Discovery and mechanistic study of thiazole-4-acylsulfonamide derivatives as potent and orally active ChemR23 inhibitors with a long-acting effect in cynomolgus monkeys.

Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that can secrete large amounts of type I interferon. ChemR23, a G protein-coupled receptor (GPCR) expressed on the surface of pDCs, contributes to the recruitment of pDCs to inflamed tissues through chemotaxis signaling, and is therefore considered an attractive target for the treatment of autoimmune diseases. We previously reported benzoxazole-based compounds that can inhibit ChemR23 signaling through receptor internalization. Although these compounds showed ChemR23 internalization on pDCs in cynomolgus monkeys after oral administration, further improvement of the pharmacokinetics profile was needed for a clinical candidate and we therefore attempted scaffold-hopping from the benzoxazole core structure leading to novel thiazole derivatives. In this report, the design, synthesis, and biological evaluation of new thiazole-based ChemR23 inhibitors were described. Through sequential structure-activity relationship studies regarding (i) the side chain of the N-acylsulfonamide moiety, (ii) the 5-position of the thiazole ring, and (iii) the 1,2,4-oxadiazol-5-one moiety, we have succeeded in finding a potent thiazole-based ChemR23 inhibitor, 14f (IC80 = 12 nM). In addition, the oral administration of 14f at 30 mg/kg to cynomolgus monkeys demonstrated a sustained pharmacological effect of ChemR23 internalization on pDCs until 8 h after dosing, which was considered a longer effect in comparison to previously reported 2-aminobenzoxazole-based ChemR23 inhibitors. This report also shows the synthesis and evaluation of fluorescein-labeled compound 45c for a mechanistic study, and we could confirm the direct binding of our thiazole derivative to ChemR23. We believe that our research on small molecule ChemR23 inhibitors and chemical probe will contribute to the elucidation and analysis of the functions of ChemR23 as well as identifying novel therapeutics for autoimmune diseases.

A case of pyogenic spondylitis caused by Paludibacteriumpurpuratum.

Paludibacterium purpuratum was first reported as a Gram stain-negative, curved, rod-shaped bacterium isolated from a wetland soil in 2016. We report the first case in the world, to our knowledge, of pyogenic spondylitis caused by P. purpuratum. The patient, a 78-year-old man, came to our hospital complaining chiefly of fever and pain in the left knee. He did not complain of low back pain at the time of examination, although increased low back pain was observed for the first time after admission. Magnetic resonance imaging of the lumbar spine and percutaneous needle biopsy at the L2/L3 disc level were performed, and pyogenic spondylitis was diagnosed. A curved, Gram stain-negative rod was detected in the blood culture obtained at admission that was identified as P. purpuratum by 16S rDNA gene analysis.

Magnetic control of heterogeneous ice nucleation with nanophase magnetite: Biophysical and agricultural implications.

In supercooled water, ice nucleation is a stochastic process that requires ∼250-300 molecules to transiently achieve structural ordering before an embryonic seed crystal can nucleate. This happens most easily on crystalline surfaces, in a process termed heterogeneous nucleation; without such surfaces, water droplets will supercool to below -30 °C before eventually freezing homogeneously. A variety of fundamental processes depends on heterogeneous ice nucleation, ranging from desert-blown dust inducing precipitation in clouds to frost resistance in plants. Recent experiments have shown that crystals of nanophase magnetite (Fe3O4) are powerful nucleation sites for this heterogeneous crystallization of ice, comparable to other materials like silver iodide and some cryobacterial peptides. In natural materials containing magnetite, its ferromagnetism offers the possibility that magneto-mechanical motion induced by external oscillating magnetic fields could act to disrupt the water-crystal interface, inhibiting the heterogeneous nucleation process in subfreezing water and promoting supercooling. For this to act, the magneto-mechanical rotation of the particles should be higher than the magnitude of Brownian motions. We report here that 10-Hz precessing magnetic fields, at strengths of 1 mT and above, on ∼50-nm magnetite crystals dispersed in ultrapure water, meet these criteria and do indeed produce highly significant supercooling. Using these rotating magnetic fields, we were able to elicit supercooling in two representative plant and animal tissues (celery and bovine muscle), both of which have detectable, natural levels of ferromagnetic material. Tailoring magnetic oscillations for the magnetite particle size distribution in different tissues could maximize this supercooling effect.

