP in monotherapy and PHP combined with a conventional hemostatic method. At 30 days after the therapy, there were no significant PHP-related complications or mortality. CONCLUSIONS: Given its safety, the PHP proved feasible for endoscopic treatment of UGIB, having similar effectiveness as that of conventional therapy. The PHP may become a promising hemostatic method for non-variceal UGIB.

Rectal Mucinous Adenocarcinoma: MR Imaging Assessment of Response to Concurrent Chemotherapy and Radiation Therapy-A Hypothesis-generating Study.

Purpose To develop a system for assessment of tumor regression grade (TRG) with magnetic resonance (MR) imaging that is applicable to rectal mucinous adenocarcinoma (RMAC) and to obtain a preliminary evaluation of the association of MR imaging assessment of TRG with response to preoperative concurrent chemotherapy and radiation therapy (CCRT). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. Pre- and post-CCRT MR images of 59 patients with RMAC (median age, 59 years; range, 29-80 years; 42 men [median age, 59 years; range, 36-80 years] and 17 women [median age, 57 years; range, 29-79 years]) who underwent CCRT and subsequent elective resection from July 2005 to June 2015 were analyzed. Two experienced gastrointestinal radiologists independently analyzed imaging parameters such as T stage, mesorectal fascia status, extramural vascular invasion status, and TRG by using modified criteria developed for assessment of RMAC. Interobserver variability was calculated with weighted κ analysis, and disagreement was settled in consensus. MR imaging TRG results were compared with those from pathologic TRG analysis (Mandard grade). Logistic regression analyses were performed to evaluate associations between imaging parameters and pathologic TRG. Results There was moderate to substantial agreement for imaging parameters (post-CCRT T stage-weighted κ, 0.7134; post-CCRT mesorectal fascia status, 0.618; TRG, 0.5023). Modified MR imaging TRG results were significantly associated with pathologic responsiveness (responsive group, Mandard grade 1 or 2; nonresponsive group, Mandard grades 3-5; P = .023). Results of univariate and multivariate logistic regression analyses indicated that MR imaging TRG was the only factor significantly associated with CCRT responsiveness (univariate analysis, P = .023; multivariate analysis, P = .0261). Conclusion The modified MR imaging assessment of TRG was associated with treatment response to CCRT in patients with RMAC. © RSNA, 2017 Online supplemental material is available for this article.

Clinicopathological and prognostic significance of programmed death ligand-1 expression in breast cancer: a meta-analysis.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) may be a useful molecule for targeted immunotherapy. Therefore, this meta-analysis aimed to investigate PD-L1 expression in breast cancer and its associations with clinicopathological factors and outcomes, which may help determine whether PD-L1 expression is a useful prognostic marker. METHODS: The Medline Ovid, Cochrane, PubMed, Google Scholar, and Web of Knowledge databases were searched for studies that evaluated the prognostic or clinicopathological significance of PD-L1 expression in patients with breast cancer, and reported at least one survival-related outcome. RESULTS: Six studies that included 7877 cases were selected for the analysis. Higher PD-L1 expression in all cells was related to higher histological grade and lymph node metastasis. Higher PD-L1 expression in tumor cell was related to larger tumor size, estrogen receptor negativity, progesterone receptor negativity, human epidermal growth factor type-2 positivity, and triple-negative breast cancer. PD-L1 positivity in all cells was associated with poorer disease-free survival, although it was not significantly associated with overall survival. CONCLUSION: The present meta-analysis revealed that cases of breast cancer with PD-L1 positivity in all cells exhibited higher histological grades, lymph node metastasis, and poorer disease-free survival. Therefore, positive expression of PD-L1 may be a useful prognostic marker in breast cancer.

Safety and immunogenicity of the Euvichol-S oral cholera vaccine for prevention of Vibrio cholerae O1 infection in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial.

BACKGROUND: In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. FINDINGS: Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. INTERPRETATION: A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.

Practice-related changes in neural activation patterns investigated via wavelet-based clustering analysis.

