An Examination of Donor Factors That Impact the Results of the Glucagon Stimulation Test as an Assessment of the Pancreatic Graft Endocrine Function.

OBJECTIVES: Delta C-peptide derived by the glucagon stimulation test is a reliable value for the evaluation of the pancreatic endocrine function after pancreas transplantation. We examined the associations between delta C-peptide as pancreatic graft endocrine function and donor background factors. METHODS: Sixty-five cases of pancreatic transplantation from brain-dead donors, which were performed in our facility, were enrolled in this study. Enrolled recipients underwent a glucagon stimulation test within 1 to 3 months after transplantation to evaluate the pancreatic graft endocrine function with delta C-peptide to compare donor background factors. RESULTS: The following factors were associated with significant deterioration of the delta C-peptide: age of 50 years or greater, death from cerebrovascular accident, hemoglobin A1c level of 5.6% or greater, creatinine level of 1.0 mg/dL or greater, C-reactive protein level of 25 mg/dL or greater, and sodium level of 150 mmol/L or greater. In addition, increased numbers of these donor factors indicated significantly greater deterioration of the posttransplant pancreatic endocrine function ( P < 0.001). CONCLUSIONS: To secure insulin independence after pancreas transplantation, which means maintaining a delta C-peptide level of 1.0 ng/mL or greater on a glucagon stimulation test, the utilization of donors, who possesses more than equal to 3 of the donor factors identified in this study, should be carefully considered.

The survival benefit of increasing the number of active drugs for metastatic colorectal cancer: A multicenter retrospective study.

BACKGROUND: The development of chemotherapy and treatment strategies for metastatic colorectal cancer (mCRC) have provided patients with significant survival benefits. Currently, molecular targeting agents and late-line treatment with regorafenib and trifluridine/tipiracil (FTD/TPI) are available. However, the impact of this increase in drug availability on overall survival (OS) in mCRC remains a clinical question. METHODS: We retrospectively collected data on consecutive mCRC patients who were treated at three institutions in Japan. We divided the patients into three cohorts: patients who initiated first-line treatment from Jan 2005 to Dec 2006 (cohort A: only cytotoxic drugs available), Jan 2007 to Dec 2011 (cohort B: molecular targeting drugs available), and Jan 2012 to Sep 2016 (cohort C: late-line treatment available). RESULTS: A total of 1409 consecutive patients were analyzed. The median survival time (MST) in cohorts A, B, and C was 18.6, 25.4, and 26.4 months, respectively. The hazard ratio (HR) for cohort B versus A was 0.81 (95% CI 0.68-0.97), for cohort C versus A was 0.74 (95% CI 0.61-0.89), and for cohort C versus B was 0.92 (0.81-1.03). The median number of administered drugs (range) was 3 (1-5) in cohort A, 4 (1-7) in cohort B, and 4 (1-7) in cohort C. The increase in drug availability extended the MST from 15.5 months in patients treated with ≤3 drugs to 36.0-37.3 months in patients treated with six to seven drugs. CONCLUSION: The development of chemotherapy including late-line treatments could improve the prognosis of mCRC patients.

Persistence of Robust Humoral Immune Response in Coronavirus Disease 2019 Convalescent Individuals Over 12 Months After Infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits varying degrees of protective immunity conferred by neutralizing antibodies (nAbs). In this study, we report the persistence of nAb responses over 12 months after infection despite their decreasing trend noticed from 6 months. METHODS: The study included sera from 497 individuals who had been infected with SARS-CoV-2 between January and August 2020. Samples were collected at 6 and 12 months after onset. The titers of immunoglobulin (Ig)G to the viral nucleocapsid protein (NP) and receptor-binding domain (RBD) of the spike protein were measured by chemiluminescence enzyme immunoassay. The nAb titer was determined using lentivirus-based pseudovirus or authentic virus. RESULTS: Antibody titers of NP-IgG, RBD-IgG, and nAbs were higher in severe and moderate cases than in mild cases at 12 months after onset. Although the nAb levels were likely to confer adequate protection against wild-type viral infection, the neutralization activity to recently circulating variants in some of the mild cases (~30%) was undermined, implying the susceptibility to reinfection with the variants of concerns (VOCs). CONCLUSIONS: Coronavirus disease 2019 convalescent individuals have robust humoral immunity even at 12 months after infection albeit that the medical history and background of patients could affect the function and dynamics of antibody response to the VOCs.

