Reducing chemotherapy administration time on an inpatient oncology unit.

PURPOSE: Due to the multifaceted chemotherapy workflow within the hospital, many patients often experience delays in receiving their treatment. This study aims to evaluate the causes for chemotherapy administration delays and implement new methods to reduce delays from order release to chemotherapy administration on an inpatient oncology unit at a community-focused academic medical center. METHODS: In this prospective quality improvement study, we developed a process map to track baseline time stamps and utilized performance improvement tools to identify causes for chemotherapy delays. Based on recognized areas for improvement, the Plan-Do-Study-Act (PDSA) model was used to implement one cycle of interventions. Chemotherapy orders were collected, and benchmark time stamps were documented from the electronic medical record. RESULTS: The primary outcome for the number of chemotherapy delays, based on compliance rate, was reduced from 63/100 (63.0%) to 48/100 (48.0%), a 15% reduction (p = 0.046). Our primary outcome of chemotherapy delays, based on our institutional benchmark of <3 hours, did not show statistical significance. Median time from chemotherapy order release to administration decreased from 7.08 hours at baseline to 6.10 hours post-intervention, a 13.8% reduction (p < 0.0001). Median verification, preparation, and delivery times were all reduced post-intervention by 13.0% (p < 0.0001), 3.9% (p = 0.024), and 14.8% (p < 0.0001) respectively. CONCLUSIONS: This study allowed our institution to evaluate our current practice and reformulate the chemotherapy administration process. With the continuing education on the chemotherapy administration process and additional PDSA cycle interventions, it will help standardize our process and ultimately continue to reduce chemotherapy delays.

Decreased Cephalosporin Susceptibility of Oropharyngeal Neisseria Species in Antibiotic-using Men Who Have Sex With Men in Hanoi, Vietnam.

BACKGROUND: Neisseria gonorrhoeae (NG) infections are a global health burden. NG resistance to cephalosporins, which is increasingly reported, is an imminent threat to public health. Many hypothesize that commensal Neisseria species are an important reservoir for genetic material conferring antimicrobial resistance in NG; however, clinical data are lacking. METHODS: Men who have sex with men (MSM) in Hanoi, Vietnam, completed a questionnaire regarding antibiotic use. We collected pharyngeal specimens, cultured Neisseria species, and measured minimum inhibitory concentrations (MICs) to ciprofloxacin, cefixime, ceftriaxone, and cefpodoxime. Using MIC criteria for antimicrobial susceptibility in NG, we categorized the Neisseria species and compared mean MIC levels between different antibiotic user groups. RESULTS: Of 207 participants, 38% used at least 1 antibiotic in the past 6 months; 52% without a prescription. A median of 1 Neisseria species was cultured from each participant (range, 1-4) with 10 different Neisseria species identified overall. The proportion of Neisseria with reduced susceptibility to ciprofloxacin was 93%, cefpodoxime 84%, cefixime 31%, and ceftriaxone 28%. Antibiotic use within the past month was strongly associated with Neisseria species having increased MICs to cefixime, ceftriaxone, and cefpodoxime (mean MIC ratios of 6.27, 4.11, and 7.70, respectively), compared with those who used antibiotics between 1 and 6 months prior (P < .05, all comparisons). CONCLUSIONS: MSM in our study often used antibiotics without a prescription. At least 1 commensal Neisseria species colonized all men. Recent use of any antibiotics may select for oropharyngeal Neisseria species with antimicrobial resistance. The normal flora of the oropharynx may be an important source of antimicrobial resistance in Neisseria gonorrhoeae.

RBM3 regulates temperature sensitive miR-142-5p and miR-143 (thermomiRs), which target immune genes and control fever.

Fever is commonly used to diagnose disease and is consistently associated with increased mortality in critically ill patients. However, the molecular controls of elevated body temperature are poorly understood. We discovered that the expression of RNA-binding motif protein 3 (RBM3), known to respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients with fever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C). Notably, RBM3 expression is reduced during fever whether or not infection is demonstrable. Reduced RBM3 expression resulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termed thermomiRs. ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogens including IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may be crucial to prevent pathological hyperthermia. Using normal PBMCs that were exogenously exposed to fever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3 were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h time course. Collectively, our results indicate the existence of a negative feedback loop that regulates fever via reduced RBM3 levels and increased expression of miR-142-5p and miR-143.

