Major depressive disorder (MDD) is a chronic mental illness that affects an estimated 5-26% of adults at some time in their lives. Treatment is often started as pharmacotherapy using a single drug such as a selective serotonin reuptake inhibitor. If a patient fails to respond adequately to the initial antidepressant, typically three pharmacotherapy options are available to the practitioner. The dose of the current therapy can be maximized, a change can be made to a different drug, or the current regimen can be augmented with another drug. Atypical antipsychotics have recently become a major focus for augmentation of traditional antidepressant therapy. This review summarizes the evidence for efficacy and safety of augmenting treatment-refractory or treatment-resistant depression with atypical antipsychotics. The National Library of Medicine's MEDLINE database was searched for all English-language articles published from January 1966-December 2011 describing the use of atypical antipsychotics in treatment-resistant depression. The literature retrieved was limited to case series, open-label trials, and randomized controlled trials (RCT). Studies of bipolar depression, psychotic depression, or studies conducted in children and adolescents were excluded. Thirty-five studies using atypical antipsychotics for augmentation treatment of depression were included in this analysis. Trials were identified for aripiprazole (six open-label; three RCT), clozapine (one case series), olanzapine (three open-label, including two case series; four RCT), quetiapine (four open-label; five RCT), risperidone (two open-label; five RCT), and ziprasidone (two open-label). The atypical antipsychotics may be effective as adjunctive therapy in MDD; however, their adverse effect profile may be unfavorable to some patients. Trying at least one alternative treatment strategy after an initial antidepressant is indicated before augmentation is implemented with these agents. If atypical antipsychotics are used, safety and efficacy should be frequently reassessed and dosage should be individualized.

The amounts of muscle and fat in a person's body, known as body composition, are correlated with cancer risks, cancer survival, and cardiovascular risk. The current gold standard for measuring body composition requires time-consuming manual segmentation of CT images by an expert reader. In this work, we describe a two-step process to fully automate the analysis of CT body composition using a DenseNet to select the CT slice and U-Net to perform segmentation. We train and test our methods on independent cohorts. Our results show Dice scores (0.95-0.98) and correlation coefficients (R=0.99) that are favorable compared to human readers. These results suggest that fully automated body composition analysis is feasible, which could enable both clinical use and large-scale population studies. Equal contribution

Glioblastoma multiforme (GBM) is the most common and severe form of brain cancer. The median survival time of patients is approximately 12 months due to poor responses to surgery and chemoradiation. In order to understand the mechanisms involved in radioresistance, we conducted a genetic screen using an shRNA library to identify genes whose inhibition would sensitize cells to radiation. The results were cross-referenced with the Oncomine and Rembrandt databases to focus on genes that are highly expressed in GBM tumors and associated with poor patient outcomes. Spermidine/spermine-N1-acetyltransferase 1 (SAT1), an enzyme involved in polyamine catabolism, was identified as a gene that promotes resistance to ionizing radiation (IR), is overexpressed in brain tumors, and correlates with poor outcomes. Knockdown of SAT1 using shRNA and siRNA approaches in multiple cell and neurosphere lines resulted in sensitization of GBM cells to radiation in colony formation assays and tumors, and decreased tumorigenesis in vivo. Radiosensitization occurred specifically in G2/M and S phases, suggesting a role for SAT1 in homologous recombination (HR) that was confirmed in a DR-GFP reporter system. Mechanistically, we found that SAT1 promotes acetylation of histone H3, suggesting a new role of SAT1 in chromatin remodeling and regulation of gene expression. In particular, SAT1 depletion led to a dramatic reduction in BRCA1 expression, explaining decreased HR capacity. Our findings suggest that the biological significance of elevated SAT1 expression in GBM lies in its contribution to cell radioresistance and that SAT1 may potentially be a therapeutic target to sensitize GBM to cancer therapies.

The macrophage migration inhibitory factor (MIF) is a hypoxia regulated gene that has a variety of tumorigenic functions. In clear cell renal carcinoma (CCRC), hypoxic signaling is constitutively active because of the frequent loss of function of the von Hippel-Lindau tumor suppressor protein. We therefore sought to assess the expression of MIF in CCRC and its biological functions. We stained tumor tissue microarrays comprising sections of 128 CCRC tumors and found MIF to be moderately or highly expressed in >98%. MIF expression was further found to be dramatically elevated in blood plasma of individuals with CCRC compared with healthy controls, suggesting that measurement of MIF levels in the blood may have utility as a diagnostic marker in CCRC. At a functional level, MIF has been reported to engage the CD74 and CD44 receptors and induce signal transduction. In CCRC cell lines, depletion of MIF, CD74 or CD44 by small hairpin RNA led to a significant reduction in growth rate, and clonogenic survival, coinciding with the degree of knockdown. Interruption of the MIF pathway also decreased tumorigenic potential. Biochemically, we found that in CCRC cells MIF signaling leads to activation of the mitogen-activated protein kinase pathway and to Src phosphorylation, which is critical for regulation of p27. Together, our studies establish MIF as a protumorigenic signaling molecule that functions in an autocrine fashion to promote renal cell carcinoma and may be useful as a minimally invasive marker of disease status.

