Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition.

Dietary phytochemicals are currently being studied with great interest due to their ability to regulate the epigenome resulting in prevention of cancer. Some natural botanicals have been reported to have enhanced and synergistic impact on cancer suppression when administered at optimum concentrations and in-conjunction. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables and sodium butyrate (NaB) is a short-chain fatty acid produced by gut microbiota. They have been intensively explored due to numerous anti-cancerous properties and ability to modulate epigenetic machinery by inhibition of histone deacetylase (HDAC). Genistein (GE), present in soy, is a known DNA methyltransferase (DNMT) inhibitor. While combined chemoprotective epigenetic effects induced by SFN and GE have been investigated, the key impact of combinatorial SFN-NaB, GE-NaB, and SFN-GE-NaB bioactive components in regulation of various mechanisms are poorly defined. In the present study, we found that combinations of dietary compounds had synergistic effects in decreasing cellular viability at lower dosages than their single dosages in breast cancer cell lines. The respective combinations limited growth and increased apoptosis and necrosis in cancerous cells among which the tri-combination displayed the most significant impact. Additionally, the respective combinations of compounds arrested MDA-MB-231 and MCF-7 breast cancer cells at G2/M phase. Our further mechanistic evaluation revealed that respective di-combinations and tri-combination had higher impact in down-regulation of DNMTs (DNMT3A and DNMT3B), HDACs (HDAC1, HDAC6 and HDAC11), histone methyltransferases (EZH2 and SUV39H1) and histone acetyltransferases (GCN5, PCAF, P300 and CBP) levels as compared to singly administered compounds. We also found that these combinations exhibited global epigenetic changes by inhibition of DNMT and HDAC activity, histone H3 at lysine 27 methylation (H3K27me) and histone H3 at lysine 9 methylation (H3K9me) levels, and by induction of histone acetyltransferases activity. Collectively, our investigation indicates that combined SFN, GE and NaB is highly effective in inhibiting breast cancer genesis by, at least in part, regulating epigenetic modifications, which may have implications in breast cancer therapy.

Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE exposure on early-life breast cancer development in offspring mice. Through integrated transcriptome and methylome analyses, we identified several candidate genes showing significantly differential gene expression and DNA methylation changes. We further found maternal long-term GE treatment can induce inherited epigenetic landmark changes in a candidate tumor suppressor gene, Trp63, resulting in transcriptional activation of Trp63 and induction of the downstream target genes. Our results suggest that maternal long-term exposure to soybean GE may influence early-life epigenetic reprogramming processes, which may contribute to its temporal preventive effects on breast cancer in the offspring. This study provides important mechanistic insights into an appropriate maternal administration of soybean products on prevention of breast cancer later in offspring life.

Dose-dependent relation between metformin and the risk of hormone receptor-positive, her2-negative breast cancer among postmenopausal women with type-2 diabetes.

PURPOSE: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM). METHODS: This nested case-control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008-2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0-30,000, (3)30,001-136,000, (4)136,001-293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1-500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use. RESULTS: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55-0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42-0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46-0.82,p < 0.01) compared to the 0 mg/day group. CONCLUSIONS: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect.

Jasmonic acid coordinates with light, glucose and auxin signalling in regulating branching angle of Arabidopsis lateral roots.

The role of jasmonates (JAs) in primary root growth and development and in plant response to external stimuli is already known. However, its role in lateral root (LR) development remains to be explored. Our work identified methyl jasmonate (MeJA) as a key phytohormone in determining the branching angle of Arabidopsis LRs. MeJA inclines the LRs to a more vertical orientation, which was dependent on the canonical JAR1-COI1-MYC2,3,4 signalling. Our work also highlights the dual roles of light in governing LR angle. Light signalling enhances JA biosynthesis, leading to erect root architecture; whereas, glucose (Glc) induces wider branching angles. Combining physiological and molecular assays, we revealed that Glc antagonises the MeJA response via TARGET OF RAPAMYCIN (TOR) signalling. Moreover, physiological assays using auxin mutants, MYC2-mediated transcriptional activation of LAZY2, LAZY4 and auxin biosynthetic gene CYP79B2, and asymmetric distribution of DR5::GFP and PIN2::GFP pinpointed the role of an intact auxin machinery required by MeJA for vertical growth of LRs. We also demonstrated that light perception and signalling are indispensable for inducing vertical angles by MeJA. Thus, our investigation highlights antagonism between light and Glc signalling and how they interact with JA-auxin signals to optimise the branching angle of LRs.

