Monitoring drug therapy.

Drug development has improved over recent decades, with refinements in analytical techniques, population pharmacokinetic-pharmacodynamic (PK-PD) modelling and simulation, and new biomarkers of efficacy and tolerability. Yet this progress has not yielded improvements in individualization of treatment and monitoring, owing to various obstacles: monitoring is complex and demanding, many monitoring procedures have been instituted without critical assessment of the underlying evidence and rationale, controlled clinical trials are sparse, monitoring procedures are poorly validated and both drug manufacturers and regulatory authorities take insufficient account of the importance of monitoring. Drug concentration and effect data should be increasingly collected, analyzed, aggregated and disseminated in forms suitable for prescribers, along with efficient monitoring tools and evidence-based recommendations regarding their best use. PK-PD observations should be collected for both novel and established critical drugs and applied to observational data, in order to establish whether monitoring would be suitable. Methods for aggregating PK-PD data in systematic reviews should be devised. Observational and intervention studies to evaluate monitoring procedures are needed. Miniaturized monitoring tests for delivery at the point of care should be developed and harnessed to closed-loop regulated drug delivery systems. Intelligent devices would enable unprecedented precision in the application of critical treatments, i.e. those with life-saving efficacy, narrow therapeutic margins and high interpatient variability. Pharmaceutical companies, regulatory agencies and academic clinical pharmacologists share the responsibility of leading such developments, in order to ensure that patients obtain the greatest benefit and suffer the least harm from their medicines.

A multicenter, cross-sectional study on the prevalence and risk factors for nasal colonization with Staphylococcus aureus in patients admitted to children's hospitals in Switzerland.

The rate of nasal carriage of Staphylococcus aureus and associated risk factors were determined in a cross-sectional study involving Swiss children's hospitals. S. aureus was isolated in 562 of 1363 cases. In a stepwise multivariate analysis, the variables age, duration of antibiotic use, and hospitalization of a household member were independently associated with carriage of S. aureus.

Traitements de fer: preuves de t'efficacité et bonne pratique clinique [Iron therapy: proof of efficacy and good clinical practice].

Efficacy of iron therapy, whether oral or intravenous, on biological markers of body iron stores is well recognized in medical literature, but current studies are heterogeneous, of sometimes dubious quality, and rarely address clinical outcomes. Precise practical guidelines appear available only for indications related to kidney disease. First-line intravenous use is reserved for situations comprising chronic renal failure, or patients presenting with malabsorption syndromes such as in inflammatory bowel disease. In all other situations, because of the non-negligible risk of hypersensitivity reactions, intravenous iron use is considered justified only in clinically sustained indications, for patients in whom oral administration of iron is unsatisfactory or impossible.

Vulnerability to schizophrenia: relevance of patients' subjective experience for empirical and clinical work.

Efforts are being made by clinicians and researchers to accurately delineate phenotypic traits of individuals at enhanced risk of schizophrenia. This issue is important for a better understanding of the etiopathogenic mechanisms of the disease and for the building up of programs of primary prevention. We suggest that disturbances of subjective experience, although difficult to operationalize, are an important-but until now neglected-core component of schizophrenia spectrum disorders. We advocate the development of valid and reliable instruments in order to allow the assessment of basic symptoms and disturbances of Self-experience. Delineation of vulnerability to schizophrenia cannot rely solely on neuropsychological and neurophysiological data, as prevention programs will be performed mainly by clinicians.

Magmatic fluids in the Breccia-hosted epithermal Au-Ag deposit of Rosia Montana, Romania

