Evaluation of the antimicrobial activity of ridinilazole and six comparators against Chinese, Japanese and South Korean strains of Clostridioides difficile

BACKGROUND: Clostridioides difficile is the most common cause of antimicrobial-associated diarrhoea in high-income countries. Fluoroquinolone resistance enabled the emergence and intercontinental spread of the epidemic ribotype (RT) 027 strain of C. difficile in the early 2000s. Despite frequent inappropriate antimicrobial use in Asia, RT 027 is rarely isolated in the region, but the often fluoroquinolone- and clindamycin-resistant RT 017 strain predominates. OBJECTIVES: This study evaluated the antimicrobial activity of ridinilazole, a novel antimicrobial agent with highly specific activity for C. difficile, against clinical strains of C. difficile from Asia. METHODS: C. difficile strains from Japan (n = 64), South Korea (n = 32) and China (n = 44) were tested by the agar dilution method for susceptibility to ridinilazole, metronidazole, vancomycin, clindamycin, moxifloxacin, rifaximin and fidaxomicin. RESULTS: All strains were susceptible to ridinilazole, with low MICs (0.03-0.25 mg/L). Several strains showed multiresistance profiles, particularly RT 017 (100% clindamycin resistant, 91.3% moxifloxacin resistant, 82.6% rifaximin resistant) and RT 369 (94.4% clindamycin resistant, 100% moxifloxacin resistant). Rifaximin resistance was absent in all strains from Japan. Multiresistance to clindamycin, moxifloxacin and rifaximin was found in 19 RT 017 strains (from China and South Korea), 2 RT 001 strains (South Korea) and 1 RT 046 strain (South Korea). CONCLUSIONS: Ridinilazole showed potent activity against a range of Asian C. difficile strains, which otherwise frequently displayed resistance to several comparator antimicrobial agents. Ongoing surveillance of antimicrobial resistance profiles is required to monitor and control the spread of resistant strains

Gabapentin Drug Misuse Signals: A Pharmacovigilance Assessment Using the FDA Adverse Event Reporting System

Background: Although there have been increasing reports of intentional gabapentin misuse, epidemiological evidence for the phenomenon is limited. The purpose of this study was to determine whether there are pharmacovigilance abuse signals for gabapentin.Methods: Using FDA Adverse Events Reporting System reports from January 1, 2005 to December 31, 2015, we calculated pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayes geometric mean) for abuse-related adverse event (AR-AE)-gabapentin pairs. Loglinear modeling assessed the frequency of concurrent reporting of abuse-related and abusespecific AEs (AS-AEs) associated with gabapentin. Findings were compared to a positive (pregabalin) and negative (duloxetine) control.Results: From 2005-2015 there were 5,951,229 unique AE reports submitted to the FDA including 99,977 for gabapentin, 73,977 for duloxetine, and 97,813 for pregabalin. Significant drug-AR-AE pair signals involving gabapentin included: drug abuser, multiple drug overdose, and substance-induced psychotic disorder. Significant drug AR-AE signals involving gabapentin and pregabalin, but not duloxetine, were: ataxia, dependence, drug abuse, increased drug tolerance, and overdose. Compared to duloxetine, gabapentin had significantly greater odds of a coreport for an AS-AE with drug withdrawal syndrome (OR: 6.55), auditory hallucinations (OR: 4.57), delusions (OR: 2.36), euphoric mood (OR: 5.45), ataxia (OR: 2.85), drug abuser (OR: 3.01), aggression (OR: L98), psychotic disorder (OR: 1.96), and feeling abnormal (OR: 1.31).Conclusions: We identified abuse-related signals for gabapentin and highlighted several CNS effects that may be associated with its abuse. Gabapentin prescribers should be aware of the drug\u27s abuse liability and effects that may accompany its use

Combined linkage and association analysis of classical Hodgkin lymphoma

Peer reviewedPublisher PD

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care

Central obesity as a precursor to the metabolic syndrome in the AusDiab study and Mauritius

