Cost-Effectiveness of Aripiprazole Tablets with Sensor versus Oral Atypical Antipsychotics for the Treatment of Schizophrenia Using a Patient-Level Microsimulation Modeling Approach.

Objective: Strategies designed to track drug ingestion may improve medication adherence and clinical outcomes in adults with schizophrenia. This study aimed to estimate the cost-effectiveness of aripiprazole tablets with sensor (AS; Abilify MyCite®) versus generic oral atypical antipsychotics (AAPs) in schizophrenia from the United States payer and societal perspectives over 12 months. Methods: An individual-level microsimulation was developed to generate individual trajectories using data from a phase 3b multicenter, open-label, mirror-image trial in adults with schizophrenia treated prospectively for 6 months with AS. The patient's clinical characteristics and outcomes were computed as a function of the Positive and Negative Syndrome Scale (PANSS) scores. Direct and indirect medical cost estimates were sourced from the literature; EuroQol 5-Dimensions (EQ-5D) utilities were derived using risk equations based on patient and clinical characteristics. Scenario analyses were also conducted to assess outcomes under the assumption of treatment durability over 12 months. Results: Over 12 months, AS showed a 12.2% improvement in PANSS score. AS had an incremental cost of $2168 and incremental cost savings of $22,343 from the payer and societal perspectives, respectively, with an incremental quality-adjusted life-year (QALY) gain of 0.0298 versus oral AAPs. Further, AS resulted in a 28.2% reduction in hospitalizations over 12 months. At a willingness-to-pay of $100,000 per QALY, the net monetary benefit over 12 months was $25,323 from the payer perspective. Under the assumption of the durability of the treatment effect of AS, the findings were similar to those of the base case analyses, though with greater cost savings and QALYs gained with AS. The results from the sensitivity analyses were consistent with those of the base case analysis. Conclusion: AS may be a cost-effective strategy, with lower costs and improved quality of life among patients with schizophrenia over 12 months, from the payer and societal perspectives.

The current use and evolving landscape of nutraceuticals.

The nutraceutical market is currently a high-impact multi-billion-dollar industry, and it is anticipated to grow rapidly over the next decade. Nutraceuticals comprise diverse food-derived product categories that have become widespread due to increased consumer awareness of potential health benefits and the need for improved wellness. This targeted review is designed to identify the current global trends, market opportunities, and regulations that drive the nutraceutical industry. Safety and efficacy concerns are also explored with a view to highlighting areas that necessitate further research and oversight. Key drivers of the nutraceutical market include aging populations, consumer awareness, consumer lifestyle, increasing cost of healthcare, and marketing channels. Although some nutraceuticals hold promising preventive and therapeutic opportunities, there is a lack of a universal definition and regulatory framework among countries. Moreover, there is a lack of adequate evidence for their efficacy, safety, and effectiveness, which was even further highlighted during the ongoing coronavirus pandemic. Future prospective epidemiological studies can delineate the health impact of nutraceuticals and help set the scientific basis and rationale foundation for clinical trials, reducing the time and cost of trials themselves. Together, an understanding of the key drivers of the nutraceutical market alongside a consistent and well-defined regulatory framework will provide further opportunities for growth, expansion, and segmentation of nutraceuticals applications.

Estimating the global prevalence of transthyretin familial amyloid polyneuropathy.

INTRODUCTION: This study sought to estimate the global prevalence of transthyretin familial amyloid polyneuropathy (ATTR-FAP). METHODS: Prevalence estimates and information supporting prevalence calculations was extracted from records yielded by reference-database searches (2005-2016), conference proceedings, and nonpeer reviewed sources. Prevalence was calculated as prevalence rate multiplied by general population size, then extrapolated to countries without prevalence estimates but with reported cases. RESULTS: Searches returned 3,006 records; 1,001 were fully assessed and 10 retained, yielding prevalence for 10 "core" countries, then extrapolated to 32 additional countries. ATTR-FAP prevalence in core countries, extrapolated countries, and globally was 3,762 (range 3639-3884), 6424 (range, 1,887-34,584), and 10,186 (range, 5,526-38,468) persons, respectively. DISCUSSION: The mid global prevalence estimate (10,186) approximates the maximum commonly accepted estimate (5,000-10,000). The upper limit (38,468) implies potentially higher prevalence. These estimates should be interpreted carefully because contributing evidence was heterogeneous and carried an overall moderate risk of bias. This highlights the requirement for increasing rare-disease epidemiological assessment and clinician awareness. Muscle Nerve 57: 829-837, 2018.