Use of Colistin and Other Critical Antimicrobials on Pig and Chicken Farms in Southern Vietnam and Its Association with Resistance in Commensal Escherichia coli Bacteria.

UNLABELLED: Antimicrobial resistance (AMR) is a global health problem, and emerging semi-intensive farming systems in Southeast Asia are major contributors to the AMR burden. We accessed 12 pig and chicken farms at key stages of production in Tien Giang Province, Vietnam, to measure antimicrobial usage and to investigate the prevalence of AMR to five critical antimicrobials (ß-lactams, third-generation cephalosporins, quinolones, aminoglycosides, and polymyxins) and their corresponding molecular mechanisms among 180 Escherichia coli isolates. Overall, 94.7 mg (interquartile range [IQR], 65.3 to 151.1) and 563.6 mg (IQR, 398.9 to 943.6) of antimicrobials was used to produce 1 kg (live weight) of chicken and pig, respectively. A median of 3 (out of 8) critical antimicrobials were used on pig farms. E. coli isolates exhibited a high prevalence of resistance to ampicillin (97.8% and 94.4% for chickens and pigs, respectively), ciprofloxacin (73.3% and 21.1%), gentamicin (42.2% and 35.6%), and colistin (22.2% and 24.4%). The prevalence of a recently discovered colistin resistance gene, mcr-1, was 19 to 22% and had strong agreement with phenotypic colistin resistance. We conducted plasmid conjugation experiments with 37 mcr-1 gene-positive E. coli isolates and successfully observed transfer of the gene in 54.0% of isolates through a plasmid of approximately 63 kb, consistent with one recently identified in China. We found no significant correlation between total use of antimicrobials at the farm level and AMR. These data provide additional insight into the role of mcr-1 in colistin resistance on farms and outline the dynamics of phenotypic and genotypic AMR in semi-intensive farming systems in Vietnam. IMPORTANCE: Our study provides accurate baseline information on levels of antimicrobial use, as well as on the dynamics of phenotypic and genotypic resistance for antimicrobials of critical importance among E. coli over the different stages of production in emerging pig and poultry production systems in Vietnam. E. coli isolates showed a high prevalence of resistance (>20%) to critically important antimicrobials, such as colistin, ciprofloxacin, and gentamicin. The underlying genetic mechanisms identified for colistin (the mcr-1 gene) and quinolone (gyrA gene mutations) are likely to play a major role in AMR to those compounds. Conjugation experiments led to the identification of a 63-kb plasmid, similar to one recently identified in China, as the potential carrier of the mcr-1 gene. These results should encourage greater restrictions of such antimicrobials in Southeast Asian farming systems.

The electrophoretic mobility of DNA fragments differing by a single 3'-terminal nucleotide in an automated capillary DNA sequencer.

The electrophoretic mobility of DNA fragments that differ by a single 3'-terminal nucleotide was assessed by capillary electrophoresis. This was accomplished using dideoxy sequencing with a 5'-fluorescently labelled primer to generate DNA fragments with 3'-hydrogen ends. The resulting DNA fragments were electrophoresed on the ABI 3730 automated capillary sequencer, and the data were analysed with the GeneMapper software to determine the electrophoretic mobility differences on addition of a 3'-terminal nucleotide. It was found that the 3'-terminal nucleotide gave rise to different electrophoretic mobility profiles depending on the identity of the terminal nucleotide. The apparent electrophoretic mobility was (faster) -C > -A > -T > -G (slower). The C-terminated fragments were the fastest and the G-terminated fragments the slowest, relative to other nucleotides. It was proposed that the terminal nucleotide effect was due to changes in partial net charges on the nucleotides that resulted in alterations in the electrophoretic mobility of the DNA fragments in the automated capillary DNA sequencer. Other alternative explanations are also discussed.

Prevalence of depressive symptoms and associated factors among foreign caregivers: A cross-sectional study.

AIM: To understand the prevalence of depressive symptoms among foreign caregivers and the associated factors. DESIGN: A cross-sectional study. METHODS: Data from 178 Indonesian foreign caregivers, selected based on convenience and snowball sampling in Taiwan, were collected between July 2019 and February 2020 using questionnaires. Stepwise multiple linear regression was used to identify the factors associated with depressive symptoms. RESULTS: Approximately 30.3% of the foreign caregivers displayed depressive symptoms. The symptoms were more prevalent among the participants who were younger; had more social support; shared a bed with others; and experienced higher work-related stress, more loneliness and physical discomfort. The findings suggest that nurses or nurse practitioners visiting patients at home should not only deliver care for them but also show concern for the psychological well-being of the foreign caregivers of these patients. Moreover, interventions should be developed to alleviate or prevent the emergence of depressive symptoms among foreign caregivers.

