Promoter hypomethylation and overexpression of TSTD1 mediate poor treatment response in breast cancer.

Epigenetic alterations play a pivotal role in cancer treatment outcomes. Using the methylation array data and The Cancer Genome Atlas (TCGA) dataset, we observed the hypomethylation and upregulation of thiosulfate sulfurtransferase-like domain containing 1 (TSTD1) in patients with breast cancer. We examined paired tissues from Taiwanese patients and observed that 65.09% and 68.25% of patients exhibited TSTD1 hypomethylation and overexpression, respectively. A significant correlation was found between TSTD1 hypomethylation and overexpression in Taiwanese (74.2%, p = 0.040) and Western (88.0%, p < 0.001) cohorts. High expression of TSTD1 protein was observed in 68.8% of Taiwanese and Korean breast cancer patients. Overexpression of TSTD1 in tumors of breast cancer patients was significantly associated with poor 5-year overall survival (p = 0.021) and poor chemotherapy response (p = 0.008). T47D cells treated with TSTD1 siRNA exhibited lower proliferation than the control group, and transfection of TSTD1 in MDA-MB-231 induced the growth of MDA-MB-231 cells compared to the vector control. Additionally, overexpression of TSTD1 in MCF7 cells mediated a poor response to chemotherapy by epirubicin (p < 0.001) and docetaxel (p < 0.001) and hormone therapy by tamoxifen (p =0.025). Circulating cell-free hypomethylated TSTD1 was detected in plasma of Taiwanese breast cancer patients with disease progression and poor chemotherapy efficacy. Our results indicate that promoter hypomethylation and overexpression of TSTD1 in patients with breast cancer are potential biomarkers for poor 5-year overall survival and poor treatment response.

Antimicrobial stewardship for acute-care hospitals: An Asian perspective.

Inappropriate use of antibiotics is contributing to a serious antimicrobial resistance problem in Asian hospitals. Despite resource constraints in the region, all Asian hospitals should implement antimicrobial stewardship (AMS) programs to optimize antibiotic treatment, improve patient outcomes, and minimize antimicrobial resistance. This document describes a consensus statement from a panel of regional experts to help multidisciplinary AMS teams design programs that suit the needs and resources of their hospitals. In general, AMS teams must decide on appropriate interventions (eg, prospective audit and/or formulary restriction) for their hospital, focusing on the most misused antibiotics and problematic multidrug-resistant organisms. This focus is likely to include carbapenem use with the goal to reduce carbapenem-resistant gram-negative bacteria. Rather than initially trying to introduce a comprehensive, hospital-wide AMS program, it would be practical to begin by pilot testing a simple program based on 1 achievable core intervention for the hospital. AMS team members must work together to determine the most suitable AMS interventions to implement in their hospitals and how best to put them into practice. Continuous monitoring and feedback of outcomes to the AMS teams, hospital administration, and prescribers will enhance sustainability of the AMS programs.

APSIC guidelines for disinfection and sterilization of instruments in health care facilities.

Background: The Asia Pacific Society of Infection Control launched its revised Guidelines for Disinfection and Sterilization of Instruments in Health Care Facilities in February 2017. This document describes the guidelines and recommendations for the reprocessing of instruments in healthcare setting. It aims to highlight practical recommendations in a concise format designed to assist healthcare facilities at Asia Pacific region in achieving high standards in sterilization and disinfection. Method: The guidelines were revised by an appointed workgroup comprising experts in the Asia Pacific region, following reviews of previously published guidelines and recommendations relevant to each section. Results: It recommends the centralization of reprocessing, training of all staff with annual competency assessment, verification of cleaning, continual monitoring of reprocessing procedures to ensure their quality and a corporate strategy for dealing with single-use and single-patient use medical equipment/devices. Detailed recommendations are also given with respect to reprocessing of endoscopes. Close working with the Infection Prevention & Control department is also recommended where decisions related to reprocessing medical equipment/devices are to be made. Conclusions: Sterilization facilities should aim for excellence in practices as this is part of patient safety. The guidelines that come with a checklist help service providers identify gaps for improvement to reach this goal.

Dissemination of Carbapenem-resistant Klebsiella pneumoniae clinical isolates with various combinations of Carbapenemases (KPC-2, NDM-1, NDM-4, and OXA-48) and 16S rRNA Methylases (RmtB and RmtC) in Vietnam.

