Amikacin use and therapeutic drug monitoring in adults : do dose regimens and drug exposures affect either outcome or adverse events? A systematic review

Objectives To identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. Methods A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles of randomised controlled trials, controlled clinical trials, interrupted time series trials and controlled before and after studies involving amikacin TDM and dose adjustment were considered for inclusion. Results Seventeen included studies were identified, comprising 1677 participants. Amikacin doses ranged from 11-15 mg/kg/day with thirteen studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only eleven papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 – 40 mg/L and target troughs were typically <10 mg/L or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice daily dosing and 40-45 mg/L for once daily dosing; troughs averaged 5 mg/L and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in twelve and eight studies. Conclusions This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximise therapeutic outcomes and minimise toxicity with amikacin

Adsorption of para-Hydrogen on Krypton pre-plated graphite

Adsorption of para-Hydrogen on the surface of graphite pre-plated with a single layer of atomic krypton is studied thoretically by means of Path Integral Ground State Monte Carlo simulations. We compute energetics and density profiles of para-hydrogen, and determine the structure of the adsorbed film for various coverages. Results show that there are two thermodynamically stable monolayer phases of para-hydrogen, both solid. One is commensurate with the krypton layer, the other is incommensurate. No evidence is seen of a thermodynamically stable liquid phase, at zero temperature. These results are qualitatively similar to what is seen for for para-hydrogen on bare graphite. Quantum exchanges of hydrogen molecules are suppressed in this system.Comment: 12 pages, 6 figures, to appear in the proceedings of "Advances in Computational Many-Body Physics", Banff, Alberta (Canada), January 13-16 200

Retrospective observational study to assess the clinical management and outcomes of hospitalised patients with complicated urinary tract infection in countries with high prevalence of multidrug resistant Gram-negative bacteria (RESCUING)

INTRODUCTION: The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB. METHODS AND ANALYSIS: This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5–7 with appropriate antibiotic therapy, (2) new cUTI-related symptoms that have developed within 30 days of diagnosis, (3) urine culture taken within 30 days of diagnosis, either during or after completion of therapy, that grows ≥104 colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30 days of the cUTI diagnosis. SAMPLE SIZE: 1000 patients afford a power of 0.83 (α=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure. ETHICS AND DISSEMINATION: Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE)

School feeding for improving the physical and psychosocial health of disadvantaged elementary school children.

BACKGROUND: Early malnutrition and/or micronutrient deficiencies can adversely affect physical, mental, and social aspects of child health. School feeding programs are designed to improve attendance, achievement, growth, and other health outcomes. OBJECTIVES: The main objective was to determine the effectiveness of school feeding programs in improving physical and psychosocial health for disadvantaged school children. SEARCH STRATEGY: We searched a number of databases including CENTRAL (2006 Issue 2), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), PsycINFO (1980 to May 2006) and CINAHL (1982 to May 2006). Grey literature sources were also searched. Reference lists of included studies and key journals were handsearched and we also contacted selected experts in the field. SELECTION CRITERIA: Data from randomized controlled trials (RCTs), non-randomised controlled clinical trials (CCTs), controlled before and after studies (CBAs), and interrupted time series studies (ITSs) were included. Feeding had to be done in school; the majority of participants had to be socio-economically disadvantaged. DATA COLLECTION AND ANALYSIS: Two reviewers assessed all searches and retrieved studies. Data extraction was done by one of four reviewers and reviewed by a second. Two reviewers independently rated quality. If sufficient data were available, they were synthesized using random effects meta-analysis, adjusting for clustering if needed. Analyses were performed separately for RCTs and CBAs and for higher and lower income countries. MAIN RESULTS: We included 18 studies. For weight, in the RCTs and CBAs from Lower Income Countries, experimental group children gained an average of 0.39 kg (95% C.I: 0.11 to 0.67) over an average of 19 months and 0.71 kg (95% C.I.: 0.48 to 0.95) over 11.3 months respectively. Results for weight were mixed in higher income countries. For height, results were mixed; height gain was greater for younger children. Attendance in lower income countries was higher in experimental groups than in controls; our results show an average increase of 4 to 6 days a year. Math gains were consistently higher for experimental groups in lower income countries; in CBAs, the Standardized Mean Difference was 0.66 (95% C.I. = 0.13 to 1.18). In short-term studies, small improvements in some cognitive tasks were found. AUTHORS' CONCLUSIONS: School meals may have some small benefits for disadvantaged children. We recommend further well-designed studies on the effectiveness of school meals be undertaken, that results should be reported according to socio-economic status, and that researchers gather robust data on both processes and carefully chosen outcomes

Consistent Anisotropic Repulsions for Simple Molecules

We extract atom-atom potentials from the effective spherical potentials that suc cessfully model Hugoniot experiments on molecular fluids, e.g., $O_2$ and $N_2$. In the case of $O_2$ the resulting potentials compare very well with the atom-atom potentials used in studies of solid-state propertie s, while for $N_2$ they are considerably softer at short distances. Ground state (T=0K) and room temperatu re calculations performed with the new $N-N$ potential resolve the previous discrepancy between experimental and theoretical results.Comment: RevTeX, 5 figure

Genomic sequences of Streptococcus agalactiae with high-level gentamicin resistance, collected in the BSAC bacteraemia surveillance