Nursing students' critical thinking and associated factors in Vietnam: A multicenter cross-sectional study.

AIMS: This study aimed to evaluate the critical thinking abilities of senior nursing students in Vietnam and determine factors associated with their critical thinking disposition and skills. BACKGROUND: Assessing critical thinking competence is crucial for determining senior nursing students' preparedness for entering the healthcare workforce and can be used to examine current nursing education's ability to cultivate nursing students' critical thinking. However, little research was found on critical thinking among Vietnamese nursing students. DESIGN: A multicenter cross-sectional research design. METHODS: A convenience sample of 533 senior nursing students from six universities in Vietnam participated in this study. All participants completed the online questionnaires, including basic information, a subscale of the Motivated Strategy for Learning Questionnaire (MSLQ), Critical Thinking Disposition Scale (CTDS), and Critical Thinking Self-Assessment Scale (CTSAS). RESULTS: The mean score for the CTDS was 42.81 (standard deviation (SD) = 5.29), while the mean score for the CTSAS was 168.29 (SD = 44.43). Results of the multiple linear-regression analysis showed that an increase in self-study hours per day (B = 0.41, p = 0.007), higher self-efficacy in learning and performance (B = 0.26, p < 0.001), and a more-supportive environment (B = 0.97, p < 0.001) were predictors of critical thinking disposition. Moreover, an increase in self-study hours per day (B = 4.09, p = 0.001), higher self-efficacy in learning and performance (B = 2.65, p < 0.001), a more-supportive environment (B = 7.74, p < 0.001), and more experience with research (B = 7.03, p = 0.03) were predictors of critical thinking skills. CONCLUSIONS: This study revealed that senior nursing students in Vietnam possess a moderate level of critical thinking abilities. Those students who dedicate more hours to self-study, demonstrate higher self-efficacy in learning and performance, experience a supportive environment, and engage in more research activities exhibit better critical thinking disposition and skills. The findings highlight the ongoing need to enhance critical thinking disposition and skills of nursing students in Vietnam. It is suggested that nursing faculty members should develop the appropriate strategies to improve nursing students' critical thinking disposition and skills.

Assessment of the psychometric properties of the Vietnamese version of the Critical Thinking Disposition Scale.

BACKGROUND: The Critical Thinking Disposition Scale is a valid and reliable tool for assessing an individual's attitudes towards critical thinking. However, it is unclear if the scale can be used with Vietnamese nursing students. OBJECTIVES: This study aimed to translate the scale into Vietnamese and examine the psychometric properties of the Vietnamese version of the Critical Thinking Disposition Scale (CTDS-V). SETTINGS: Data were collected from senior nursing students at four universities in southern Vietnam in October and December 2022. PARTICIPANTS: In total, 398 senior nursing students participated in this study. METHODS: A cross-cultural adaptation of the CTDS-V was carried out with participants obtained through convenience sampling. Data were collected through an online survey. The study evaluated the validity of the CTDS-V by examining the content validity, concurrent validity, and construct validity, employing both Exploratory and Confirmatory Factor Analyses. The study also reported the internal consistency reliability using Cronbach's alpha and test-retest stability of the CTDS-V. RESULTS: The CTDS-V had a good content validity index with a score of at least 0.85 for each item and an excellent overall content validity index of 0.96. Exploratory Factor Analysis identified two factors, critical openness, and reflective scepticism, with 11 items. Confirmatory Factor Analysis provided an acceptable fit model and supported the factor structure of the original scale. Cronbach's alpha coefficient of the scale was 0.88, and those of the two subscales were each 0.84. The test-retest stability of the CTDS-V was good with an intraclass correlation coefficient of 0.98 (95 % confidence interval = 0.96, 0.99). CONCLUSIONS: This study indicated that the CTDS-V is a valid and reliable tool for assessing the critical thinking disposition of nursing students. The scale is short, rendering it feasible for regular use in education and research.

Myenteric neurons of the mouse small intestine undergo significant electrophysiological and morphological changes during postnatal development.

