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Background Health care and well-being are 2 main interconnected application areas of conversational agents (CAs). There is a significant increase in research, development, and commercial implementations in this area. In parallel to the increasing interest, new challenges in designing and evaluating CAs have emerged. Objective This study aims to identify key design, development, and evaluation challenges of CAs in health care and well-being research. The focus is on the very recent projects with their emerging challenges. Methods A review study was conducted with 17 invited studies, most of which were presented at the ACM (Association for Computing Machinery) CHI 2020 conference workshop on CAs for health and well-being. Eligibility criteria required the studies to involve a CA applied to a health or well-being project (ongoing or recently finished). The participating studies were asked to report on their projects’ design and evaluation challenges. We used thematic analysis to review the studies. Results The findings include a range of topics from primary care to caring for older adults to health coaching. We identified 4 major themes: (1) Domain Information and Integration, (2) User-System Interaction and Partnership, (3) Evaluation, and (4) Conversational Competence. Conclusions CAs proved their worth during the pandemic as health screening tools, and are expected to stay to further support various health care domains, especially personal health care. Growth in investment in CAs also shows the value as a personal assistant. Our study shows that while some challenges are shared with other CA application areas, safety and privacy remain the major challenges in the health care and well-being domains. An increased level of collaboration across different institutions and entities may be a promising direction to address some of the major challenges that otherwise would be too complex to be addressed by the projects with their limited scope and budget.

Chromatographic separation on the liquid-state fermented products produced by the fungal strain

Background Cataract surgery in combination with or after trabeculectomy is often required for improving vision in glaucoma patients. Intraocular pressure (IOP) changes may influence refractive outcomes after cataract surgery. We compared refractive outcomes of the combined and sequential approaches in managing glaucoma and cataract. Methods This retrospective case–control study included 52 patients (57 eyes) who underwent phacotrabeculectomy (combined group) and 39 patients (42 eyes) who underwent phacoemulsification at least three months post-trabeculectomy (sequential group). The IOP and refraction prediction error were compared at three months after cataract surgery. Univariate regression analyses were used to assess risk factors for the postoperative refraction prediction error. Results Anti-glaucomatous medications were not administered to either group. The mean postoperative IOP (12.96 vs. 13.80 mmHg; P = .392), refraction prediction error (−0.32 ± 1.53 vs. −0.47 ± 1.14 D, P = .594), mean absolute error (1.02 ± 1.18 vs. 0.8 ± 0.93 D, P = .320), and surgically induced astigmatism (1.85 ± 1.40 vs. 2.16 ± 1.16 D, P = .161) did not differ significantly between the combined and sequential groups. In the sequential group, the refraction prediction error correlated to the IOP change, with a 1-mm Hg rise resulting in a −0.07-diopter shift between the expected and observed refraction (r = −0.380, R2 = 0.144, P = .013); no such correlation was observed in the combined group. Conclusion Both approaches resulted in similar effective IOP control and accurate intraocular lens predictability. The IOP change affected the postoperative refraction prediction error only in the sequential approach.

Oral cavity squamous cell carcinoma (OSCC) is a leading cause of death in Taiwan. Most of the patients in the literature are male. The risk factors, cancer characteristics, and treatment outcomes were investigated in female patients and compared with male patients in this study. This retrospective study recruited 2046 OSCC patients between 1995 and 2019. The age, tumor subsites, and survival were reviewed and recorded. Overall survival and disease-free survival were the main outcomes. Female patients represented 6.7% of the entire study cohort. Females were diagnosed at an older age and an earlier local stage than male patients (P

Background: Early injection laryngoplasty (EIL) using hyaluronic acid (HA) is an effective treatment for glottic insufficiency in patients with acute unilateral vocal fold paralysis (UVFP). Most patients benefit by showing improvement in voice and quality of life and implied reduced need for permanent laryngoplasty. However, injected HA might resolve within a short period, so its long-term outcomes and the need for secondary procedures need to be clarified. Methods: Patients who underwent EIL with HA for acute UVFP from January 2015 to December 2018 were included. The factors that may associate with the prognosis including voice performance and laryngeal configuration at presentation, the cause of UVFP, and the type of HA for EIL were analyzed. Results: Ninety-four patients were included for analysis, with a mean follow-up period of 25.1 months (95% CI: 22.8–27.4 months). After primary HA injection, 22 patients (23.4%) underwent secondary procedures (rate: 13.1% per person-year), and most (63.6%) of the events occurred after one year from the first injection. The rate of secondary procedures within the first 12 months was 9.0% (14.1% and 4.3% for low-concentrated HA (LHA) and high-concentrated HA (HHA), respectively). The incidence of the secondary procedures was higher in the LHA group (18.2%) (p = 0.026) than in the HHA group (7.5%). Conclusions: The rate of secondary procedures was lower than the prediction based on the resorption time of HA, a finding that could be partly accounted for by both natural nerve recovery and a long-lasting effect of EIL. EIL with HHA had a lower rate of re-treatment than that with LHA, suggesting a better clinical utility for acute UVFP.