The (PATAN)-CheY-Like Response Regulator PixE Interacts with the Motor ATPase PilB1 to Control Negative Phototaxis in the Cyanobacterium Synechocystis sp. PCC 6803.

The cyanobacterium Synechocystis sp. PCC 6803 can move directionally on a moist surface toward or away from a light source to reach optimal light conditions for its photosynthetic lifestyle. This behavior, called phototaxis, is mediated by type IV pili (T4P), which can pull a single cell into a certain direction. Several photoreceptors and their downstream signal transduction elements are involved in the control of phototaxis. However, the critical steps of local pilus assembly in positive and negative phototaxis remain elusive. One of the photoreceptors controlling negative phototaxis in Synechocystis is the blue-light sensor PixD. PixD forms a complex with the CheY-like response regulator PixE that dissociates upon illumination with blue light. In this study, we investigate the phototactic behavior of pixE deletion and overexpression mutants in response to unidirectional red light with or without additional blue-light irradiation. Furthermore, we show that PixD and PixE partly localize in spots close to the cytoplasmic membrane. Interaction studies of PixE with the motor ATPase PilB1, demonstrated by in vivo colocalization, yeast two-hybrid and coimmunoprecipitation analysis, suggest that the PixD-PixE signal transduction system targets the T4P directly, thereby controlling blue-light-dependent negative phototaxis. An intriguing feature of PixE is its distinctive structure with a PATAN (PatA N-terminus) domain. This domain is found in several other regulators, which are known to control directional phototaxis. As our PilB1 coimmunoprecipitation analysis revealed an enrichment of PATAN domain response regulators in the eluate, we suggest that multiple environmental signals can be integrated via these regulators to control pilus function.

The design, synthesis and evaluation of 2-aminobenzoxazole analogues as potent and orally efficacious ChemR23 inhibitors.

We previously reported 2-aminobenzoxazole analogue 1 as a potent ChemR23 inhibitor. The compound showed inhibitory activity against chemerin-induced calcium signaling through ChemR23 internalization in CAL-1 cells, which are cell lines of plasmacytoid dendric cells (pDCs). Furthermore, compound 2 inhibited chemotaxis of CAL-1 triggered by chemerin in vitro. However, we noted a difference in the ChemR23 response to our inhibitor between rodents and non-rodents in a previous study. To address this issue, we performed optimization of ChemR23 inhibitors using CAL-1 cells endogenously expressing human ChemR23 and conducted a pharmacokinetics study in cynomolgus monkeys. Various substituents at the 4-position of the benzoxazole ring exhibited potent in vitro bioactivity, while those at the 6-position were not tolerated. Among substituents, a carboxyl group was identified as key for improving the oral bioavailability in cynomolgus monkeys. Compound 38a with the acidic part changed from a tetrazole group to a 1,2,4-oxadiazol-5-one group to improve bioactivity and pharmacokinetic parameters exhibited inhibitory activity against chemerin-induced chemotaxis in vitro. In addition, we confirmed the ChemR23 internalization of pDCs by compound 38a orally administered to cynomolgus monkeys. These 2-aminobenzoxazole-based ChemR23 inhibitors may be useful as novel immunotherapeutic agents capable of suppressing the migration of pDCs, which are known to be major producers of type I interferons in the lesion area of certain autoimmune diseases, such as systemic lupus erythematosus and psoriasis.

The discovery and optimization of a series of 2-aminobenzoxazole derivatives as ChemR23 inhibitors.

