Investigation of the Optimal Cocktailed Probiotics for Decolonization of Vancomycin-resistant Enterococci in Human Gut

Enterococci are one of the commensal gut flora in humans and have become an important pathogenic bacterium of opportunistic infection. Enterococci can cause severe infection when the patients become immunocompromised and subsequent serious problem in medical therapy because last line antibiotics could be ineffective. The incidences of vancomycin-resistant enterococci (VRE) have been increasing all over the world in recent years. VRE have become a global threat in human health and medical care because of the possible spreading of antibiotic resistance genes. So far probiotic bacteria have played various important roles in regulation of gut functions and some positive impact on diabetes, liver function impairment, and psychiatric disorders. Recently a few probiotic studies indicated that VRE could possibly be decolonized from human gut. However, it remains controversial because of different probiotic strains, dosages, durations of administrations, and study designs in these reports. Therefore, further in vitro studies and clinical trials are warranted for validation of the hypothesis that VRE could be decolonized by probiotic bacteria from human gut. In the preliminary study using Microbiome analysis pipeline to dissect the NGS (next generation sequencing) data from the co-cultures of two VRE strains (Enterococcus faecium, Enterococcus faecalis) and ten TFDA (Taiwan Food and Drug Administration)-approved probiotic bacteria, investigators have confirmed that the mixture of the ten probiotic bacteria significantly suppressed the bacterial amounts of VRE during the in vitro co-cultures. The results will provide a formula of optimal cocktailed probiotics in which a specific combination of the selected probiotic bacteria could exert a maximal effect on suppression of growth of VRE. First, An in vitro co-culture of VRE and the optimal cocktailed probiotics selected by Microbiome analysis pipeline will be conducted for validation of the results from the preliminary study. Gastric acid-resistant capsules containing the probiotic cocktail validated with in vitro co-culture model, will then be prepared in dosage of 10^10 CFU (Colony Forming Unit). Second, in the proposed clinical trial, participants of age between 20 and 90-year-old will be selected and admitted to Taipei Medical University Hospital with isolated vancomycin-resistance enterococci (VRE) from their stools after hospitalization. Exclusion criteria in this study are individuals: (1) with routine probiotic uptake in daily life, or being prescribed with probiotics in clinic one-week before or in the period of clinical trial; (2) being prescribed with oral antibiotic uptake in the period of clinical trial; (3) with diarrhea symptom; (4) in pregnancy; (5) of immuno-compromised conditions or being prescribed with steroid-type medicines; (6) with diabetes mellitus; (7) critically ill patients. When the conditions of their underlying diseases are stabilized, these patients who sign the informed consents will be randomly assigned into two groups receiving the cocktailed probiotics or placebo for 3 weeks in double-blind masking. The stool samples will be collected before and after the 3-week administration of the cocktailed probiotics or placebo. After completion of enrolling 80 patients in total umber, the double-blinded capsules will be unlabeled and at least 50 patients with 25 completed paired stool samples in both groups will be further processed for genomic DNA isolation and 16s rDNA (ribosomal DNA) NGS analysis. Finally, the quantities of VRE in stool samples will be analyzed with colony formation number on selective medium, and alterations of gut microbiota will be analyzed through stool microbiome 16s rDNA NGS. The results will be compared between the cocktailed probiotics group and the placebo group for evaluation of the VRE decolonization effect of probiotics.

Cranial Electrotherapy Stimulation on Anesthetics Consumption and Postoperative Pain

