Impact of HIV status on prognosis of malignancies among people living with HIV in Japan.

BACKGROUND: Antiretroviral therapy has reduced the incidence and mortality of AIDS-defining malignancies (ADM); however, non-AIDS-defining malignancies (NADM) are a major cause of death among people living with HIV (PLWH) today. Though current guidelines suggest that PLWH should receive the same treatment as the general population, there are limited studies focused on how HIV status affects the prognosis of cancers. The present study aimed to investigate the characteristics and prognosis of malignant diseases among PLWH in Japan. METHODS: Patients with HIV diagnosed with malignant diseases at our institution between 2011 and 2021 were retrospectively reviewed. RESULTS: There were 205 patients who were diagnosed with malignancies. Of these, 87 (42.4%) were diagnosed with ADM and 118 (57.6%) were diagnosed with NADM. Among 69 patients who received chemotherapy for ADM, 24 (34.8%) developed AIDS-defining opportunistic infections during treatment. In contrast, only one (1.8%) of the 56 patients administered chemotherapy for NADM developed AIDS-defining opportunistic infections. Complications of opportunistic infections at diagnosis of malignancies, low CD4+ T-cell count, positive HIV RNA, and nonadministration of antiretroviral therapy were associated with 5-year overall survival among patients with malignant lymphomas. However, the variables associated with HIV did not affect NADM prognosis. CONCLUSIONS: In this analysis, HIV status had a small impact on the prognosis of malignant diseases in PLWH. Few patients with NADM developed AIDS-defining opportunistic infections after receiving chemotherapy.

The octapeptide-repeat surface protein of Entamoeba nuttalli is a novel virulence factor that promotes adherence to host cells.

Entamoeba nuttalli is genetically the closest to Entamoeba histolytica, the causative agent of human amebiasis, and its natural host is Macaca species. A unique E. nuttalli specific surface protein (PTORS) containing 42 repeats of octapeptide was identified by comparative genomic analysis of Entamoeba species. We aimed to elucidate the function of this protein. When trophozoites from various E. nuttalli strains were examined by immunofluorescence microscopy and flow cytometry using a PTORS-specific monoclonal antibody, only a limited proportion of trophozoites were stained, indicating that the protein was not commonly expressed in all E. nuttalli trophozoite. The proportion of trophozoites expressing PTORS increased after passage in hamster livers, suggesting that the protein functions in the virulence of trophozoites in the liver tissue. Single-cell analysis revealed that in the cluster including trophozoites with PTORS gene expression, genes of virulence-related proteins were also upregulated. Trophozoites of E. histolytica transfected with PTORS showed enhanced adherence and subsequent phagocytic activity towards human Jurkat cells, independent of the lectin. E. histolytica trophozoites expressing PTORS formed larger liver abscesses in hamsters. These results demonstrate that PTORS is a novel virulence factor in Entamoeba species.

Gene expression of axenically-isolated clinical Entamoeba histolytica strains and its impact on disease severity of amebiasis.

The severity of Entamoeba histolytica infection is determined by host immunology, pathogen virulence, and the intestinal environment. Conventional research for assessing pathogen virulence has been mainly performed using laboratory strains, such as a virulent HM-1: IMSS (HM-1) and an avirulent Rahman, under various artificial environmental conditions because of the difficulties of axenic isolation of the clinical strains. However, it is still unclear whether scientific knowledge based on laboratory strains are universally applicable to the true pathogenesis. Hereby, we performed transcriptomic analysis of clinical strains from patients with different degrees of disease severity, as well as HM-1 under different conditions. Even after several months of axenization, Clinical strains show the distinct profile in gene expression during in vitro passage, moreover, difference between any 2 of these strains was much greater than the changes on the liver challenge. Interestingly, 26 DEGs, which were closely related to the biological functions, were oppositely up- or down regulated between virulent Ax 19 (liver abscess) and avirulent Ax 11 (asymptomatic carrier). Additionally, RNAseq using laboratory strain (HM1) showed more than half of genes were differently expressed between continuously in vitro passaged HM1 (in vitro HM1) and periodically liver passaged HM1 (virulent HM1), which was much greater than the changes on the liver passage of virulent HM1. Also, transcriptomic analysis of a laboratory strain revealed that continuous environmental stress enhances its virulence via a shift in its gene expression profile. Changes in gene expression patterns on liver abscess formation were not consistent between clinical and laboratory strains.