Background/purpose Limited data are available on the role of illicit non-injecting drug use in a prolonged HIV outbreak that predominantly affected men who have sex with men (MSM) in Taiwan since 2006. We aimed to assess associations between specific types of drug use and incident HIV infections in this outbreak. Methods We conducted a retrospective case–control study among MSM clients at voluntary counselling and testing (VCT) service at National Taiwan University Hospital (Taipei, Taiwan). We used BED IgG-capture enzyme immunoassay to identify incident HIV infection (cases), individually matched to HIV-negative MSM clients (controls) by HIV testing date. We used a structured questionnaire to obtain the information on illicit drug use and sexual risk behaviors. Results From a total of 15,305 MSM client visits during 2006–2015, 387 cases were matched to 1012 controls. Use of inhaled nitrites (adjusted odds ratio [aOR] 2.1), MDMA (aOR 2.9), amphetamines (aOR 1.6), and ketamine (aOR 1.5) were independently associated with incident HIV infection. Polydrug (≥2 drugs) use was associated with the highest risk (aOR 4.3; 95% CI 2.6–7.2). While the proportion of MSM VCT clients who reported use of any recreational drug remained stable during 2006–2015 (average: 9.7%, P: 0.38), there was a shift in specific types of drug use, from MDMA/ketamine to inhaled nitrites/amphetamine, after 2011 (all Ps Conclusion Non-opioid recreational drugs use is associated with incident HIV infection in this prolonged HIV outbreak. There is an urgent need to formulate an effective public health response to mitigate the risk.

To prospectively evaluate the effect of benzalkonium chloride (BAK)-preserved latanoprost on ocular surface damage and identify the associated risk factors among treatment-naive glaucoma patients.The basal Schirmer's test results, corneal Oxford staining score, non-invasive keratograph tear-breakup time, oculus hyperemia index score (objective metrics), and ocular surface disease index (OSDI) questionnaire (subjective metric) were evaluated at baseline, 1 month, and 4 months after receiving latanoprost eye drops. Associated risk factors were assessed by multivariate linear regression.Seventy-four eyes (44 patients) were enrolled. Basal Schirmer's test tear-flow and Oxford scores gradually deteriorated (β = -0.14, P = 0.001 and β = 0.1, P0.001, respectively). The percentage of unstable tear-film (breakup time10 s) increased significantly at 4 months (6.21% vs 9.11%, P = 0.042). Hyperemic scores increased significantly at 1 month and normalized at 4 months (P = 0.01 and P = 0.16, respectively); total OSDI scores tended to improve (β = -0.76, P = 0.06). Older age was associated with additional corneal Oxford staining (P = 0.005); female sex was associated with increased unstable tear-film scores (P = 0.01). Artificial tear use was associated with a smaller decrease in basal Schirmer's test values (P = 0.01) and a smaller increase in unstable tear-film scores (P = 0.02).Preserved latanoprost eye drops affected ocular surface changes in glaucoma patients through decreased basal tear secretion. Artificial tears represent an early intervention in vulnerable glaucoma patients with reduced tear secretion and impaired tear-film stability.

Objectives Real-world experience regarding the effectiveness of co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (EVG/C/FTC/TAF) as a switch regimen is sparse among people living with HIV (PLWH) harbouring the M184V/I mutation with or without thymidine analogue-associated mutations (TAMs). Methods In this retrospective multicentre study, PLWH who were switched to EVG/C/FTC/TAF after having achieved viral suppression (plasma HIV RNA Results Overall, 100 case patients with the M184V/I mutation were identified, including 6 (6.0%) with K65R and 13 (13.0%) with at least one TAM, and were matched to 400 controls in terms of gender, age (mean = 40.3 versus 39.7 years) and cumulative exposure duration to tenofovir disoproxil fumarate (median = 146 versus 143 weeks). At Week 48, the rate of virological non-success for the case patients and controls was 5.0% (5/100) and 3.3% (13/400), respectively (difference = 1.7%; 95% CI = −2.9%–6.3%), while the rate of virological success was 88.0% and 89.5% for the case patients and controls, respectively. The presence of the K65R mutation or TAMs was not associated with virological non-response. Conclusions Among virally suppressed PLWH, EVG/C/FTC/TAF is effective in maintaining viral suppression at Week 48 despite archived M184V/I mutation with or without TAMs.