Antibody titers against the Alpha, Beta, Gamma, and Delta variants of SARS-CoV-2 induced by BNT162b2 vaccination measured using automated chemiluminescent enzyme immunoassay.

BACKGROUND: Levels of 50% neutralizing titer (NT50) reflect the a vaccine-induced humoral immunity after the vaccination against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Measurements of NT50 are difficult to implement in large quantities. A high-throughput laboratory test is expected for determining the level of herd immunity against SARS-CoV-2. METHODS: We analyzed samples from 168 Japanese healthcare workers who had completed two doses of the BNT162b2 vaccine. We analyzed immunoglobulin G (IgG) index values against spike protein (SP) using automated chemiluminescent enzyme immunoassay system AIA-CL and analyzed the background factors affecting antibody titer. SP IgG index was compared with 50% neutralization titers. RESULTS: The median SP IgG index values of the subjects (mean age = 43 years; 75% female) were 0.1, 1.35, 60.80, and 97.35 before and at 2, 4, and 6 weeks after the first dose, respectively. At 4 and 6 weeks after the first dose, SP IgG titers were found to have positive correlation with NT50 titer (r = 0.7535 in 4 weeks; r = 0.4376 in 6 weeks). Proportions of the SP IgG index values against the Alpha, Beta, Gamma, and Delta variants compared with the original strain were 2.029, 0.544, 1.017, and 0.6096 respectively. Older age was associated with lower SP IgG titer index 6 weeks after the first dose. CONCLUSIONS: SP IgG index values were rised at 3 weeks after two doses of BNT162b2 vaccination and have positive correlation with NT50. SP IgG index values were lower in the older individuals and against Beta and Delta strain.

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.

Objective: There is scarce evidence regarding the long-term persistence of neutralizing antibodies among coronavirus disease 2019 (COVID-19) survivors. This study determined neutralizing antibody titers (NT50) and antibodies against spike protein (SP) or nucleocapsid protein (NP) antigens approximately 6 months after the diagnosis of COVID-19. Methods: COVID-19 survivors in Japan were recruited. Serum samples and data related to patients' characteristics and COVID-19 history were collected. NT50 and titers of antibodies against NP and SP antigens were measured at 20-32 weeks after the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results. Factors associated with NT50 were identified using the multivariable linear regression and the correlations among NT50 and titers of immunoglobulin G (IgG) and total immunoglobulins (Igs) against NP and SP were assessed by Spearman's correlation. Results: Among 376 participants (median [range] days after testing positive for SARS-CoV-2, 180 (147-224); median [range] years of age, 50 (20-78); 188 [50%] male), most tested positive for NT50 (n = 367, 98%), SP-IgG (n = 344, 91%), SP-total Ig (n = 369, 98%), NP-IgG (n = 314, 84%), and NP-total Ig (n = 365, 97%). Regression analysis indicated that higher BMI, fever, and the requirement of mechanical ventilation or extracorporeal membrane oxygenation were significantly associated with higher NT50. Anti-SP antibodies correlated moderately with NT50 (Spearman's correlation: 0.63 for SP IgG; 0.57 for SP-total Ig), while the correlation was weak for anti-NP antibodies (0.37 for NP IgG; 0.32 for NP-total Ig). Conclusions: Most COVID-19 survivors had sustained neutralizing antibodies and tested positive for SP-total Ig and NP-total Ig approximately 6 months after infection.

Error grid analysis for risk management in the difference between invasive and noninvasive blood pressure measurements.