Effect of tenofovir-based HIV pre-exposure prophylaxis against HBV infection in men who have sex with men.

BACKGROUND AND AIMS: Men who have sex with men (MSM) are vulnerable to contracting HBV as a sexually transmitted infection. We evaluated the incidence of HBV infection (HBI) and the prophylactic effect of tenofovir-based pre-exposure prophylaxis (PrEP) on HBI in an MSM cohort. METHODS AND RESULTS: MSM who were older than 16 years were enrolled from January 2018 and followed up until June 2021 and tested for HIV, bacterial sexually transmitted infections, and HBsAg/ HBsAb and HBcAb every 3 months based on inclusion criteria, including HBsAg, HBcAb, HBsAb, and HIV negativity at enrollment. HBI was defined as seroconversion of HBsAg or HBcAb status. The log-rank test was used to evaluate the prophylactic effect of PrEP against HBI. As a substudy, individuals excluded from the main study due to HBs Ab positivity were evaluated for HBI incidence. Among 1577 MSM, 786 participants (546 PrEP nonusers, 131 daily PrEP users, and 109 event-driven PrEP users) met the criteria and were included. The annual incidence of HBV among PrEP nonusers (3.8%, 21 infections, with 559.5 person-years) was significantly higher ( p = 0.018, log-rank test) than that among daily PrEP users [0.77%, 1 infection (admitted nonadherence), with 129.3 person-years] and event-driven PrEP users (no infection with 93.8 person-years). Although the incidence of HBI and HIV infection decreased with PrEP use, the incidence of other sexually transmitted infections was higher in both daily and event-driven PrEP users. The annual incidence of HBV among HBsAb-positive and HBcAb-negative PrEP nonusers was 1.8% (3 infections, with 167.5 person-years). CONCLUSIONS: Tenofovir-based PrEP prevented HBI among MSM in a real-world setting.

Development of irreversible pancreatic ductal change triggered by pancreatic duct stenting in chronic pancreatitis.

BACKGROUND AND AIM: Stent-induced ductal change is a complication of endoscopic pancreatic stent placement for chronic pancreatitis, potentially leading to irreversible changes that may contribute to pancreatic dysfunction. This study aimed to examine the long-term outcomes of stent-induced ductal change and evaluate factors that correlate with the development of irreversible ductal changes. METHODS: Between January 2008 and December 2022, 52/223 patients with chronic pancreatitis in whom an S-type plastic stent was successfully placed from the main papilla for duct stricture were detected with stent-induced ductal change on pancreatography at stent removal. We retrospectively investigated the clinical features of patients whose main pancreatic duct was reassessed by endoscopic pancreatography after >1 month without stent and whose residual stent-induced ductal change was irreversible. RESULTS: The patients with chronic pancreatitis with stent-induced ductal change (n = 28) (elevated change, 15; stricture change, 13) were evaluated using follow-up pancreatography. Eleven patients (39.3%) showed residual change associated with stent-induced ductal change, the degree of which was partial improvement, no change, and obstructive change in one, seven, and three patients, respectively. Stricture changes during stent removal and duration of stent placement that triggered ductal changes were significantly associated with the development of residual ductal changes. CONCLUSIONS: Irreversible stent-induced ductal change in patients with chronic pancreatitis was associated with stricture changes in the main pancreatic duct and continued plastic-stent placement. Careful evaluation of the pancreatic duct is required during plastic-stent placement. Early plastic-stent removal may result in an effective response to the development of stent-induced ductal change.

High plasma concentration of tenofovir alafenamide in people living with HIV with ABCB1 genetic variants.