A glucose-target of rapamycin signaling axis integrates environmental history of heat stress through maintenance of transcription-associated epigenetic memory in Arabidopsis.

In nature, plants cope with adversity and have established strategies that recall past episodes and enable them to better cope with stress recurrences by establishing a 'stress memory'. Emerging evidence suggests that glucose (Glc) and target of rapamycin (TOR), central regulators of plant growth, have remarkable functions in stress adaptation. However, whether TOR modulates a stress memory response is so far unknown. Global transcriptome profiling identified that Glc, through TOR, regulates the expression of numerous genes involved in thermomemory. Priming of TOR overexpressors with mild heat showed better stress endurance, whereas TOR RNAi showed reduced thermomemory. This thermomemory is linked with histone methylation at specific sites of heat stress (HS) genes. TOR promotes long-term accumulation of H3K4me3 on thermomemory-associated gene promoters, even when transcription of those genes reverts to their basal level. Our results suggest that ARABIDOPSIS TRITHORAX 1 (ATX1), an H3K4 methyltransferase already shown to regulate H3K4me3 levels at the promoters of HS recovery genes, is a direct target of TOR signaling. The TOR-activating E2Fa binds to the promoter of ATX1 and regulates its expression, which ultimately regulates thermomemory. Collectively, our findings reveal a mechanistic framework in which Glc-TOR signaling determines the integration of stress and energy signaling to regulate thermomemory.

Prescribing trends of proton pump inhibitors, antipsychotics and benzodiazepines of medicare part d providers.

BACKGROUND: Proton pump inhibitors, benzodiazepines, and antipsychotics are considered potentially inappropriate medications in older adults according to the American Geriatric Society Beers Criteria, and deprescribing algorithms have been developed to guide use of these drug classes. The objective of this study was to describe the number of beneficiaries prescribed these medications, provider specialty and regional trends in prescribing, and the aggregate costs for these claims in Medicare Part D. METHODS: This was a retrospective cross-sectional study using publicly available Medicare Provider Utilization and Payment Data: Part D Prescriber data for years 2013-2019. Descriptive statistics and the Cochrane-Armitage test were used to summarize the trends. RESULTS: Overall, 30.1%, 25.6%, 4.6% of Medicare Part D beneficiaries had a proton pump inhibitor, benzodiazepine, and antipsychotic claim in 2013, respectively. These rates decreased to 27.5%, 17.5%, 4.1% in 2019 (p-value < 0.0001). However, the number of standardized 30-day claims increased from 63 million in 2013 to 84 million in 2019 for proton pump inhibitors, remained steady for benzodiazepines and slightly increased (10 million to 13 million) for antipsychotics. Total aggregate costs decreased by almost $1.5 billion for proton pump inhibitor, $100 million for benzodiazepine, and $700 million for antipsychotic from 2013 to 2019 (p-value < 0.0001). Almost 93% of gastroenterologists prescribed a proton pump inhibitor, and 60% of psychiatrists prescribed benzodiazepines and antipsychotics all seven years. The Other region had the highest percentage of providers prescribing all three classes and the highest number of standardized 30-day benzodiazepine claims. CONCLUSIONS: The overall rate of use of proton pump inhibitors, benzodiazepines, and antipsychotics decreased from 2013-2019 among Medicare Part D beneficiaries. Despite the increase in raw number of standardized 30-day claims, the costs decreased which is likely due to generics made available. These prescribing trends may aid in identifying and targeting potential deprescribing interventions.

Understanding the Intricate Web of Phytohormone Signalling in Modulating Root System Architecture.

