Mila Blooms: A Mobile Phone Application and Behavioral Intervention for Promoting Physical Activity and a Healthy Diet Among Adolescent Survivors of Childhood Cancer.

Objectives: Smartphone applications ("apps") can be used to promote health behavior change and expand the reach of behavioral interventions. To date, only a few existing apps have been developed for health promotion among adolescent survivors of childhood cancer. To address this gap, we developed an app-based intervention, using game design characteristics, theory-based behavioral strategies, and assistance from a health coach to motivate health behavior change for adolescent survivors of childhood cancer. This article describes the development and initial feasibility evaluation of the intervention. Methods: Using a theoretical framework and an extensive formative process, we developed an app-based game ("Mila Blooms") that promotes healthy eating and physical activity among adolescent survivors of childhood cancer. A single-arm 8-week intervention, using this app-based game, with assistance from a health coach, was conducted among a sample of pediatric cancer survivors (n = 15) to evaluate its initial feasibility for promoting health behavior change. Results: Results from the feasibility evaluation were encouraging. The majority of enrolled participants were retained throughout the 8-week intervention (93.8%). Participant satisfaction feedback indicated positive experiences, related to ease of use and enjoyment of the app. Although there was little evidence for behavior change attributable to the app in this first stage of development, there was a solid demonstration of the viability and appeal of the game features, and there were no adverse side effects. Conclusions: Results provide insights into how gamification can be used to promote health behaviors through an app-based intervention. Mila Blooms holds promise for promoting health behavior change. Lessons learned from our experiences could be useful for the future development and implementation of app-based adolescent health interventions.

Change in brain volume and cortical thickness after behavioral and surgical weight loss intervention.

Obesity is associated with reduced cortical thickness and brain volume, which may be related to poor nutrition. Given that brain atrophy in anorexia nervosa recovers with nutritional improvements and weight gain, it is worth examining how brain structure changes at the other end of the weight spectrum with weight loss. Thus, this study aimed to examine change in cortical thickness and brain volume in 47 patients with severe obesity who participated in no treatment, behavioral weight loss, or bariatric surgery. T1-weighted MRI scans were conducted pre-treatment and approximately four months later. Measures of cortical thickness, gray matter volume, and white matter volume were compared between time points. Despite overall reduction in BMI, there was no significant change in cortical thickness. There was a significant increase in left hemisphere gray matter and white matter volumes across the sample. At baseline and follow-up, there was no relationship between cortical thickness or brain volumes and BMI. This study is the first to examine changes in cortical thickness and brain volume with weight loss in adults with obesity and the findings show partial support for the hypotheses that weight loss results in increased cortical gray and white matter.

Level of Alcohol Consumption and Successful Smoking Cessation.

INTRODUCTION: The negative association between heavy alcohol use and likelihood of successful smoking cessation is well established. However, evidence on the effects of moderate alcohol consumption on smoking cessation is sparse. This analysis evaluated the association between alcohol use and smoking and the interaction of alcohol use and use of pharmacotherapy interventions in relation to smoking cessation. METHODS: Data from adults (n = 923) recruited through a smoking cessation website between November 2011 and March 2012 were analyzed. Data on past-year alcohol use, tobacco use, and demographics were collected at baseline. Self-reported smoking abstinence and current alcohol use data were collected at 1 and 7 months posttreatment. Chi-square and multivariate logistic regression analyses were conducted. RESULTS: At 1 month, adjusted odds of continued smoking were 1.54 times greater (95% confidence interval [CI] = 1.05% to 2.23%) for moderate drinkers and 2.59 times greater (95% CI = 1.33% to 4.28%) for heavy drinkers than nondrinkers. At 7 months, adjusted odds of continued smoking were not greater for moderate drinkers than nondrinkers, and were 2.32 times greater (95% CI = 1.35% to 3.96%) among heavy alcohol drinkers than nondrinkers. At 1 month, adjusted odds of smoking cessation were 2.33 times greater (95% CI = 1.04% to 3.09%) for alcohol users assigned to nicotine replacement therapy than for those not assigned to nicotine replacement therapy. This relationship was not observed at 7 months. CONCLUSIONS: Moderate and heavy drinking might impact smoking cessation efforts. Recent moderate drinking may be associated with short-term continued smoking and heavy drinking associated with relapse in the short and long term. IMPLICATIONS: This study suggests that moderate drinking may influence the process to quit smoking. Further study is needed to better understand the implications of moderate drinking for smoking cessation. Providing information alone may not be effective in helping people abstain from drinking during smoking cessation, especially if moderate drinkers do not perceive their behavior as reducing their chance for a successful quit attempt. Tailoring smoking cessation interventions to include strategies to reduce moderate-to-heavy alcohol consumption may improve smoking cessation outcomes among alcohol users attempting to quit smoking.