A structural class of 2-aminobenzoxazole derivatives possessing biphenyltetrazole was discovered to be potent human ChemR23 inhibitors. We initially tried to improve the potency of compound 1, which was found through in-house screening using the human plasmacytoid dendritic cell (pDC)-like cell line CAL-1. The introduction of a chiral methyl moiety at a benzylic position in a center of compound 1 showed a large impact on the inhibitory activity against calcium signaling of ChemR23 induced by the natural ligand chemerin. As a result of further investigations at the benzylic position, (R)-isomer 6b was found to show a 30-fold increased potency over desmethyl compound 1. In addition, an extensive structure-activity relationship study on the benzoxazole moiety successfully led to a further increase in the potency. The antagonistic effect of the compounds was based on the induction of ChemR23 internalization. In addition, we observed that compound 31, which contained an amide moiety on benzoxazole, inhibited chemotaxis of CAL-1 cells induced by chemerin in vitro. These results suggest that our ChemR23 inhibitors are attractive compounds for the treatment of pDC-related autoimmune diseases, such as systemic lupus erythematosus and psoriasis.

Team-based parent training by child specialists helps maltreated children.

BACKGROUND: This study assessed the effects of the parent training (PT) technique, in which child specialists (CS) such as preschool and school teachers promote secure attachment in children with aberrant social behavior following maltreatment, using a team approach. METHODS: Child specialists confirmed the presence of child abuse, according to Japanese Ministry of Health, Labour and Welfare criteria. CS such as homeroom, special education-related, student guidance-related, nursing teachers and co-workers received a PT course conducted by the authors. A homeroom teacher provided classroom management to model good examples of social life for the target child. A nursing teacher and assistant offered individualized instruction to foster the formation of secure attachments by the target child. RESULT: Behavioral abnormalities in both school and home resolved in seven out of 12 cases. These subjects received the intervention for 2-4 years. In the other cases, behavioral abnormalities disappeared or decreased at school, but continued at home. Almost all children met the alternative criteria of attachment disorder proposed by Boris and Zeanah. One child met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for reactive attachment disorder. This intervention is significantly more effective for children who have yet to begin elementary school than those in elementary school. CONCLUSIONS: The PT technique as applied by CS using a team approach may be a useful intervention for fostering secure attachment in children with maltreatment who exhibit behavioral abnormalities. Early detection and intervention are necessary to successfully address the behavioral abnormalities of children with maltreatment.

Comparison of the efficacy of three topical antiseptic solutions for the prevention of catheter colonization: a multicenter randomized controlled study.

BACKGROUND: To compare the efficacy of three antiseptic solutions [0.5%, and 1.0% alcohol/chlorhexidine gluconate (CHG), and 10% aqueous povidone-iodine (PVI)] for the prevention of intravascular catheter colonization, we conducted a randomized controlled trial in patients from 16 intensive care units in Japan. METHODS: Adult patients undergoing central venous or arterial catheter insertions were randomized to have one of three antiseptic solutions applied during catheter insertion and dressing changes. The primary endpoint was the incidence of catheter colonization, and the secondary endpoint was the incidence of catheter-related bloodstream infections (CRBSI). RESULTS: Of 1132 catheters randomized, 796 (70%) were included in the full analysis set. Catheter-tip colonization incidence was 3.7, 3.9, and 10.5 events per 1000 catheter-days in 0.5% CHG, 1% CHG, and PVI groups, respectively (p = 0.03). Pairwise comparisons of catheter colonization between groups showed a significantly higher catheter colonization risk in the PVI group (0.5% CHG vs. PVI: hazard ratio, HR 0.33 [95% confidence interval, CI 0.12-0.95], p = 0.04; 1.0% CHG vs. PVI: HR 0.35 [95% CI 0.13-0.93], p = 0.04). Sensitivity analyses including all patients by multiple imputations showed consistent quantitative conclusions (0.5% CHG vs. PVI: HR 0.34, p = 0.03; 1.0% CHG vs. PVI: HR 0.35, p = 0.04). No significant differences were observed in the incidence of CRBSI between groups. CONCLUSIONS: Both 0.5% and 1.0% alcohol CHG are superior to 10% aqueous PVI for the prevention of intravascular catheter colonization. TRIAL REGISTRATION: Japanese Primary Registries Network; No.: UMIN000008725 Registered on 1 September 2012.

