The Increasing Economic Burden with Additional Steps of Pharmacotherapy in Major Depressive Disorder.

OBJECTIVES: Major depressive disorder (MDD) is a common and serious disorder with significant impact on patients and families. The goal of this retrospective cohort study was to determine the economic burden among patients with MDD stratified by number of treatment lines needed for episode resolution. METHODS: Truven Health Analytics MarketScan® claims data were used to identify US patients (≥ 18 years) who were diagnosed with MDD and started on an antidepressant between 2013 and 2017. A generalized linear model estimated direct and employment-related costs for the first 12 months following initiation of treatment across cohorts with increasing number of lines of MDD pharmacotherapy. Analyses were adjusted for demographics and clinical factors. RESULTS: A total of 73,597 patients with MDD comprising the commercial (n = 66,459) and Medicare (n = 7138) populations met selection criteria. Patients who completed treatment for their episode with a single line of antidepressant had the lowest total adjusted direct costs (commercial $9975; Medicare $14,628) followed by those who completed with two lines (commercial $11,723; Medicare $15,526) and those treated with three or more lines of antidepressant regimens (commercial $21,259; Medicare $20,964). Patients who completed treatment with two lines as opposed to one incurred significantly higher direct costs (commercial +$1748, p < 0.0001; Medicare +$898, p = 0.0092). Patients who completed treatment with one line had the lowest employment-related costs compared to other groups. CONCLUSIONS: There was an increased economic burden associated with delay of episode resolution as early as the second line compared to the first line in MDD.

Impact of Fluid Choice in Systemic Inflammatory Response Syndrome Patients on Hospital Cost Savings.

BACKGROUND: There is growing evidence of the benefits of intravenous fluid therapy with balanced crystalloids over 0.9% 'normal' saline. This analysis evaluated the economic impact of increasing usage of a calcium-free balanced crystalloid solution (BAL) in patients with systemic inflammatory response syndrome (SIRS) on an annual hospital budget. METHODS: An Excel®-based economic model was developed to estimate costs associated with increased BAL usage (i.e., use in a greater proportion of patients), from the US hospital perspective, over a 5-year time horizon. Clinical inputs were based on the results of a retrospective Electronic Health Record (EHR) database analysis identifying significantly fewer complications among SIRS patients receiving predominantly BAL versus saline. Complication-associated costs, adjusted to 2015, were obtained from published reports. Scenario analyses examined cost impacts for hospitals of various sizes, with different BAL adoption levels and rates. RESULTS: Base-case scenario analysis (300-bed hospital, 80% occupancy, current and year 5 BAL usage in 5 and 75% of SIRS patients, respectively, exponential year-over-year adoption) showed year 1 hospital savings of US$29,232 and cumulative 5-year savings of US$1.16M. Cumulative 5-year pharmacy savings were US$172,641. Scenario analyses demonstrated increasing cumulative 5-year savings with increasing hospital size, year 5 BAL usage in greater proportions of patients, and rapid/early BAL adoption. CONCLUSIONS: Increased BAL usage represents an opportunity for hospitals and pharmacy departments to reduce complication-related costs associated with managing SIRS patients. The model suggests that savings could be expected across a range of scenarios, likely benefiting hospitals of various sizes and with different adoption capabilities.

Cost Savings from Reduced Hospitalizations with Use of Home Noninvasive Ventilation for COPD.

BACKGROUND: Although evidence suggests significant clinical benefits of home noninvasive ventilation (NIV) for management of severe chronic obstructive pulmonary disease (COPD), economic analyses supporting the use of this technology are lacking. OBJECTIVES: To evaluate the economic impact of adopting home NIV, as part of a multifaceted intervention program, for severe COPD. METHODS: An economic model was developed to calculate savings associated with the use of Advanced NIV (averaged volume assured pressure support with autoexpiratory positive airway pressure; Trilogy100, Philips Respironics, Inc., Murrysville, PA) versus either no NIV or a respiratory assist device with bilevel pressure capacity in patients with severe COPD from two distinct perspectives: the hospital and the payer. The model examined hospital savings over 90 days and payer savings over 3 years. The number of patients with severe COPD eligible for home Advanced NIV was user-defined. Clinical and cost data were obtained from a quality improvement program and published reports. Scenario analyses calculated savings for hospitals and payers covering different COPD patient cohort sizes. RESULTS: The hospital base case (250 patients) revealed cumulative savings of $402,981 and $449,101 over 30 and 90 days, respectively, for Advanced NIV versus both comparators. For the payer base case (100,000 patients), 3-year cumulative savings with Advanced NIV were $326 million versus no NIV and $1.04 billion versus respiratory assist device. CONCLUSIONS: This model concluded that adoption of home Advanced NIV with averaged volume assured pressure support with autoexpiratory positive airway pressure, as part of a multifaceted intervention program, presents an opportunity for hospitals to reduce COPD readmission-related costs and for payers to reduce costs associated with managing patients with severe COPD on the basis of reduced admissions.

The Role of the C-Clamp in Wnt-Related Colorectal Cancers.

T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed.

Distinct DNA binding sites contribute to the TCF transcriptional switch in C. elegans and Drosophila.

Regulation of gene expression by signaling pathways often occurs through a transcriptional switch, where the transcription factor responsible for signal-dependent gene activation represses the same targets in the absence of signaling. T-cell factors (TCFs) are transcription factors in the Wnt/ß-catenin pathway, which control numerous cell fate specification events in metazoans. The TCF transcriptional switch is mediated by many co-regulators that contribute to repression or activation of Wnt target genes. It is typically assumed that DNA recognition by TCFs is important for target gene location, but plays no role in the actual switch. TCF/Pangolin (the fly TCF) and some vertebrate TCF isoforms bind DNA through two distinct domains, a High Mobility Group (HMG) domain and a C-clamp, which recognize DNA motifs known as HMG and Helper sites, respectively. Here, we demonstrate that POP-1 (the C. elegans TCF) also activates target genes through HMG and Helper site interactions. Helper sites enhanced the ability of a synthetic enhancer to detect Wnt/ß-catenin signaling in several tissues and revealed an unsuspected role for POP-1 in regulating the C. elegans defecation cycle. Searching for HMG-Helper site clusters allowed the identification of a new POP-1 target gene active in the head muscles and gut. While Helper sites and the C-clamp are essential for activation of worm and fly Wnt targets, they are dispensable for TCF-dependent repression of targets in the absence of Wnt signaling. These data suggest that a fundamental change in TCF-DNA binding contributes to the transcriptional switch that occurs upon Wnt stimulation.

Structure-function analysis of the C-clamp of TCF/Pangolin in Wnt/ß-catenin signaling.

The evolutionarily conserved Wnt/ß-catenin (Wnt/ß-cat) pathway plays an important role in animal development in metazoans. Many Wnt targets are regulated by members of the TCF/LEF1 (TCF) family of transcription factors. All TCFs contain a High Mobility Group (HMG) domain that bind specific DNA sequences. Invertebrate TCFs and some vertebrate TCF isoforms also contain another domain, called the C-clamp, which allows TCFs to recognize an additional DNA motif known as the Helper site. While the C-clamp has been shown to be important for regulating several Wnt reporter genes in cell culture, its physiological role in regulating Wnt targets is less clear. In addition, little is known about this domain, except that two of the four conserved cysteines are functionally important. Here, we carried out a systematic mutagenesis and functional analysis of the C-clamp from the Drosophila TCF/Pangolin (TCF/Pan) protein. We found that the C-clamp is a zinc-binding domain that is sufficient for binding to the Helper site. In addition to this DNA-binding activity, the C-clamp also inhibits the HMG domain from binding its cognate DNA site. Point mutations were identified that specifically affected DNA-binding or reduced the inhibitory effect. These mutants were characterized in TCF/Pan rescue assays. The specific DNA-binding activity of the C-clamp was essential for TCF/Pan function in cell culture and in patterning the embryonic epidermis of Drosophila, demonstrating the importance of this C-clamp activity in regulating Wnt target gene expression. In contrast, the inhibitory mutation had a subtle effect in cell culture and no effect on TCF/Pan activity in embryos. These results provide important information about the functional domains of the C-clamp, and highlight its importance for Wnt/ß-cat signaling in Drosophila.