OBJECTIVES: To evaluate brain activation using functional magnetic resonance imaging (fMRI) and specifically, activation changes across time associated with practice-related cognitive control during eye movement tasks. EXPERIMENTAL DESIGN: Participants were engaged in antisaccade performance (generating a glance away from a cue) while fMR images were acquired during two separate test sessions: (1) at pre-test before any exposure to the task and (2) at post-test, after 1 week of daily practice on antisaccades, prosaccades (glancing toward a target), or fixation (maintaining gaze on a target). PRINCIPAL OBSERVATIONS: The three practice groups were compared across the two test sessions, and analyses were conducted via the application of a model-free clustering technique based on wavelet analysis. This series of procedures was developed to avoid analysis problems inherent in fMRI data and was composed of several steps: detrending, data aggregation, wavelet transform and thresholding, no trend test, principal component analysis (PCA), and K-means clustering. The main clustering algorithm was built in the wavelet domain to account for temporal correlation. We applied a no trend test based on wavelets to significantly reduce the high dimension of the data. We clustered the thresholded wavelet coefficients of the remaining voxels using PCA K-means clustering. CONCLUSION: Over the series of analyses, we found that the antisaccade practice group was the only group to show decreased activation from pre-test to post-test in saccadic circuitry, particularly evident in supplementary eye field, frontal eye fields, superior parietal lobe, and cuneus.

Prevalence of HPV infection among Thai schoolgirls in the north-eastern provinces in 2018: implications for HPV immunization policy.

Objective: The aim of this study was to determine the prevalence of high-risk (HR) and vaccine-type human papillomavirus (HPV) infection among Thai schoolgirls who were not included in the national HPV immunization program. Methods: Cross-sectional surveys were conducted among grade 10 (15-16 years old) and grade 12 (17-18 years old) schoolgirls in two provinces of Thailand. Urine samples were collected using the Colli-PeeⓇ device from November 2018 to February 2019. The samples were initially tested using CobasⓇ 4800. Subsequently, all Cobas-positive samples and 1:1 matched Cobas-negative samples were tested by AnyplexⓇ assay. Prevalences of any HPV, any HR HPV, vaccine-type HPV, and individual HR HPV types were estimated by school grade. Results: Prevalences of any HPV and any HR HPV were 11.6% and 8.6% for grade 10, and 18.5% and 12.4% for grade 12 schoolgirls, respectively. Prevalences of bivalent vaccine-type HPV infection in grades 10 and 12 were 3.4% and 4.5%, respectively. Prevalences of quadrivalent and nonavalent vaccine-type HPV infections were 4.0%/6.6% and 6.4%/10.4% in grades 10 and 12, respectively. HPV16 was the most common type detected, followed by HPV58, 51, and 52. Circulating HR HPV types were similar between the school grades. Conclusion: A substantial burden of HR HPV infections was found among unvaccinated high school girls in Thailand.

Conducting a phase III clinical trial in children during the COVID- 19 pandemic: Experience and lessons learnt from a clinical research facility of Nepal.

Clinical trials in humans are vital to test safety and efficacy of new interventions and are accompanied with the complexity of related regulatory guidelines, stringent time frame and financial burden particularly when participants are children. Conducting clinical trials in low and middle income countries, where 90% of global diseases occur, increases the complexity as resources, infrastructures, and experience related to clinical trials may be limited in some countries. During the COVID-19 pandemic, due to multiple infection control measures such as social distancing, lock-down of the societies, and increased work load of hospital workers, conducting clinical trials seemed very challenging. Related guidelines and recommendations on clinical trials required updates to adapt the situation for ongoing clinical trials to be continued and new clinical trials to be initiated. In this review report, we described the lessons learnt through our experiences, challenges we faced, and the mitigation measures implemented as a response while conducting a phase III clinical trial on a non-COVID-19 vaccine at a government children's hospital during the COVID-19 pandemic. We hope this report will contribute in lowering the obstacles to allow the successful completion of future studies, in countries where people live with the burden of vaccine-preventable diseases.

Prognostic value of the delta neutrophil index in pediatric cardiac arrest.