METHODS: Twenty-seven clinical isolates of carbapenem-resistant Klebsiella pneumoniae with MICs ≥4 mg/L for imipenem or meropenem were obtained from inpatients in a hospital in Vietnam. Antimicrobial susceptibility tests and whole genome sequencing were performed. Multilocus sequence typing and the presence of drug resistant genes were determined and a maximum-likelihood phylogenetic tree was constructed by SNP alignment of whole genome sequencing data. RESULTS: All the isolates harbored one of genes encoding carbapenemases, including KPC-2, NDM-1, NDM-4 and OXA-48. Of the isolates, 13 were resistant to arbekacin with MICs ≥256 mg/L and to amikacin with MICs ≥512 mg/L. These isolates harbored a gene encoding a 16S rRNA methylase, either RmtB or RmtC. Eighteen and 4 isolates belonged to international clones, ST15 and ST16, respectively. None of the isolates had colistin-resistant factors. CONCLUSION: Carbapenem-resistant K. pneumoniae isolates belonged to international clones spread in a medical setting in Vietnam, and that these isolates harbored genes encoding various combinations of carbapenemases and 16S rRNA methylases. This is the first report of KPC-2, NDM-4 and OXA-48 producers in a medical setting in Vietnam.

APSIC guide for prevention of Central Line Associated Bloodstream Infections (CLABSI).

This document is an executive summary of the APSIC Guide for Prevention of Central Line Associated Bloodstream Infections (CLABSI). It describes key evidence-based care components of the Central Line Insertion and Maintenance Bundles and its implementation using the quality improvement methodology, namely the Plan-Do-Study-Act (PDSA) methodology involving multidisciplinary process and stakeholders. Monitoring of improvement over time with timely feedback to stakeholders is a key component to ensure the success of implementing best practices. A surveillance program is recommended to monitor outcomes and adherence to evidence-based central line insertion and maintenance practices (compliance rate) and identify quality improvement opportunities and strategically targeting interventions for the reduction of CLABSI.

Dissemination of clonal complex 2 Acinetobacter baumannii strains co-producing carbapenemases and 16S rRNA methylase ArmA in Vietnam.

BACKGROUND: Acinetobacter baumannii strains co-producing carbapenemase and 16S rRNA methylase are highly resistant to carbapenems and aminoglycosides. METHODS: Ninety-three isolates of multidrug-resistant A. baumannii were obtained from an intensive care unit in a hospital in Vietnam. Antimicrobial susceptibility tests and whole genome sequencing were performed. Multilocus sequence typing and the presence of drug resistant genes were determined and a maximum-likelihood phylogenetic tree was constructed by SNP alignment of whole genome sequencing data. RESULTS: The majority of isolates belonged to clonal complex 2 (ST2, ST570 and ST571), and carried carbapenemase encoding genes bla OXA-23 and bla OXA-66. Two isolates encoded carbapenemase genes bla NDM-1 and bla OXA-58 and the 16S rRNA methylase encoding gene armA and did not belong to clonal complex 2 (ST16). CONCLUSION: A. baumannii isolates producing 16S rRNA methylase ArmA and belonging to clonal complex 2 are widespread, and isolates co-producing NDM-1 and ArmA are emerging, in medical settings in Vietnam.

APSIC Guidelines for environmental cleaning and decontamination.

This document is an executive summary of APSIC Guidelines for Environmental Cleaning and Decontamination. It describes best practices in routine cleaning and decontamination in healthcare facilities as well as in specific settings e.g. management of patients with isolation precautions, food preparation areas, construction and renovation, and following a flood. It recommends the implementation of environmental hygiene program to keep the environment safe for patients, staff and visitors visiting a healthcare facility. Objective assessment of cleanliness and quality is an essential component of this program as a method for identifying quality improvement opportunities. Recommendations for safe handling of linen and bedding; as well as occupational health and safety issues are included in the guidelines. A training program is vital to ensure consistent adherence to best practices.

Emergence of 16S rRNA methylase-producing Acinetobacter baumannii and Pseudomonas aeruginosa isolates in hospitals in Vietnam.

BACKGROUND: 16S rRNA methylase-producing Gram-negative bacteria are highly resistant to all clinically important aminoglycosides. We analyzed clinical strains of 16S rRNA methylase-producing Acinetobactor baumannii and Pseudomonas aeruginosa obtained from clinical isolates in medical settings in Vietnam. METHODS: From 2008 to 2011, 101 clinical strains of A. baumannii and 15 of P. aeruginosa were isolated from patients in intensive care units (ICUs) in two medical settings in Vietnam. Antimicrobial susceptibilities were determined using the microdilution method and epidemiological analysis was performed by pulsed-field gel electrophoresis and MLST. Genes encoding the 16S rRNA methylases, OXAs and CTX-Ms were analyzed by PCR and sequence analysis. RESULTS: 16S rRNA methylase-producing Gram-negative pathogens were detected in two hospitals in Vietnam. Of the 101 clinical isolates of A. baumannii and the 15 of P. aeruginosa isolated from two ICUs in these hospitals, 72 (71.3%) were highly resistant to amikacin, arbekacin and gentamicin, with MICs greater than 1,024 mg/L. The 16S rRNA methylases ArmA and RmtB were produced by 61 and 9 isolates of A. baumannii, respectively, and RmtB was produced by 2 isolates of P. aeruginosa. Moreover, 52 of the A. baumannii isolates producing 16S rRNA methylases harbored both blaOXA-23-like and blaOXA-51-like genes. Most A. baumannii isolates producing 16S rRNA methylase obtained in hospital A in Hanoi were ST91 and ST231, whereas most from hospital B in Ho Chi Minh City were ST136, ST195, and ST254. CONCLUSIONS: Gram-negative bacteria producing the 16S rRNA methylases ArmA and RmtB are emerging in medical settings in Vietnam. A. baumannii isolates in northern and southern regions of Vietnam may be of different lineages.

