Efficacy and safety of rifaximin in patients with chronic intestinal pseudo-obstruction: a randomized, double-blind, placebo-controlled, phase II-a exploratory trial.

Chronic intestinal pseudo-obstruction (CIPO) is a rare intractable disease with limited treatment options. Small intestinal bacterial overgrowth (SIBO) often co-occurs with several diseases, including CIPO. While rifaximin (RFX) is effective in treating SIBO, its efficacy for CIPO remains unclear. Here, we aimed to investigate the efficacy and safety of RFX in adult patients with CIPO. Twelve patients were randomly assigned to receive RFX (400 mg three times daily, n=8) or a placebo (PBO, n=4) for 4 weeks. The global symptom score for abdominal bloating (GSS-bloating) and an original whole gastrointestinal symptoms score (O-WGSS) were collected, and a glucose hydrogen breath test (GHBT) and abdominal computed tomography (CT) were performed. No significant differences were observed in the primary endpoint. GSS-bloating improved by 75% and 25% in the PBO and RFX groups, respectively, and O-WGSS improved by 25% in both groups. No significant differences were observed in secondary and other endpoints, including the SIBO eradication rate in the GHBT and small intestinal volume on CT. In a post hoc analysis of SIBO-positive patients with CIPO (4/4 and 4/8 in the PBO and RFX groups), SIBO was eradicated in 25% and 75% of the patients (PBO and RFX groups, respectively) at the end of treatment, indicating a high eradication rate in the RFX group. Furthermore, the small intestinal gas volume decreased in the RFX group, and no severe adverse events occurred. Although no significant improvements were observed in subjective indicators, RFX may be beneficial in alleviating SIBO and reducing the small intestinal gas volume in SIBO-positive patients with CIPO.

Impact of interpregnancy weight changes and perinatal outcomes: A retrospective study in Japan.

Previous studies have shown that interpregnancy weight fluctuations impact perinatal outcomes. In order to examine this in Japanese women, we analyzed the data of 2,861 women in their first and second pregnancies who delivered singletons between 2000 and 2022. We compared the second pregnancy perinatal outcomes of women whose interpregnancy body mass index (BMI) change was -1 to 1 unit with those of women whose BMI change was < -1 or ≥ 1 unit. An interpregnancy BMI change ≥ 1 unit was associated with an increased risk of developing gestational diabetes mellitus (adjusted odds ratio [aOR], 1.51; 95% confidence interval [CI], 1.18-1.95) and delivering a large for gestational age neonate (aOR, 1.67; 95% CI, 1.15-2.42) but a decreased risk of preterm birth (aOR, 0.66; 95% CI, 0.46-0.95). An interpregnancy BMI change < -1 unit was associated with a decreased risk of developing gestational diabetes mellitus (aOR, 0.51; 95% CI, 0.31-0.85). In a subgroup analysis of three groups divided according to prepregnancy BMI, interpregnancy BMI changes ≥ 1 unit in women with a BMI of < 18.5 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing preterm birth (aOR, 0.30; 95% CI, 0.11-0.81). Interpregnancy BMI changes < -1 unit in women with a BMI of ≥ 25 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing gestational diabetes mellitus (aOR, 0.33; 95% CI, 0.12-0.88). Weight gain during interpregnancy period was related to an increased risk of gestational diabetes mellitus and delivery of a large-for-gestational-age neonate, whereas weight loss was related to a decreased risk of developing gestational diabetes mellitus. These results indicate the importance of interpregnancy weight control as part of preconception care; therefore, women considering additional pregnancies should be educated on the importance of maintaining a healthy weight.

The epidemiology of postoperative dobutamine and phosphodiesterase inhibitors after adult elective cardiac surgery and its impact on the length of hospital stay: a post hoc analysis from the multicenter retrospective observational study.