Organized motility patterns in the gut depend on circuitry within the enteric nervous system (ENS), but little is known about the development of electrophysiological properties and synapses within the ENS. We examined the electrophysiology and morphology of myenteric neurons in the mouse duodenum at three developmental stages: postnatal day (P)0, P10­11, and adult. Like adults, two main classes of neurons could be identified at P0 and P10­11 based on morphology: neurons with multiple long processes that projected circumferentially (Dogiel type II morphology) and neurons with a single long process. However, postnatal Dogiel type II neurons differed in several electrophysiological properties from adult Dogiel type II neurons. P0 and P10­11 Dogiel type II neurons exhibited very prominent Ca(2+)-mediated after depolarizing potentials (ADPs) following action potentials compared to adult neurons. Adult Dogiel type II neurons are characterized by the presence of a prolonged after hyperpolarizing potential (AHP), but AHPs were very rarely observed at P0. The projection lengths of the long processes of Dogiel type II neurons were mature by P10­11. Uniaxonal neurons in adults typically have fast excitatory postsynaptic potentials (fEPSPs, 'S-type' electrophysiology) mainly mediated by nicotinic receptors. Nicotinic-fEPSPs were also recorded from neurons with a single long process at P0 and P10­11. However, these neurons underwent major developmental changes in morphology, from predominantly filamentous neurites at birth to lamellar dendrites in mature mice. Unlike Dogiel type II neurons, the projection lengths of neurons with a single long process matured after P10­11. Slow EPSPs were rarely observed in P0/P10­11 neurons. This work shows that, although functional synapses are present and two classes of neurons can be distinguished electrophysiologically and morphologically at P0, major changes in electrophysiological properties and morphology occur during the postnatal development of the ENS.

Sites of action of ghrelin receptor ligands in cardiovascular control.

Circulating ghrelin reduces blood pressure, but the mechanism for this action is unknown. This study investigated whether ghrelin has direct vasodilator effects mediated through the growth hormone secretagogue receptor 1a (GHSR1a) and whether ghrelin reduces sympathetic nerve activity. Mice expressing enhanced green fluorescent protein under control of the promoter for growth hormone secretagogue receptor (GHSR) and RT-PCR were used to locate sites of receptor expression. Effects of ghrelin and the nonpeptide GHSR1a agonist capromorelin on rat arteries and on transmission in sympathetic ganglia were measured in vitro. In addition, rat blood pressure and sympathetic nerve activity responses to ghrelin were determined in vivo. In reporter mice, expression of GHSR was revealed at sites where it has been previously demonstrated (hypothalamic neurons, renal tubules, sympathetic preganglionic neurons) but not in any artery studied, including mesenteric, cerebral, and coronary arteries. In rat, RT-PCR detected GHSR1a mRNA expression in spinal cord and kidney but not in the aorta or in mesenteric arteries. Moreover, the aorta and mesenteric arteries from rats were not dilated by ghrelin or capromorelin at concentrations >100 times their EC(50) determined in cells transfected with human or rat GHSR1a. These agonists did not affect transmission from preganglionic sympathetic neurons that express GHSR1a. Intravenous application of ghrelin lowered blood pressure and decreased splanchnic nerve activity. It is concluded that the blood pressure reduction to ghrelin occurs concomitantly with a decrease in sympathetic nerve activity and is not caused by direct actions on blood vessels or by inhibition of transmission in sympathetic ganglia.

Human telomeric DNA sequences are a major target for the antitumour drug bleomycin.

The DNA sequence specificity of the cancer chemotherapeutic agent bleomycin was examined in a human telomeric DNA sequence and compared with that of non-telomeric sequences. The target DNA sequence contained 17 repeats of the human telomeric sequence and other primary sites of bleomycin cleavage. The 377-base-pair target DNA was fluorescently labelled at the 3'-end, damaged with bleomycin and electrophoresed in an ABI 3730 automated capillary sequencer to determine the intensity and sequence specificity of bleomycin damage. The results revealed that bleomycin cleaved primarily at 5'-GT in the telomeric sequence 5'-GGGTTA. Maxam-Gilbert chemical sequencing reactions were utilised as DNA size markers to determine the precise sites of bleomycin cleavage. The telomeric region contained strong sites of bleomycin cleavage and constituted 57% of the 30 most intense bleomycin damage sites in the DNA sequence examined. These data indicated that telomeric DNA sequences are a major site for bleomycin damage.

Effects of board game play on nursing students' medication knowledge: A randomized controlled trial.

