The effects of antifungal stewardship programs at a tertiary-care teaching hospital in Japan

Patients with invasive fungal diseases (IFDs) generally have a high mortality rate, and resistance to antifungal drugs and the high costs associated with it have led to recent problems, necessitating the appropriate use of antifungals. To this end, we launched Antifungal Stewardship Programs (AFSPs) in our hospital. Patients who were systemically administered antifungals from January 2011 to December 2016 were enrolled this study and divided into pre-intervention and intervention groups. No significant difference was observed in defined daily doses per 1000 patient-days (23.3 ± 8.0 vs 20.4 ± 10.8, p = 0.251) between the groups. The monthly average for the days of therapy per 1000 patient-days was significantly lower in the intervention group (15.1 ± 3.1 vs 12.7 ± 4.3, p = 0.009). The cost of the antifungals reduced over the 3-year period by $260,520 (13.5%). Furthermore, a decreasing trend was observed in both the 30-day mortality (40.9% vs 30.0%, p = 0.414) and in-hospital mortality (63.6% vs 36.7%, p = 0.054) in patients with candidemia. Our results indicate that AFSPs are efficacious and cost-effective approaches.     

Cyclooxygenase-2 mRNA expression is associated with c-fos mRNA expression and transient water ADC reduction detected with diffusion MRI during acute focal ischemia in rats

Cyclooxygenase-2 (COX-2) plays an important role in the development of injury during cerebral ischemia and inhibition of its activity can reduce infarct size. COX-2 expression during acute ischemia is caused by activation of post-synaptic glutamate receptors, which occurs during spreading depression and ischemic depolarization. Both of these phenomena cause a reduction in the apparent diffusion coefficient of water (ADC), which can be detected with diffusion-weighted magnetic resonance imaging. The reduction is believed to be caused by cellular swelling that occurs as cells depolarize. The goal of this work was to determine the spatial relationship between cyclooxygenase-2 mRNA (cox-2) expression, c-fos mRNA expression and ADC reduction during acute focal cerebral ischemia. Adult rats were subjected to either 30- or 60-min permanent occlusion of the middle cerebral artery. A 2-Tesla scanner was used to acquire diffusion-weighted echo-planar images throughout the ischemic period, which were used to calculate ADC maps. Cox-2 and c-fos mRNA were detected with (35)S in situ hybridization. The results indicate that, for rats subjected to 60-min ischemia, cox-2 was observed in superficial layers of cortex, where transient ADC reduction and c-fos expression were observed. The same was true for most rats subjected to 30-min ischemia. However, in a small number of rats of the 30-min group, cox-2 mRNA expression was observed in regions exhibiting transient and persistent ADC reduction with no c-fos expression. The results suggest that cox-2 mRNA expression during acute MCA occlusion is caused by either or both spreading depression and transient ischemic depolarization.     

Mild hypothermia decreases the incidence of transient ADC reduction detected with diffusion MRI and expression of c-fos and hsp70 mRNA during acute focal ischemia in rats

The effects of mild hypothermia on the apparent diffusion coefficient of water (ADC) and expression of c-fos and hsp70 mRNA were examined during acute focal cerebral ischemia. Young adult rats were subjected to 60-min middle cerebral artery occlusion under either normothermia (37.5°C) or hypothermia (33°C). Diffusion-weighted echo-planar magnetic resonance imaging was used to monitor changes in ADC throughout the ischemic period. Perfusion MRI with dysprosium contrast was used at the end of the ischemic period to verify that the occlusion was successful. C-fos and hsp70 mRNA expression were examined with in situ hybridization at the end of the ischemic period. The results indicate that the size of the region that exhibited reduced ADC was smaller during hypothermia than during normothermia. Hypothermia also decreased the frequency of occurrence of transient ADC reductions, especially in dorsal aspects of cortex. Expression of both c-fos and hsp70 mRNA were markedly reduced by hypothermia. Transient ADC reduction and c-fos expression are associated with spreading depression, which is believed to contribute to lesion expansion during acute focal ischemia. The results suggest that part of the neuroprotective effect of hypothermia may be due to a reduced incidence of spreading depression.     

