In Vitro activity of the new azole isavuconazole (BAL4815) compared with six other antifungal agents against 162 Cryptococcus neoformans isolates from Cuba

Cuban Cryptococcus isolates (n = 165) were tested in vitro against amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, giving MIC90 values of 0.25, 8, 4, 0.25, 0.125, 0.016, and 0.016 microg/ml, respectively. Isavuconazole and posaconazole seem to be potentially active drugs for treating cryptococcal infections.     

An evaluation of a Shockroom located CT scanner: a randomized study of early assessment by CT scanning in trauma patients in the bi-located trauma center North-West Netherlands (REACT trial)

Background

Trauma is a major source of morbidity and mortality, especially in people below the age of 50 years. For the evaluation of trauma patients CT scanning has gained wide acceptance in and provides detailed information on location and severity of injuries. However, CT scanning is frequently time consuming due to logistical (location of CT scanner elsewhere in the hospital) and technical issues. An innovative and unique infrastructural change has been made in the AMC in which the CT scanner is transported to the patient instead of the patient to the CT scanner. As a consequence, early shockroom CT scanning provides an all-inclusive multifocal diagnostic modality that can detect (potentially life-threatening) injuries in an earlier stage, so that therapy can be directed based on these findings.

Methods/design

The REACT-trial is a prospective, randomized trial, comparing two Dutch level-1 trauma centers, respectively the VUmc and AMC, with the only difference being the location of the CT scanner (respectively in the Radiology Department and in the shockroom). All trauma patients that are transported to the AMC or VUmc shockroom according to the current prehospital triage system are included. Patients younger than 16 years of age and patients who die during transport are excluded. Randomization will be performed prehospitally. Study parameters are the number of days outside the hospital during the first year following the trauma (primary outcome), general health at 6 and 12 months post trauma, mortality and morbidity, and various time intervals during initial evaluation. In addition a cost-effectiveness analysis of this shockroom concept will be performed. Regarding primary outcome it is estimated that the common standard deviation of days spent outside of the hospital during the first year following trauma is a total of 12 days. To detect an overall difference of 2 days within the first year between the two strategies, 562 patients per group are needed. (alpha 0.95 and beta 0.80).

Discussion

The REACT-trial will provide evidence on the effects of a strategy involving early shockroom CT scanning compared with a standard diagnostic imaging strategy in trauma patients on both patient outcome and operations research.

Trial registration

ISRCTN55332315     

Submicroscopic Plasmodium falciparum gametocyte carriage is common in an area of low and seasonal transmission in Tanzania

OBJECTIVE: Recently developed molecular gametocyte detection techniques have shown that submicroscopic Plasmodium falciparum gametocytes are common in symptomatic patients and can infect mosquitoes. The relevance for the infectious reservoir of malaria in the general population remains unknown. In this study, we investigated submicroscopic asexual parasitaemia and gametocytaemia in inhabitants of an area of hypoendemic and seasonal malaria in Tanzania. METHODS: Two cross-sectional malariometric surveys were conducted in the dry and wet seasons of 2005 in villages in lower Moshi, Tanzania. Finger prick blood samples were taken to determine the prevalence of P. falciparum parasites by microscopy, rapid diagnostic test and real-time nucleic acid sequence-based amplification (QT-NASBA). RESULTS: 2752 individuals participated in the surveys, of whom 1.9% (51/2721) had microscopically confirmed asexual parasites and 0.4% (10/2721) had gametocytes. In contrast, QT-NASBA revealed that 32.5% (147/453) of the individuals harboured asexual parasites and 15.0% (68/453) had gametocytes. No age dependency or seasonality was observed in submicroscopic parasite carriage. DISCUSSION: Molecular detection techniques reveal that carriage of submicroscopic asexual parasite and gametocyte densities is relatively common in this low transmission area. Submicroscopic gametocytaemia is likely to be responsible for maintaining malarial transmission in the study area.     

Sociological refigurations of patient safety; ontologies of improvement and ‘acting with’ quality collaboratives in healthcare

The increasing focus on patient safety in the field of health policy is accompanied by research programs that articulate the role of the social sciences as one of contributing to enhancing safety in healthcare. Through these programs, new approaches to studying safety are facing a narrow definition of ‘usefulness’ in which researchers are to discover the factors that support or hamper the implementation of existing policy agendas. This is unfortunate since such claims for useful involvement in predefined policy agendas may undo one of the strongest assets of good social science research: the capacity to complexify the taken-for-granted conceptualizations of the object of study. As an alternative to this definition of ‘usefulness’, this article proposes a focus on multiple ontologies in the making when studying patient safety. Through such a focus, the role of social scientists becomes the involvement in refiguring the problem space of patient safety, the relations between research subjects and objects, and the existing policy agendas. This role gives medical sociologists the opportunity to focus on the question of which practices of ‘effective care’ are being enacted through different approaches for dealing with patient safety and what their consequences are for the care practices under study.     

Vitamin B12 Deficiency Stimulates Osteoclastogenesis via Increased Homocysteine and Methylmalonic Acid

The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B₁₂ deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B₁₂, Hcy, and MMA on differentiation and activity of bone cells. B₁₂ deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B₁₂ deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B₁₂, Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase–positive osteoclasts from mouse bone marrow. We observed that B₁₂ did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B₁₂ deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels.     

Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen

Tamoxifen is a largely inactive pro-drug, requiring metabolism into its most important metabolite endoxifen. Since the cytochrome P450 (CYP) 2D6 enzyme is primarily involved in this metabolism, genetic polymorphisms of this enzyme, but also drug-induced CYP2D6 inhibition can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy of tamoxifen treatment. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have been effectively used for the treatment of depression and hot flashes, both of which occur frequently in tamoxifen-treated women. Due to the drug–drug interaction considerably reduced endoxifen concentrations by inhibition of CYP2D6 will be the result. Evidence of a significant influence of strong CYP2D6-inhibiting drugs on the pharmacokinetics of tamoxifen has resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants (e.g., paroxetine, fluoxetine) in patients treated with tamoxifen for breast cancer. Nevertheless, dispensing data for tamoxifen and seven regularly used SSRIs/SNRIs in the period between 2005 and 2010, obtained from a large community pharmacy database in the Netherlands (3,000,000 people), show that the potent CYP2D6-inhibiting drug paroxetine remains one of the most frequently used antidepressants in tamoxifen-treated patients. Moreover, trends in the use of SSRIs/SNRIs in the population of all women were similar with trends in women using tamoxifen. Apparently, the recommendations to avoid paroxetine in tamoxifen-treated women have not been implemented into clinical practice. Several reasons may underlie continued use of this drug–drug combination. Contrary to CYP2D6 polymorphisms, drug-induced CYP2D6 inhibition can easily be avoided, since alternative drugs are available. In clinical practice, one should strive to avoid potent CYP2D6 inhibitors as much as possible in tamoxifen-treated patients to reduce the risk of compromising the efficacy of the hormonal therapy. Co-medication should be reviewed by both physicians and pharmacists and potent CYP2D6 inhibitors ought to be switched to weaker alternatives.     

Symptoms and treatment in cancer therapy-induced early menopause

Young women with breast cancer often experience early menopause as a result of the therapy for their malignant disease. The sudden occurrence of menopause resulting from chemotherapy, oophorectomy, radiation, or gonadal dysgenesis frequently results in hot flashes that begin at a younger age and may occur at a greater frequency and intensity than hot flashes associated with natural menopause. Hormone therapy relieves symptoms effectively in 80%-90% of women who initiate treatment. This therapy, however, is generally contraindicated in estrogen-dependent cancers, such as breast cancer, because of the potentially increased risk for recurrence. Many agents have been investigated as potential means for alleviating hot flashes in survivors of breast cancer, such as progestagens, clonidine, gabapentin, and anti-depressants. Several complementary and alternative medicines frequently used by patients have also been studied. These include black cohosh, phytoestrogens, homeopathy, vitamin E, acupuncture, and behavior strategies. To support the use of one of more of these nonpharmacological or pharmacological options in the treatment of hot flashes in breast cancer patients, more evidence from well-controlled clinical trials is needed. In particular, soundly based scientific research with complementary and alternative medicine therapies is lacking. Pharmacological treatments appear to be more beneficial than nonpharmacological treatments. This article reviews the current literature to assess the epidemiology and diagnosis of hot flashes and the nonpharmacological and pharmacological options for the treatment of hot flashes, in breast cancer patients in particular. When specific treatment options have not been evaluated in breast cancer patients specifically, published data on the management of hot flashes with this modality in healthy postmenopausal women are described.     

Anti-interleukin-2 receptor antibodies in transplantation: what is the basis for choice?

Two monoclonal antibody preparations against the alpha-chain of the interleukin-2 receptor (IL-2Ralpha) are available for use, basiliximab and daclizumab, a chimeric and a humanised antibody, respectively. The first clinical studies have demonstrated the efficacy of these agents as induction therapy to reduce the rate of acute rejection after organ transplantation. Basiliximab and daclizumab have a similar effect on prevention of acute rejection. Likewise, incidence of infections and malignancies are not different between the two treatment options. Anti-IL-2Ralpha therapy was very well tolerated in clinical trials. Phase III studies with basiliximab have been undertaken with a two-dose regimen, consisting of two doses of 20mg, in an attempt to saturate the IL-2Ralpha on peripheral blood T lymphocytes for an average of 4-6 weeks. In contrast, the daclizumab dose is corrected for bodyweight and the goal is to achieve IL-2Ralpha blockade for 12 weeks. Phase III efficacy trials with daclizumab have, therefore, been developed with five doses of 1 mg/kg every 2 weeks in the first 2 months after transplantation. Whether or not it is a benefit to have blockade of the IL-2Ralpha for 10-12 weeks (daclizumab) compared with 4-6 weeks (basiliximab) remains unknown. Assuming 4-6 weeks would be sufficient for prevention of acute rejection, many centres have changed the protocol of daclizumab administration to two doses, the first dose given at the time of transplantation, the second 10 or 14 days after, with good success. Therefore, it seems feasible to limit the dose of daclizumab, which increases the ease of administration and probably also the cost effectiveness of this agent. There are no controlled studies comparing basiliximab and daclizumab, nor have different dose regimens been directly compared in renal transplantation. The data available suggest the differences are small, if present at all, and it is unlikely that such a trial will ever be done. With both compounds, a significant reduction in the number of acute rejection episodes following solid organ transplantation can be obtained without an increase in adverse effects or infectious complications.