The delta neutrophil index (DNI), which reflects the ratio of circulating immature neutrophils, has been reported to be highly predictive of mortality in systemic inflammation. We investigated the prognostic significance of DNI value for early mortality and neurologic outcomes after pediatric cardiac arrest (CA). We retrospectively analyzed the data of eligible patients (<19 years in age). Among 85 patients, 55 subjects (64.7%) survived and 36 (42.4%) showed good outcomes at 30 days after CA. Cox regression analysis revealed that the DNI values immediately after the return of spontaneous circulation, at 24 hours and 48 hours after CA, were related to an increased risk for death within 30 days after CA (P < 0.001). A DNI value of higher than 3.3% at 24 hours could significantly predict both 30-day mortality (hazard ratio: 11.8; P < 0.001) and neurologic outcomes (odds ratio: 8.04; P = 0.003). The C statistic for multivariable prediction models for 30-day mortality (incorporating DNI at 24 hours, compression time, and serum sodium level) was 0.799, and the area under the receiver operating characteristic curve of DNI at 24 hours for poor neurologic outcome was 0.871. Higher DNI was independently associated with 30-day mortality and poor neurologic outcomes after pediatric CA.

Effect of sex hormones on coronavirus disease 2019: an analysis of 5,061 laboratory-confirmed cases in South Korea.

OBJECTIVE: To evaluate the effect of female sex hormones on the clinical outcomes of coronavirus disease 2019 patients using national claims data. METHODS: This retrospective cohort study used the Health Insurance Review and Assessment data of 5,061 adult patients with laboratory-confirmed coronavirus disease 2019 in South Korea from January 20 to April 8, 2020. To evaluate the effect of hormone therapy on clinical outcomes among women, subgroup analyses using age-matched case-control data were performed. RESULTS: Coronavirus disease 2019 was most prevalent in women in the 20-39 years age group (1,250 [44.14%]). Men were more likely to receive oxygen therapy (144 [6.46%] vs 131 [4.63%], P = 0.004), be admitted to the intensive care unit (60 [2.69%] vs 53 [1.87%], P = 0.049), and have a longer length of stay after admission to the intensive care unit (19.70 ± 11.80 vs 14.75 ±â€Š9.23, P = 0.016). However, there was no significant difference in the mortality rate (men vs women: 42 [1.88%] vs 42 [1.48%], P = 0.267). In the multivariable Cox analysis, older age and underlying comorbidities, but not sex, were independent risk factors for mortality. Hormone therapy was not significantly associated with clinical outcomes. CONCLUSIONS: This study, using nationwide data, suggests that female sex hormones are not associated with the morbidity and clinical outcomes of coronavirus disease 2019 in South Korea.

Natural History of Untreated HBeAg-Positive Chronic HBV Infection With Persistently Elevated HBV DNA but Normal Alanine Aminotransferase.

OBJECTIVES: Nucleos(t)ide analogues (NUCs) are not routinely recommended for patients with hepatitis B e antigen-positive chronic hepatitis B virus (HBV) infection who have persistently elevated serum HBV DNA level (>20,000 IU/mL) but normal alanine aminotransferase (<40 IU/L) level. Here, we evaluated the cumulative risks of hepatocellular carcinoma (HCC) in such patients (the untreated persistently elevated serum HBV DNA [pEDNA] group) compared with inactive carriers (the IC group). METHODS: Patients with untreated pEDNA (n = 126) and IC (n = 621) were enrolled between 2006 and 2012. Patients with cirrhosis or HCC at enrollment or a history of NUC treatment were excluded. RESULTS: The cumulative HCC risks at 5 and 9 years in the untreated pEDNA group were 1.1% and 1.9%, which were comparable with those of the IC group (P = 0.549). Inverse probability of treatment weighting and propensity score matching also showed similar HCC risks. In the untreated pEDNA group, there were no cases of HCC in the subgroup with serum HBV DNA level >1,000,000 IU/mL (immune-tolerant phase), which was significantly (P = 0.002) different compared with those with an intermediate serum HBV DNA level (20,000-1,000,000 IU/mL). DISCUSSION: The cumulative HCC risk in the untreated pEDNA group was minimal and comparable with that of the IC group. Further studies are required to determine whether early NUC treatment, indeed, reduces the HCC risk in patients with an intermediate serum HBV DNA level.

Long-term fine particulate matter exposure and cardiovascular mortality in the general population: a nationwide cohort study.