Attention detection is important for many applications. Automatic determination of users' visual attention state is challenging because attention involves numerous complex and internal human cognitive functions. Behavioral observations, such as eye gaze or response to external stimuli, can provide clues for users' visual attention state; however, users' cognitive state cannot be easily known. Conventional electroencephalography-based methods detect attention by observing the dynamic changes in the frontal lobe of the brain, especially in the anterior cingulate cortex (ACC). However, that area in the brain is associated with many functions, some of which correlate with conscious experience but are not directly related to attention. In this paper, we design an attention monitoring system to detect whether the brain experiences a visual stimulus consciously. Our experiments verified the feasibility of our design, and the average classification rate ranged from 72% to 82%.

ObjectivesWe aimed to investigate the awareness and willingness towards pre-exposure prophylaxis (PrEP) among individuals seeking voluntary counselling and testing (VCT) for HIV in Taiwan, where PrEP is currently not reimbursed by the insurance.MethodsBetween April and October 2016, a questionnaire interview was conducted among VCT clients to inquire about the attitudes towards PrEP against HIV infection. Multivariate logistic regression analysis was performed to identify the associated factors with willingness to initiate PrEP.ResultsDuring the 6-month period, 1173 VCT clients (99.8%) completed the interviews, with 67.4% being homosexual or bisexual male. While 67.2% of the clients knew of postexposure prophylaxis, 40.2% heard of PrEP. Overall, 546 clients (46.5%) were willing to initiate PrEP and 89.5% of them would choose event-driven PrEP. In multivariate analysis, male gender (OR 1.796; 95% CI 1.165 to 2.768), full-time job (OR 1.354; 95% CI 1.052 to 1.742), one-night stand (OR 1.374; 95% CI 1.043 to 1.810), having casual sex partners within 3 months (OR 1.329; 95% CI 1.031 to 1.714), condomless anal sex (OR 1.405; 95% CI 1.122 to 1.878) and ever having chemsex or attending a drug party in the past 1 year (OR 2.571; 95% CI 1.541 to 4.287), regular screening for HIV infection (OR 1.321; 95% CI 1.021 to 1.711) and knowledge of PrEP (OR 1.504; 95% CI, 1.159 to 1.953) were associated with willingness to initiate PrEP.ConclusionsUnderstanding the willingness to initiate PrEP against HIV among the VCT clients in Taiwan, which was associated with male gender, risky sexual behaviours and awareness of PrEP, will help inform the implementation of PrEP programme.

Objectives Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs. Methods Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study. According to the national HIV treatment guidelines, patients were assessed at baseline, 2 and 4 weeks of cART initiation, and subsequently every 8 to 12 weeks. Plasma HIV RNA load, CD4 cell count and aminotransferases were determined. The toxicity grading scale of the Division of AIDS (DAIDS) 2014 was used for reporting clinical and laboratory adverse events. Results During the 3.5-year study period, 2,341 patients initiated nNRTI-containing cART: NVP in 629 patients, EFV 1,363 patients, and RPV 349 patients. Rash of any grade occurred in 14.1% (n = 331) of the patients. In multiple logistic regression analysis, baseline CD4 cell counts (per 100-cell/μl increase, adjusted odds ratio [AOR], 1.125; 95% confidence interval [95% CI], 1.031-1.228) and use of NVP (AOR, 2.443; 95% CI, 1.816-3.286) (compared with efavirenz) were independently associated with the development of skin rashes. Among the 1,455 patients (62.2%) with aminotransferase data both at baseline and week 4, 72 (4.9%) developed grade 2 or greater hepatotoxicity. In multiple logistic regression analysis, presence of antibody for hepatitis C virus (HCV) (AOR, 2.865; 95% CI, 1.439-5.704) or hepatitis B surface antigen (AOR, 2.397; 95% CI, 1.150-4.997), and development of skin rashes (AOR, 2.811; 95% CI, 1.051-7.521) were independently associated with the development of hepatotoxicity. Conclusions The baseline CD4 cell counts and use of NVP were associated with increased risk of skin rashes, while hepatotoxicity was independently associated with HCV or hepatitis B virus coinfection, and development of skin rashes in antiretroviral-naive HIV-positive Taiwanese patients within 4 weeks of initiation of nNRTI-containing regimens.