The optimal administration of inotrope after cardiac surgery is unknown. This study aimed to investigate the impact of postoperative inotrope on clinical outcomes in adult elective cardiac surgery patients. Data from the Blood Pressure and Relative Optimal Target after Heart Surgery in Epidemiologic Registry study were analyzed, employing propensity score considering the hospital of admission. The primary outcome was the length of hospital stay evaluated using quantile regression. Secondary outcomes were kidney injury progression, renal replacement therapy, atrial fibrillation, mortality, mechanical ventilation duration, and length of intensive care unit (ICU) stay. Among 870 patients from 14 ICUs in Japan, 535 received inotropes within 24 h of ICU admission, with usage rates ranging from 40 to 100% among facilities. After propensity score matching, 218 patients were included in each group. The inotrope group had a significantly longer hospital stay compared to the control group (16 days vs. 14 days; median difference 1.78 [95% confidence interval [CI] 0.31-3.24]; p = 0.018). However, no significant differences were observed in the secondary outcomes, except for mechanical ventilation duration. The results of the sensitivity analysis using a mixed-effects quantile regression analysis considering the hospital of admission for length of hospital stay in the original cohort were consistent with the results of the propensity analyses (median difference in days, 2.35 [95% CI, 0.35-4.36]; p = 0.022). The use of inotropes within 24 h of ICU admission in adult elective cardiac surgery patients was associated with an extended hospitalization period of approximately 2 days, without offering any prognostic benefit. Clinical trial registration: UMIN-CTR, https://www.umin.ac.jp/ctr/index-j.htm , UMIN000037074.

Effects of hybrid closed-loop system on glycemic control and psychological aspects in persons with type 1 diabetes treated with sensor-augmented pump: A prospective single-center observational study.

AIMS/INTRODUCTION: This study evaluated the effects of the Medtronic MiniMed 770G hybrid closed-loop system on glycemic control and psychological aspects in persons with type 1 diabetes mellitus. MATERIALS AND METHODS: This 3-month prospective observational study included 22 participants with type 1 diabetes mellitus who used the Medtronic MiniMed 640G predictive low-glucose suspend system and were switched to the 770G system. Time in the range of 70-180 mg/dL and glycated hemoglobin levels were evaluated; satisfaction, emotional distress and quality of life were assessed using self-reported questionnaires, including the Diabetes Treatment Satisfaction Questionnaire Status, Problem Area in Diabetes and Diabetes Therapy-Related Quality of Life. RESULTS: Time in the range of 70-180 mg/dL increased (63.5 ± 13.4 to 73.0 ± 10.9% [mean ± standard deviation], P = 0.0010), and time above the range of 181-250 mg/dL decreased (26.9 ± 8.9 to 19.6 ± 7.1%, P < 0.0005). Glycated hemoglobin levels decreased (7.7 ± 1.0 to 7.2 ± 0.8%, P = 0.0021). The percentage of participants with time below the range of 54-69 mg/dL <4% of readings increased from 91% to 100% (P < 0.0005). No significant changes were detected in the satisfaction, emotional distress and quality of life levels, but increased sensor calibration might be related to worsened emotional distress and quality of life. CONCLUSIONS: The hybrid closed-loop system decreased hyperglycemia and minimized hypoglycemia, but did not improve psychological aspects compared with the predictive low-glucose suspend system, probably because sensor calibration was increased.

Inappropriate shock incidence in patients with subcutaneous implantable cardioverter-defibrillators with concomitant cardiac implantable electronic devices: A single-center cohort study.