Reducing neonatal infections in south and south central Vietnam: the views of healthcare providers.

BACKGROUND: Infection causes neonatal mortality in both high and low income countries. While simple interventions to prevent neonatal infection are available, they are often poorly understood and implemented by clinicians. A basic understanding of healthcare providers' perceptions of infection control provides a platform for improving current practices. Our aim was to explore the views of healthcare providers in provincial hospitals in south and south central Vietnam to inform the design of programmes to improve neonatal infection prevention and control. METHODS: All fifty-four participants who attended a workshop on infection prevention and control were asked to complete an anonymous, written questionnaire identifying their priorities for improving neonatal infection prevention and control in provincial hospitals in south and south central Vietnam. RESULTS: Hand washing, exclusive breastfeeding and safe disposal of medical waste were nominated by most participants as priorities for preventing neonatal infections. Education through instructional posters and written guidelines, family contact, kangaroo-mother-care, limitation of invasive procedures and screening for maternal GBS infection were advocated by a smaller proportion of participants. CONCLUSIONS: The opinions of neonatal healthcare providers at the workshop accurately reflect some of the current international recommendations for infection prevention. However, other important recommendations were not commonly identified by participants and need to be reinforced. Our results will be used to design interventions to improve infection prevention in Vietnam, and may be relevant to other low-resource countries.

International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004-2009.

The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium's ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries' ICUs was remarkably similar to that reported in US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia).

International Nosocomial Infection Control Consortium (INICC) report, data summary for 2003-2008, issued June 2009.

We report the results of the International Infection Control Consortium (INICC) surveillance study from January 2003 through December 2008 in 173 intensive care units (ICUs) in Latin America, Asia, Africa, and Europe. During the 6-year study, using Centers for Disease Control and Prevention (CDC) US National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infection, we collected prospective data from 155,358 patients hospitalized in the consortium's hospital ICUs for an aggregate of 923,624 days. Although device utilization in the developing countries' ICUs was remarkably similar to that reported from US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were markedly higher in the ICUs of the INICC hospitals: the pooled rate of central venous catheter (CVC)-associated bloodstream infections (BSI) in the INICC ICUs, 7.6 per 1000 CVC-days, is nearly 3-fold higher than the 2.0 per 1000 CVC-days reported from comparable US ICUs, and the overall rate of ventilator-associated pneumonia (VAP) was also far higher, 13.6 versus 3.3 per 1000 ventilator-days, respectively, as was the rate of catheter-associated urinary tract infection (CAUTI), 6.3 versus 3.3 per 1000 catheter-days, respectively. Most strikingly, the frequencies of resistance of Staphylococcus aureus isolates to methicillin (MRSA) (84.1% vs 56.8%, respectively), Klebsiella pneumoniae to ceftazidime or ceftriaxone (76.1% vs 27.1%, respectively), Acinetobacter baumannii to imipenem (46.3% vs 29.2%, respectively), and Pseudomonas aeruginosa to piperacillin (78.0% vs 20.2%, respectively) were also far higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 23.6% (CVC-associated bloodstream infections) to 29.3% (VAP).

Glucose and lactate turnover in adults with falciparum malaria: effect of complications and antimalarial therapy.