Root system architecture (RSA) is an important developmental and agronomic trait that is regulated by various physical factors such as nutrients, water, microbes, gravity, and soil compaction as well as hormone-mediated pathways. Phytohormones act as internal mediators between soil and RSA to influence various events of root development, starting from organogenesis to the formation of higher order lateral roots (LRs) through diverse mechanisms. Apart from interaction with the external cues, root development also relies on the complex web of interaction among phytohormones to exhibit synergistic or antagonistic effects to improve crop performance. However, there are considerable gaps in understanding the interaction of these hormonal networks during various aspects of root development. In this review, we elucidate the role of different hormones to modulate a common phenotypic output, such as RSA in Arabidopsis and crop plants, and discuss future perspectives to channel vast information on root development to modulate RSA components.

Prevalence of fibromyalgia in medical students and its association with lifestyle factors - a cross-sectional study.

OBJECTIVES: Fibromyalgia (FM) is a chronic widespread pain syndrome, known to be associated with several other symptoms. Chronic stress is suspected to be a contributing factor in the pathogenesis of FM. It is known that medical students are under a constant state of stress originating from personal and social expectations. The aim of the study was to assess the prevalence of FM in this population and identify lifestyle parameters influencing FM severity. MATERIAL AND METHODS: An online survey of first- and final-year medical students was conducted using the ACR modified 2016 criteria and FANTASTIC checklist. The survey acquired demographic information such as age, gender, year, and division of studies. A subgroup analysis based on gender, year of studies, and division of studies was performed. RESULTS: 439 medical students (71% females) completed the survey. The overall prevalence of FM in our cohort was 10.48%. The ratio of females to males was 3 : 1. A significant negative correlation between better quality of lifestyle and worse FM severity was observed in all subgroups. The "insight", "sleep and stress", "behavior" and "career" domains of lifestyle were found to have a significant negative correlation with FM severity on univariate analysis. CONCLUSIONS: The prevalence of FM in medical students seems to be considerably higher than in the general population. Chronic stress levels, sleep problems, social support, and behavior seem to be the major factors influencing FM severity in this population. Our findings suggest that medical students must be considered a "high-risk" group for FM, and hence must be identified, educated, and managed accordingly. It is, therefore, important for medical universities to implement programs educating students about FM, the importance of a healthy lifestyle, and stress coping strategies, while also making systemic changes to curb stressors in medical training.

Real-World Patterns of Everolimus Use in Patients with Metastatic Breast Cancer.

BACKGROUND: There is limited literature on patterns of everolimus use and subsequent hospitalizations and emergency room (ER) visits in real-world clinical practice. In this study, we describe patterns of everolimus use and hospitalizations and ER visits in a large cohort of patients with breast cancer (BC). MATERIALS AND METHODS: Patients with BC treated with everolimus were identified in the MarketScan database from 2009 to 2016. The pattern of everolimus use and frequency of associated ER visits and hospitalizations during treatment (between the first claim and 30 days after the last claim for everolimus) were identified. Descriptive statistics and regression models were used. RESULTS: A total of 3,556 everolimus users were identified (median age of 60 years; median days of use, 112). The initial prescribed dose was 10 mg in 74.8% of the patients. Compared with the initial dose, 23.5% of patients had a dose change. Forty-six percent of patients were hospitalized or had an ER visit during the treatment with everolimus. Age greater than 71, higher comorbidity score, treatment year prior to 2012, and lower initial dose were found to be significantly associated with ER visit/hospitalization in the regression models. CONCLUSIONS: A significant proportion of patients receiving everolimus had an ER visit or hospitalization during the use of everolimus. These results provide data regarding risks and benefits of treatment with everolimus. These results will be helpful in identifying patients at higher risk of hospitalizations or ER visits and facilitate evidence-based decision making to avoid serious complications. IMPLICATIONS FOR PRACTICE: Everolimus, a mammalian target of rapamycin inhibitor, is approved in combination with exemestane in patients with hormone receptor-positive tumors previously treated with anastrozole or letrozole. As new drugs become available, it is crucial to understand the adverse events and potential complications associated with the use of such drugs in the general population, outside of the controlled clinical trial setting. This study describes the patterns of everolimus use and adverse events, including hospitalization and emergency room visits, in a large cohort of patients with metastatic breast cancer in routine practice.