Effects of time-varying changes in tobacco and alcohol use on depressive symptoms following pharmaco-behavioral treatment for smoking and heavy drinking.

BACKGROUND: Complete abstinence from alcohol as well as smoking cessation have been shown to predict reductions in depressive symptoms over time. However, whether reducing alcohol use or smoking positively affect depressive symptoms has yet to be examined. The current study examined depressive symptoms as a function of time-varying changes in alcohol use and smoking status following a pharmaco-behavioral treatment addressing smoking cessation and alcohol reduction. METHODS: Participants were heavy-drinking smokers (n = 150) followed for 26 weeks after their quit smoking date, with assessments of smoking, alcohol use, and depressive symptoms at baseline and 2, 8, 16, and 26 weeks. RESULTS: Abstinence from smoking was associated with significantly lower depressive symptoms, as compared to little to no reduction in smoking (B = -6.1) as well as significant reductions in smoking (B = 4.01). Exploratory analyses, which excluded observations in which a participant was abstinent, revealed a significant effect of percent change in cigarettes smoked, modeled continuously, on depressive symptoms, (B = 4.39). By contrast, no differences were observed in depressive symptoms in relation to changes in alcohol use. CONCLUSION: It appears that smoking abstinence is associated with improvements in depression as compared to any level of sustained or reduced use and that the magnitude of smoking reduction may be associated with lower depressive symptoms among those who did not quit successfully. If replicated, these findings may inform treatment for individuals for whom depression is a major barrier to cessation and who have been unable or are unwilling to be completely abstinent from smoking.

Marijuana eCHECKUPTO GO: Effects of a personalized feedback plus protective behavioral strategies intervention for heavy marijuana-using college students.

BACKGROUND: Marijuana use is common among U.S. college students. Liberalization of marijuana use policies is hypothesized to decrease social norms discouraging use, which protects against marijuana use. This may increase the importance of protective behavioral strategies (PBS) to reduce marijuana use harm. METHODS: This study tested direct and moderated (by sex) program effects of an adapted version of the Marijuana eCHECKUPTO GO, a web-based marijuana use intervention providing university-specific personalized feedback (PF) with normative information and PBS to students attending a university in a state with legalized adult recreational marijuana. Participants were 298 heavy-using college students randomly assigned to receive Marijuana eCHECKUPTO GO or strategies for healthy stress management (HSM). General linear models (GLMs) tested direct program effects on proximal intervention targets, marijuana use, and use consequences. Multi-group GLMs then tested the moderating effect of sex on direct intervention effects. RESULTS: Marijuana eCHECKUPTO GO participants reported decreases in estimated use prevalence (i.e., descriptive norms), self-reported hours high per week, days high per week, periods high per week, and weeks high per month. Sex moderated intervention effects on the use of PBS such that females in the PF condition increased their use of PBS more than males. CONCLUSION: Results demonstrate preliminary support for the adapted Marijuana eCHECKUPTO GO in reducing marijuana use for "heavy college-aged users". Future research should test adapted Marijuana eCHECKUPTO GO sustained effects over time, and examine whether program effects on harm reduction manifest after sustained (e.g., booster) program implementation.

Exercise-Induced Laryngeal Obstruction and Performance Psychology: Using the Mind as a Diagnostic and Therapeutic Target.

Exercise-induced laryngeal obstruction causes severe shortness of breath during exercise. Episodes are associated with severe distress. These patients and those with inducible laryngeal obstruction triggered by other factors have been noted to demonstrate mental health disorders, personality features that may be associated with symptoms, and dysfunctional stress responses. This literature review calls attention to the observation that patients with isolated exercise-induced laryngeal obstruction are generally mentally healthy. We review available metrics to assess traits and stress responses in performance psychology. We also discuss a therapeutic performance psychology framework.