Hypoglycaemia and lactic acidosis are potentially life-threatening, poorly understood sequelae of Plasmodium falciparum infections. We investigated relationships between clinical status, treatment, and glucose and lactate kinetics during management of falciparum malaria in 14 Vietnamese adults. Nine had severe malaria, of whom 4 were administered quinine (Group 1a) and 5 artesunate (Group 1b). Five uncomplicated cases received artesunate (Group 2). Glucose and lactate turnover were studied on 3 occasions: (i) immediately after initial antimalarial treatment, (ii) at parasite clearance a median of 3 days later, and (iii) at discharge from hospital a median of 9 days post-admission. Steady-state glucose and lactate kinetics were derived from plasma isotopic enrichment during a primed-continuous infusion of D-[6,6-D2]glucose and a parallel infusion of L-[1-13C]lactate. Group 1a patients had the lowest plasma glucose concentrations in the admission study (median [range] 3.9 [3.6-5.1] vs 6.3 [4.9-7.1] and 4.5 [4.3-5.5] mmol/L in Groups 1b and 2 respectively; P < 0.05 vs Group 1b), but glucose production rates and serum insulin concentrations that were similar to those in the other groups (P > 0.17). This was also the case at parasite clearance and suggested an inappropriate beta cell response. Group 1a patients had the highest admission lactate production (60 [36-77] vs 26 [21-47] and 22 [4-31] mumol/kg.min in Group 1b and 2 respectively; P < 0.05 vs Group 2). Amongst the 9 severe cases, there was an inverse association between plasma glucose and lactate production at admission and parasite clearance (P < 0.05), but no correlation between admission lactate production and serum bicarbonate (P = 0.73). The present data confirm previous studies showing that quinine depresses plasma glucose through stimulation of insulin secretion. It is hypothesized that the low plasma glucose activates Na+,K(+)-ATPase through increased plasma catecholamine concentrations, leading to accelerated glycolysis and increased lactate production in well-oxygenated tissues. In some severely ill patients with falciparum malaria, a raised plasma lactate on its own may, therefore, be an unreliable index of a developing acidosis.

Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases.

The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Human liver microsomes were incubated with [12-(3)H]DHA and cofactors for either glucuronidation or cytochrome P450-catalyzed oxidation. Human liver cytosol was incubated with cofactor for sulfation. Metabolites were detected by HPLC-MS and/or HPLC with radiochemical detection. Metabolism of DHA by recombinant human UDP-glucuronosyltransferases (UGTs) was studied. HPLC-MS analysis of urine identified alpha-DHA-beta-glucuronide (alpha-DHA-G) and a product characterized as the tetrahydrofuran isomer of alpha-DHA-G. DHA was present only in very small amounts. The ratio of the tetrahydrofuran isomer, alpha-DHA-G, was highly variable (median 0.75; range 0.09-64). Nevertheless, alpha-DHA-G was generally the major urinary product of DHA glucuronidation in patients. The tetrahydrofuran isomer appeared to be at least partly a product of nonenzymic reactions occurring in urine and was readily formed from alpha-DHA-G by iron-mediated isomerization. In human liver microsomal incubations, DHA-G (diastereomer unspecified) was the only metabolite found (V(max) 177 +/- 47 pmol min(-1) mg(-1), K(m) 90 +/- 16 microM). Alpha-DHA-G was formed in incubations of DHA with expressed UGT1A9 (K(m) 32 microM, V(max) 8.9 pmol min(-1) mg(-1)) or UGT2B7 (K(m) 438 microM, V(max) 10.9 pmol mg(-1) min(-1)) but not with UGT1A1 or UGT1A6. There was no significant metabolism of DHA by cytochrome-P450 oxidation or by cytosolic sulfotransferases. We conclude that alpha-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.

The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria.

AIMS: To obtain pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.m. ARTS and rectal DHA administration. METHODS: Twelve Vietnamese patients with uncomplicated falciparum malaria were randomized to receive either i.v. or i.m. ARTS (120 mg), with the alternative preparation given 8 h later in an open crossover design. A further 12 patients were given i.v. ARTS (120 mg) at 0 h and rectal DHA (160 mg) 8 h later. RESULTS: Following i.v. bolus, ARTS had a peak concentration of 42 microm (16 mg l(-1), elimination t1/2 = 3.2 min, CL = 2.8 l h(-1) kg(-1) and V = 0.22 l kg(-1) . The Cmax for DHA was 9.7 microm (2.7 mg l(-1) ), t1/2 = 59 min, CL = 0.64 l h(-1) kg(-1) and V = 0.8 l kg(-1) . Following i.m. ARTS, Cmax was 2.3 microm (3.7 mg l(-1)), the apparent t1/2 = 41 min, CL = 2.9 l h(-1) kg(-1) and V = 2.6 l kg(-1). The relative bioavailability of DHA was 88%, Cmax was 4.1 microm (1.16 mg l(-1)) and t1/2 = 64 min. In the rectal DHA study, relative bioavailability of DHA was 16%. CONCLUSIONS: For patients with uncomplicated falciparum malaria i.m. ARTS is a suitable alternative to i.v. ARTS, at equal doses. To achieve plasma DHA concentrations equivalent to parenteral administration of ARTS, rectal DHA should be given at approximately four-fold higher milligram doses. Further studies are needed to determine whether these recommendations can be applied to patients with severe malaria.