BACKGROUND: Subcutaneous implantable cardioverter defibrillators (S-ICDs) are occasionally used in combination with other cardiac implantable electronic devices (CIEDs). However, whether the incidence of inappropriate shock increases in patients with S-ICDs and concomitant CIEDs remains unclear. This study aimed to investigate the association between the concomitant use of CIEDs and the incidence of inappropriate shock in patients with current-generation S-ICDs. METHODS: A total of 127 consecutive patients received an S-ICD. Patients were assigned to two groups depending on concomitant use of CIEDs at the time of S-ICD implantation: patients without other CIEDs (non-combined group, 106 patients) and patients with other CIEDs (combined group, 21 patients). CIEDs included pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy pacemakers, and cardiac resynchronization therapy defibrillators. The primary outcome was inappropriate shock, defined as a shock other than ventricular arrhythmia. Hazard ratios and 95% confidence intervals were calculated using a time-varying Cox proportional hazards model which was adjusted for age because age differed between the groups and could be a confounder. RESULTS: During a median follow-up period of 2.2 years (interquartile range, 1.0-3.4 years), inappropriate shock events occurred in 17 (16%) and five (19%) patients of the non-combined and combined groups, respectively. While the age-adjusted hazard ratio for inappropriate shock was 24% higher in the combined than in the non-combined group (hazard ratio = 1.24, 95% confidence interval, 0.39-3.97), this difference was insignificant (p = .71). CONCLUSION: The incidence of inappropriate shock did not differ between patients with and without concomitant use of CIEDs, suggesting that S-ICDs could potentially be combined with other CIEDs without increasing the number of inappropriate shocks. Further studies are warranted to confirm the safety and feasibility of concomitant use of S-ICDs and CIEDs.

Difficulty in Serologic Screening for Subclinical Rubella during Pregnancy.

In Japan, rubella antibodies are tested in all pregnant women to detect subclinical infections. This study aimed to assess the validity of measuring rubella antibodies for detecting subclinical rubella among pregnant women in Japan. This single-center retrospective study measured rubella hemagglutination inhibition (HI) titers and rubella-specific IgM antibody index (IgM) values. IgM values were measured by conducting enzyme immunoassay, and IgM-values >1.2 were considered positive. Of 14,965 included pregnant women, 186 (1.2%) were IgM-positive. Only one patient was clinically diagnosed with rubella (HI titer, 1:2,048; IgM value, 10) and developed fever and skin rash. She decided to terminate her pregnancy without undergoing repeated blood tests. Of the IgM-positive patients, 136 (73.1%) had rubella HI titers of < 1:256. The correlation coefficient between rubella HI and IgM titers was weakly positive (0.2527; P < 0.0001). This study showed that a single combination of rubella HI and rubella-specific IgM measurements alone could not detect subclinical rubella. Creating awareness among pregnant women by informing them that almost all rubella-specific IgM-positive individuals without symptoms are not acutely infected could decrease their anxiety and prevent unnecessary pregnancy termination.

Braided-type stent versus laser-cut-type stent for patients with unresectable distal malignant biliary obstruction: a randomized controlled trial.

BACKGROUND AND AIMS: Fully covered self-expandable metallic stents (SEMSs) are laser-cut (L) or braided (B); however, it remains unclear which approach is more effective for distal malignant biliary obstruction (DMBO). This study compared the clinical outcomes of using L-type and B-type stents because we believe that recurrent biliary obstruction (RBO) is less likely to occur with L-type stents. METHODS: Patients diagnosed with unresectable DMBO were randomly assigned to groups L and B in a stratified block fashion, and outcomes were compared. The primary outcome was the rate of RBO within 1 year; secondary outcomes were adverse events, clinical success rate, time to RBO (TRBO), and overall survival. RESULTS: Of the 60 enrolled participants, 56 (group L, n = 27; group B, n = 29) were included. The rates of RBO within 1 year were 44.4% and 17.2% in groups L and B, respectively (odds ratio, 2.57; 95% confidence interval [CI], 1.045-6.353). Early adverse events, which improved with conservative treatment, included pancreatitis (n = 4) in group L and pancreatitis (n = 3) and cholecystitis (n = 1) in group B (P = .913). The median TRBO (220 days [95% CI, 56-272] vs 418 days [95% CI, 232-454]) was significantly longer in group B than in group L (log-rank test, P = .0118). The median overall survival (group L, 158 days; group B, 204 days) after stenting was not significantly different between groups (P = .8544). CONCLUSIONS: In the setting of DMBO, B-type stents are associated with less recurrent obstruction than L-type stents, although there was no difference in safety. (UMIN Clinical Trials Registry number: UMIN000027239.).