The breccia-hosted epithermal Au-Ag deposit of Rosia Montana is located 7 kin northeast of Abrud, in the northern part of the South Apuseni Mountains, Romania. Estimated total reserves of 214.91 million metric toils (Mt) of ore at 1.46 g/t An and 6.9 g/t Ag (10.1 Moz of An and 47.6 Moz of Ag) make Rosia Montana one of the largest gold deposits in Europe. At this location, Miocene calc-alkaline magmatic and hydrothermal activity was associated with local extensional tectonics within a strike-slip regime related to the indentation of the Adriatic microplate into the European plate during the Carpathian orogenesis. The host rocks of the magmatic complex consist of pre-Mesozoic metamorphosed continental crust covered by Cretaceous turbiditic sediment (flysch). Magmatic activity at Rosia Montana and its surroundings occurred in several pulses and lasted about 7 m.y, Rosia Montana is a breccia-hosted epithermal system related to strong phreatomagmatic activity due to the shallow emplacement of the Montana dacite. The Montana dacite intruded Miocene volcaniclastic material (volcaniclastic breccias) and crops out at Cetate and Carnic Hills. Current mining is focused primarily on the Cetate open pit, which was mapped in detail, leading to the recognition of three distinct breccia bodies: the dacite breccia with a dominantly hydrothermal matrix, the gray polymict breccia with a greater proportion of sand-sized matrix support, and the black polymict breccia, which reached to the surface, contains carbonized tree trunks and has a dominantly barren elastic matrix. The hydrothermal alteration is pervasive. Adularia alteration with a phyllic overprint is ubiquitous; silicification and argillic alteration occur locally. Mineralization consists of quartz, adularia, carbonates (commonly Mn-rich), pyrite, Fe-poor sphalerite, galena, chalcopyrite, tetrahedrite, and native gold and occurs as disseminations, as well as in veins and filling vugs within the Montana dacite and the different breccias. The age of mineralization (12.85 +/- 0.07 Ma) was determined by Ar-40- Ar-39 dating on hydrothermal adularia crystals from vugs in the dacite breccia in the Cetate open pit. Microthermometric measurements of fluid inclusions in quartz phenocrysts from the Montana dacite revealed two fluid types that are absent from the hydrothermal breccia and must have been trapped at depth prior to dacite dome emplacement: brine inclusions (32-55 -wt % NaCl equiv, homogenizing at T-h > 460 degrees C) and intermediate density fluids (4.9-15.6 wt % NaCl equiv, T, between 345 degrees-430 degrees C). Secondary aqueous fluid inclusion assemblages in the phenocrysts have salinities of 0.2 to 2.2 wt percent NaCl equiv and T-h of 200 degrees to 280 degrees C. Fluid inclusion assemblages in hydrothermal quartz from breccias and veins have salinities of 0.2 to 3.4 wt percent NaCl equiv and T-h, from 200 degrees to 270 degrees C. The oxygen isotope composition of several zones of an ore-related epithermal quartz crystal indicate a very constant delta O-18 of 4.5 to 5.0 per mil for the mineralizing fluid, despite significant salinity and temperature variation over time. Following microthermometry, selected fluid inclusion assemblages were analyzed by laser ablation-inductively coupled-plasma mass spectrometry (LA-ICMS). Despite systematic differences in salinity between phenocryst-hosted fluids trapped at depth and fluids from quartz in the epithermal breccias, all fluids have overlapping major and trace cation ratios, including identical Na/K/Rb/Sr/Cs/Ba. Consistent with the constant near-magmatic oxygen isotope composition of the hydrothermal fluids, these data strongly indicate a common magmatic component of these chemically conservative solutes in all fluids. Cu, Pb, Zn, and Mn show variations in concentration relative to the relatively non-reactive alkalis, reflecting the precipitation of sulfide minerals together with An in the epithermal breccia, and possibly of Cu in an inferred subjacent porphyry environment. The magmatic-hydrothermal processes responsible for epithermal Au-Ag mineralization at Rosia Montana are, however, not directly related to the formation of the spatially associated porphyry Cu-Au deposit of Rosia Poieni, which occurred lout 3 m.y. later.

Epidemiology and new developments in the diagnosis of prosthetic joint infection.

Although prosthetic joint infection (PJI) is a rare event after arthroplasty, it represents a significant complication that is associated with high morbidity, need for complex treatment, and substantial healthcare costs. An accurate and rapid diagnosis of PJI is crucial for treatment success. Current diagnostic methods in PJI are insufficient with 10-30% false-negative cultures. Consequently, there is a need for research and development into new methods aimed at improving diagnostic accuracy and speed of detection. In this article, we review available conventional diagnostic methods for the diagnosis of PJI (laboratory markers, histopathology, synovial fluid and periprosthetic tissue cultures), new diagnostic methods (sonication of implants, specific and multiplex PCR, mass spectrometry) and innovative techniques under development (new laboratory markers, microcalorimetry, electrical method, reverse transcription [RT]-PCR, fluorescence in situ hybridization [FISH], biofilm microscopy, microarray identification, and serological tests). The results of highly sensitive diagnostic techniques with unknown specificity should be interpreted with caution. The organism identified by a new method may represent a real pathogen that was unrecognized by conventional diagnostic methods or contamination during specimen sampling, transportation, or processing. For accurate interpretation, additional studies are needed, which would evaluate the long-term outcome (usually >2 years) with or without antimicrobial treatment. It is expected that new rapid, accurate, and fully automatic diagnostic tests will be developed soon.

Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy

Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signalling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic targets (glycogen synthase kinase-3beta (GSK-3beta), mTOR, p70(s6k) and 4E-BP1) and catabolic targets (Foxo1, Foxo3, atrogin-1 and MuRF1). All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. Following resistance training a muscle hypertrophy ( approximately 10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content were observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1 were observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signalling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes

When physician-expressed uncertainty leads to patient dissatisfaction: a gender study.

CONTEXT: Communication guidelines often advise physicians to disclose to their patients medical uncertainty regarding the diagnosis, origin of the problem, and treatment. However, the effect of the expression of such uncertainty on patient outcomes (e.g. satisfaction) has produced conflicting results in the literature that indicate either no effect or a negative effect. The differences in the results of past studies may be explained by the fact that potential gender effects on the link between physician-expressed uncertainty and patient outcomes have not been investigated systematically. OBJECTIVES: On the basis of previous research documenting indications that patients may judge female physicians by more severe criteria than they do male physicians, and that men are more prejudiced than women towards women, we predicted that physician-expressed uncertainty would have more of a negative impact on patient satisfaction when the physician in question was female rather than male, and especially when the patient was a man. METHODS: We conducted two studies with complementary designs. Study 1 was a randomised controlled trial conducted in a simulated setting (120 analogue patients Analogue patients are healthy participants asked to put themselves in the shoes of real medical patients by imagining being the patients of physicians shown on videos); Study 2 was a field study conducted in real medical interviews (36 physicians, 69 patients). In Study 1, participants were presented with vignettes that varied in terms of the physician's gender and physician-expressed uncertainty (high versus low). In Study 2, physicians were filmed during real medical consultations and the level of uncertainty they expressed was coded by an independent rater according to the videos. In both studies, patient satisfaction was assessed using a questionnaire. RESULTS: The results confirmed that expressed uncertainty was negatively related to patient satisfaction only when the physician was a woman (Studies 1 and 2) and when the patient was a man (Study 2). CONCLUSIONS: We believe that patients have the right to be fully informed of any medical uncertainties. If our results are confirmed in further research, the question of import will refer not to whether female physicians should communicate uncertainty, but to how they should communicate it. For instance, if it proves true that uncertainty negatively impacts on (male) patients' satisfaction, female physicians might want to counterbalance this impact by emphasizing other communication skills.

Does the working environment influence health care professionals' values, meaning in life and religiousness? Palliative care units compared with maternity wards.

CONTEXT: Increased altruism, self-transcendence, and quests for meaning in life (MiL) have been found in palliative care (PC) patients and their families who experience the finiteness of life. Similar changes were observed in healthy subjects who were experimentally confronted with their mortality. OBJECTIVES: The study investigated how daily experiences of the transitoriness of life influence PC health care professionals' (HCPs) values, MiL, and religiousness. METHODS: In a cross-sectional study, the Schwartz Value Survey, the Schedule for Meaning in Life Evaluation, and the Idler Index of Religiosity were used to investigate personal values, MiL, and private religiousness. HCPs working in PC (confronted with death) were compared with a control group of HCPs working at maternity wards (MWs) using multivariate models. Differences were considered to be statistically significant at P < 0.05. RESULTS: Seventy PC- and 70 MW-HCPs took part in the study (response rate 74.0%). No differences between the groups were found in overall MiL satisfaction scores. PC-HCPs were significantly more religious than MW-HCPs; they listed spirituality and nature experience more often as areas in which they experience MiL. Furthermore, hedonism was more important for PC-HCPs, and they had higher scores in openness-to-change values (stimulation and self-direction). MW-HCPs were more likely to list family as a MiL area. They assigned more importance to health and scored higher in conservation values (conformity and security). Duration of professional experience did not influence these results. CONCLUSION: Basic differences in values, MiL, and religiousness between PC-HCPs and MW-HCPs might have influenced the choice of working environment because no effect of job duration was observed. Longitudinal research is needed to confirm this hypothesis.

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data.

BACKGROUND: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. METHODS: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. FINDINGS: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). INTERPRETATION: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. FUNDING: Bill & Melinda Gates Foundation.