A first test of the hypothesis of biogenic magnetite-based heterogeneous ice-crystal nucleation in cryopreservation.

An outstanding biophysical puzzle is focused on the apparent ability of weak, extremely low-frequency oscillating magnetic fields to enhance cryopreservation of many biological tissues. A recent theory holds that these weak magnetic fields could be inhibiting ice-crystal nucleation on the nanocrystals of biological magnetite (Fe3O4, an inverse cubic spinel) that are present in many plant and animal tissues by causing them to oscillate. In this theory, magnetically-induced mechanical oscillations disrupt the ability of water molecules to nucleate on the surface of the magnetite nanocrystals. However, the ability of the magnetite crystal lattice to serve as a template for heterogeneous ice crystal nucleation is as yet unknown, particularly for particles in the 10-100 nm size range. Here we report that the addition of trace-amounts of finely-dispersed magnetite into ultrapure water samples reduces strongly the incidence of supercooling, as measured in experiments conducted using a controlled freezing apparatus with multiple thermocouples. SQUID magnetometry was used to quantify nanogram levels of magnetite in the water samples. We also report a relationship between the volume change of ice, and the degree of supercooling, that may indicate lower degassing during the crystallization of supercooled water. In addition to supporting the role of ice-crystal nucleation by biogenic magnetite in many tissues, magnetite nanocrystals could provide inexpensive, non-toxic, and non-pathogenic ice nucleating agents needed in a variety of industrial processes, as well as influencing the dynamics of ice crystal nucleation in many natural environments.

A ferromagnetic model for the action of electric and magnetic fields in cryopreservation.

Recent discussions in the literature have questioned the ability of electromagnetic exposure to inhibit ice crystal formation in supercooled water. Here we note that strong electric fields are able to disrupt the surface boundary layer of inert air on the surface of materials, promoting higher rates of heat transport. We also note that most biological tissues contain ferromagnetic materials, both biologically precipitated magnetite (Fe3O4) as well as environmental contaminants that get accidentally incorporated into living systems. Although present at trace levels, the number density of these particulates is high, and they have extraordinarily strong interactions with weak, low-frequency magnetic fields of the sort involved in claims of electromagnetic cryopreservation. Magnetically-induced mechanical oscillation of these particles provides a plausible mechanism for the disruption of ice-crystal nucleation in supercooled water.

Distribution of Candida species isolated from blood cultures in hospitals in Osaka, Japan.

BACKGROUND: Candida species are clinically important causes of bloodstream infections because their mortality is very high. Given that some species of Candida are azole-resistant, identifying the distributions of Candida species could facilitate the formulation of an appropriate empirical antifungal therapy. It has been shown that the distribution varies depending on the continent, country, city, and hospital. In this paper, we describe the distributions of species in hospitals in northern Osaka, Japan. METHOD: We evaluated blood culture results obtained from six tertiary hospitals in the northern Osaka area between 2004 and 2011. We also obtained comorbidity information from the patients' hospital medical records. Kaplan-Meier curves were drawn to compare the risk of death related to the different species. RESULTS: Of the 165 cases of candidemia confirmed by blood culture, 66% were male and the mean age was 62 years (range = 0-96). Overall, Candida albicans comprised 70 cases (43%), followed by Candida parapsilosis with 36 cases (22%), Candida glabrata with 25 cases (15%), Candida tropicalis with 11 cases (7%), Candida krusei with 10 cases (6%), and other Candida species with 13 cases (8%). C. tropicalis had higher associated mortality than other species, although it was not statistically significant. CONCLUSIONS: C. albicans was the most frequently isolated species, but the proportion of non-albicans Candida species was not negligible. The relatively high frequency of non-albicans Candida species distinguished the Japanese distribution from other areas. This characteristic distribution may have important implications when formulating an empirical antifungal therapy for Japanese clinical practice.

[Correlates of mental health in Japanese caseworkers employed at social welfare offices].