Association of Reversal of Renin Suppression With Long-Term Renal Outcome in Medically Treated Primary Aldosteronism.

BACKGROUND: Renin suppression in primary aldosteronism indicates mineralocorticoid receptor activation via excessive aldosterone secretion, inducing renal damage. We investigated whether the reversal of renin suppression after the initiation of mineralocorticoid receptor antagonist therapy was associated with long-term renal outcomes in medically treated patients with primary aldosteronism. METHODS: This retrospective cohort study included 318 patients with primary aldosteronism treated with mineralocorticoid receptor antagonist between 2008 and 2020 at the Yokohama Rosai Hospital in Japan. The posttreatment renin status was defined as unsuppressed (ie, reversal of renin suppression) when individual plasma renin activity after the initiation of mineralocorticoid receptor antagonist (post-plasma renin activity) was ≥1.0 ng/mL per hour; otherwise, it was defined as suppressed. We analyzed the association of posttreatment renin status with subsequent longitudinal estimated glomerular filtration rate changes using linear mixed-effects models for repeated measurements, adjusting for potential confounders. RESULTS: The posttreatment renin status of 119 patients was unsuppressed (median post-plasma renin activity, 1.7 ng/mL per hour) and that of 199 patients was suppressed (median post-PRA, 0.5 ng/mL per hour). Through the median follow-up period of 3.1 years, the decline in estimated glomerular filtration rate was milder among patients with the unsuppressed posttreatment renin (-0.46 [95% CI, -0.63 to -0.28] mL/min per 1.73 m2 per year) than those with suppressed posttreatment renin (-1.41 [95% CI, -1.56 to -1.27] mL/min per 1.73 m2 per year; difference, 0.96 [95% CI, 0.72-1.20] mL/min per 1.73 m2 per year). CONCLUSIONS: Our findings may highlight the importance of reversing renin suppression with optimal mineralocorticoid receptor antagonist titration in medically treated primary aldosteronism, which could mitigate adverse renal outcomes.

Usual source and better quality of primary care are associated with lower loneliness scores: a cross-sectional study.

BACKGROUND: Loneliness is a global issue, and primary care physicians play an important role in assessing and intervening with loneliness. This study aimed to examine the association between having a usual source of care (USC) or a good quality of primary care, and loneliness. METHODS: This cross-sectional study was conducted in Japan in 2022. A total of 6,000 residents were randomly sampled from the general population, aged 20-74 years. The outcome was the total score of the University of California, Los Angeles (UCLA) 3-item loneliness scale. The exposure included USC and the Person-Centered Primary Care Measure (PCPCM), which assesses the quality of primary care. We conducted a linear regression analysis to adjust for age, sex, educational status, annual household income, self-rated health, living status (whether alone or not), and the existence of physical health problems. RESULTS: Of the 6,000 residents, 1,277 responded to the survey. The median score of the UCLA 3-item loneliness scale was 6.0 and the mean total score of the PCPCM was 2.62. Of the 1,277 individuals, 713 (55.8%) had USC. Having USC was significantly associated with lower scores on the UCLA 3-item loneliness scale; the coefficient was -0.34 (95% confidence interval (CI): -0.57 to -0.12). Also, the total PCPCM score was significantly associated with lower loneliness scores; the coefficient was -0.56 (P < 0.001, 95% CI: -0.78 to -0.35). CONCLUSIONS: Having USC and a better quality primary care were associated with a lower loneliness score. The quality of primary care could be a factor to mitigate patient loneliness.

Loneliness is a global issue, and primary care physicians play an important role in assessing and intervening with loneliness. This study aimed to examine the association between having a usual source of care (USC) or a good quality of primary care, and loneliness. The study was conducted in Japan in 2022. Of the 6,000 residents, 1,277 responded to the survey. After adjusting age, sex, educational status, annual household income, self-rated health, living status, and the existence of physical health problems, having USC was statistically significantly associated with lower scores on the UCLA 3-item loneliness scale. The total scores of the Person-Centered Primary Care Measure were also associated with lower loneliness scale scores. The quality of primary care could be a factor to mitigate patient loneliness.