Cranial electrotherapy stimulation (CES) is a non-invasive and safe intervention, transmitting microcurrents of brain stimulation and releasing various neurotransmitters such as endorphin and downstream hormones to modulate autonomic nervous system, as a result, for treating anxiety, depression, insomnia, and pain. Acute postoperative pain annoys patients receiving surgery. Once acute postoperative pain is poorly controlled, it may result in adverse acute effects (i.e., physiologic and psychologic stress), chronic effects (i.e., delayed long-term recovery and chronic pain), and, in consequence, excess length of hospitalization and extra costs. Besides, inflammatory reactions mediated by immune system are formed after tissue injury (e.g. trauma, surgery, etc), release serial inflammatory cytokines and are related to pain signal transmission. However, clinical studies and applications of CES focus on management of chronic pain, modulation of mood and insomnia rather than acute postoperative pain in recent years. The investigators investigate a double-blind, randomized controlled trial to figure out if intraoperative CES could decrease dosage of intraoperative anesthetics and patient-controlled analgesia (PCA) consumption in patients undergoing colon cancer surgery. The investigators also collect blood samples before and after surgery for analysis of serum cytokines. Meanwhile, Bispectral IndexTM (BISTM) monitoring and Analgesia Nociception Index (ANI) are prescribed during the surgery not only for measuring of the effects of anesthetics and sedatives on the brain, but also evaluating perioperative analgesia. Thereby, the effectiveness of CES for management of acute postoperative pain may introduce clinicians for alternative application of pain control after surgery in the future.

Transpacific TAVR Registry

This study is connected with Asian TAVR registry(NCT02308150). Some subjects from Asian TAVR registry continue 10 years follow-up on this TP-TAVR registry.

Effects of Aerobic Exercise Modulation on Brain Physiology and Cognition in Young Adults With Depression

The study are interested in the physiological foundation of the impact of aerobic exercise on cognitive performance in youth MDD subjects. Combined application of neurophysiological intervention and recording tools, including non-invasive brain stimulation, is suited to explore the impact of aerobic exercise on brain physiology and cognition in humans. We will apply transcranial magnetic stimulation (TMS) to obtain evoked potentials with electromyography (EMG) to explore cortical excitability. In the same participants, we will combine motor learning, working memory, and attention task to explore the association between the physiological effect of aerobic exercise and respective cognitive alterations. This project aims to explore the impact of aerobic exercise on cortical excitability and cognitive performance, and the association between these phenomena in youth MDD subjects. The study will improve our understanding of the role of aerobic exercise in cortical excitability, an important physiological basis for cognitive processes in humans, the underlying physiological mechanisms with regard to the aerobic exercise, and their functional relevance in youth MDD subjects.

Comparison of Vonoprazan-based Versus Lansoprazole-based Triple Therapy, High Dose Dual Therapy, Bismuth and Non-bismuth Quadruple Therapy in the First-line Treatment of Helicobacter Pylori Infection