BACKGROUND: Although eastern Asian countries are exposed to high levels of air pollution, the impact of long-term exposures to fine particulate matter (PM2.5) air pollution on all-cause and cardiovascular mortality is not well identified. We assessed the relationship between long-term PM2.5 exposure and all-cause/cardiovascular mortalities. METHODS: We included 436,933 subjects who received national health examinations from the Korean National Health Insurance Service-based National Sample Cohort. We matched subjects' residential-address areas with hourly-measurements of PM2.5 concentration data. We estimated the risk of mortality with average PM2.5 exposure during the study period using a Cox proportional-hazards model. RESULTS: During 1,683,271 person·years, all-cause and cardiovascular mortalities were observed in 6432 and 1603 subjects (382 and 95 per 100,000 person·years, respectively). An increase in 10 µg/m3 in PM2.5 was associated with increases in all-cause and cardiovascular mortalities by 3.4 % [2.7-4.1] and 4.7 % [3.6-5.8], respectively (each p < 0.001). PM2.5 was linearly and significantly correlated with these all-cause and cardiovascular mortalities above 18 µg/m3 of PM2.5 (p < 0.001), but it was not significant below 18 µg/m3 of PM2.5. To investigate the specific PM2.5 concentration for raising cardiovascular mortality more, we analyzed the sensitivities/specificities for different PM2.5 levels, and 18 µg/m3 showed the highest Youden's index (sensitivity + specificity-1) with c-index of 0.85 (0.84-0.86). PM2.5 effect on all-cause mortality was more profound in subjects with previous myocardial infarction compared to the opposite population. CONCLUSIONS: In the Korean general population exposed to high-air pollution, long-term PM2.5 exposure was linearly associated with increased risk for all-cause and cardiovascular mortality, especially above 18 µg/m3 of PM2.5.

Nonspecific intraventricular conduction delay is associated with future occurrence of atrial fibrillation in patients with structurally normal heart.

BACKGROUND: We aimed to elucidate the long-term prognosis of nonspecific intraventricular conduction delay (NIVCD) in patients with structurally normal heart. METHODS: We included 107,838 patients (age, 52.1 ±â€¯15.5 years; men, 46.8%) who underwent electrocardiography in outpatient clinics or medical checkup (unmatched cohort). NIVCD was defined as QRS duration ≥110 ms without meeting the criteria for bundle branch block. Patients with structurally normal heart and sinus rhythm were assigned to the NIVCD and normal QRS groups according to propensity score with matching variables of age, sex, hypertension, and diabetes (matched cohort 1), and additional PR interval (matched cohort 2). Baseline characteristics, electrocardiographic parameters, and clinical outcomes were compared in the unmatched cohort and the matched cohort. RESULTS: In the unmatched cohort, the frequencies of male sex and preexisting atrial fibrillation were significantly higher in the NIVCD group than in the normal QRS group. In matched cohort 1 (n = 690), the NIVCD group exhibited significant slower sinus rate and longer PR interval than the normal QRS group. In matched cohort 2 (n = 598), the cumulative incidence of atrial fibrillation was significantly higher in the NIVCD group than in the normal QRS group during a follow-up period of 8.8 ±â€¯2.9 years. NIVCD significantly increased the risk for AF (hazard ratio, 2.571; 95% confidence interval, 1.074-6.156; p = 0.034). CONCLUSIONS: It is suggested that NIVCD may be associated with future occurrence of atrial fibrillation in patients with structurally normal heart and sinus rhythm.

Manchester Operation: An Effective Treatment for Uterine Prolapse Caused by True Cervical Elongation.

PURPOSE: Descent of the uterus is a major etiology of uterine prolapse. However, true cervical elongation can cause uterine prolapse without uterine descent. The aim of study was to investigate the clinical outcomes of Manchester operation in patients with uterine prolapse caused by "true cervical elongation," compared with vaginal hysterectomy (VH). MATERIALS AND METHODS: Medical records of patients who underwent Manchester operation or VH from 2006 to 2015 were reviewed. True cervical elongation was defined on the basis of C point of the Pelvic Organ Prolapse Quantification (POP-Q) system ≥0 and D point ≤-4, as well as estimated cervical length of ≥5 cm. The primary outcome was recurrence of pelvic organ prolapse (POP) evaluated by POP-Q system. The outcomes of two groups were compared after propensity score matching, for age, parity, and preoperative POP-Q stage. RESULTS: During the study period, 23 patients underwent Manchester operation and 374 patients underwent VH. The recurrence rate of POP (p=0.317) and complication rate were not statistically significant different between the two study groups. Manchester operation exhibited shorter operation time than VH (p=0.033). In subgroup analysis (POP-Q stage III), body mass index [odds ratio (OR)=1.74; 95% confidence interval (CI), 1.08-2.81] and not having concurrent anterior colporrhaphy (OR for concurrent anterior colporrhaphy, 0.06; 95% CI, 0.01-0.75) were identified as significant risk factors for recurrence of POP. CONCLUSION: The Manchester operation technique seems to be an effective and safe alternative procedure for the treatment of uterine prolapse caused by true cervical elongation, compared with VH.