Evidence from epidemiologic studies that central obesity precedes future metabolic change and does not occur concurrently with the appearance of the blood pressure, glucose, and lipid abnormalities that characterize the metabolic syndrome (MetS) has been lacking. Longitudinal surveys were conducted in Mauritius in 1987, 1992, and 1998, and in Australia in 2000 and 2005 (AusDiab). This analysis included men and women (aged 25 years) in three cohorts: AusDiab 2000&ndash;2005 (n = 5,039), Mauritius 1987&ndash;1992 (n = 2,849), and Mauritius 1987&ndash;1998 (n = 1,999). MetS components included waist circumference, systolic blood pressure, fasting and 2-h postload plasma glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, and homeostasis model assessment of insulin sensitivity (HOMA-S) (representing insulin sensitivity). Linear regression was used to determine which baseline components predicted deterioration in other MetS components over 5 years in AusDiab and 5 and 11 years in Mauritius, adjusted for age, sex, and ethnic group. Baseline waist circumference predicted deterioration (P &lt; 0.01) in four of the other six MetS variables tested in AusDiab, five of six in Mauritius 1987&ndash;1992, and four of six in Mauritius 1987&ndash;1998. In contrast, an increase in waist circumference between baseline and follow-up was only predicted by insulin sensitivity (HOMA-S) at baseline, and only in one of the three cohorts. These results suggest that central obesity plays a central role in the development of the MetS and appears to precede the appearance of the other MetS components.<br /

Sixty Years of CA: A Cancer Journal for Clinicians

The first issue of CA: A Cancer Journal for Clinicians was published in November of 1950. On the 60th anniversary of that date, we briefly review several seminal contributions to oncology and cancer control published in our journal during its first decade. CA Cancer J Clin 2010. © 2010 American Cancer Society, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78301/1/20088_ftp.pd

The Impossibility of a Perfectly Competitive Labor Market

Using the institutional theory of transaction cost, I demonstrate that the assumptions of the competitive labor market model are internally contradictory and lead to the conclusion that on purely theoretical grounds a perfectly competitive labor market is a logical impossibility. By extension, the familiar diagram of wage determination by supply and demand is also a logical impossibility and the neoclassical labor demand curve is not a well-defined construct. The reason is that the perfectly competitive market model presumes zero transaction cost and with zero transaction cost all labor is hired as independent contractors, implying multi-person firms, the employment relationship, and labor market disappear. With positive transaction cost, on the other hand, employment contracts are incomplete and the labor supply curve to the firm is upward sloping, again causing the labor demand curve to be ill-defined. As a result, theory suggests that wage rates are always and everywhere an amalgam of an administered and bargained price. Working Paper 06-0

Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia

Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children

Perceptual impairment and psychomotor control in virtual laparoscopic surgery

Background: It is recognised that one of the major difficulties in performing laparoscopic surgery is the translation of two-dimensional video image information to a three-dimensional working area. However, research has tended to ignore the gaze and eye-hand coordination strategies employed by laparoscopic surgeons as they attempt to overcome these perceptual constraints. This study sought to examine if measures related to tool movements, gaze strategy, and eye-hand coordination (the quiet eye) differentiate between experienced and novice operators performing a two-handed manoeuvres task on a virtual reality laparoscopic surgical simulator (LAP Mentor™). Methods: Twenty-five right-handed surgeons were categorised as being either experienced (having led more than 60 laparoscopic procedures) or novice (having performed fewer than 10 procedures) operators. The 10 experienced and 15 novice surgeons completed the "two-hand manoeuvres" task from the LAP Mentor basic skills learning environment while wearing a gaze registration system. Performance, movement, gaze, and eye-hand coordination parameters were recorded and compared between groups. Results: The experienced surgeons completed the task significantly more quickly than the novices, used significantly fewer movements, and displayed shorter tool paths. Gaze analyses revealed that experienced surgeons spent significantly more time fixating the target locations than novices, who split their time between focusing on the targets and tracking the tools. A more detailed analysis of a difficult subcomponent of the task revealed that experienced operators used a significantly longer aiming fixation (the quiet eye period) to guide precision grasping movements and hence needed fewer grasp attempts. Conclusion: The findings of the study provide further support for the utility of examining strategic gaze behaviour and eye-hand coordination measures to help further our understanding of how experienced surgeons attempt to overcome the perceptual difficulties inherent in the laparoscopic environment. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201