Regional differences in epidermal growth factor receptor-tyrosine kinase inhibitor therapy in lung cancer treatment using a national database in Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are extensively used in the treatment of non-small cell lung cancer (NSCLC); hence, equal access to them is important. Therefore, this study aimed to identify regional differences in the prescription of EGFR-TKIs and the factors contributing to these differences. In this ecological study, we collected data using the National Database Open Data and the National Cancer Registry. The standardized claim ratio (SCR) was used as an indicator of the number of EGFR-TKI prescriptions. Additionally, we examined the association between SCR and various factors to identify the factors associated with this difference. The average SCR for the top three provinces was 153.4, while the average for the bottom three provinces was 61.6. Multivariate analysis used for evaluating the association of SCR with variables revealed that the number of designated cancer hospitals and radiation therapies were independent factors associated with the SCR of EGFR-TKIs. There were significant regional differences in the prescriptions of EGFR-TKIs in Japan based on the number of coordinated designated cancer hospitals and the number of patients receiving radiotherapy alone. These findings emphasize the need to implement policies to increase the number of hospitals to reduce regional differences.

Blunted humoral immune response to the fourth dose of BNT162b2 COVID-19 vaccine in patients undergoing hemodialysis.

BACKGROUND: We aimed to investigate the impact of a fourth dose of BNT162b2 vaccine (Comirnaty®, Pfizer-BioNTech) on anti-SARS-CoV-2 (anti-S IgG) antibody titers in patients receiving hemodialysis (HD) and healthcare workers (HCWs). METHODS: A multi-institutional retrospective study at five dialysis clinics in Japan was conducted using 238 HD patients and 58 HCW controls who received four doses of the BNT162b2 mRNA vaccine. Anti-S IgG titers were measured at 1, 3, and 6 months after the second dose, at 1 and 5/6 months after the third dose, and at 1 month after the fourth dose of vaccine. RESULTS: The log anti-S IgG titers of the HD patients after the second vaccination were significantly lower than those of the control group, but equalized 1 month after the third vaccination: 9.94 (95% CI 9.82-10.10) vs. 9.81 (95% CI 9.66-9.96), (P = 0.32). In both groups, the fold-increase in anti-S IgG titers was significantly lower after the fourth dose than after the third dose of vaccine. In addition, there was a strong negative correlation between antibody titers 1 month after the fourth vaccination and antibody titers immediately before the vaccination. In both groups, the waning rate of anti-S IgG titers from the post-vaccination peak level after the third vaccine dose was significantly slower than that after the second dose. CONCLUSIONS: These findings suggest that the humoral immune response was blunted after the fourth dose of the conventional BNT162b2 vaccine. However, multiple vaccinations could extend the window of humoral immune protection.

Low skeletal muscle mass predicts poor prognosis for patients with stage III cervical cancer on concurrent chemoradiotherapy.

OBJECTIVES: The aim of this study was to evaluate whether low skeletal muscle mass before initial treatment is an independent prognostic factor defining overall survival (OS) and progression-free survival (PFS) in patients diagnosed with stage III cervical cancer. METHODS: Body composition and clinicopathologic data were collected retrospectively. Information was extracted and analyzed from the medical records of 92 patients with stage III cervical cancer and undergoing concurrent chemoradiotherapy. Skeletal muscle mass in the L3 region was measured using cross-sectional computed tomography images and corrected for body surface area to calculate the skeletal muscle index (SMI). The primary outcome was OS, and the secondary outcome was PFS. Statistical analyses were performed using the Mann-Whitney U test. The Kaplan-Meier method was used to determine OS and PFS. Univariate and multivariate analyses were performed with Cox proportional hazard ratios. RESULTS: The optimal cutoff value for predicting 5-y survival was 35.6 cm2/m2, defined based on data derived from 24 patients with a low SMI and 68 patients without a low SMI. A low SMI was significantly associated with shorter OS (hazard ratio [HR], 2.470; 95% confidence interval [CI], 1.208-5.053; P = 0.013), with no significant difference in PFS (HR, 1.651; 95% CI, 0.876-3.110; P = 0.121). Multivariate analysis also identified a low SMI as an independent OS-defining prognostic factor (HR, 2.473; 95% CI, 1.151-5.314; P = 0.020). CONCLUSION: A low pretreatment SMI is an independent prognostic factor for OS in patients diagnosed with stage III cervical cancer and treated with concurrent chemoradiotherapy.