OBJECTIVES: We aimed to analyze the relationships between single nucleotide polymorphisms in the ATP-binding cassette transporter B1 (ABCB1) and G2 (ABCG2) genes and plasma concentrations of tenofovir alafenamide (TAF), tenofovir (TFV), and emtricitabine (FTC). METHODS: We recruited 10 people living with HIV receiving once-daily treatment with a single tablet containing TAF (25 mg), FTC (200 mg), and bictegravir (50 mg). Peripheral blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. Plasma concentrations of TAF, TFV, and FTC were quantified using liquid chromatography-tandem mass spectrometry. Genotyping for allelic variants of ABCB1, including 1236C > T (rs1128503), 2677 G > T/A (rs2032582), 3435C > T (rs1045642), 4036 A > G (rs3842) and ABCG2 421C > A (rs2231142), was performed using TaqMan Drug Metabolism Assays. RESULTS: None of the genotypes for ABCB1 1236C > T, 2677 G > T/A, 3435C > T, and ABCG2 421C > A exhibited correlations with plasma concentrations of TAF, TFV, and FTC. In contrast, individuals with the ABCB1 4036 AG genotype (188.7 ng/mL, n = 3) exhibited a significantly higher mean peak plasma concentration of TAF than those with the ABCB1 4036 AA genotype (67.7 ng/mL, n = 7) (p = 0.0167). However, these genotypes did not affect the elimination of terminal half-lives of TAF. CONCLUSIONS: The allelic variant ABCB1 4036 A > G is associated with reduced protein expression and function of ABCB1. Individuals with this genetic variant exhibited significantly high peak plasma concentrations of TAF, potentially due to the reduced expression of efflux transporters in the intestines linked to this variant.

Local radiotherapy for chemotherapy-refractory Kaposi's sarcoma in an HIV-infected patient: A case report and literature review.

Human immunodeficiency virus-associated Kaposi's sarcoma (HIV-KS) is a well-documented vascular tumor with a pathogenesis involving human herpesvirus-8 (HHV-8) infection. While antiretroviral therapy (ART) and chemotherapy are effective for treating most KS cases, some become refractory. In this report, we present a case of a 58-year-old man with refractory HIV-KS treated with ART and chemotherapy. Chemotherapy was eventually discontinued due to an adverse reaction, and the patient presented with painful plantar lesions that impaired ambulation. With the exclusion of visceral metastases, localized radiotherapy was administered, which resulted in significant cosmetic and functional improvements. The patient regained ambulation and lived independently, receiving additional radiotherapy as needed. This case underscores the potential use of radiotherapy for the treatment of ART-resistant KS, particularly when the patient is unresponsive to conventional chemotherapy. It also highlights the need for future research in this area.

Combination of Amoxicillin 3000 mg and Probenecid Versus 1500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients With Human Immunodeficiency Virus: An Open-Label, Randomized, Controlled, Non-Inferiority Trial.

BACKGROUND: Amoxicillin plus probenecid is an alternative to intramuscular benzathine penicillin G for treating syphilis in the United Kingdom. Low-dose amoxicillin is an alternative treatment option used in Japan. METHODS: We conducted an open-label, randomized, controlled, non-inferiority trial between 31 August 2018, and 3 February 2022, to compare 1500 mg low-dose amoxicillin monotherapy with the combination of 3000 mg amoxicillin and probenecid (non-inferiority margin 10%). Patients with human immunodeficiency virus (HIV) infection and syphilis were eligible. The primary outcome was the cumulative serological cure rate within 12 months post-treatment, measured using the manual rapid plasma reagin card test. Secondary outcomes included safety assessment. RESULTS: A total of 112 participants were randomized into 2 groups. Serological cure rates within 12 months were 90.6% and 94.4% with the low-dose amoxicillin and combination regimens, respectively. Serological cure rates for early syphilis within 12 months were 93.5% and 97.9% with the low-dose amoxicillin and combination regimens, respectively. Non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid overall and for early syphilis was not confirmed. No significant side effects were detected. CONCLUSIONS: This is the first randomized controlled trial to demonstrate a high efficacy of amoxicillin-based regimens for treating syphilis in patients with HIV infection, and the non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid was not seen. Therefore, amoxicillin monotherapy could be a good alternative to intramuscular benzathine penicillin G with fewer side effects. However, further studies comparing with benzathine penicillin G in different populations and with larger sample sizes are needed. TRIALS REGISTRATION: (UMIN000033986).