Associations of Polypharmacy and Inappropriate Medications with Adverse Outcomes in Older Adults with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Polypharmacy (PP) and potentially inappropriate medications (PIM) are highly prevalent in older adults with cancer. This study systematically reviews the associations of PP and/or PIM with outcomes and, through a meta-analysis, obtains estimates of postoperative outcomes associated with PP in this population. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Register of Clinical Trials using standardized terms for concepts of PP, PIM, and cancer. Eligible studies included cohort studies, cross-sectional studies, meta-analyses, and clinical trials which examined outcomes associated with PP and/or PIM and included older adults with cancer. A random effects model included studies in which definitions of PP were consistent to examine the association of PP with postoperative complications. RESULTS: Forty-seven articles met the inclusion criteria. PP was defined as five or more medications in 57% of the studies. Commonly examined outcomes included chemotherapy toxicities, postoperative complications, functional decline, hospitalization, and overall survival. PP was associated with chemotherapy toxicities (4/9 studies), falls (3/3 studies), functional decline (3/3 studies), and overall survival (2/11 studies). A meta-analysis of four studies indicated an association between PP (≥5 medications) and postoperative complications (overall odds ratio, 1.3; 95% confidence interval [1.3-2.8]). PIM was associated with adverse outcomes in 3 of 11 studies. CONCLUSION: PP is associated with postoperative complications, chemotherapy toxicities, and physical and functional decline. Only three studies showed an association between PIM and outcomes. However, because of inconsistent definitions, heterogeneous populations, and variable study designs, these associations should be further investigated in prospective studies. IMPLICATIONS FOR PRACTICE: Polypharmacy and potentially inappropriate medications (PIM) are prevalent in older adults with cancer. This systematic review summarizes the associations of polypharmacy and PIM with health outcomes in older patients with cancer. Polypharmacy and PIM have been associated with postoperative complications, frailty, falls, medication nonadherence, chemotherapy toxicity, and mortality. These findings emphasize the prognostic importance of careful medication review and identification of PIM by oncology teams. They also underscore the need to develop and test interventions to address polypharmacy and PIM in older patients with cancer, with the goal of improving outcomes in these patients.

The enemy of my enemy: multiple interacting selection pressures lead to unexpected anti-predator responses.

Despite being a major selective force, predation can induce puzzling variability in anti-predator responses-from lack of predator aversion to lifelong predator-induced fear. This variability is hypothesised to result from variation in the trade-offs associated with avoiding predators. But critical information on fitness outcomes of these trade-offs associated with anti-predator behaviours is lacking. We tested this trade-off hypothesis in Aedes aegypti, by examining oviposition site selection decisions in response towards larval predation risk and comprehensively measuring the fitness implications of trade-offs of avoiding larval predators, using three fitness measures: larval survival, development time and size. In a field study, we find that adult females show a surprisingly variable response to predators, ranging from attraction to avoidance. This variation is explained by fitness outcomes of oviposition along a predation-risk gradient that we measured in the laboratory. We show that ovipositing females could gain fitness benefits from ovipositing in pools with a low density of predators, rather than in predator-free pools, as predators provide a release from negative density effects of conspecific larvae that might co-occur in a pool. Interacting selection pressures may thus explain diverse prey responses. We suggest other systems in which similarly unexpected prey behaviour is likely to occur.

FCS-like zinc finger 6 and 10 repress SnRK1 signalling in Arabidopsis.

SNF1-related protein kinase 1 (SnRK1) is a central regulator of plant growth during energy starvation. The FCS-like zinc finger (FLZ) proteins have recently been identified as adaptor proteins which facilitate the interaction of SnRK1 with other proteins. In this study, we found that two starvation-induced FLZ genes, FLZ6 and FLZ10, work as repressors of SnRK1 signalling. The reduced expression of these genes resulted in an increase in the level of SnRK1α1, which is the major catalytic subunit of SnRK1. This lead to a concomitant increase in phosphorylated protein and SnRK1 activity in the flz6 and flz10 mutants. FLZ6 and FLZ10 specifically interact with SnRK1α subunits in the cytoplasmic foci, which co-localized with the endoplasmic reticulum. In physiological assays, similar to the SnRK1α1 overexpression line, flz mutants showed compromised growth. Further, growth promotion in response to favourable growth conditions was found to be attenuated in the mutants. The enhanced SnRK1 activity in the mutants resulted in a reduction in the level of phosphorylated RIBOSOMAL S6 KINASE and the expression of E2Fa and its targets, indicating that TARGET OF RAPAMYCIN-dependent promotion of protein synthesis and cell cycle progression is impaired. Taken together, this study uncovers a plant-specific modulation of SnRK1 signalling.