Transient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats

Cerebral ischemia induces immediate early genes such as c-fos and stress genes such as hsp70. In this study, the spatial relationships between c-fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion magnetic resonance (MR) imaging were examined. The middle cerebral artery (MCA) of young adult rats was occluded for 30 or 60 min. Diffusion MR (D-MR) images were acquired continuously during the ischemic period and dysprosium-contrast perfusion (P-MR) images were acquired at the end of the ischemic period. C-fos and hsp70 mRNA expression were examined with in situ hybridization. The most significant finding of this work was that for both durations of ischemia, c-fos induction was observed in cortical and sub-cortical regions exhibiting a transient reduction in the apparent diffusion coefficient of water (ADC). Transients which occurred on a time scale of 3 min may have been caused by spreading depression. Those occurring on a 10-min time scale may have been caused by an initial reduction in blood flow with occlusion that was followed by an ischemia-induced increase in collateral blood flow. P-MR imaging showed that perfusion in c-fos positive regions was higher than in regions with persistently reduced ADC. Hsp70 induction did not correlate with transient ADC reduction. It was induced in the MCA territory in regions showing persistent ADC changes, with induction being greatest at the periphery of these regions. It was also induced in regions that exhibited both spontaneous reversal of the diffusion changes and decreased perfusion.     

The surgical treatment of myelopathy secondary to rheumatoid arthritis of the lower cervical spine

Summary There are few reports in the literature of the surgical treatment of cervical myelopathy secondary to rheumatoid arthritis below the level of the axis. Three cases are presented. All had severe motor and sensory loss in the upper and lower extremities. The cause of myelopathy differed in each case: in the first, the dura mater was infiltrated with rheumatoid material; the second was due to a stenotic spinal canal narrowed by a fixed subluxation of the cervical spine; in the third, traction myelopathy resulted from sub-axial subluxation and posterior angulation combined with cervical instability.Neurological assessment is particularly difficult in patients with rheumatoid arthritis of the cervical spine. Skull or halo traction is useful to gauge neurological improvement, to reduce the dislocation and to immobilise the cervical spine before, during and after surgery. Surgery is considered where conservative treatment is either ineffective or not tolerated, and is indicated if severe myelopathy is evident or progressive. Anterior interbody fusion is the operation of choice for mobile subluxation. Laminectomy is recommended in fixed subluxation where compression of the cord is demonstrated on myelography.

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Résumé Il n'existe qu'un petit nombre de publications concernant le traitement chirurgical des myélopathies secondaires à une polyarthrite rhumatoïde siégeant audessous de l'axis. Les auteurs en rapportent trois cas. Tous les malades présentaient un déficit sensitivomoteur sévère au niveau des membres supérieurs et inférieurs. Dans chacun des cas la cause de la myélopathie était différente: chez le premier malade, la duremère était infiltrée de productions rhumatoïdes; chez le second, il existait une sténose du canal rachidien due à une subluxation permanente des vertèbres cervicales; chez le troisième, une myélopathie par élongation résultait d'une subluxation sous-axoïdienne et d'une angulation postérieure, associées à une instabilité cervicale.Le bilan neurologique est particulièrement difficile à établir chez les malades atteints d'une polyarthrite rhumatoïde du rachis cervical. La traction crânienne ou par halo est utile pour apprécier l'amélioration neurologique, pour réduire la luxation et pour immobiliser le rachis cervical, avant, pendant et après l'intervention. Le recours à la chirurgie doit être envisagé lorsque le traitement conservateur est inefficace ou mal toléré, et il est indiqué si une myélopathie sévère est évidente ou évolutive. L'intervention de choix, en présence d'une subluxation mobile, est l'arthrodèse corporéale antérieure. La laminectomie est préconisée dans les cas de subluxation fixée, quand la myélographie met en évidence une compression médullaire.