OBJECTIVES: The aim of this study was to evaluate the correlation between the mental health status of caseworkers at welfare offices and factors affecting mental health (i.e., working conditions, participation in training courses and workshops, lifestyle habits, presence of illness, social support, and self-efficacy). METHODS: The welfare offices in Japan (1,230 locations) were arranged in descending order according to their establishment and region. Systematic sampling was then conducted to select 20% (n =246) of the welfare institutions for this study. A total of 1,230 caseworkers on welfare (five from each institution) were administered anonymous self-completed questionnaires. The questionnaires involved the General Health Questionnaire (GHQ)-28 Japanese version and questions regarding basic attributes, working conditions, social support (i.e., family, friends, superiors, and colleagues), participation in training courses and workshops, presence of illness, lifestyle habits, mental health, and self-efficacy. Subjects were divided into the following 2 groups: low-score group (GHQ-28 score ≤5) and high-score group (GHQ-28 score ≥6). Data were analyzed using a t-test, χ(2) test, and Fisher's exact test. The GHQ-28 high- and low-score groups were considered gender-specific dependent variables due to the sex differences observed in the univariate analysis. Significant variables in the univariate analysis were considered independent variables in the multiple logistic regression analysis (forward stepwise selection). RESULTS: Five hundred and six people (410 male and 96 female) provided valid responses. Most respondents had poor mental health (66%, high-score group; 34%, low-score group). Both men and women who worked ≥10 hours/day had significantly poorer mental health than individuals who worked ≤9 hours/day. Individuals with low self-efficacy had significantly poorer mental health compared to people with high self-efficacy. Men who were able to maintain moderate hours of sleep and received support from colleagues, friends, and family had good mental health. Among women, mental health deteriorated with age. Furthermore, women who devoted most work time to home visit had good mental health. CONCLUSION: The mental health of caseworkers at welfare offices can be improved by reducing overtime work hours, ensuring sufficient hours of sleep for each worker, and fostering supportive communication and self-efficacy in the workplace. Furthermore, sex differences should be considered when assessing the mental health of workers at welfare offices in Japan.

No improvement in mortality among critically ill patients with carbapenems as initial empirical therapy and more detection of multi-drug resistant pathogens associated with longer use: a post hoc analysis of a prospective cohort study.

Whether empirical therapy with carbapenems positively affects the outcomes of critically ill patients with bacterial infections remains unclear. This study aimed to investigate whether the use of carbapenems as the initial antimicrobial administration reduces mortality and whether the duration of carbapenem use affects the detection of multidrug-resistant (MDR) pathogens. This was a post hoc analysis of data acquired from Japanese participating sites from a multicenter, prospective observational study [Determinants of Antimicrobial Use and De-escalation in Critical Care (DIANA study)]. A total of 268 adult patients with clinically suspected or confirmed bacterial infections from 31 Japanese intensive care units (ICUs) were analyzed. The patients were divided into two groups: patients who were administered carbapenems as initial antimicrobials (initial carbapenem group, n = 99) and those who were not administered carbapenems (initial non-carbapenem group, n = 169). The primary outcomes were mortality at day 28 and detection of MDR pathogens. Multivariate logistic regression analysis revealed that mortality at day 28 did not differ between the two groups [18 (18%) vs 27 (16%), respectively; odds ratio: 1.25 (95% confidence interval (CI): 0.59-2.65), P = 0.564]. The subdistribution hazard ratio for detecting MDR pathogens on day 28 per additional day of carbapenem use is 1.08 (95% CI: 1.05-1.13, P < 0.001 using the Fine-Gray model with death regarded as a competing event). In conclusion, in-hospital mortality was similar between the groups, and a longer duration of carbapenem use as the initial antimicrobial therapy resulted in a higher risk of detection of new MDR pathogens.IMPORTANCEWe found no statistical difference in mortality with the empirical use of carbapenems as initial antimicrobial therapy among critically ill patients with bacterial infections. Our study revealed a lower proportion of inappropriate initial antimicrobial administrations than those reported in previous studies. This result suggests the importance of appropriate risk assessment for the involvement of multidrug-resistant (MDR) pathogens and the selection of suitable antibiotics based on risk. To the best of our knowledge, this study is the first to demonstrate that a longer duration of carbapenem use as initial therapy is associated with a higher risk of subsequent detection of MDR pathogens. This finding underscores the importance of efforts to minimize the duration of carbapenem use as initial antimicrobial therapy when it is necessary.