This study investigated the correlations between consumption of antifungal agents and species distribution in candidaemia. The incidence of patients with community-acquired candidaemia (CAC) (per 1000 admissions) and healthcare-associated candidaemia (HCAC) (per 1000 admissions) as well as data on annual consumption [defined daily doses (DDD)/1000 patient-days] of various antifungal agents at a medical centre in Taiwan from 2000 to 2010 were evaluated. A total of 2682 episodes of candidaemia were identified, including 2468 HCAC (92.0%) and 214 CAC (8.0%). The most prevalent species was Candida albicans (53.3%), followed by Candida tropicalis (20.5%), Candida glabrata (15.4%), Candida parapsilosis (14.1%), Candida guilliermondii (1.7%) and Candida krusei (1.5%). The overall incidence of candidaemia remained stable, whereas that of candidaemia due to C. parapsilosis and C. guilliermondii decreased significantly with time. Significant negative correlations were found between the use of echinocandins and voriconazole and the incidence of C. parapsilosis candidaemia and between the use of caspofungin and the incidence of C. guilliermondii candidaemia. In contrast, there were significant positive correlations between the use of echinocandins and the incidence of C. tropicalis candidaemia, the use of azoles and the incidence of C. glabrata and non-albicans Candida candidaemia, and the use of itraconazole and the incidence of C. parapsilosis and C. guilliermondii candidaemia. Increased use of fluconazole was associated with an increased incidence of HCAC due to non-albicans Candida spp. In conclusion, the impact of consumption of antifungal agents on the incidence of candidaemia caused by different Candida spp. varies and warrants further studies to confirm these findings.

Background With the introduction of combination antiretroviral therapy (cART) that has significantly improved survival, human immunodeficiency virus (HIV)-positive patients may be potential organ donors to HIV-positive recipients in a few countries. Organ shortage remains a challenge for organ transplantation in Taiwan, where organ donation by HIV-positive patients remains prohibited by law. Methods We assessed the willingness of organ donation (should they be pronounced brain death, and the ban on HIV-positive organ donation be lifted) among HIV-positive patients who received regular HIV care at a university hospital in a cross-sectional survey between May and August 2015 with the use of an anonymous, self-administered questionnaire interview. Results Of the 1010 participants, 93.7% were receiving cART with the latest mean CD4 count and plasma HIV RNA load of 587 cells/mm3 and 2.73 log10 copies/mL, respectively. Overall, 71.9% were willing to donate organs. In multivariate analysis, factors associated with willingness to donate organs included college or graduate school diploma (odds ratio [OR] 1.571, 95% confidence interval [CI] 1.166–2.191), registered willingness in the National Health Insurance system (OR 9.430, 95% CI 1.269–70.051), and knowledge of the information on HIV-positive deceased donors (HIVDD) (OR 1.673, 95% CI 1.073–2.608). Conclusions We concluded that a significant proportion (71.9%) of HIV-positive Taiwanese patients were willing to donate their organs. The willingness was associated with a higher education level, prior registered willingness to donate organs, and awareness of HIVDD. This article is protected by copyright. All rights reserved.

Background/Purpose: To obtain current epidemiological data for better vaccination policies, this study aimed to assess the incidence and risk factors of herpes zoster in human immunodeficiency virus (HIV)-positive patients initiating combination antiretroviral therapy (cART) in Taiwan. Methods: Between June, 2012 and May, 2015, we prospectively identified zoster cases in HIV-positive patients initiating cART. Clinical information was collected on demographics, prior zoster, plasma HIV-1 RNA load (PVL), and CD4 count at baseline and during follow up. A case–control study by 1:2 matched pairs was used to identify the risk factors for zoster development. Results: During the 3-year study period, 826 patients with a mean age of 32.9 years were included, and 7.7% had prior zoster. The mean baseline CD4 count and PVL were 286 cells/μL and 4.90 log10 copies/mL, respectively. Fifty-four (6.5%) patients developed zoster after initiation of cART, with 43 episodes (79.6%) occurring within 1 year of cART initiation, which corresponded to an overall incidence rate of 3.61/100 person-years. The multivariate analysis revealed that prior zoster (adjusted odds ratio = 3.143; 95% confidence interval, 1.385–7.133) and baseline CD4 count 5 log10 copies/mL were risk factors for zoster development after cART initiation in multivariate analysis. Conclusions: Herpes zoster occurred in 6.5% of HIV-positive Taiwanese patients after initiation of cART, which was associated with prior zoster and baseline CD4 count < 200 cells/μL or baseline PVL > 5 log10 copies/mL.