AIM: This study aimed to examine the effectiveness of an educational board game in improving nursing students' medication knowledge. BACKGROUND: Maintaining patient safety is a core practice for nurses. Medication management is a central principle of patient safety. Nurses acquire pharmacology knowledge and medication safety skills in the classroom training. Thus, solidifying and strengthening nursing students' medication knowledge are crucial tasks for nursing faculty members. In recent years, board games, which offer both entertainment and competitive play, have been employed to educate students in a variety of disciplines and settings. Through board game play, students can learn in an enjoyable and fun atmosphere. DESIGN: A randomized controlled trial design. METHODS: A convenience sample of 69 nursing students was obtained from a university in Taiwan. Participants were randomly assigned either to an experimental (board game) group (n = 35) or a comparison group (n = 34) using block randomization. The experimental group engaged in board game play to learn about medications, whereas the comparison group attended a one-hour didactic lecture. Using questionnaires, data were collected before the intervention, immediately post intervention and one month post intervention. RESULTS: Following the intervention, regardless of the learning method, both groups showed significant improvements in their immediate recall of medication information. However, when retested after one month, the experimental group obtained significantly higher scores than the comparison group. Moreover, students in the experimental group reported more satisfaction with the learning method than those in the comparison group. CONCLUSIONS: The study results suggest that learning through board games could enhance nursing students' retention of knowledge. Students reported favorable reactions to using a board game learning method for increasing knowledge of medication. With respect to this finding, faculty members may consider employing board games as teaching tools in nursing and other health science courses. Moreover, the findings of this study can also provide additional information for nursing managers in hospital wards or long-term care facilities where nurses are trained to familiarize themselves with frequently administered medications. TWEETABLE ABSTRACT: Board game play can enhance nursing students' retention of knowledge; students reported positive reactions to game-based learning for medication training.

Slow synaptic transmission in myenteric AH neurons from the inflamed guinea pig ileum.

We investigated the effect of inflammation on slow synaptic transmission in myenteric neurons in the guinea pig ileum. Inflammation was induced by the intraluminal injection of trinitrobenzene sulfonate, and tissues were taken for in vitro investigation 6-7 days later. Brief tetanic stimulation of synaptic inputs (20 Hz, 1 s) induced slow excitatory postsynaptic potentials (EPSPs) in 49% and maintained postsynaptic excitation that lasted from 27 min to 3 h in 13% of neurons from the inflamed ileum. These neurons were classified electrophysiologically as AH neurons; 10 were morphological type II neurons, and one was type I. Such long-term hyperexcitability after a brief stimulus is not encountered in enteric neurons of normal intestine. Electrophysiological properties of neurons with maintained postsynaptic excitation were similar to those of neurons with slow EPSPs. Another form of prolonged excitation, sustained slow postsynaptic excitation (SSPE), induced by 1-Hz, 4-min stimulation, in type II neurons from the inflamed ileum reached its peak earlier but had lower amplitude than that in control. Unlike slow EPSPs and similar to SSPEs, maintained excitation was not inhibited by neurokinin-1 or neurokinin-3 receptor antagonists. Maintained postsynaptic excitation was not influenced by PKC inhibitors, but the PKA inhibitor, H-89, caused further increase in neuronal excitability. In conclusion, maintained excitation, observed only in neurons from the inflamed ileum, may contribute to the dysmotility, pain, and discomfort associated with intestinal inflammation.

DNA methylation/hydroxymethylation regulate gene expression and alternative splicing during terminal granulopoiesis.

AIM: To determine whether epigenetic modifications of DNA regulate gene expression and alternative splicing during terminal granulopoiesis. MATERIALS & METHODS: Using whole genome bisulfite sequencing, reduced representation hydroxymethylation profiling and mRNA sequencing, we compare changes in DNA methylation, DNA hydroxymethylation, gene expression and alternative splicing in mouse promyelocytes and granulocytes. RESULTS & CONCLUSION: We show reduced DNA methylation at the promoters and enhancers of key granulopoiesis genes, indicating a regulatory role in the activation of lineage-specific genes during differentiation. Notably, increased DNA hydroxymethylation in exons is associated with preferential inclusion of specific exons in granulocytes. Overall, DNA methylation and hydroxymethylation changes at particular genomic loci may play specific roles in gene regulation or alternative splicing during terminal granulopoiesis. Data deposition: Whole genome bisulfite sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE85517); mRNA sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE48307); reduced representation 5-hydroxymethylation profiling of mouse promyelocytes and granulocytes: Bioproject (PRJNA495696).