Prevalence of Asymptomatic Mpox among Men Who Have Sex with Men, Japan, January-March 2023.

We prospectively assessed asymptomatic monkeypox virus infections among men who have sex with men in Tokyo, Japan, during the initial phase of the mpox epidemic. Our findings suggest that asymptomatic infections were likely underestimated and were comparable in magnitude to symptomatic infections, highlighting the need to improve testing accessibility among high-risk populations.

Effectiveness of sitafloxacin monotherapy for quinolone-resistant rectal and urogenital Mycoplasma genitalium infections: a prospective cohort study.

BACKGROUND: Mycoplasma genitalium has a tendency to develop macrolide and quinolone resistance. OBJECTIVES: We investigated the microbiological cure rate of a 7 day course of sitafloxacin for the treatment of rectal and urogenital infections in MSM. PATIENTS AND METHODS: This open-label, prospective cohort study was conducted at the National Center for Global Health and Medicine, Tokyo, Japan from January 2019 to August 2022. Patients with M. genitalium urogenital or rectal infections were included. The patients were treated with sitafloxacin 200 mg daily for 7 days. M. genitalium isolates were tested for parC, gyrA and 23S rRNA resistance-associated mutations. RESULTS: In total, 180 patients (median age, 35 years) were included in this study, of whom 77.0% (97/126) harboured parC mutations, including 71.4% (90/126) with G248T(S83I) in parC, and 22.5% (27/120) harboured gyrA mutations. The median time to test of cure was 21 days. The overall microbiological cure rate was 87.8%. The cure rate was 100% for microbes harbouring parC and gyrA WTs, 92.9% for microbes harbouring parC G248T(S83I) and gyrA WT, and 41.7% for microbes harbouring parC G248T(S83I) and gyrA with mutations. The cure rate did not differ significantly between urogenital and rectal infection (P = 0.359). CONCLUSIONS: Sitafloxacin monotherapy was highly effective against infection caused by M. genitalium, except strains with combined parC and gyrA mutations. Sitafloxacin monotherapy can be used as a first-line treatment for M. genitalium infections in settings with a high prevalence of parC mutations and a low prevalence of gyrA mutations.

Focal pancreatic ductal change induced by 10-Fr S-type plastic stent in chronic pancreatitis.

BACKGROUND AND AIM: Stent-induced ductal change (SIDC) is a complication of endoscopic pancreatic stenting (EPS) in patients with chronic pancreatitis (CP). However, the evaluation of SIDC associated with S-type pancreatic plastic stent (PS) and large-caliber PS, such as 10 Fr, is limited. This study aimed to analyze the SIDC of the main pancreatic duct (MPD) associated with 10-Fr S-type PS in patients with CP. METHODS: Between January 2008 and December 2021, 132 patients with CP in whom a 10-Fr S-type PS had been installed by EPS were retrospectively reviewed. The SIDC incidence rate was examined, and the clinical features of patients with and without SIDC were investigated, including the outcomes for detected SIDC. RESULTS: Stent-induced ductal change during EPS was confirmed in 41 patients (31.1%) of 132 patients at a site coincident with the PS tip or distal flap in the MPD. All patients were asymptomatic during the development of SIDC. Morphological changes in the MPD were detected as elevated (75.6%) or bearing stricture changes (24.4%). A total of 90.2% of SIDC developed after the first 10-Fr PS installation. No significant differences were noted between the patients with and without SIDC. The outcomes of continued PS installment for SIDC showed persistence and secondary change. CONCLUSIONS: Stent-induced ductal change-associated 10-Fr PS installation was performed in just under one-third of the patients, indicating a substantial incidence rate and a possible development of SIDC from early stages onwards. More emphasis should be placed on SIDC as the complication.

Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial.

BACKGROUND AND AIM: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS: This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION: In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.

A four-year observation of HIV and sexually transmitted infections among men who have sex with men before and during pre-exposure prophylaxis in Tokyo.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC) has been recommended worldwide. We evaluated the safety and efficacy of daily PrEP with TDF/FTC in Tokyo. METHODS: This single-center, single-arm study was performed with 124 men who have sex with men (MSM) between January 2017 and March 2021. MSM who entered into an MSM cohort from January 2017 through March 2018 and had a pre-PrEP observational period of 1 year were eligible and recruited to the study between April 2018 and March 2019 and followed for 2 years. The primary outcome was the incidence of HIV infection (per 100 person-years). Secondary outcomes were the incidence of sexually transmitted infections and adverse events, and the rate of retention and adherence to PrEP. RESULTS: There were 309 MSM registered in the cohort (mean age, 36.6 years); 124 fulfilled the criteria and were included in the study. The remaining patients were continuously followed. There was a significant decrease in incidental HIV infection among PrEP users (0 infections, 235.5 person-years) compared to non-PrEP users (11 infections [3.4%/year], 318.9 person-years; p = 0.01). The average adherence rate was consistently greater than 95%, and the retention rate at two years was approximately 80%. CONCLUSIONS: The present study showed a high prophylactic effect against HIV infection, retention, and adherence to PrEP. PrEP is feasible and highly recommended in Japan. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000031040, www.umin.ac.jp), Japan Registry of Clinical Trials (jRCTs031180134).

Increased afternoon step count increases heart rate variability in patients with cardiovascular risk factors.

AIMS AND OBJECTIVES: The present study investigated whether morning or afternoon activity is more effective at increasing the high-frequency (HF) index, a parasympathetic index, in patients with cardiovascular risk factors. BACKGROUND: A decreased HF index, a heart rate variability (HRV) parameter, is a well-established marker of poor cardiovascular prognosis. Because blood pressure and sympathetic tone are higher in the morning, physical activity and exercise in the afternoon has been recommended for patients with cardiovascular diseases. However, there have been no reports concerning the superior effects of afternoon exercise on parasympathetic activity and sleep. DESIGN: This observational study was a post hoc comparison. METHODS: Patients' physical activity was measured for 1 month to determine their habits. Patients' HF index was measured by 24-h Holter electrocardiography. The study enrolled 56 patients. Each patient's morning step count (before lunch) and afternoon step count (between lunch and dinner) were compared. We adhered to the STROBE guidelines in the present study. RESULTS: Thirty-one patients took more steps in the morning, and 25 patients took more steps in the afternoon. The present study showed that those who took more steps in the afternoon had a significantly higher HF index during the first hour after sleep onset and during sleep than those who took more steps in the morning (p = .003, .047). CONCLUSIONS: The present study showed that those who took more steps in the afternoon had a significantly higher HF index during the first hour after sleep onset and a higher HF index during sleep than those who took more steps in the morning. RELEVANCE TO CLINICAL PRACTICE: Exercise in the afternoon may improve the prognosis in patients with cardiovascular disease by not only preventing excessive blood pressure, afterload, and sympathetic tone but also positively influencing the parasympathetic system and sleep.

Efficacy of 1 g Ceftriaxone Monotherapy Compared to Dual Therapy With Azithromycin or Doxycycline for Treating Extragenital Gonorrhea Among Men Who Have Sex With Men.

BACKGROUND: Evidence on efficacy of high-dose ceftriaxone monotherapy for extragenital Neisseria gonorrhoeae (NG) infection is lacking. METHODS: A cohort of men who have sex with men (MSM) were tested for NG/Chlamydia trachomatis (CT) every 3 months, in a single-center observational study in Tokyo, Japan. MSM aged > 19 years diagnosed with extragenital NG infection between 2017 and 2020 were included. A single dose of 1 g ceftriaxone monotherapy was provided, while dual therapy with a single oral dose of 1 g azithromycin or 100 mg doxycycline administered orally twice daily for 7 days were given, for those coinfected with CT, according to infected sites. Efficacy of these treatments was calculated by the number of NG-negative subjects at test-of-cure divided by the number of subjects treated. Fisher exact tests were used to compare the efficacy between the 2 groups. RESULTS: Of 320 cases diagnosed with extragenital NG, 208 were treated with monotherapy and 112 were treated with dual therapy. The efficacy against total, pharyngeal, and rectal infections was 98.1% (204/208, 95% confidence interval [CI]: 95.2-99.3%), 97.8% (135/138, 95% CI: 93.8-99.4%), and 98.6% (69/70, 95% CI: 92.3-99.9%), respectively, in the monotherapy group, whereas the corresponding efficacy in the dual therapy was 95.5% (107/112, 95% CI: 90.0-98.1%), 96.1% (49/51, 95% CI: 86.8-99.3%), and 95.1% (58/61, 95% CI: 86.5-98.7%), respectively. No significant difference in the corresponding efficacy was observed between the two groups (P = .29, P = .61, P = .34, respectively). CONCLUSIONS: High-dose ceftriaxone monotherapy is as effective as dual therapy for extragenital NG among MSM.

Clinical Features and Gut Microbiome of Asymptomatic Entamoeba histolytica Infection.

BACKGROUND: Entamoeba histolytica infection is a sexually transmitted disease in some developed countries. Asymptomatic infection often occurs and can be a source of transmission; however, limited data are available regarding the pathogenesis of E. histolytica. METHODS: This was a single-center, cross-sectional study. Specimens were prospectively collected from patients with clinically suspected cases. Entamoeba histolytica infection was defined as a case in which the identification of E. histolytica was confirmed by polymerase chain reaction (PCR) of a clinical specimen. Data from asymptomatic cases were compared with those from symptomatic invasive cases. RESULTS: Sixty-four E. histolytica-infected cases, including 13 asymptomatic cases, were identified during the study period. Microbiological diagnosis was made by endoscopic sampling in 26.6% of these cases (17/64). Endoscopy identified macroscopically visible lesions in all cases; however, the sensitivity of histopathology on biopsy samples was low (45.5%) compared with PCR (94.7%). In asymptomatic cases, infection sites were limited around the proximal colon; moreover, trophozoites were frequently identified at infection sites whereas cystic forms were commonly detected in stools. Gut microbiome analyses showed more uniform composition in asymptomatic cases than in symptomatic invasive cases, which were represented by a relatively high abundance of Ruminococcaceae, Coriobacteriaceae, and Clostridiaceae, and a low abundance of Streptococcaceae. CONCLUSIONS: These results indicate that the encystation and attenuation of E. histolytica are highly affected by the intestinal contents, including the gut microbiome.

Effectiveness of doxycycline 100 mg twice daily for 7 days and azithromycin 1 g single dose for the treatment of rectal Chlamydia trachomatis infection among men who have sex with men.

OBJECTIVES: To compare the effectiveness of doxycycline 100 mg twice daily for 7 days and azithromycin 1 g single dose for the treatment of rectal Chlamydia trachomatis infection among MSM in a real clinical setting. METHODS: A prospective study was performed to compare the effectiveness of doxycycline and azithromycin for the treatment of rectal C. trachomatis among MSM in Tokyo, Japan. Subjects diagnosed with rectal C. trachomatis infection were treated and test-of-cure examination (TOC) was performed at least 3 weeks after the treatment. Treatment of rectal C. trachomatis infection was decided prospectively in a time-dependent manner; in the period between January 2017 and October 2018, azithromycin was administered to all subjects, whereas from October 2018 through March 2020, doxycycline was administered to all subjects. Effectiveness of these treatments was calculated by the number of rectal C. trachomatis-negative subjects at TOC divided by the number of subjects treated. RESULTS: Two hundred and ninety-six MSM with rectal C. trachomatis infection were treated with azithromycin (80 patients) and doxycycline (216 patients) in a time-dependent manner. Of the 296 MSM, 274 (92.6%) were treated successfully [67 (83.7%, 95% CI = 79.6%-87.9%) in the azithromycin group versus 207 (95.8%, 95% CI = 94.5%-97.2%) in the doxycycline group, P < 0.001]. To evaluate factors associated with treatment failure, we performed logistic regression analysis. In univariate and multivariate analysis, only doxycycline treatment was inversely associated with treatment failure (OR = 0.29, 95% CI = 0.084-0.976, P = 0.046). CONCLUSIONS: The treatment with doxycycline 100 mg twice daily for 7 days was superior to that with azithromycin 1 g single dose for rectal C. trachomatis among MSM in a real-world setting.

Modified self-obtained pooled sampling to screen for Chlamydia trachomatis and Neisseria gonorrhoeae infections in men who have sex with men.

OBJECTIVES: To assess whether pooled sample testing with nucleic acid amplification tests was a potential alternative to three single-site sample testing to screen for Chlamydia trachomatis and Neisseria gonorrhoeae infections in asymptomatic men who have sex with men. METHODS: We prospectively compared pooled sample testing with single-site sample testing in asymptomatic MSM. Self-obtained paired rectal samples, one gargle sample and one first-void urine sample were collected from participants to generate two sets of samples: one for pooled sample testing and the other for single-site testing. We used modified pooled sampling, which is defined as the use of gargle samples, instead of swabs, for the pooled sample to test for pharyngeal infection. RESULTS: This study included 513 MSM. The positive rates of C. trachomatis and N. gonorrhoeae were 20.3% and 11.7%, respectively, for single-site sample testing. Compared with the sensitivity of single-site testing as the gold standard, the sensitivities of pooled sample testing for C. trachomatis and N. gonorrhoeae were 94.2% (95% CI 88.0% to 97.3%) and 98.3% (95% CI 90.9% to 99.9%), respectively. The concordance rate and kappa coefficient were 98.3% (95% CI 96.7% to 99.2%) and 0.945 (95% CI 0.859 to 1.000), respectively, for C. trachomatis and 98.8% (95% CI 90.1% to 100%) and 0.943 (95% CI 0.857 to 1.000), respectively, for N. gonorrhoeae. CONCLUSIONS: The modified pooled sampling had a comparably high consistency with single-site sample testing. The results strongly suggest that the gargle sample is suitable as a part of pooled sample for STI screening of C. trachomatis and N. gonorrhoeae.

Gallbladder wall thickening in patients with IgG4-related diseases, with special emphasis on IgG4-related cholecystitis.

OBJECTIVES: Gallbladder (GB) wall thickening sometimes occurs in patients with autoimmune pancreatitis (AIP), a condition for which the name, IgG4-related cholecystitis, was proposed. We examined the radiological findings of the GB in patients with IgG4-related diseases and clinical features of patients with GB wall thickening and presented a hypothesis of its pathogenesis. MATERIALS AND METHODS: GB wall thickening was defined by thickness ≥ 4 mm. GB wall thickness was examined in 258 patients with IgG4-related disease. Clinical and imaging findings of 200 patients with AIP with and without GB wall thickening were then compared. RESULTS: GB wall thickening was detected in 58 patients (29%) with AIP and two patients with isolated IgG4-related sclerosing cholangitis. In the 60 GBs examined, wall thickening was diffuse, with the walls possessing a smooth inner surface. No GB wall thickening was detected among the 56 patients with IgG4-related disease without AIP or IgG4-related sclerosing cholangitis. Bile duct stenosis was detected in 56 patients (97%) with AIP with GB wall thickening. Intraductal ultrasonography indicated cystic duct wall thickening connected to bile duct wall thickening in 11 of 14 (79%) patients with AIP or IgG4-related sclerosing cholangitis with GB wall thickening. Forty-eight patients in whom IgG4-related cholecystitis was diagnosed experienced resolution of the GB wall thickening after receiving steroid therapy. CONCLUSIONS: Most cases of GB wall thickening in IgG4-related diseases are closely associated with IgG4-related sclerosing cholangitis and may be a manifestation of IgG4-related disease throughout the biliary tract, including the bile duct, cystic duct, and GB.

Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.