Perioperative Factors for Predicting the Need for Postoperative Intensive Care after Major Lung Resection.

Postoperative management after major lung surgery is critical. This study evaluates risk factors for predicting mandatory intensive care unit (ICU) admission immediately after major lung resection. We retrospectively reviewed patients for whom the surgeon requested an ICU bed before major lung resection surgery. Patients were classified into three groups. Univariable and multivariable logistic regression analyses were performed, and a clinical nomogram was constructed. Among 340 patients, 269, 50, and 21 were classified into the no need for ICU, mandatory ICU admission, and late-onset complication groups, respectively. Predictive postoperative diffusion capacity of the lung for carbon monoxide (47.2 (interquartile range (IQR) 43.3-65.7)% versus vs. 67.8 (57.1-79.7)%; p = 0.003, odds ratio (OR) 0.969, 95% confidence interval (CI) 0.95-0.99), intraoperative blood loss (400.00 (250.00-775.00) mL vs. 100.00 (50.00-250.00) mL; p = 0.040, OR 1.001, 95% CI 1.000-1.002), and open thoracotomy (p = 0.030, OR 2.794, 95% CI 1.11-7.07) were significant predictors for mandatory ICU admission. The risk estimation nomogram demonstrated good accuracy in estimating the risk of mandatory ICU admission (concordance index 83.53%). In order to predict the need for intensive care after major lung resection, preoperative and intraoperative factors need to be considered.

Risk of osteoporosis in patients with chronic inflammatory neuropathy- a population-based cohort study.

The risk of osteoporosis in patients with chronic inflammatory neuropathy (CIN) has not been evaluated in detail. We conducted a population-based case-control study nested in a retrospective cohort to analyze osteoporosis risk among patients with CIN using a nationwide database. Patients with CIN based on the Korean Classification of Disease diagnostic code were included and were matched to controls. A Cox proportional hazards regression model was used to evaluate the effect of CIN on osteoporosis. After propensity score matching, 585 CIN patients and 585 controls were selected. Patients with CIN had an increased osteoporosis risk (hazard ratio [HR] = 2.293, 95% confidence interval [CI] 1.460-3.601) compared with controls. The osteoporosis risk was higher among male patients with CIN than among male controls (HR = 5.404, 95% CI 2.252-12.969), while there were no significant differences among women. Among the CIN patients, the average daily dose of corticosteroids was higher in those who developed osteoporosis (19.6 mg [10.8-49.3]) than those who did not (16.2 mg [7.2-29.1], p = 0.001). The osteoporosis risk among CIN patients is higher than among controls. High risk of osteoporosis in male patients may indicate that osteoporosis in CIN patients results from the disease itself or related treatments.

Developing a preoperative serum metabolome-based recurrence-predicting nomogram for patients with resected pancreatic ductal adenocarcinoma.

We investigated the potential application of preoperative serum metabolomes in predicting recurrence in patients with resected pancreatic cancer. From November 2012 to June 2014, patients who underwent potentially curative pancreatectomy for pancreatic ductal adenocarcinoma were examined. Among 57 patients, 32 were men; 42 had pancreatic head cancers. The 57 patients could be clearly categorized into two main clusters using 178 preoperative serum metabolomes. Patients within cluster 2 showed earlier tumor recurrence, compared with those within cluster 1 (p = 0.034). A nomogram was developed for predicting the probability of early disease-free survival in patients with resected pancreatic cancer. Preoperative cancer antigen (CA) 19-9 levels and serum metabolomes PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful preoperative clinical variables with which to predict 6-month and 1-year cancer recurrence-free survival after radical pancreatectomy, with a Harrell's concordance index of 0.823 (95% CI: 0.750-0.891) and integrated area under the curve of 0.816 (95% CI: 0.736-0.893). Patients with resected pancreatic cancer could be categorized according to their different metabolomes to predict early cancer recurrence. Preoperative detectable parameters, serum CA 19-9, PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful predictors of early recurrence of pancreatic cancer.