To investigate the clinical and microbiological characteristics of infections caused by Tsukamurella spp., the computerised database of the Bacteriology Laboratory at National Taiwan University Hospital (Taipei, Taiwan) was reviewed retrospectively to identify patients with infections caused by this species during the period January 1997 to December 2008. All of the isolates had been initially misidentified as Rhodococcus spp. Identification of Tsukamurella isolates to species level was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the heat shock protein gene (hsp65) as well as 16S rRNA gene sequencing. During the study period, a total of eight patients with Tsukamurella infection and two patients with Tsukamurella colonisation were identified. Tsukamurella tyrosinosolvens (n=6) was the most prevalent species, followed by Tsukamurella spumae (n=3) and Tsukamurella pulmonis (n=1). Keratitis was the most common type of infection (n=3), followed by catheter-related bloodstream infection (n=2). One of the patients with Tsukamurella infection died due to bacteraemia; the other seven patients with Tsukamurella infection had favourable outcomes. The three species had different drug susceptibility patterns; T. pulmonis was the most resistant pathogen, with higher minimum inhibitory concentrations of clindamycin (>2 mg/L), erythromycin (2 mg/L) and tetracycline (8 mg/L) than those for the other Tsukamurella spp. In conclusion, strains of Tsukamurella spp., including T. spumae, are uncommon causative agents of ocular infections and bacteraemia in cancer patients. Molecular diagnostic methods are essential to distinguish species in the Tsukamurella genus from species in other phylogenetically related genera such as Rhodococcus.

Objectives: CNS infections caused by non-tuberculous mycobacteria (NTM) are rare and only three cases of CNS infections due to Mycobacterium abscessus complex have been reported. Methods: We searched the Mycobacteriology Database of the National Taiwan University Hospital and identified patients with CNS infections due to NTM. Results: A total of 15 patients, namely 4 HIV-seropositive patients and 11 HIV-seronegative patients, with CNS infections caused by NTM were identified during 2000‐10. All of the HIV-seropositive patients had disseminated Mycobacterium avium complex infections. Among the 11 HIV-seronegative patients, NTM CNS infections were due to M. abscessus complex in 8 patients, M. avium complex in 2 patients and Mycobacterium kansasii in 1 patient. All the six preserved M. abscessus complex isolates were confirmed to be Mycobacterium massiliense by erm(41) PCR and 23S rRNA gene sequence analysis. Among the eight patients with infections due to M. abscessus complex, three had otolaryngological diseases, four had received neurosurgery and one had disseminated disease. Five patients received surgical debridement or intracranial device removal and three patients died of M. abscessus complex CNS infection. Among the five patients who survived, all received clarithromycin-based combination therapy with a median duration of 12 months and four received surgical intervention. All six isolates available for drug susceptibility testing showed uniform susceptibility to clarithromycin and five were susceptible to amikacin. Conclusions: Our study revealed that M. abscessus complex isolates, particularly M. massiliense, should be considered potential pathogens causing CNS infections. Long-duration clarithromycin-based combination therapy plus surgical intervention may provide the best chance of cure.

To investigate the clinical impact of different genospecies of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex (ACB complex; A. baumannii, Acinetobacter gen. sp. 13TU and Acinetobacter gen. sp. 3) on the severity of bacteraemia.We retrospectively compared the clinical features and outcomes of patients with bacteraemia caused by A. baumannii, Acinetobacter gen. sp. 13TU or Acinetobacter gen. sp. 3. The genospecies were identified using oligonucleotide array sequence analysis (interspacer sequence), and the clonality of Acinetobacter gen. sp. 13TU and 3 isolates was determined by PFGE analysis.A total of 215 patients with bacteraemia due to ACB complex were evaluated. Among them, 117 (54.4%) had A. baumannii bacteraemia, 77 (35.8%) had Acinetobacter gen. sp. 13TU bacteraemia and 21 (9.8%) had Acinetobacter gen. sp. 3 bacteraemia. A. baumannii bacteraemia was associated with a higher 14 day mortality rate (P0.001), a higher 30 day mortality rate (P0.001) and a higher in-hospital mortality rate than bacteraemia due to Acinetobacter gen. sp. 13TU or Acinetobacter gen. sp. 3. Independent prognostic factors for the 30 day mortality included the Charlson co-morbidity index (P0.001) and Pitt bacteraemia score (P0.001). Bloodstream infection caused by a multidrug-resistant A. baumannii isolate appeared to be associated with a poor outcome (P = 0.069). There was no clonal spread of Acinetobacter gen. sp. 13TU or Acinetobacter gen. sp. 3 during the study period.Bacteraemia due to multidrug-resistant strains but not A. baumannii per se appears to be associated with poor outcome.