The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: Prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer.

BACKGROUND: The concomitant use of tyrosine kinase inhibitors (TKIs) and proton pump inhibitors (PPIs) is a significant concern because of potential drug-drug interaction that reduces TKI absorption, thus potentially reducing the effectiveness of TKIs. The objective of this study was to evaluate the prevalence and predictors of concomitant TKI-PPI receipt and its impact on survival and therapy discontinuation in older adults with cancer. METHODS: This retrospective study used linked Surveillance, Epidemiology, and End Results-Medicare data for the years 2007 through 2012. In total, 12,538 patients with lung cancer, renal cell cancer, chronic myelogenous leukemia, liver cancer, or pancreatic cancer were included. The primary exposure variable was concomitant receipt of TKI-PPI, defined as at least 30 days of PPI use in the first 90 days from the start of the TKI (exposure period). The outcomes measured were overall survival and discontinuation of therapy in 90 days and 1 year after the end of the exposure period. Cox proportional-hazards regression with inverse probability of treatment weighting was used to evaluate the association between exposure and outcome. RESULTS: The overall prevalence of TKI-PPI receipt was 22.7%. Predictors that were associated with increased use included polypharmacy and prior PPI receipt. TKI-PPI use decreased survival in 90 days (hazard ratio, 1.16; 95% confidence interval, 1.05-1.28) and in 1 year (hazard ratio, 1.10; 95% confidence interval, 1.04-1.18) but was not associated with discontinuation. CONCLUSIONS: Nearly 1 in 4 older adults with cancer who receive TKIs also receive PPIs concomitantly, and concomitant use is associated with an increased risk of death. Concerted efforts to manage medications are needed to identify and reduce the receipt of PPIs when TKIs are initiated.

Evaluation of the prescribing patterns, adverse effects, and drug interactions of oral chemotherapy agents in an outpatient cancer center.

PURPOSE: Although oral chemotherapy offers advantages over intravenous chemotherapy, it creates a unique set of challenges. Potential barriers include treatment complexity, patient responsibility for medication adherence and monitoring, reduced healthcare contact, and increased financial burden. The purpose of this study is to estimate the prevalence of drug-related problems among a sample of patients treated with oral chemotherapy agents. METHODS: A single-center, retrospective chart review was conducted on patients prescribed oral chemotherapy at our institution between 1 January 2017 and 31 August 2017. The primary endpoint was the incidence of drug-related toxicities within 90 days of starting treatment. Secondary endpoints included incidence of drug-drug interactions, proportion of patients receiving medication education by a clinical pharmacist, and quantification of issues related to medication access. RESULTS: Charts of 100 patients were reviewed. Median time to oral chemotherapy receipt by the patient from the day the order was written was eight days. Prior to initiating therapy, 27% of patients received education by a clinical pharmacist. Toxicity checks were conducted by the provider at 30, 60, and 90 days for 80%, 65%, and 48% of patients, respectively. Treatment-related toxicities secondary to oral chemotherapy were reported by 79% of patients, with 55% classified as severe. Potential drug interactions were in 55% of the patients. CONCLUSION: Data from this study have highlighted avenues for pharmacists to make an impact on patients newly started on oral chemotherapy. Opportunities exist to increase patient education, ensure appropriate follow-up, and assess adherence while preventing and managing treatment-related toxicities.

Combinatorial Epigenetics Impact of Polyphenols and Phytochemicals in Cancer Prevention and Therapy.

Polyphenols are potent micronutrients that can be found in large quantities in various food sources and spices. These compounds, also known as phenolics due to their phenolic structure, play a vital nutrient-based role in the prevention of various diseases such as diabetes, cardiovascular diseases, neurodegenerative diseases, liver disease, and cancers. However, the function of polyphenols in disease prevention and therapy depends on their dietary consumption and biological properties. According to American Cancer Society statistics, there will be an expected rise of 23.6 million new cancer cases by 2030. Due to the severity of the increased risk, it is important to evaluate various preventive measures associated with cancer. Relatively recently, numerous studies have indicated that various dietary polyphenols and phytochemicals possess properties of modifying epigenetic mechanisms that modulate gene expression resulting in regulation of cancer. These polyphenols and phytochemicals, when administrated in a dose-dependent and combinatorial-based manner, can have an enhanced effect on epigenetic changes, which play a crucial role in cancer prevention and therapy. Hence, this review will focus on the mechanisms of combined polyphenols and phytochemicals that can impact various epigenetic modifications such as DNA methylation and histone modifications as well as regulation of non-coding miRNAs expression for treatment and prevention of various types of cancer.