The indicators for early blood transfusion in patients with placental abruption with intrauterine fetal death: a retrospective review.

BACKGROUND: Placental abruption (PA) with intrauterine fetal death (IUFD) is associated with a high risk of postpartum hemorrhage (PPH) resulting from severe disseminated intravascular coagulation (DIC). Therefore, blood products that are sufficient for coagulation factor replacement must be prepared, and delivery should occur at referral medical institutions that are equipped with sufficient blood products and emergency transfusion protocols. We retrospectively reviewed the records of patients with PA and IUFD (PA-IUFD) to identify possible factors that may indicate the need for early blood transfusion and investigated whether the Japanese scoring system for PPH can be applied in such cases. METHODS: We used a database of 16,058 pregnant patients who delivered at Yokohama City University Medical Center between January 2000 and February 2016. Thirty-three patients were diagnosed with PA-IUFD before delivery and categorized into two groups-blood transfusion and non-transfusion-to compare the maternal characteristics and pregnancy outcomes. RESULTS: In patients with PA-IUFD, the transfusion group exhibited significantly more blood loss; lower fibrinogen levels and platelet counts; higher levels of fibrin degradation products (FDP), D-dimer, and prothrombin time; and a tendency for tachycardia on admission, compared to the non-transfusion group. Many patients in the transfusion group had normal fibrinogen levels on admission but later displayed markedly decreased fibrinogen levels. The Japan Society of Obstetrics and Gynecology (JSOG) DIC score was significantly higher in the transfusion than in the non-transfusion group. CONCLUSIONS: In PA-IUFD, the fibrinogen level, platelet count, D-dimer, FDP, heart rate, and JSOG DIC score on admission may indicate the need for blood transfusion. However, even with normal fibrinogen levels on admission, continuous monitoring is indispensable for identifying progressive fibrinogen reductions in patients with PA-IUFD.

A 3-step approach to predict advanced fibrosis in nonalcoholic fatty liver disease: impact on diagnosis, patient burden, and medical costs.

A 2-step approach, Fibrosis-4 index (FIB-4) followed by vibration-controlled transient elastography (VCTE), has been proposed to predict advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to develop a novel 3-step approach for predicting advanced fibrosis. We enrolled 284 biopsy-confirmed NAFLD patients from two tertiary care centers and developed subgroups (n = 190), including 3.7% of patients with advanced fibrosis, assuming a primary care setting. In the 3-step approach, patients with intermediate-to-high FIB-4 in the first step underwent an enhanced liver fibrosis test or measurement of type IV collagen 7S domain as the second step, and VCTE was performed if the second step value was higher than the cutoff. In 284 cases, a tertiary care cohort with 36.3% advanced fibrosis, the 3-step approach showed significantly higher specificity and positive predictive value than the 2-step approach. In the subgroup with 3.7% advanced fibrosis, the 3-step approach significantly reduced the referral rate to specialists, the number of high-risk patients (i.e., liver biopsy candidates), and healthcare costs by 12.5% to 15.8%. The 3-step approach may improve the diagnostic performance to predict advanced fibrosis in NAFLD, which could lower rates of referrals to specialists, liver biopsies, and medical costs.

Fragmentation of ambulatory care among older adults: an exhaustive database study in an ageing city in Japan.