Risk perception for diabetes in Appalachian women.

The social and economic burden of diabetes is large and growing. Diabetes is a significant public health issue in the Appalachian region; women constitute approximately 50% of those diagnosed with diabetes. This cross-sectional study examined the relationship among sociodemographic, anthropometric, lifestyle, and psychosocial factors (cognitive and affective representations) and perceived risk of diabetes in non-diabetic, non-elderly (21-50 years) Appalachian women residing in West Virginia (N = 202). Participants were recruited through social media, flyers, and a newsletter from the West Virginia University Extension. The final survey was conducted from March 2015 to June 2015. Bivariate analyses were used to examine unadjusted relations among sociodemographic, anthropometric, lifestyle, and psychosocial factors and comparative perceived risk of diabetes. In a multivariable logistic regression model, we found that younger age, higher body mass index, non-White race, greater diabetes knowledge, personal control, and moderate amounts of physical activity were significantly, positively associated with higher diabetes risk perception (p < .05). Our results indicated that diabetes knowledge, personal control, and physical activity were related to diabetes risk perception among Appalachian women. Understanding perceived diabetes-related risk may aid in the development of effective intervention strategies to reduce the burden of diabetes among Appalachian and other populations. These cross-sectional findings need further evaluation in longitudinal studies.

Efficient Activation of Apoptotic Signaling during Mitotic Arrest with AK301.

Mitotic inhibitors are widely utilized chemotherapeutic agents that take advantage of mitotic defects in cancer cells. We have identified a novel class of piperazine-based mitotic inhibitors, of which AK301 is the most potent derivative identified to date (EC50 < 200 nM). Colon cancer cells arrested in mitosis with AK301 readily underwent a p53-dependent apoptosis following compound withdrawal and arrest release. This apoptotic response was significantly higher for AK301 than for other mitotic inhibitors tested (colchicine, vincristine, and BI 2536). AK301-treated cells exhibited a robust mitosis-associated DNA damage response, including ATM activation, γH2AX phosphorylation and p53 stabilization. The association between mitotic signaling and the DNA damage response was supported by the finding that Aurora B inhibition reduced the level of γH2AX staining. Confocal imaging of AK301-treated cells revealed multiple γ-tubulin microtubule organizing centers attached to microtubules, but with limited centrosome migration, raising the possibility that aberrant microtubule pulling may underlie DNA breakage. AK301 selectively targeted APC-mutant colonocytes and promoted TNF-induced apoptosis in p53-mutant colon cancer cells. Our findings indicate that AK301 induces a mitotic arrest state with a highly active DNA damage response. Together with a reversible arrest state, AK301 is a potent promoter of a mitosis-to-apoptosis transition that can target cancer cells with mitotic defects.

Reviewing risks and benefits of low-dose computed tomography screening for lung cancer.

Lung cancer is the third most common cancer among men and women and is one of the leading causes of cancer-related mortality. Diagnosis at an early stage has been suggested crucial for improving survival in individuals at high-risk of lung cancer. One potential facilitator to early diagnosis is low-dose computed tomography (LDCT). The United States Preventive Services Task Force guidelines call for annual LDCT screening for individuals at high-risk of lung cancer. This recommendation was based on the effectiveness of LDCT in early diagnosis of lung cancer, as indicated by the findings from the National Lung Screening Trial conducted in 2011. Although lung cancer accounts for more than a quarter of all cancer deaths in the United States and LDCT screening shows promising results regarding early lung cancer diagnosis, screening for lung cancer remains controversial. There is uncertainty about risks, cost-effectiveness, adequacy of evidence, and application of screening in a clinical setting. This narrative review provides an overview of risks and benefits of LDCT screening for lung cancer. Further, this review discusses the potential for implementation of LDCT in clinical setting.

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice.

The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.

Follow-up care for breast cancer survivors: improving patient outcomes.