     

Bartlett‐type corrections and bootstrap adjustments of likelihood‐based inference methods for network meta‐analysis

In network meta‐analyses that synthesize direct and indirect comparison evidence concerning multiple treatments, multivariate random effects models have been routinely used for addressing between‐studies heterogeneities. Although their standard inference methods depend on large sample approximations (eg, restricted maximum likelihood estimation) for the number of trials synthesized, the numbers of trials are often moderate or small. In these situations, standard estimators cannot be expected to behave in accordance with asymptotic theory; in particular, confidence intervals cannot be assumed to exhibit their nominal coverage probabilities (also, the type I error probabilities of the corresponding tests cannot be retained). The invalidity issue may seriously influence the overall conclusions of network meta‐analyses. In this article, we develop several improved inference methods for network meta‐analyses to resolve these problems. We first introduce 2 efficient likelihood‐based inference methods, the likelihood ratio test–based and efficient score test–based methods, in a general framework of network meta‐analysis. Then, to improve the small‐sample inferences, we developed improved higher‐order asymptotic methods using Bartlett‐type corrections and bootstrap adjustment methods. The proposed methods adopt Monte Carlo approaches using parametric bootstraps to effectively circumvent complicated analytical calculations of case‐by‐case analyses and to permit flexible application to various statistical models network meta‐analyses. These methods can also be straightforwardly applied to multivariate meta‐regression analyses and to tests for the evaluation of inconsistency. In numerical evaluations via simulations, the proposed methods generally performed well compared with the ordinary restricted maximum likelihood–based inference method. Applications to 2 network meta‐analysis datasets are provided.     

High Dietary Fat Intake during Lactation Promotes the Development of Social Stress-Induced Obesity in the Offspring of Mice

This study examined how a maternal high-fat diet (HD) during lactation and exposure of offspring to isolation stress influence the susceptibility of offspring to the development of obesity. C57BL/6J mice were fed a commercial diet (CD) during pregnancy and a CD or HD during lactation. Male offspring were weaned at three weeks of age, fed a CD until seven weeks of age, and fed a CD or HD until 11 weeks of age. Offspring were housed alone (isolation stress) or at six per cage (ordinary circumstances). Thus, offspring were assigned to one of eight groups: dams fed a CD or HD during lactation and offspring fed a CD or HD and housed under ordinary circumstances or isolation stress. Serum corticosterone level was significantly elevated by isolation stress. High-fat feeding of offspring reduced their serum corticosterone level, which was significantly elevated by a maternal HD. A maternal HD and isolation stress had combined effects in elevating the serum corticosterone level. These findings suggest that a maternal HD during lactation enhances the stress sensitivity of offspring. White adipose tissue weights were significantly increased by a maternal HD and isolation stress and by their combination. In addition, significant adipocyte hypertrophy was induced by a maternal HD and isolation stress and exacerbated by their combination. Thus, a maternal HD and isolation stress promote visceral fat accumulation and adipocyte hypertrophy, accelerating the progression of obesity through their combined effects. The mechanism may involve enhanced fatty acid synthesis and lipid influx from blood into adipose tissue. These findings demonstrate that a maternal HD during lactation may increase the susceptibility of offspring to the development of stress-induced obesity.     

Pronounced synergistic promotion of N-bis(2-hydroxypropyl)nitrosamine-initiated thyroid tumorigenesis in rats treated with excess soybean and iodine-deficient diets.

We have reported that excess soybean treatment and iodine deficiency synergistically interact, resulting in remarkable induction of thyroid hyperplasias in rats. In the present study, modifying effects of excess soybean and iodine-deficient diets were investigated in the post-initiation phase of N-bis(2-hydroxypropyl)nitrosamine [DHPN]-initiated thyroid tumorigenesis in rats. AIN-93G in which casein was replaced with gluten was used as a basal diet to avoid possible iodine contamination. In Experiment 1, F-344 rats of both sexes were sc injected with DHPN at a dose of 2800 mg/kg body weight and then fed a diet containing 0%, 0.8%, 4%, or 20% defatted soybean for 12 weeks, with proportional replacement of gluten by soybean flour. Although no thyroid proliferative lesions were found in any group, the absolute thyroid weights were significantly (p < 0.01) elevated with the 20% soybean treatment. In Experiment 2, after similar sc injection of DHPN, rats were fed a basal diet or a diet containing 20% soybean under iodine normal or deficient conditions for 12 weeks. Soybean feeding to both sexes under iodine deficient but not normal conditions dramatically enhanced the development of thyroid follicular adenomas (p < 0.01) and adenocarcinomas (p < 0.05), in good agreement with decrease in thyroxine and increase in thyroid-stimulating hormone. Thus co-exposure to excess soybean and iodine deficiency results in synergistic promotion of DHPN-initiated thyroid tumorigenesis in rats, of which mechanisms appear to primarily involve effects on serum hormone levels.