Background: Bismuth quadruple therapy is currently the recommended first-line regimen for Helicobacter pylori (H. pylori) infection in regions with high clarithromycin resistance. Recent randomized trials showed that 7-day vonoprazan-based triple therapy is superior to 7-day lansoprazole-based triple therapy in Japanese. A recent trial further showed that 7-day vonoprazan-based high dose amoxicillin dual therapy was non-inferior to 7-day vonoprazan-based triple therapy in Japanese. However, whether vonoprazan based dual, triple, and quadruple therapies are superior or non-inferior to lansoprazole based triple or quadruple therapy remains unknown. Objective: The investigators aimed to compare the efficacy and safety of 14-day vonoprazan-based dual therapy, triple therapy, bismuth quadruple therapy, reverse hybrid therapy, and lansoprazole-based bismuth quadruple therapy and triple therapy in the first-line treatment of H. pylori infection in this pilot study. The long-term changes in gut microbiota, antibiotic resistance, trimethylamine-N-oxide (TMAO) levels, and metabolic parameters after eradication therapies will also be investigated. Methods: Using a block randomization with a block size of 16 in a 1:1 ratio, 1200 eligible adult subjects aged 20 years or greater with at least two positive tests for H. pylori infection will be randomized to receive one of the following regimens: (A) vonoprazan-based triple therapy for 14 days (T-V14): vonoprazan 20mg twice daily, clarithromycin-XL 500mg twice daily, amoxicillin 1000mg twice daily for 14 days ; or (B) vonoprazan-based triple therapy for 7 days (T-V7): vonoprazan 20mg twice daily, clarithromycin-XL 500mg twice daily, amoxicillin 1000mg twice daily for 7 days ; or (C): vonoprazan-based dual therapy for 14 days (D-V14): vonoprazan 20mg twice daily, amoxicillin 750mg every 8 hour for 14 days; (D): vonoprazan-based high dose dual therapy for 14 days (HD-V14): vonoprazan 20mg twice daily, amoxicillin 750mg four times a day for 14 days; or (E) vonoprazan-based bismuth quadruple therapy for 14 days (BQ-V14) vonoprazan 20mg twice daily, bismuth tripotassium dicitrate 300 mg three times a day, tetracycline 500mg three times a day, and metronidazole 500mg three times a day for 14 days; or (F) vonoprazan-based reverse hybrid therapy for 14 days (RH-V14): vonoprazan 20mg twice daily, and amoxicillin 1000mg twice daily for 14 days, plus clarithromycin-XL 500mg twice daily and metronidazole 500mg twice daily for the first 7 days ; or (G) lansoprazole-based bismuth quadruple therapy for 14 days (BQ-L14) lansoprazole 30mg twice daily, bismuth tripotassium dicitrate 300 mg three times a day, tetracycline 500mg three times a day, and metronidazole 500mg three times a day for 14 days; or (H) lansoprazole-based triple therapy for 14 days (T-L14): lansoprazole 30mg twice daily, clarithromycin-XL 500mg twice daily, amoxicillin 1000mg twice daily for 14 days. Subjects who fail after first-line therapy will be randomized to receive either vonoprazan-based levofloxacin triple therapy (LT-V14) containing vonoprazan 20mg twice daily, levofloxacin 250mg twice daily, and amoxicillin 1000mg twice daily for 14 days or vonoprazan-based levofloxacin reverse hybrid therapy (LRH-V14) containing vonoprazan 20mg twice daily, and amoxicillin 1000mg twice daily for 14 days, plus levofloxacin 250mg twice daily and metronidazole 500mg twice daily for the first 7 days. The minimum inhibitory concentrations will be determined by agar dilution test. 23S ribosomal RNA and gyrase A mutations will be determined by PCR methods followed by direct sequencing in a subgroup of patients. The TWB2.0 SNP array will be used for genotyping of genome wide single nucleotide polymorphism. Fecal and oral samples will be collected for 16S and shot-gun sequencing at baseline, week 2, week 8, year 1, and year 2. Metabolic parameters will be measured at baseline, week 8, year 1, and year 2. Modified carnitine challenge test (mCCT) will be done to assess the production of urine TMAO at baseline, week 2, week 8, year 1, and year 2 in a subgroup of study subjects. Outcome analysis: The primary outcome is the eradication rate in the first-line treatment. The secondary outcomes are the compliance, frequency of adverse events, the overall eradication rate after two treatments. The long-term outcomes are the cumulative eradication rate, the changes of gut microbiota, antibiotic resistance, TMAO production, and metabolic parameters at year 1 and year 2.

Urine Omics Predicting IO Therapy Responses in mRCC Patients

This is a multi-center single-arm translational study where patients with mRCC who are to receive pre-determined IO-based therapy will be invited to participate the study. After signing the approved informed consent, eligible and consenting subjects will donate their fresh urine samples for subsequent untargeted metabolomics and proteomics study via GS-MS/MS and/or LC-MS/MS to identify potential metabolite and protein markers that are able to predict efficacy and side effects of IO-based therapies. All subjects in the first-line, maintenance after 1st line, second-line, or subsequent lines of IO-based therapy will be invited and recruited, but those who have received any IO-based therapy before the study can NOT be recruited.

Same-day Antiretroviral Therapy With BIC/F/TAF

Background In 2015, WHO recommended that all patients be treated with combination antiretroviral therapy (cART) once the diagnosis of HIV infection was made. On the population level, starting cART soon after HIV diagnosis can prevent onward HIV transmission. Although WHO has recommended "treat-all" policy since 2015, there were still 1.8 million people becoming newly infected with HIV in 20179. The substantial loss of patients during the HIV care continuum among the most vulnerable populations have been major concerns in the cART scale-up. Therefore, the concept of rapid ART initiation, defined as starting ART within 7 days or even on the same day after HIV diagnosis was confirmed, was introduced to improve HIV care continuum. In several clinical trials, loss to follow-up was observed despite the clinical trial settings. From our prior study18, among 786 individuals who were screened positive for HIV, 2.4% never returned to the clinic for the confirmatory tests. Despite ART scale-up and the policy of rapid initiation, 30% the of patients who were diagnosed with HIV infection during 2017-2018 did not initiate cART within 7 days after HIV diagnosis was made. Prior studies revealed that point-of-care diagnostic methods for detection of HIV RNA can accelerate linkage to care and reduce anxiety. However, the cost of and the barriers to accessing the point-of-care HIV RNA testing remain high. By shortening the interval between infectious disease physician referral, time-lag between screening and confirmatory tests, with the use of newly developed point-of-care immunochromatographic confirmatory test, initiating a safe and potent antiretroviral therapy on the same day of HIV confirmation will be feasible to improve linkage to care and to shorten the interval between HIV diagnosis and viral suppression. Study aim This study objective is to investigate the feasibility and outcomes of same-day initiation with Biktarvy (Bic/F/TAF) among patients who receive a diagnosis of HIV infection by confirmatory test. Study Interventions This is a multi-center, single-arm, prospective cohort study. All individuals who fulfill the inclusion/exclusion criteria will be enrolled in our study and followed for 48 weeks. During the first visit at ID clinic, baseline clinical data will be collected by history taking, physical examination, and blood testing. The confirmatory test and baseline evaluations will be performed at the Visit 1. The test results will also be reported on the same day. Patients, who are HIV(+) by confirmatory test ,will receive a 7-day Biktarvy treatment and the first dose will be administered from Visit 1 (Day 1). The results of other evaluation including viral load, CD4 count, and coinfection will be available at visit 2. At Visit 2, the clinical symptoms and the tolerability will be recorded. If participants continue to receive Biktarvy® at the discretion of the HIV treating physicians, Biktarvy will be continued according to the national HIV treatment guidelines, which will be reimbursed by the National Health Insurance, and the patients will be followed in our study for 48 weeks. If the patients are switched to other cART regimens than Bictarvy according to physician's clinical judgements, the participants will continue their follow-up in the study. During the follow-up period, clinical information on symptoms, tolerability, and adverse effects with the use of face-to-face questionnaire interviews, and follow-up laboratory test results will be collected. to evaluate the efficacy and adverse effect according to the national HIV treatment guidelines and routine clinical practices. Monitor of Adverse event and management The subjective adverse events will be inquired during each visit and recorded with the use of questionnaire interviews. According to the national HIV treatment guidelines in Taiwan, the liver and renal functions and muscle enzymes will be followed during treatment as part of the standard of care. The study team will provide best clinical care if adverse events develop and the cost of medical care required will be covered by the insurance company. Severe adverse event and withdrawal from the study will be reported to the primary investigator on a monthly basis. When the number of drop-out is higher than 30%, the enrollment will be stopped temporarily until the investigation ensures the safety of the participants. Study Endpoints 1. Primary endpoints 1) The rate of retention in care at Week 48 2) The proportion of viral suppression (<50 copies/ml) at Week 48 2. Secondary endpoints 1) The rate of same-day initiation of ART among patients who receive a confirmed diagnosis of HIV infection 2) The proportion of viral suppression (<200 copies/ml) at Weeks 1, 4, and 48 3) Any/severe adverse effect of B/F/TAF before Weeks 4 and 48 4) Patient's satisfaction at Weeks 1, 4, and 48 Statistical analysis 1. This is a feasibility study aiming to investigate the rate of engagement in same-day ART initiation and retention in care at Week 48. No sample size calculation is needed. The sample size of 200 participants is estimated by taking into account the case numbers of newly diagnosed HIV-positive patients seeking HIV care and cART at each participating hospitals during the past 1 year. 2. Timetable for study and enrollment: 1) Total subjects expected to be enrolled: 200 2) Total subjects expected to enter treatment: 195 3) Total subjects expected to complete treatment: 191 4) Duration of enrolled period: 20 months 5) Number of subjects entering treatment per month: 10 ( 2 subjects per site)