Optimization of glycemic control is a fundamental aspect of diabetes management, and rates of diabetes-related microvascular complications are significantly decreased when glycemic control is improved. Currently, > 5 million Americans require insulin therapy to manage their diabetes, and this number is expected to multiply as the prevalence of type 2 diabetes increases secondary to several factors. The distinct pharmacodynamic properties of each insulin product help physicians decide which type of insulin is the most appropriate for each patient. The method of delivery that will ensure both patient and provider satisfaction must also be carefully considered. Insulin pen devices are designed to provide a convenient and easy means of insulin administration for the patient and can be divided into 2 categories: the reusable, durable pen, and the disposable, prefilled pen. These insulin pen devices are an alternative to the traditional insulin vial-and-syringe method and offer many advantages. Insulin pens have also been found to be less painful than the vial-and-syringe method and are often associated with greater patient preference and social acceptability. As a result, this method of insulin delivery may ultimately help to improve glycemic control and should be considered when prescribing insulin products.

The prevalence of diabetes mellitus (DM) in the elderly population currently represents almost one-half of the overall diabetic population. Treatment of DM often requires a multidrug regimen that includes insulin therapy; however, due to concomitant comorbidities such as dementia, vision loss, neuropathies, poor mobility, and poor manual dexterity, elderly patients may be at increase risk for hypoglycemia and other dosing errors that are associated with insulin administration. Insulin pen devices have been shown to provide more reliable, accurate, and simplified dosing, and therefore may be a safer, easier, and more acceptable method of insulin delivery in the elderly population. This review will describe the various insulin pen devices available today, as well as discuss the potential advantages of these devices in the elderly population.

Data on the long-term outcomes of the use of fixed-dose combinations (FDCs) or free-pill combinations (FPCs), titration of doses, and switching are currently unavailable for identifying a preferred strategy for adherence. In the lack of these evidences, adherence can be a useful guiding criteria. The authors conducted a retrospective cohort study using the BlueCross BlueShield of Texas (2008Texas ( -2012 Seven of every 10 hypertensive patients in the UnitedStates use pharmacotherapy to treat their hypertension. 1Guidelines recommend monotherapy as the first-line treatment for most patients diagnosed with hypertension, 2 but efficacy-or tolerance-related issues are common and necessitate modification of the monotherapy regimen.3-5 Healthcare providers often have to choose between treatment modification (TM) strategies including fixed-dose combinations (FDCs) or free-pill combinations (FPCs) (ie, addition strategy), uptitration (ie, increasing the drug dose), or switching to address efficacy-related issues after first-line treatment. Similarly, tolerance-related issues are addressed by either switching, or downtitration (ie, decreasing the drug dose).The expert panel appointed to the Eighth Joint National Committee (JNC 8) primarily recommends uptitration and addition (ie, FDC or a FPC) strategies for addressing efficacy-related issues. Moreover, switching can also be an alternative to these strategies. A preferred strategy for TM was not recommended by the expert panel because of the lack of evidences regarding the long-term cardiovascular (CV) outcomes and mortality of the alternative strategies used to address efficacy-related issues.2 Knowledge regarding the strategies used for addressing tolerance-related issues is also limited. Therefore, an intermediate outcome, such as adherence, can be a useful guiding criterion for selecting a TM strategy. Comparative data on adherence in the current literature are limited to FDC and FPC regimens. A direct comparison of adherence between addition, titration, and switching strategies is unavailable in the current literature.Adherence is an essential component of pharmacotherapy. It increases the odds of attaining shortterm (ie, blood pressure [BP] control) 6-8 and long-term (ie, CV risk reduction) 9-12 outcomes. Adherence is one of the crucial factors for attainment of BP goal among patients who undergo TMs. 13 However, given that TMs involve a change of dose, switch, or drug addition, they increase the risk of poor medication-taking behavior in patients who need TMs by up to 25%.14 This risk is further elevated if patients have histories of poor adherence to their first-line treatment. However, prior adherence has little impact on providers' decisions to modify treatment 15 when limitations of first-line monotherapy necessitate TMs. Given that TM predisposes patients to poor medication-taking behavior, it is worthwhile to determine whether any differences exist in patient adherence to alternative TM strategies. The information will be useful for decision-making, partic...

Objective. The objective of this analysis was to compare clinical and cost outcomes associated with patients who had suspected or documented methicillin-resistant Staphylococcus aureus (MRSA) infections treated with daptomycin, vancomycin, or linezolid in complicated skin and skin structure infections (cSSSIs). Design. This was a retrospective analysis conducted from February to June of 2007. Appropriate data was collected, collated, and subsequently evaluated with the purpose of quantifying length of stay, antibiotic therapy duration, clinical cure rates, adverse drug events, and cost of hospitalization. Results. All 82 patients included in the analysis experienced clinical cure. The duration of antibiotic therapy was similar among the three groups yet the length of hospitalization was slightly shorter in the daptomycin group. Conclusions. The incidence of resistant staphylococcal infections is increasing; therefore, judicious use of MRSA active agents is paramount. Future studies are necessary to determine if MRSA treatment options can be stratified based on the severity of the infectious process.