Objectives This study investigated the correlation between antibiotic consumption and antimicrobial resistance in Gram-negative bacteria causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009. Methods Disc susceptibility data of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus spp., Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia and other non-fermentative Gram-negative bacilli causing healthcare-associated infections were evaluated. Data on annual patient-days and annual consumption (defined daily doses per 1000 patient-days) of extended-spectrum cephalosporins, β-lactam/β-lactamase inhibitor combinations, carbapenems, aminoglycosides and fluoroquinolones were analysed. Results The trend of total consumption of extended-spectrum cephalosporins, β-lactam/β-lactamase inhibitor combinations, carbapenems, aminoglycosides and fluoroquinolones significantly increased between 2000 and 2003 and remained stable between 2004 and 2009. The decreasing use of gentamicin and amikacin in recent years was associated with increasing susceptibility of E. coli, E. cloacae, S. marcescens and P. aeruginosa to gentamicin, as well as increasing susceptibility of P. aeruginosa to amikacin. The use of piperacillin/tazobactam was positively correlated with the prevalence of piperacillin/tazobactam-resistant E. coli and S. maltophilia. In contrast, the use of cefotaxime and piperacillin/tazobactam was negatively correlated with the prevalence of cefotaxime-resistant E. coli and piperacillin/tazobactam-resistant S. maltophilia, respectively. The consumption of fluoroquinolones was positively correlated with the rates of ciprofloxacin-resistant E. coli, piperacillin/tazobactam-resistant P. aeruginosa and ceftazidime-resistant S. maltophilia. Conclusions The relationship between antibiotic prescription and the rates of resistance for Gram-negative bacteria is complicated; every type of antimicrobial agent or even individual agent can have distinct associations with different pathogens.

Background Nevirapine extended-release (NVP-XR) taken once daily remains an effective antiretroviral agent for patients infected with HIV-1 strains that do not harbor resistance mutations. Presence of tablet remnants of NVP XR in stools was reported in 1.19% and 3.05% of subjects in two clinical trials. However, the prevalence may have been underestimated because the information was retrospectively collected in the studies. Methods Between April and December 2014, we prospectively inquired about the frequency of noticing tablet remnants of NVP XR in stools in HIV-1-infected patients who switched to antiretroviral regimens containing NVP XR plus 2 nucleos(t)ide reverse-transcriptase inhibitors. Patients were invited to participate in therapeutic drug monitoring of plasma concentrations of NVP 12 or 24 hours after taking the previous dose (C12 and C24, respectively) of NVP XR using high-performance liquid chromatography. The information on clinical characteristics, including plasma HIV RNA load and CD4 lymphocyte count, at baseline and during follow-up was recorded. Results During the 9-month study period, 272 patients switched to NVP XR-based regimens and 60 (22.1%) noticed tablet remnants of NVP XR in stools, in whom 54.2% reported noticing the tablet remnants at least once weekly. Compared with patients who did not notice tablet remnants, those who noticed tablet remnants had a higher mean CD4 lymphocyte count (629 vs 495 cells/mm3, P = 0.0002) and a similar mean plasma HIV RNA load (1.57 vs 1.61 log10 copies/mL, P = 0.76) on switch. At about 12 and 24 weeks after switch, patients who noticed tablet remnants continued to have a similar mean plasma HIV RNA load (1.39 vs 1.43 log10 copies/mL, P = 0.43; and 1.30 vs 1.37 log10 copies/mL, P = 0.26, respectively), but had a lower median NVP C12 (3640 vs 4730 ng/mL, P = 0.06), and a similar median NVP C24 (3220 vs 3330 ng/ml, P = 0.95) when compared with those who did not notice tablet remnants. Conclusions The presence of tablet remnants of NVP XR in stools is not uncommon in HIV-1-infected Taiwanese patients receiving NVP XR-based antiretroviral regimens, which does not have an adverse impact on the virological and immunological outcomes.

Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative shown to have anti-inflammatory, antitumor, and neuroprotective properties. This study has investigated that nobiletin exerted inhibitory effects on the cell adhesion, invasion, and migration abilities of a highly metastatic AGS cells under non-cytotoxic concentrations. Data also showed nobiletin could inhibit the activation of focal adhesion kinase (FAK) and phosphoinositide-3-kinase/Akt (PI3K/Akt) involved in the downregulation of the enzyme activities, protein expressions, messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-2 (MMP-9). Also, our data revealed that nobiletin inhibited FAK/PI3K/Akt with concurrent reduction in the protein expressions of Ras, c-Raf, Rac-1, Cdc42, and RhoA by western blotting, whereas the protein level of RhoB increased progressively. Otherwise, nobiletin-treated AGS cells showed tremendously decreased in the phosphorylation and degradation of inhibitor of kappaBα (IκBα), the nuclear level of NF-κB, and the binding ability of NF-κB to NF-κB response element. Furthermore, nobiletin significantly decreased the levels of phospho-Akt and MMP-2/9 in Akt1-cDNA-transfected cells concomitantly with a marked reduction in cell invasion and migration. These results suggest that nobiletin can reduce invasion and migration of AGS cells, and such a characteristic may be of great value in the development of a potential cancer therapy.