BACKGROUND: Appropriate follow-up care is important for improving health outcomes in breast cancer survivors (BCSs) and requires determination of the optimum intensity of clinical examination and surveillance, assessment of models of follow-up care such as primary care-based follow-up, an understanding of the goals of follow-up care, and unique psychosocial aspects of care for these patients. The objective of this systematic review was to identify studies focusing on follow-up care in BCSs from the patient's and physician's perspective or from patterns of care and to integrate primary empirical evidence on the different aspects of follow-up care from these studies. METHODS: A comprehensive literature review and evaluation was conducted for all relevant publications in English from January 1, 1990 to December 31, 2013 using electronic databases. Studies were included in the final review if they focused on BCS's preferences and perceptions, physician's perceptions, patterns of care, and effectiveness of follow-up care. RESULTS: A total of 47 studies assessing the different aspects of follow-up care were included in the review, with a majority of studies (n=13) evaluating the pattern of follow-up care in BCSs, followed by studies focusing on BCS's perceptions (n=9) and preferences (n=9). Most of the studies reported variations in recommended frequency, duration, and intensity of follow-up care as well as frequency of mammogram screening. In addition, variations were noted in patient preferences for type of health care provider (specialist versus non-specialist). Further, BCSs perceived a lack of psychosocial support and information for management of side effects. CONCLUSION: The studies reviewed, conducted in a range of settings, reflect variations in different aspects of follow-up care. Further, this review also provides useful insight into the unique concerns and needs of BCSs for follow-up care. Thus, clinicians and decision-makers need to understand BCS's preferences in providing appropriate follow-up care tailored specifically for each patient.

Novel piperazine-based compounds inhibit microtubule dynamics and sensitize colon cancer cells to tumor necrosis factor-induced apoptosis.

We recently identified a series of mitotically acting piperazine-based compounds that potently increase the sensitivity of colon cancer cells to apoptotic ligands. Here we describe a structure-activity relationship study on this compound class and identify a highly active derivative ((4-(3-chlorophenyl)piperazin-1-yl)(2-ethoxyphenyl)methanone), referred to as AK301, the activity of which is governed by the positioning of functional groups on the phenyl and benzoyl rings. AK301 induced mitotic arrest in HT29 human colon cancer cells with an ED50 of ≈115 nm. Although AK301 inhibited growth of normal lung fibroblast cells, mitotic arrest was more pronounced in the colon cancer cells (50% versus 10%). Cells arrested by AK301 showed the formation of multiple microtubule organizing centers with Aurora kinase A and γ-tubulin. Employing in vitro and in vivo assays, tubulin polymerization was found to be slowed (but not abolished) by AK301. In silico molecular docking suggests that AK301 binds to the colchicine-binding domain on ß-tubulin, but in a novel orientation. Cells arrested by AK301 expressed elevated levels of TNFR1 on their surface and more readily activated caspases-8, -9, and -3 in the presence of TNF. Relative to other microtubule destabilizers, AK301 was the most active TNF-sensitizing agent and also stimulated Fas- and TRAIL-induced apoptosis. In summary, we report a new class of mitosis-targeting agents that effectively sensitizes cancer cells to apoptotic ligands. These compounds should help illuminate the role of microtubules in regulating apoptotic ligand sensitivity and may ultimately be useful for developing agents that augment the anti-cancer activities of the immune response.

Identification of novel compounds that enhance colon cancer cell sensitivity to inflammatory apoptotic ligands.

Immune and inflammatory death ligands expressed within neoplastic tissue could potentially target apoptosis to transformed cells. To develop approaches that accentuate the anti-cancer potential of the inflammatory response, the Chembridge DIVERSet (TM) library was screened for compounds that accentuated apoptosis in a strictly TNF-dependent manner. We identified a number of novel compounds with this activity, the most active of these, AK3 and AK10, sensitized colon cancer cells to TNF at 0.5 µM and 2 µM, respectively, without inducing apoptosis on their own. The activity of these compounds was structure-dependent and general, as they accentuated cell death by TNF or Fas ligation in multiple colon cancer cell lines. Both AK3 and AK10 arrested cells in mitosis, with live cell imaging indicating that mitotically arrested cells were the source of apoptotic bodies. AK3 accentuated caspase-8 and caspase-9 activation with little effect on NFκB target gene activation. Enhanced caspase activation corresponded to an increased expression of TNFR1 on the cell surface. To determine the general interplay between mitotic arrest and TNF sensitivity, Aurora kinase (MLN8054 and MLN8237) and PLK1 (BI2536) inhibitors were tested for their ability to sensitize cells to TNF. PLK1 inhibition was particularly effective and influenced TNFR1 surface presentation and caspase cleavage like AK3, even though it arrested mitosis at an earlier stage. We propose that AK3 and AK10 represent a new class of mitotic inhibitor and that selected mitotic inhibitors may be useful for treating colon cancers or earlier lesions that have a high level of inflammatory cell infiltrate.