OBJECTIVES: Continuity of care is a core dimension of primary care, and better continuity is associated with better patient outcomes. Therefore, care fragmentation can be an indicator to assess the quality of primary care, especially in countries without formal gatekeeping system, such as Japan. Thus, this study aimed to describe care fragmentation among older adults in an ageing city in Japan. DESIGN: Cross-sectional study. SETTING: The most populated basic municipality in Japan. PARTICIPANTS: Older adults aged 75 years and older. INTERVENTIONS: This study used a health claims database, including older adults who visited medical facilities at least four times a year in an urban city in Japan. The Fragmentation of Care Index (FCI) was used as an indicator of fragmentation. The FCI was developed from the Continuity of Care Index and is based on the total number of visits, different institutions visited and proportion of visits to each institution. We employed Tobit regression analysis to examine the association between the FCI and age, sex, type of insurance and most frequently visited facility. RESULTS: The total number of participants was 413 600. The median age of the study population was 81 years, and 41.6% were men. The study population visited an average of 3.42 clinics/hospitals, and the maximum number of visited institutions was 20. The proportion of patients with FCI >0 was 85.0%, with a mean of 0.583. Multivariable analysis showed that patients receiving public assistance had a lower FCI compared with patients not receiving public assistance, with a coefficient of 0.137. CONCLUSIONS: To our knowledge, this is the first study to demonstrate care fragmentation in Japan. Over 80% of the participants visited two or more medical facilities, and their mean FCI was 0.583. The FCI could be a basic indicator for assessing the quality of primary care.

Association of Serum and Fecal Bile Acid Patterns With Liver Fibrosis in Biopsy-Proven Nonalcoholic Fatty Liver Disease: An Observational Study.

INTRODUCTION: No reports on both blood and fecal bile acids (BAs) in patients with nonalcoholic fatty liver disease (NAFLD) exist. We simultaneously assessed the serum and fecal BA patterns in healthy participants and those with NAFLD. METHODS: We collected stool samples from 287 participants from 5 hospitals in Japan (healthy control [HC]: n = 88; mild fibrosis: n = 104; and advanced fibrosis group: n = 95). Blood samples were collected and analyzed for serum BAs and 7α-hydroxy-4-cholesten-3-one (C4)-a surrogate marker for BA synthesis ability-from 141 patients. Concentrations of BAs, including cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid (LCA), were measured using liquid chromatography-mass spectrometry. RESULTS: The total fecal BA concentration was significantly higher in the NAFLD group with worsening of fibrosis than in the HC group. Most of the fecal BAs were secondary and unconjugated. In the fecal BA fraction, CA, DCA, chenodeoxycholic acid, ursodeoxycholic acid, and LCA were significantly higher in the NAFLD than in the HC group. The total serum BA concentration was higher in the NAFLD group with worsening of fibrosis than in the HC group. In the serum BA fraction, CA, LCA, and C4 concentrations were significantly higher in the NAFLD than in the HC group. DISCUSSION: Fecal and serum BA and C4 concentrations were high in patients with NAFLD with worsening of fibrosis, suggesting involvement of abnormal BA metabolism in NAFLD with fibrosis progression. Abnormalities in BA metabolism may be a therapeutic target in NAFLD with fibrosis.

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with attention-deficit/hyperactivity disorder.

BACKGROUND: Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. METHODS: The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6-17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated. RESULTS: TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group. CONCLUSIONS: ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary. TRIAL REGISTRATION: Phase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp.

A measure of asymmetry for ordinal square contingency tables with an application to modified LANZA score data.

In clinical researches, various clinical scales with ordered categories are used to evaluate the efficacy and safety/toxicity of treatments. Such the clinical scales are sometimes summarized on the transition between the baseline and the study end point as a square contingency table. Also, clinical scales may be reclassified into three groups. However, the cutpoints can be varied depending on clinical researches or clinicians. Hence, this paper proposes a measure which is expressed by using same weights for collapsed tables and which can see the directionality for two kinds of asymmetries. Also, this paper shows an application of the proposed measure to clinical data, and that the proposed measure is a useful statistical method for analyzing ordered categorical data.