PURPOSE: Invasive arterial blood pressure (IAP) and noninvasive blood pressure (NIBP) measurements are both common methods. Recently, a new method of error grid analysis was proposed to compare blood pressure obtained using two measurement methods. This study aimed to compare IAP and NIBP measurements using the error grid analysis and investigate potential confounding factors affecting the discrepancies between IAP and NIBP. METHODS: Adult patients who underwent general anesthesia in the supine position with both IAP and NIBP measurements were retrospectively investigated. The error grid analyses were performed to compare IAP and NIBP. In the error grid analysis, the clinical relevance of the discrepancies between IAP and NIBP was evaluated and classified into five zones from no risk (A) to dangerous risk (E). RESULTS: Overall, data of 1934 IAP/NIBP measurement pairs from 100 patients were collected. The error grid analysis revealed that the proportions of zones A-E for systolic blood pressure were 96.4%, 3.5%, 0.05%, 0%, and 0%, respectively. In contrast, the proportions for mean blood pressure were 82.5%, 16.7%, 0.8%, 0%, and 0%, respectively. The multiple regression analysis revealed that continuous phenylephrine administration (p = 0.016) and age (p = 0.044) were the significant factors of an increased clinical risk of the differences in mean blood pressure. CONCLUSIONS: The error grid analysis indicated that the differences between IAP and NIBP for mean blood pressure were not clinically acceptable and had the risk of leading to unnecessary treatments. Continuous phenylephrine administration and age were the significant factors of an increased clinical risk of the discrepancies between IAP and NIBP.

Mortality and risk factors on admission in toxic epidermal necrolysis: A cohort study of 59 patients.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening disorders characterized by widespread epidermal necrosis of the skin and mucosa. The severity-of-illness scoring system for TEN (SCORTEN) was widely used since 2000 as a standard prognostic tool consisting of seven clinical values. METHODS: To evaluate the prognosis using current treatments and risk factors for mortality, we retrospectively analyzed 59 cases of TEN, including SJS/TEN overlap treated in two university hospitals from January 2000 to March 2020. RESULTS: The mortality rate of TEN was 13.6% (8/59). All patients treated with high-dose steroid administration in combination with plasma exchange and/or immunoglobulin therapy recovered. Logistic regression analysis showed nine clinical composite scores, namely: heart rate (≧120 bpm), malignancy present, percentage of body surface area with epidermal detachment (>10%), blood urea nitrogen (>28 mg/dL), serum bicarbonate level (<20 mEq/L), serum glucose level (>252 mg/dL), age (≧71 years), the interval between disease onset and treatment initiation at the specialty hospital (≧8 days), and respiratory disorder within 48 h after admission. The receiver operating characteristic curves confirmed a high potential for predicting the prognosis of TEN. CONCLUSIONS: Recent developments in treatment strategies have contributed to the improved prognosis of TEN patients. A modified severity scoring model composed of nine scores may be helpful in the prediction of TEN prognosis in recent patients. Further large-scale studies are needed to confirm mortality findings to improve prognostication in patients with TEN.

A Multivariable Regression Model-based Nomogram for Estimating the Overall Survival of Patients Previously Treated With Nivolumab for Advanced Non-small-cell Lung Cancer.

AIM: Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms. PATIENTS AND METHODS: Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS. RESULTS: The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab. CONCLUSION: The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC.

Independent association of plasma xanthine oxidoreductase activity with serum uric acid level based on stable isotope-labeled xanthine and liquid chromatography/triple quadrupole mass spectrometry: MedCity21 health examination registry.

Background We developed a novel high-sensitive assay for plasma xanthine oxidoreductase (XOR) activity that is not affected by the original serum uric acid level. However, the association of plasma XOR activity with that level has not been fully examined. Methods This cross-sectional study included 191 subjects (91 males, 100 females) registered in the MedCity21 health examination registry. Plasma XOR activity was determined using our assay for plasma XOR activity with [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Serum levels of uric acid and adiponectin, and visceral fat area (VFA) obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index. Results The median values for uric acid and plasma XOR activity were 333 µmol/L and 26.1 pmol/h/mL, respectively. Multivariable linear regression analysis showed a significant and positive association of serum uric acid level (coefficient: 26.503; 95% confidence interval: 2.06, 50.945; p = 0.035) with plasma XOR activity independent of VFA and HOMA-IR, and also age, gender, alcohol drinking habit, systolic blood pressure, estimated glomerular filtration rate (eGFR), glycated hemoglobin A1c, triglyceride, and adiponectin levels. The "gender*XOR activity" interaction was not significant (p = 0.91), providing no evidence that gender modifies the relationship between plasma XOR activity and serum uric acid level. Conclusions Plasma XOR activity was found to be positively associated with serum uric acid level independent of other known confounding factors affecting that level, including gender difference, eGFR, adiponectin level, VFA, and HOMA-IR.

Medication Adherence Among Patients With Chronic Hepatitis Receiving Antiviral Treatment.

This study aimed to evaluate medication adherence and associated factors among patients with chronic viral hepatitis. A cross-sectional questionnaire survey was conducted in 171 outpatients receiving antiviral treatment of chronic viral hepatitis at 6 national/regional liver disease treatment centers in Japan. Medication adherence was calculated as the subject-reported number of antiviral tablets taken in the past 2 weeks compared with the prescribed number of tablets. Subjects were divided according to 100% adherence or nonadherence. The impact of items pertaining to everyday experiences and perceptions regarding medication adherence were examined. Factors associated with medication adherence were identified via multiple logistic regression. The mean medication adherence rate was 95.8% ± 9.5% (range = 0%-100%), although a smaller proportion (95 subjects; 55.6%) was 100% adherent. Multiple logistic regression indicated a greater "lack of understanding of need for medication" (1 point: odds ratio (OR) = 1.51, 95% confidence interval (CI) [1.30, 1.76], p ≤ .01) and greater "restriction in life due to medication" (1 point: OR = 1.26, 95% CI [1.03, 1.54], p = 0.03) as associated with nonadherence. In conclusion, to improve medication adherence, healthcare professionals should improve patients' understanding of the need for medication and minimization of life restrictions.

Insulin Resistance Associated with Plasma Xanthine Oxidoreductase Activity Independent of Visceral Adiposity and Adiponectin Level: MedCity21 Health Examination Registry.

BACKGROUND: Higher levels of uric acid production have been reported in individuals with visceral fat obesity, and obesity is known to enhance xanthine oxidoreductase (XOR) activity, although the precise mechanism remains unclear. We investigated the associations of visceral fat area (VFA), serum adiponectin level, and insulin resistance with plasma XOR activity using our novel highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. METHODS: This cross-sectional study included 193 subjects (92 males and 101 females) registered in the MedCity21 health examination registry. Plasma XOR activity, serum adiponectin level, and VFA obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index. RESULTS: The mean values for VFA, log HOMA-IR, and log plasma XOR activity were 76.8 ± 45.8 cm2, 0.14 ± 0.30, and 1.50 ± 0.44 pmol/h/mL, respectively. Multiple regression analysis showed that HOMA-IR was significantly (p=0.020) associated with plasma XOR activity independent of other factors, including VFA and adiponectin level, as well as age, sex, alcohol drinking habit, smoking habit, alanine transaminase, HbA1c, and eGFR. The "sex∗HOMA - IR" interaction was not significant (p=0.020) associated with plasma XOR activity independent of other factors, including VFA and adiponectin level, as well as age, sex, alcohol drinking habit, smoking habit, alanine transaminase, HbA1c, and eGFR. The ". CONCLUSIONS: Our results indicate that insulin resistance is associated with plasma XOR activity and that relationship is independent of visceral adiposity and adiponectin level, suggesting that the development of insulin resistance resulting from increased visceral adiposity and/or reduced serum adiponectin contributes to increased uric acid production by stimulating XOR activity.