Background: Like other streptococci, Streptococcus agalactiae typically has intrinsic low-level aminoglycoside resistance. High-level gentamicin resistance was seen in 2 of 1125 isolates collected in the BSAC Bacteraemia Surveillance Programme between 2001 and 2014. These organisms, both isolated in 2014, were characterized. Methods: Identifications were by latex agglutination, MICs by BSAC agar dilution and sequencing by Illumina methodology. Results: Gentamicin MICs were >1024 mg/L versus a species mode of 8 mg/L; both isolates also were unusually ciprofloxacin resistant with MICs of 64 mg/L versus a species mode of 1 mg/L. They were distinct by sequence, but both belonged to the ST19 clone, which occurs globally. Both had aac(6′)-aph(2″), carried by different transposons, explaining their gentamicin resistance, and had gyrA[81:S-L];parC[79:S-Y], accounting for ciprofloxacin resistance. Conclusions: These are the first multiresistant S. agalactiae with the bifunctional AAC(6′)-APH(2″) enzyme to be reported in the UK for >10 years. Despite belonging to the same clonal complex, the two isolates and their resistance transposons were distinct. Both retained full susceptibility to penicillin, but any penicillin/gentamicin synergy is likely to be lost

Relating Therapist Characteristics to Client Engagement and the Therapeutic Alliance in an Adolescent Custodial Group Substance Misuse Treatment Program

Background: Client engagement in substance misuse treatment programs is directly associated with positive treatment outcomes. The nature of these programs means there are often difficulties engaging and retaining clients, but authors have consistently found a strong therapeutic alliance is associated with client engagement. While research has focused on the association between the alliance and engagement, the factors that influence the therapeutic alliance have received less attention. Objective: To examine therapists’ characteristics, namely therapists’ stress and empathy levels, as potential predictors of client engagement and the therapeutic alliance, within an adolescent substance misuse group treatment program. Method: The sample included 84 adolescent clients and 14 therapists from a Secure Training Centre in England. Client engagement in the treatment program was observed, while self-reporting measures assessed the therapeutic alliance (client and therapist-rated), and therapists’ stress and empathy levels. Results: Multiple regression analysis revealed that therapists’ stress levels negatively influenced the therapeutic alliance and had a curvilinear relationship with client engagement, indicating that stress is not exclusively negatively related to engagement. Although stress was found to negatively impact both cognitive and affective empathy, neither cognitive nor affective empathy were significantly related to client engagement or the therapeutic alliance.Conclusions: This study demonstrates the importance of therapist characteristics on client engagement and the TA. Within practice stress can have a positive impact on clients’ engagement. Nevertheless, therapists may need additional support to deal with stress effectively. Therapists’ empathy may too be fundamental to client engagement, but only it if is perceived by clients.<br/

Cost of hospitalised patients due to complicated urinary tract infections: a retrospective observational study in countries with high prevalence of multidrug-resistant Gram-negative bacteria: the COMBACTE-MAGNET, RESCUING study

OBJECTIVE: Complicated urinary tract infections (cUTIs) impose a high burden on healthcare systems and are a frequent cause of hospitalisation. The aims of this paper are to estimate the cost per episode of patients hospitalised due to cUTI and to explore the factors associated with cUTI-related healthcare costs in eight countries with high prevalence of multidrug resistance (MDR). DESIGN: This is a multinational observational, retrospective study. The mean cost per episode was computed by multiplying the volume of healthcare use for each patient by the unit cost of each item of care and summing across all components. Costs were measured from the hospital perspective. Patient-level regression analyses were used to identify the factors explaining variation in cUTI-related costs. SETTING: The study was conducted in 20 hospitals in eight countries with high prevalence of multidrug resistant Gram-negative bacteria (Bulgaria, Greece, Hungary, Israel, Italy, Romania, Spain and Turkey). PARTICIPANTS: Data were obtained from 644 episodes of patients hospitalised due to cUTI. RESULTS: The mean cost per case was €5700, with considerable variation between countries (largest value €7740 in Turkey; lowest value €4028 in Israel), mainly due to differences in length of hospital stay. Factors associated with higher costs per patient were: type of admission, infection source, infection severity, the Charlson comorbidity index and presence of MDR. CONCLUSIONS: The mean cost per hospitalised case of cUTI was substantial and varied significantly between countries. A better knowledge of the reasons for variations in length of stays could facilitate a better standardised quality of care for patients with cUTI and allow a more efficient allocation of healthcare resources. Urgent admissions, infections due to an indwelling urinary catheterisation, resulting in septic shock or severe sepsis, in patients with comorbidities and presenting MDR were related to a higher cost

Current Antibiotic Treatment and Outcome for Lower Respiratory Tract Infections

A number of national guidelines have been published to aid the antimicrobial management of community-acquired pneumonia. However, data on prescriptions for lower respiratory tract infection (LRTI) indicate considerable variation in the choice of first-line and subsequent therapy at national and local levels. Outcomes research in LRTI, whether based on clinical, economic or patient-focused criteria, is still evolving. Clinical outcomes are best studied for both pneumonia and exacerbation of chronic obstructive pulmonary disease. Economic evaluations often do not encompass all of the costs, for example, time off from work or the economic impact of antibacterial resistance. Duration of hospital stay is a good marker of costs for hospital providers and may be affected by age. marital status and comorbidities. Antibiotic choice may have an impact on the duration of hospital stay by increasing side effects, predisposing patients to hospitalacquired infection or reduced clinical efficacy. Patient expectation is largely unstudied in pulmonary infection

Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies

SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex-determination. We identified two individuals with 46,XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46,XY DSD and a missense mutation in the HMG-box of SOX8. In-vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analyzed SOX8 in a cohort of infertile men (n = 274) and two independent cohorts of women with primary ovarian insufficiency (POI; n = 153 and n = 104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; p<0.05) and POI (5.06%; p=4.5x10-5) as compared to fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared to the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46,XY DSD, male infertility and 46,XX POI