COPD and disease-specific health status in a working population.

BACKGROUND: It has been debated whether treatment should be started early in subjects with mild to moderate COPD. An impaired health status score was associated with a higher probability of being diagnosed with COPD as compared with undiagnosed COPD. PURPOSE: To investigate the health status in a healthy working population, to determine reference scores for healthy non-smoking subjects, and to investigate the relationship between their health status and airflow limitation. METHODS: A total of 1333 healthy industrial workers aged ≥40 years performed spirometry and completed the St. George's Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT). RESULTS: The prevalence of COPD defined by the fixed ratio of the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was 10.9%, and the prevalence defined by the Lower Limit of Normal was 5.0%. All SGRQ and CAT scores were skewed to the milder end. In 512 non-smoking subjects with normal spirometry, the mean SGRQ score was 5.7, and the mean CAT score was 5.8. In 145 people with COPD defined by the fixed ratio, the mean SGRQ score was 7.9, with a zero score in 6.9% of the subjects. Using the CAT, the mean score was 7.3, with 7.6% of the scores being zero. The scores in patients identified using the Lower Limit of Normal approach were: SGRQ 8.4 (13.4% had a score of zero) and CAT 7.4 (13.4% had a score of zero). Although the 95th percentiles of the Total, Symptoms, Activity, and Impact scores of the SGRQ and CAT sores were 13.8, 34.0, 23.4, 7.2 and 13.6 in the 512 healthy non-smoking subjects, respectively, they were also distributed under their upper limits in over 80% of the COPD subjects. CONCLUSION: The COPD-specific health status scores in a working population were good, even in those with spirometrically diagnosed COPD. All scores were widely distributed in both healthy non-smoking subjects and in subjects with COPD, and the score distribution overlapped remarkably between these two groups. This suggests that symptom-based methods are not suitable screening tools in a healthy general population.

Effects of adherence to ventilator-associated pneumonia treatment guidelines on clinical outcomes.

Two guidelines are currently available to guide Japanese clinicians caring for patients with ventilator-associated pneumonia (VAP): the 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines or the 2008 Japanese Respiratory Society (JRS) guidelines. We aimed to measure compliance with guideline recommendations for VAP in Japanese intensive care units (ICUs) and to assess the effects of guideline-compliant treatment on outcomes. We retrospectively reviewed the records of all patients with microbiologically confirmed VAP in five Japanese ICUs between January 1, 2006, and December 31, 2009. We evaluated whether empiric antibiotic prescriptions were guideline compliant and correlated compliance with clinical outcomes. Among the 95 patients with VAP who were included, 85 patients received empiric antibiotics. Of these, therapy of 62 patients (73 %) was appropriate based on in vitro sensitivity testing. Using ATS/IDSA criteria, 16 patients (19 %) received guideline-compliant therapy and 69 patients (81 %) received noncompliant treatment. Using JRS criteria, 24 patients (28 %) received guideline-compliant therapy and 61 patients (72 %) received noncompliant treatment. All-cause 28-day mortality was 24 %. When compared to patients who received noncompliant therapy, there were no differences in 28-day mortality rates for patients who received ATS/IDSA guideline-compliant regimens (25 vs. 25 %, p = 1.00) or JRS guideline-compliant regimens (21 vs. 26 %, p = 0.78). Our study demonstrates poor compliance with guideline-recommended antibiotic therapy for VAP in Japanese ICUs. Compliance with current VAP guidelines was not associated with increased rates of appropriate antibiotic treatment or improved 28-day mortality.