An Active and Placebo-Controlled Study of Brazikumab in Participants With Moderately to Severely Active Ulcerative Colitis

Stripping Massage After Thoracoscopy

This study investigated the effects of stripping massage (SM) on myofascial trigger points in the rhomboid after thoracoscopic surgery. Sixty patients with chest pain after thoracoscopic surgery were randomized divided into two equal groups (A and B). Group A (n = 100) received conventional analgesics. Group B (n = 100) received SM twice daily in the active trigger points of the rhomboid for two weeks. The visual analogue scale, a pressure algometer, will be used to evaluate patients' pre- and post-treatment statuses. This study will compare differences between the current traditional method (using analgesics) and the SM for rhomboid myofascial trigger points for post-thoracoscopic chest pain, and analyze the variables generated by the two different methods including demand time of analgesics, acceptance, and differences of visual analogue scale. The results of the study will use scientific data to prove which way is a good way to take into account of the relief of patient's chest pain.

HCV Reinfection in HD Patients Achieving SVR

Hepatitis C virus (HCV) infection is an important public health problem. Compared to the global prevalence of HCV infection to be around 1.0%, the prevalence of HCV infection in hemodialysis patients is around 10%. The high prevalence of HCV infection in hemodialysis patients receiving long-term renal replacement therapy may be reasoned by the nosocomial transmission in hemodialysis units. If chronic HCV infection is left untreated, the survival, hospitalization and the quality of life are significantly compromised in hemodialysis patients. In contrast, the survival is improved following successful treatment-induced HCV clearance Interferon (IFN)-based therapy is the treatment of choice for hemodialysis patients with HCV infection in earlier years. However, the treatment responses are far from ideal and the treatment-emergent adverse events (AEs) are frequently encountered, making the global treatment uptake rate by IFN-based therapies to be only 1.5%. Based on the excellent efficacy and safety, IFN-free direct acting antivirals (DAAs) have been the mainstay of therapy for HCV. Furthermore, the world health organization (WHO) has set the goal of global HCV elimination by 2030. The microelimination of HCV among hemodialysis patients is also listed as the prioritized target by WHO. The updated definition of sustained virologic response (SVR) is the presence of serum undetectable HCV RNA level at week 12 after the stopping of antiviral therapy. However, the consensus in Taiwan mandates that hemodialysis patients who achieve SVR at off-therapy week 24 can be moved from HCV-segregated zone to cleat zone in hemodialysis unit, instead of the global definition of off-therapy week 12. The delay of bed-transfer from HCV-infective zone to clear zone might increase the risk of reinfection in hemodialysis patients achieving SVR. Therefore, we aim to assess the risk of short-term of HCV reinfection in hemodialysis patients achieving SVR at week 12 after antiviral therapy, which may be great relevance and importance for health policy making. Among the hemodialysis units, the global incidence of HCV infection ranges from 1.2% to 2.9%. Data regarding the long-term risk of reinfection among hemodialysis patients achieving SVR are limited. To our best knowledge, only one study assessed the long-term negativity of serum HCV RNA in hemodialysis patients who achieved SVR after IFN-based therapies. With a median follow-up of 48 months following SVR, the life-time cumulative survival for HCV RNA negativity was 86% among the 121 participants who were on maintenance dialysis. Furthermore, the life-time cumulative survival for HCV RNA negativity was 95% among the 45 participants who underwent renal transplantation from HCV-negative donors. Because the literatures regarding the long-term follow-up of viral outcome, the patient numbers to be recruited are still limited, and all studies are focused on IFN-based treatment, we aim to assess the long-term risk of HCV reinfection in hemodialysis patients attaining SVR by IFN-based or IFN-free therapies.