A Systematic Review of Genetic Testing and Lifestyle Behaviour Change: Are We Using High-Quality Genetic Interventions and Considering Behaviour Change Theory?

BACKGROUND: Studying the impact of genetic testing interventions on lifestyle behaviour change has been a priority area of research in recent years. Substantial heterogeneity exists in the results and conclusions of this literature, which has yet to be explained using validated behaviour change theory and an assessment of the quality of genetic interventions. The theory of planned behaviour (TPB) helps to explain key contributors to behaviour change. It has been hypothesized that personalization could be added to this theory to help predict changes in health behaviours. PURPOSE: This systematic review provides a detailed, comprehensive identification, assessment, and summary of primary research articles pertaining to lifestyle behaviour change (nutrition, physical activity, sleep, and smoking) resulting from genetic testing interventions. The present review further aims to provide in-depth analyses of studies conducted to date within the context of the TPB and the quality of genetic interventions provided to participants while aiming to determine whether or not genetic testing facilitates changes in lifestyle habits. This review is timely in light of a recently published "call-to-action" paper, highlighting the need to incorporate the TPB into personalized healthcare behaviour change research. METHODS: Three bibliographic databases, one key website, and article reference lists were searched for relevant primary research articles. The PRISMA Flow Diagram and PRISMA Checklist were used to guide the search strategy and manuscript preparation. Out of 32,783 titles retrieved, 26 studies met the inclusion criteria. Three quality assessments were conducted and included: (1) risk of bias, (2) quality of genetic interventions, and (3) consideration of theoretical underpinnings - primarily the TPB. RESULTS: Risk of bias in studies was overall rated to be "fair." Consideration of the TPB was "poor," with no study making reference to this validated theory. While some studies (n = 11; 42%) made reference to other behaviour change theories, these theories were generally mentioned briefly, and were not thoroughly incorporated into the study design or analyses. The genetic interventions provided to participants were overall of "poor" quality. However, a separate analysis of studies using controlled intervention research methods demonstrated the use of higher-quality genetic interventions (overall rated to be "fair"). The provision of actionable recommendations informed by genetic testing was more likely to facilitate behaviour change than the provision of genetic information without actionable lifestyle recommendations. Several studies of good quality demonstrated changes in lifestyle habits arising from the provision of genetic interventions. The most promising lifestyle changes were changes in nutrition. CONCLUSIONS: It is possible to facilitate behaviour change using genetic testing as the catalyst. Future research should ensure that high-quality genetic interventions are provided to participants, and should consider validated theories such as the TPB in their study design and analyses. Further recommendations for future research are provided.

Trends in Modification of Smoking Behaviors Among Pregnant Women in West Virginia.

Background Rates of smoking among pregnant women in West Virginia are higher than national prenatal smoking rates. Recent research has pointed to the benefit of smoking reduction among a sample of pregnant women who participated in a clinical study in West Virginia. The purpose of the current study is to examine trends associated with reduced smoking exposure among a representative sample of pregnant women in the state. Method Secondary data analysis was conducted using de-identified weighted PRAMS 2005-2010 data from West Virginia examining factors associated with favorable change in prenatal smoking behavior, either quitting or reducing smoking in pregnancy. Results Multivariable analyses results demonstrate that pregnant women are more likely to engage in a favorable smoking behavior change if they were younger (<35 years of age), were primiparous, and had a higher level of education. Discussion Findings from the study identified factors that contribute to women's likelihood of quitting or reducing smoking in pregnancy in West Virginia. Health care providers and policy makers should consider these factors in implementing approaches that will be effective in promoting smoking cessation and reduction among pregnant women in the state thereby reducing prenatal smoking exposure. Conclusion Population-based research has been used to identify factors associated with smoking cessation or reduction that can be used to develop appropriate and effective approaches to modifying health behaviors in specific populations.

Future directions of multiple behavior change research.