Association between industry payments and prescribing costly medications: an observational study using open payments and medicare part D data.

BACKGROUND: While many new medications may offer advantages over existing drugs, some newer drugs are reformulations of existing products that provide little innovation or incremental benefit while driving up drug costs. Despite the lack of benefit of these medications, prescribers may be motivated by payments made by the pharmaceutical industry. The objective of the study was to determine the association between payments made to physicians by the pharmaceutical industry and prescriptions for certain selected costly brand name drugs. METHODS: This was a cross-sectional, retrospective study linking the Open Payments Database and Medicare Part D Prescriber Public Use File for 2014, including 667,278 physicians who prescribed one of 6 brand-name drugs with less costly but similarly effective alternatives: lovastatin ER, almotriptan, amlodipine+olmesartan, ibuprofen+famotidine, saxagliptin+metformin and naproxen+esomeprazole. The primary outcome was the odds of a physician prescribing one of the selected drugs, and the primary predictor was the receipt of any payment from the pharmaceutical industry. RESULTS: The odds of prescribing 3 of the 6 drugs were increased among physicians who received industry payment, compared to those without payment: amlodipine+olmesartan, aOR 1.42, (95% CI 1.36-1.49); saxagliptin+metformin, aOR 1.50, (95% CI 1.42-1.59); and naproxen+esomeprazole, aOR 1.45, (95% CI 1.25-1.68). Payment from the manufacturer of the specific drug, compared to not receiving payment from the drug's manufacturer, was associated with increased odds of prescribing 4 of the 6 drugs: amlodipine+olmesartan, aOR 2.40, (95% CI 2.29-2.52), ibuprofen+famotidine, aOR 8.06, (95% CI 5.42-12.00), saxagliptin+metformin, aOR 2.21, (95% CI 2.10-2.34) and naproxen+esomeprazole, aOR 5.96, (95% CI 5.08-7.00). CONCLUSIONS: A physician-industry financial relationship was associated with increased odds of prescribing costly brand-name drugs of uncertain medical benefit. Patients, as healthcare consumers, should demand transparency from their physicians about payment from the pharmaceutical industry to increase shared decision-making. Physician and policy makers need increased awareness and reflection on how industry payment influences their prescribing practices.

Comparative Performance of Diagnosis-based and Prescription-based Comorbidity Scores to Predict Health-related Quality of Life.

OBJECTIVES: To compare the performance of the health-related quality of life-comorbidity index (HRQoL-CI) with the diagnosis-based Charlson, Elixhauser, and combined comorbidity scores and the prescription-based chronic disease score (CDS) in predicting HRQoL in Agency of Healthcare Research and Quality priority conditions (asthma, breast cancer, diabetes, and heart failure). METHODS: The Medical Expenditure Panel Survey (2005 and 2007-2011) data was used for this retrospective study. Four disease-specific cohorts were developed that included adult patients (age 18 y and above) with the particular disease condition. The outcome HRQoL [physical component score (PCS) and mental component score (MCS)] was measured using the Short Form Health Survey, Version 2 (SF-12v2). Multiple linear regression analyses were conducted with the PCS and MCS as dependent variables. Comorbidity scores were compared using adjusted R. RESULTS: Of 140,046 adult participants, the study cohort included 7436 asthma (5.3%), 1054 breast cancer (0.8%), 13,829 diabetes (9.9%), and 937 heart failure (0.7%) patients. Among individual scores, HRQoL-CI was best at predicting PCS and MCS. Adding prescription-based comorbidity scores to HRQoL-CI in the same model improved prediction of PCS and MCS. HRQoL-CI+CDS performed the best in predicting PCS (adjusted R): asthma (43.7%), breast cancer (31.7%), diabetes (32.7%), and heart failure (20.0%). HRQoL-CI+CDS and Elixhauser+CDS had superior and comparable performance in predicting MCS (adjusted R): asthma (HRQoL-CI+CDS=20.1%; Elixhauser+CDS=19.6%), breast cancer (HRQoL-CI+CDS=12.9%; Elixhauser+CDS=14.1%), diabetes (HRQoL-CI+CDS=17.7%; Elixhauser+CDS=17.7%), and heart failure (HRQoL-CI+CDS=18.1%; Elixhauser+CDS=17.7%). CONCLUSIONS: HRQoL-CI performed best in predicting HRQoL. Combining prescription-based scores to diagnosis-based scores improved the prediction of HRQoL.