Use of broad-spectrum antimicrobials for more than 72 h and the detection of multidrug-resistant bacteria in Japanese intensive care units: a multicenter retrospective cohort study.

BACKGROUND: Large multicenter studies reporting on the association between the duration of broad-spectrum antimicrobial administration and the detection of multidrug-resistant (MDR) bacteria in the intensive care unit (ICU) are scarce. We evaluated the impact of broad-spectrum antimicrobial therapy for more than 72 h on the detection of MDR bacteria using the data from Japanese patients enrolled in the DIANA study. METHODS: We analyzed the data of ICU patients in the DIANA study (a multicenter international observational cohort study from Japan). Patients who received empirical antimicrobials were divided into a broad-spectrum antimicrobial group and a narrow-spectrum antimicrobial group, based on whether they received broad-spectrum antimicrobials for more or less than 72 h, respectively. Differences in patient characteristics, background of infectious diseases and empirical antimicrobial administration, and outcomes between the two groups were compared using the chi-square tests (Monte Carlo method) for categorical variables and the Mann-Whitney U-test for continuous variables. We also conducted a logistic regression analysis to investigate the factors associated with the detection of new MDR bacteria. RESULTS: A total of 254 patients from 31 Japanese ICUs were included in the analysis, of whom 159 (62.6%) were included in the broad-spectrum antimicrobial group and 95 (37.4%) were included in the narrow-spectrum antimicrobial group. The detection of new MDR bacteria was significantly higher in the broad-spectrum antimicrobial group (11.9% vs. 4.2%, p = 0.042). Logistic regression showed that broad-spectrum antimicrobial continuation for more than 72 h (OR [odds ratio] 3.09, p = 0.047) and cerebrovascular comorbidity on ICU admission (OR 2.91, p = 0.041) were associated with the detection of new MDR bacteria. CONCLUSIONS: Among Japanese ICU patients treated with empirical antimicrobials, broad-spectrum antimicrobial usage for more than 72 h was associated with the increased detection of new MDR bacteria. Antimicrobial stewardship programs in ICUs should discourage the prolonged use of empirical broad-spectrum antimicrobial therapy. Trial registration ClinicalTrials.gov, NCT02920463, Registered 30 September 2016, https://clinicaltrials.gov/ct2/show/NCT02920463.

Case identification of subjects with airflow limitations using the handheld spirometer "Hi-Checker™" : comparison against an electronic desktop spirometer.

BACKGROUND: Systematic case identification has been proposed as a strategy to improve diagnosis rates and to enable the early detection of subjects with COPD. We hypothesized that case identification could be possible using the handheld spirometer Hi-Checker™. AIM: To determine how to modify the FEV(1)/FEV(6) values obtained using the Hi-Checker™ to screen for cases with airflow limitation. METHODS: Spirometry was performed with both an electronic desktop spirometer and with the Hi-Checker™ in 312 male subjects. RESULTS: The average FEV(1) (mean ± SD) measured using a conventional spirometer and the Hi-Checker™ was 2.99 ± 0.56L and 3.07 ± 0.57L, respectively. These results were significantly different (P<0.001, paired t-test for both). This difference of -0.08 ± 0.13L (95% confidence interval: -0.094-0.066L) was normally distributed, and thought to be random. Statistically significant correlations were found for all measurements between the spirometer and the Hi-Checker™ ; the Pearson's correlation coefficient (R) between the FEV(1)/FVC and FEV(1)/FEV(6) values was 0.881. If one defines a FEV(1/)FVC smaller than 0.7 measured by the spirometer as airflow limitation, then a FEV(1)/FEV(6) smaller than 0.746 measured by the Hi-Checker™ best matches this definition, and Cohen's kappa coefficient was 0.672. CONCLUSION: Although the Hi-Checker™ estimates resembled those from conventional spirometry, it should be emphasized that the two methods did not produce identical results due to random measurement error. Although one must be careful about overinterpreting these results, since the Hi-Checker™ is small and inexpensive, it could make a significant contribution in facilitating the case selection of patients with airflow limitation.