Non-communicable diseases (i.e., chronic diseases including cardiovascular disease, cancer, chronic respiratory disease, diabetes and obesity) result in 36 million deaths each year. Individuals' habitual participation in a single health-risk behaviors substantially contribute to morbidity and mortality (e.g., tobacco use, daily fast food intake, etc.); however, more concerning is the impact of typically co-occurring or clustering of multiple health-risk behaviors. This burden can be minimized through successful cessation of health-risk behaviors and adoption of healthy behaviors; namely healthy lifestyle adoption or multiple health behavior change (MHBC). MHBC is a developing field and future research recommendations are provided to advance MHBC research. A valid measure of MHBC (i.e., lifestyle) is warranted to provide the needed basis for MHBC investigations and evaluations. MHBC is thought to occur through shared co-variation of underlying motivating mechanisms, but how these relationships influence behavior remains unclear. A better understanding of the relationship between behaviors and the related motivating mechanisms (and potential cross-relationship of influences) is needed. Future research should also aim to improve lifestyles through understanding how to change multiple health behaviors. Finally, MHBC research should target the development of sustainable interventions which result in lasting effects (e.g., capacity, systems, policy and environmental changes), with dissemination considered during development. Focusing MHBC research in these areas will increase our understanding and maximize the impact on the health of populations.

Chronic Pain and Mental Health Disorders: Shared Neural Mechanisms, Epidemiology, and Treatment.

Chronic pain and mental health disorders are common in the general population, and epidemiological studies suggest that a bidirectional relationship exists between these 2 conditions. The observations from functional imaging studies suggest that this bidirectional relationship is due in part to shared neural mechanisms. In addition to depression, anxiety, and substance use disorders, individuals with chronic pain are at risk of other mental health problems including suicide and cigarette smoking and many have sustained sexual violence. Within the broader biopsychosocial model of pain, the fear-avoidance model explains how behavioral factors affect the temporal course of chronic pain and provides the framework for an array of efficacious behavioral interventions including cognitive-behavioral therapy, acceptance-based therapies, and multidisciplinary pain rehabilitation. Concomitant pain and mental health disorders often complicate pharmacological management, but several drug classes, including serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and anticonvulsants, have efficacy for both conditions and should be considered first-line treatment agents.

Comparative analysis of smoking cessation smartphone applications available in 2012 versus 2014.

BACKGROUND AND AIMS: Smartphone applications (apps) offer a potentially cost-effective and a wide-reach aid to smoking cessation. In 2012, a content analysis of smoking cessation apps suggested that most apps did not adopt behaviour change techniques (BCTs), which according to previous research had suggested would promote higher success rates in quitting smoking. This study examined whether or not, this situation had changed by 2014 for free smoking cessation apps available in the Apple App Store. It also compared the use of engagement and ease-of-use features between the two time points. METHODS: 137 free apps available in the Apple App Sore in 2014 were coded using an established framework for the presence or absence of evidence-based BCTs, and engagement and ease-of-use features. The results from the 2014 data were compared with a similar exercise conducted on 83 free apps available in 2012. RESULTS: BCTs supporting identity change, rewarding abstinence and advising on changing routines were less prevalent in 2014 as compared with 2012 (14.6% vs. 42.2%, 18.2% vs. 48.2%, and 17.5% vs. 24.1%, respectively). Advice on coping with cravings and advice on the use of stop-smoking medication were more prevalent in 2014 as compared with 2012 (27.7% vs. 20.5% and 14.6% vs 3.6%, respectively). The use of recognised engagement features was less common in 2014 than in 2012 (45.3% vs. 69.6%) while ease-of-use features remained very high (94.5% vs. 82.6%). CONCLUSION: There was little evidence of improvement in the use of evidence-based BCTs in free smoking cessation iPhone-based apps between 2012 and 2014.

Perspectives in Implementing a Pragmatic Pediatric Primary Care-Based Intervention Trial.

The 2013 U.S. Preventive Services Task Force (USPSTF) concluded that behavioral interventions are effective in reducing initiation of smoking in youth, recommending primary care clinicians provide education or brief counseling to prevent initiation, and that there are promising trends toward behavioral interventions improving cessation in this population. Our primary care-based intervention RCT conducted between 2000 and 2004, Air It Out, informed these USPSTF recommendations. Our trial was designed to determine whether a pediatric primary care practice-based smoking prevention and cessation intervention would be effective in increasing abstinence rates among adolescents under usual clinic conditions, to inform clinical practice. Therefore, the trial was designed to be largely a pragmatic trial. In this paper, we describe where each of the Air It Out study components falls along the pragmatic-explanatory continuum regarding participant eligibility criteria, intervention and comparison condition design, follow-up and outcomes, compliance and adherence assessments, and analysis. Such an assessment assists researchers by providing a framework to guide decisions regarding study design and implementation. We then share a few principles and lessons learned in developing and implementing the primary care-based intervention trial, focusing on study setting selection, engaging providers who will be delivering the intervention and the target population who will be receiving it in designing the trial and interventions to be tested, and the need to carefully plan recruitment and retention procedures. The hope is to increase the number of well-designed studies that can be included in the evidence reviews to guide future USPSTF recommendation statements.

Personalising nutritional guidance for more effective behaviour change.

Improving diet and other lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing wellbeing. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Evidence-based, personalised (or stratified) interventions which incorporate effective behaviour change techniques (BCT) and which are delivered digitally are likely to be an important route to scalable and sustainable interventions. Progress in developing such interventions will depend on the outcomes of research on: (i) the best bases for personalisation of dietary advice; (ii) identification of BCT which are proven to enhance intervention efficacy; (iii) suitable platforms (digital-based tools) for collection of relevant participant characteristics (e.g. socioeconomic information, current diet and lifestyle and dietary preferences) linked with intelligent systems which use those characteristics to offer tailored feedback and advice in a cost-effective and acceptable manner. Future research should focus on such interventions aiming to reduce health inequalities and to improve overall public health.

A review of unmet needs in obesity management.

The prevalence of obesity continues to escalate in the USA; however, there is no consensus regarding the optimal therapy for obesity. For the vast majority of severely obese patients, conventional medical therapies (i.e., diet, exercise, behavioral counseling) often fail over the long term. Existing pharmacotherapy adjunctive to behavioral therapy has limited effectiveness and an imperfect safety record. In contrast, bariatric surgery has a high degree of weight loss efficacy, yet only a small fraction of the qualifying obese population undergoes these procedures because of the associated perioperative risks and potential late complications. In addition, the role of bariatric surgery is unclear in certain patient populations, such as patients with lower body mass index (BMI, 30-35 kg/m(2)), the high-risk super-super obese patients (BMI > 60), the morbidly obese adolescent, and obese patients requiring weight reduction in preparation for other procedures, such as orthopedic, transplant, or vascular surgeries. In these circumstances, there is a need for an effective but less invasive treatment to bridge the gap between medical and surgical therapy. This review examines current treatment outcomes, identifies prominent areas of unmet clinical needs, and provides an overview of two minimally invasive "temporary procedures for weight loss" that may eventually address some of the unmet needs in obesity management.

Therapeutic drug monitoring for busulfan in plasma during conditioning chemotherapy for autologous stem cell transplantation in relapsed primary cerebral lymphoma.

Therapeutic drug monitoring for busulfan in plasma during conditioning chemotherapy for autologous stem cell transplantation in relapsed primary cerebral lymphoma has not previously been reported. This case involved a 49-year-old man with relapsed primary cerebral lymphoma who received busulfan (8 mg/kg total dose; 2.67 mg/kg as a 3-hour IV infusion each of days -6 through -4) as part of a multiagent chemotherapy conditioning regimen. Multiple plasma samples were collected for all 3 doses and busulfan was quantified by liquid chromatography tandem mass spectrometry. A 1-compartment model was individually fitted to the concentration-time data for each dose. Clearance decreased across the 3 days of treatment (4.84, 4.06, and 3.04 mL/min/kg, respectively), whereas at the same times half-life increased (2.64, 3.18, and 4.17 hours, respectively), as did area under the plasma concentration-time curve0-infinity (9170, 10,900, and 14,600 microg h/L, respectively). Volume of distribution was similar across this time (1-1.1 L/kg). Indices of both renal and hepatic function did not indicate any significant diminution in likely clearance capacity for busulfan. There was also no compelling evidence for drug interactions that could decrease clearance. We conclude that therapeutic drug monitoring should be recommended for future cases of this rare disease, with a view to developing a target-concentration intervention strategy and improving outcomes.

Behavior therapy for obesity: where are we now?

PURPOSE OF REVIEW: To describe the short-term and long-term results of lifestyle modification for obesity. RECENT FINDINGS: Randomized controlled trials, which compared different diet and activity interventions were reviewed. Studies that investigated the efficacy of new technologies to provide lifestyle modification, such as web-based delivery, also were examined. SUMMARY: In general, comprehensive lifestyle modification programs delivered in person induce a loss of approximately 10% of initial weight in 16-26 weeks of treatment. The use of portion-controlled diets, which typically involve the use of meal replacement products, was associated with significantly larger weight losses in the short term. In contrast, interventions delivered via the Internet induced a loss of approximately 5%. However, web-based programs appear to have potential in facilitating the continuation on patient-provider contact, which along with high levels of physical activity, appear to be key strategies for successful long-term weight control. Recent studies also have suggested that the combination of lifestyle modification with long-term use of pharmacotherapy holds promise for maximizing initial weight losses and promoting long-term maintenance.

Current alternative and complementary therapies used in menopause.

OBJECTIVE: To determine the efficacy and safety of common complementary and alternative medicine (CAM) therapies used to relieve the menopausal symptoms. DESIGN: Comprehensive literature search was conducted through the databases Medline, EMBASE, Cochrane, AMED (Allied and Complementary Medicine), NCCAM (The National Centre for Complementary and Alternative Medicine) to identify relevant monographs in English language. RESULTS: Studies have shown that some therapies such as clonidine, selective serotonin receptor inhibitors (SSRIs) and gabapentin are effective in decreasing the degree and frequency of somatic symptoms in menopause, while phytooestrogens and black cohosh have shown mixed results. Use of Ginseng, evening primrose, Dong Quai or vitamin E appears not to be efficacious for the relieving hot flushes. Other effects of these therapies including possible improvements in mood are yet to be substantiated. INCLUSION CRITERIA: All available human complementary medicine studies on menopausal women with regard to the relief of menopausal symptoms. EXCLUSION CRITERIA: Studies not meeting the inclusion criteria, published in languages other than English or animal studies. CONCLUSION: There is a general lacking of longer-term follow-up beyond the trial lengths of 6-12 weeks in the use of CAM, although women may be taking these medications for many years. Well-designed, randomised control trials are needed to elucidate the true effect of these therapies above the placebo effect.

Behavioural therapy in the treatment of obesity (I): new directions for clinical practice.

OBJECTIVES: Behavioural therapy (BT) in obesity treatment helps individuals to develop skills to achieve healthier body weights. Instead of helping to decide what to change, it helps to identify how to change; lifestyle modification is essential for any treatment of obesity, be it dieting, medication, surgery, etc. Physicians often tend to be unwilling to use BT considering it time-consuming and skill-intensive. However, BT can be standardized and used more readily in clinical practice. Besides, new approaches have been developed which contribute to increase the success of the treatments, like non face-to-face techniques, or the new cognitive therapy. SETTING: Classical knowledge on BT has been updated with recent publications and information on these new approaches, combined with our own experience in the clinical treatment of obesity. RESULTS: Most research on BT has been conducted in university-based programs which, despite their importance, tell us little about its effectiveness in actual clinical practice. Future research might focus on determining how BT can be best applied in a real-world setting. Examples of new directions are increased maintenance periods, use of Internet, and new cognitive therapy. Besides, elucidating the genetic component in the prognosis of weight management -the nutrigenomic approach- could assist in the development of more effective and individually tailored therapeutic strategies; indeed, single nucleotide polymorphisms in candidate genes have been related with eating patterns. CONCLUSIONS: This review gives a renewed perspective of BT for obesity, offers key-pointers and describes specific ways in which medical professionals can promote and encourage self-care of patients.

Medical therapy for obesity: present and future.

The prevalence of obesity worldwide has risen sharply during the last four decades. The etiology of obesity is complex and includes a host of genetic influences in addition to the overconsumption of energy coupled with a sedentary lifestyle. Obesity is known to cause or exacerbate many co-morbid conditions such as diabetes, hypertension, dyslipidemia, coronary heart disease, stroke, certain cancers, arthritis and obstructive sleep apnea. Modest weight losses of 5-10% of actual weight are related to significant improvements in co-morbid conditions, but unfortunately the rate of recidivism with short-term therapy for obesity is high. The recent recognition of obesity as a chronic disease that should be treated with long-term programs and possibly with polypharmacy, and the alarming increase in its prevalence, have prompted extensive research and the development of new pharmacotherapy.