Predicting and reducing potential parasite infection between migratory livestock and resident Asiatic ibex of Pin valley, India.

Disease cross-transmission between wild and domestic ungulates can negatively impact livelihoods and wildlife conservation. In Pin valley, migratory sheep and goats share pastures seasonally with the resident Asiatic ibex (Capra sibirica), leading to potential disease cross-transmission. Focussing on gastro-intestinal nematodes (GINs) as determinants of health in ungulates, we hypothesized that infection on pastures would increase over summer from contamination by migrating livestock. Consequently, interventions in livestock that are well-timed should reduce infection pressure for ibex. Using a parasite life-cycle model, that predicts infective larval availability, we investigated GIN transmission dynamics and evaluated potential interventions. Migratory livestock were predicted to contribute most infective larvae onto shared pastures due to higher density and parasite levels, driving infections in both livestock and ibex. The model predicted a c.30-day antiparasitic intervention towards the end of the livestock's time in Pin would be most effective at reducing GINs in both hosts. Albeit with the caveats of not being able to provide evidence of interspecific parasite transmission due to the inability to identify parasite species, this case demonstrates the usefulness of our predictive model for investigating parasite transmission in landscapes where domestic and wild ungulates share pastures. Additionally, it suggests management options for further investigation.

Regulation of PIN polarity in response to abiotic stress.

Plants have evolved robust adaptive mechanisms to withstand the ever-changing environment. Tightly regulated distribution of the hormone auxin throughout the plant body controls an impressive variety of developmental processes that tailor plant growth and morphology to environmental conditions. The proper flow and directionality of auxin between cells is mainly governed by asymmetrically localized efflux carriers - PINs - ensuring proper coordination of developmental processes in plants. Discerning the molecular players and cellular dynamics involved in the establishment and maintenance of PINs in specific membrane domains, as well as their ability to readjust in response to abiotic stressors is essential for understanding how plants balance adaptability and stability. While much is known about how PINs get polarized, there is still limited knowledge about how abiotic stresses alter PIN polarity by acting on these systems. In this review, we focus on the current understanding of mechanisms involved in (re)establishing and maintaining PIN polarity under abiotic stresses.

Spoilt for choice: Do female mosquitoes experience choice overload when deciding where to lay eggs?

Animals live in complex natural environments. Based on the effects of natural selection, theory on animal information use says that it is optimal for animals to make "rational" decisions, i.e., to choose alternatives which maximize fitness gains, irrespective of the number of alternatives presented to them. Yet, animals commonly make seemingly "irrational" choices in the face of complex and variable stimuli that challenge their cognitive machinery. Here, we test the choice overload hypothesis - decision-making is negatively affected when animals experience an overload of choice. Using simultaneous-choice trials that varied in choice repertoire size, we examined oviposition site selection behaviour in Aedes aegypti towards larval predators, the nymphs of Bradinopyga geminata. Based on the underlying fitness trade-offs of oviposition decision-making, we predicted that female oviposition preference would be weaker and variation in this response would be higher in complex, multiple-choice trials than in binary-choice trials. In partial support of our hypothesis, oviposition preference was weaker in the complex, multiple-choice trials, but the variation in response depended on predator density, and did not depend on choice repertoire size. We suggest that information overload can negatively affect certain aspects of animal decision-making, resulting in choices appearing as "irrational" if the complexity of the decision-making context is not incorporated. Information overload can potentially lead to alternative strategies, such as bet-hedging or decision-making with reduced discrimination.