Lung cancer is the leading cause of death among cancers worldwide and non-small cell lung cancer (NSCLC) comprises more than 80% of lung cancer cases. Treatment options for patients with advanced NSCLC have evolved in the last decade with the advent of novel biological agents. Andrographolide, a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to have the potential to be developed as a chemotherapeutic agent. In order to understand the anti-cancer properties of andrographolide, we examined its effect on migration and invasion in human NSCLC A549 cells. The results of wound-healing assay and in vitro transwell assay revealed that andrographolide inhibited dose-dependently the migration and invasion of A549 cells under non-cytotoxic concentrations. Molecular data showed that the effect of andrographolide in A549 cells might be mediated via sustained inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt signal involved in the up-regulation of matrix metalloproteinases (MMPs). Our results showed that andrographolide exerted an inhibitory effect on the activity and the mRNA and protein levels of MMP-7, but not MMP-2 or MMP-9. The andrographolide-inhibited MMP-7 expression or activity appeared to occur via activator protein-1 (AP-1) because of its DNA binding activity was suppressed by andrographolide. Additionally, the transfection of Akt over-expression vector (Akt1 cDNA) to A549 cells could result in an increase expression of MMP-7 concomitantly with a marked induction on cell invasion. These findings suggested that the inhibition on MMP-7 expression by andrographolide may be through suppression on PI3K/Akt/AP-1 signaling pathway, which in turn led to the reduced invasiveness of the cancer cells.

This study first investigates the anti-metastatic effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer cells, A549. First, the result demonstrated plumbagin could inhibit TPA induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed plumbagin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the down-regulating enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, plumbagin also strongly inhibited TPA-induced phosphorylation and degradation of inhibitor of kappaBalpha (IkappaBalpha), and the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1) by plumbagin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Presented data reveals that plumbagin is a novel, effective, anti-metastatic agent that functions by down-regulating MMP-2 and u-PA gene expressions.

Integrons, efflux pumps, phosphoglucomutase (SpgM), and melanin and biofilm formation were investigated in 40 multidrug-resistant (MDR) and 30 non-MDR Stenotrophomonas maltophilia isolates recovered from patients treated at National Taiwan University Hospital (Taipei, Taiwan). Class 1 integrons were clearly associated with multidrug resistance. Sequencing data revealed that aminoglycoside-modifying genes occurred most frequently in the integron and disclosed a new blaIMP-8/aac6-II/aadA5 gene cassette. Semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was performed to assess the expression of Sme efflux pumps and SpgM in S. maltophilia. MDR isolates exhibited hyperexpression of SmeABC, and SmeDEF and SpgM were more frequently found in MDR isolates than non-MDR isolates. In addition, the ability of MDR isolates to form melanin-like pigment and biofilm was also greater than that of the non-MDR isolates. The SmeABC or SmeDEF pump was shown to be associated with resistance to all agents tested. The presence of an integron as well as production of pigment and biofilm was also responsible for resistance against eight, six and six of the tested agents, respectively. High SpgM expression was associated with resistance to only three of the tested agents. These findings define the important roles of integrons, efflux pumps, and melanin-like pigment and biofilm formation in the multidrug resistance of S. maltophilia. MDR isolates possessed more resistance mechanisms than susceptible strains.

Cancer metastasis, involving multiple processes and various cytophysiological changes, is a primary cause of cancer death and may complicate clinical management, even leading to death. Myricetin (3,5,7,3',4',5'-hexahydroxyflavone), a naturally occurring flavonoid, has various anticancer activities. This is the first study to explore the antimetastatic effect of myricetin in human adenocarcinoma A549 cells in vitro. First, myricetin exerted a dose- and time-dependent inhibitory effect on the adhesion, invasion, and migration of A549 cells in the absence of cytotoxicity. Gelatin or casein zymography assays showed that myricetin inhibited the matrix metalloproteinase-2 (MMP-2) and urokinase-plasminogen activator (u-PA) activities of A549 cells. Moreover, myricetin also exerted an inhibitory effect on the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inhibition of activation of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Treatment with myricetin of A549 cells also led to a dose-dependent effect on the binding abilities of NF-kappaB and AP-1. Furthermore, the ERK inhibitor (U0126) could result in reduced activities of MMP-2 and u-PA concomitantly with a marked inhibition on cell invasion and migration. These results demonstrated that the inhibition of MMP-2 and u-PA expression by myricetin may be through a suppression on ERK1/2 phosphorylation and inhibit A549 cells invasion and migration. As shown by the above results, myricetin may be a powerful candidate in developing preventive agents for cancer metastasis.

Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to have potent anti-cancer activity against human colorectal carcinoma Lovo cells by inhibiting cell-cycle progression. To further investigate the mechanism for the anti-cancer properties of Andro, it was used to examine the effect on migration and invasion of Lovo cells. The results of wound-healing assay and in vitro transwell assay revealed that Andro inhibited dose-dependently the migration and invasion of Lovo cells under non-cytotoxic concentrations. Using zymographic assay and RT-PCR, the results revealed that Andro diminished the activity and the mRNA and protein levels of MMP-7, but not MMP-2 or MMP-9. The down-regulation of MMP-7 appeared to be via the inactivation of activator protein-1 (AP-1) since the treatment with Andro suppressed the nuclear protein level of AP-1, which was accompanied by a decrease in DNA-binding level of the factor. Taken together, these results indicated that Andro reduces the MMP-7-mediated cellular events in Lovo cells, and provided a new mechanism for its anti-cancer activity.

This study first investigates the anti-metastatic effect of alpha-tomatine in the human lung adenocarcinoma cell line: A549. In this study, we first noted alpha-tomatine inhibited A549 cells invasion and migration by wound-healing assay and Boyden chamber assay. The data also showed alpha-tomatine could inhibit phosphorylation of Akt and extracellular signal-regulated kinase 1 and 2 (ERK1/2), which is involved in the up-regulating matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) or urokinase-type plasminogen activator (u-PA), whereas it did not affect phosphorylation of c-Jun N-terminal kinase (JNK) and p38. Next, alpha-tomatine significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, treating A549 cells with alpha-tomatine also leads to a dose-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1). Further, the treatment of inhibitors specific for PI3K (Wortmannin) or ERK (U0126) to A549 cells could cause reduced activities of MMP-2, MMP-9, and u-PA. These results showed alpha-tomatine could inhibit the metastatic ability of A549 cells by reducing MMP-2, MMP-9, and u-PA activities through suppressing phosphoinositide 3-kinase/Akt (PI3K/Akt) or ERK1/2 signaling pathway and inhibition NF-kappaB or AP-1 binding activities. These findings proved alpha-tomatine might be an anti-metastatic agent against human lung adenocarcinoma.

Gaseous nitrogen oxide (gNO) is an important indoor and outdoor air pollutant. Many studies have indicated gNO causes lung tissue damage by its oxidation properties and free radicals. However, there are considerably few data on the association between lung cancer and gNO exposure. The purpose of this study was to examine whether gNO could contribute to the process of malignant progression of lung cancer. The results of wound-healing assay and in vitro transwell assay revealed that gNO-induced dose and time dependently the migration and invasion of A549 cells, a human lung cancer cell line, under noncytotoxic concentrations. gNO was able to induce release of NO from A549 cells, an effect that was mediated via the activation of inducible nitric oxide synthases (iNOS), but not constitutive isoforms, during the same treatment period. An increased expression of matrix metalloproteinase (MMP) and a coincided reduction in repress tissue inhibitors of metalloprotease-2 were observed upon the treatment of gNO. The gNO-mediated MMP-2 induction appeared to be a consequence of nuclear factor kappa B and activation protein-1 activation, because that their DNA binding activity was enhanced by gNO. All these influences of gNO were efficiently repressed by the pretreatment of a NOS inhibitor (N(G)-nitro-L-arginine methyl ester). Using a mouse model, we showed that gNO promoted A549 metastasis to the lung through a mechanism involving the iNOS-dependent MMP-2 activity. Our data imply that gNO exposure, which in turn led to iNOS activation and the enhancement of MMP-mediated cellular events, was related to lung cancer development.

Background/Purpose The incidence of Clostridium difficile -associated diarrhea (CDAD) is increasing worldwide. Spread of an epidemic hypervirulent strain in southern Taiwan was associated with poor outcome. This prospective study evaluates the incidence and clinical manifestation of CDAD following a hospital-wide hand hygiene promotion program in a 2,200-bed teaching hospital in northern Taiwan. Patients and Methods From June 1, 2010 to October 31, 2010, a predefined protocol was used to actively survey CDAD at 11 high-risk units. Stool samples of patients with antibiotic-associated diarrhea (AAD) were submitted for stool culture and toxin A/B assay using a combined enzyme immunoassay. CDAD was diagnosed by a positive toxin assay. Results The incidence of CDAD was 0.45/1000 patient-days and was highest in medical intensive care units (7.9/1000 patient-days), followed by hemato-oncology wards, and infectious disease wards. Occurrence of CDAD was associated with ≥3 stool pus cells per high power field ( p = 0.018), prior use of metronidazole ( p = 0.029), high usage of beta-lactamase stable penicillins ( p = 0.046), and anaerobe-active antibiotics ( p = 0.029). No attributable mortality was found. The incidence of CDAD was lower than that previously observed (1.0/1000 patient-days in 2003, p Conclusion This study showed a lower incidence of CDAD and absence of attributable mortality. The impact of hand hygiene promotion and other infection control measures on decreasing incidence of CDAD warrants further elucidation.