Melioidosis in Vietnam: Recently Improved Recognition but still an Uncertain Disease Burden after Almost a Century of Reporting.

The first cases of human melioidosis were described in Vietnam in the 1920s, almost a century ago. It was in Vietnam in the thirties that the saprophytic nature of B. pseudomallei was first recognized. Although a significant number of French and U.S. soldiers acquired the disease during the Vietnam wars, indigenous cases in the Vietnamese population were only sporadically reported over many decades. After reunification in 1975, only two retrospective studies reported relatively small numbers of indigenous cases from single tertiary care hospitals located in the biggest cities in the South and the North, respectively. Studies from provincial hospitals throughout the country were missing until the Research Network on Melioidosis and Burkholderia pseudomallei (RENOMAB) project started in 2014. From then on seminars, workshops, and national scientific conferences on melioidosis have been conducted to raise awareness among physicians and clinical laboratory staff. This led to the recognition of a significant number of cases in at least 36 hospitals in 26 provinces and cities throughout Vietnam. Although a widespread distribution of melioidosis has now been documented, there are still challenges to understand the true epidemiology of the disease. Establishment of national guidelines for diagnosis, management, and reporting of the disease together with more investigations on animal melioidosis, genomic diversity of B. pseudomallei and its environmental distribution are required.

Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment.

While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.

Impact of clinical guidelines in the management of severe hospital-acquired pneumonia.

STUDY OBJECTIVES: To asses the impact of locally developed antimicrobial treatment guidelines in the initial empiric treatment of ICU patients with severe hospital-acquired pneumonia (HAP). DESIGN: Observational cohort study with pre-guideline and post-guideline data collection. PATIENTS: A total of 48 pre-guideline patients with 56 episodes of severe HAP defined by the National Nosocomial Infections Surveillance (NNIS) compared with 58 guideline-treated (GUIDE) patients with 61 episodes of severe HAP. RESULTS: The two groups were similar in terms of mean (+/- SD) age (NNIS group, 67.7 +/- 9.6 years; GUIDE group, 68.0 +/- 11.5 years) and simplified acute physiology score (NNIS group, 12.9 +/- 3.9; GUIDE group, 12.6 +/- 3.1) at the HAP diagnosis, and the proportion of the most frequent isolates (ie, Pseudomonas and methicillin-resistant Staphylococcus aureus). There was wide variation in initial antibiotic use in NNIS-treated patients, with cefotaxime, ceftazidime, and piperacillin being the most common agents compared with all of the GUIDE patients who received an imipenem-cilastin-based regimen. Vancomycin use was similar in both groups. The GUIDE patients had a higher percentage of adequately treated patients (81% vs 46%, respectively; p < 0.01) with a lower mortality rate at 14 days (8% vs 23%, respectively; p = 0.03). A lower mortality rate was also noted at the end of 30 days and the end of hospitalization but was not statistically significant. Appropriate imipenem use (as defined by the guidelines) occurred in 74% of the cases, and there was no increase in the number of imipenem-resistant organisms isolated during the course of the study. CONCLUSIONS: These guidelines represent a successful implementation of a "deescalation" approach, because the recommended empiric therapy with broad-spectrum antibiotics was switched to therapy with narrower spectrum agents after 3 days. Based on our experience, this approach improves the adequacy of antibiotic treatment, with improvement in short-term survival and without increasing the emergence of resistant organisms.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) gene deletion promotes cancer growth in TRAMP prostate cancer prone mice.

The divergent TGF-ß superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p<0.0001). We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread.

One year experience using mycobacterial blood cultures to diagnose tuberculosis in patients with prolonged fever in Vietnam.

INTRODUCTION: To evaluate the use of mycobacterial blood cultures (MBC) in diagnosing tuberculosis (TB) in patients with prolonged fever admitted to a Vietnamese referral hospital. RESULTS: MBCs from 94 patients (66% male; median age 33 years; 75% HIV positive) were evaluated: 14 were mycobacterium positive (all HIV positive), and MBC was the only positive specimen in 9 cases (41%). Three positive cases were identified as Mycobacterium avium and the remaining M. tuberculosis (one case could not be identified). CONCLUSION: MBC can be a valuable additional method to diagnose TB, particularly in immunosuppressed HIV patients when sputum cannot be collected.

Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor.

BACKGROUND AND PURPOSE: Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown. EXPERIMENTAL APPROACH: The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). KEY RESULTS: Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84. CONCLUSIONS AND IMPLICATIONS: Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin.