Synthesis of Piperine-Based Ester Derivatives with Diverse Aromatic Rings and Their Agricultural Bioactivities against Tetranychus cinnabarinus Boisduval, Aphis citricola Van der Goot, and Eriosoma lanigerum Hausmann.

Exploration of plant secondary metabolites or by using them as leads for development of new pesticides has become one of the focal research topics nowadays. Herein, a series of new ester derivatives of piperine were prepared via the Vilsmeier−Haack−Arnold (VHA) reaction, and their structures were characterized by infrared spectroscopy (IR), melting point (mp), proton nuclear magnetic resonance spectroscopy (1H NMR), and carbon nuclear magnetic resonance spectroscopy (13C NMR). Notably, the steric configurations of compounds 6 and 7 were confirmed by single-crystal analysis. Against T. cinnabarinus, compounds 9 and 11 exhibited 47.6- and 45.4-fold more pronounced acaricidal activity than piperine. In particular, compounds 9 and 11 also showed 2.6-fold control efficiency on the fifth day of piperine. In addition, compound 6 (>10−fold higher than piperine) displayed the most potent aphicidal activity against A. citricola. Furthermore, some derivatives showed good aphicidal activities against E. lanigerum. Moreover, the effects of compounds on the cuticles of T. cinnabarinus were investigated by the scanning electron microscope (SEM) imaging method. This study will pave the way for future high value added application of piperine and its derivatives as botanical pesticides.

Characteristics and Price Increases Among Sole-Source, Off-Patent Drugs in the United States, 2008 to 2018.

Importance: Some sole-source, off-patent drugs in the United States have undergone substantial price hikes in recent years. Despite increased attention by lawmakers, there are limited data to guide policy. Objectives: To describe key attributes of sole-source, off-patent, off-exclusivity drugs; to characterize the prevalence of price increases; and to identify attributes associated with price increases. Design, Setting, and Participants: In this cross-sectional study, 300 sole-source, off-patent, off-exclusivity drug products met inclusion criteria and were selected for analysis from January 1, 2008, to December 31, 2018. Attributes were identified from multiple sources, and yearly wholesale acquisition cost prices were determined from First Databank. Main Outcomes and Measures: The association of drug attributes with the following 2 price change thresholds was measured after adjusting for inflation: 25% or more price increase in a calendar year (wholesale acquisition cost) and 50% or more price increase in a calendar year. The rate of annual price increase over time was also measured. Results: Of the 300 drug products and 2242 observations analyzed, the overall inflation-adjusted mean increase in drug prices was 8.8% (95% CI, 7.8%-9.8%) per year. Ninety-five drugs (31.7%) increased by 25% or more during any calendar year, and 66 drugs (22.0%) increased by 50% or more during any calendar year. An initial price of less than $2 per unit (adjusted odds ratio [aOR], 2.36; 95% CI, 1.69-3.29), antineoplastic and immunomodulatory class (aOR, 2.72; 95% CI, 1.31-5.65), dermatologic class (aOR, 2.95; 95% CI, 1.80-4.84), oral route (aOR, 2.01; 95% CI, 1.45-2.79), and US Food and Drug Administration (FDA) approval before 1990 (aOR, 1.52; 95% CI, 1.14-2.03) were attributes of drugs that were more likely to be associated with a 25% or more price increase in a calendar year after adjusting for by initial price. Similarly, an initial price of less than $2 per unit (aOR, 2.68; 95% CI, 1.76-4.09), antineoplastic and immunomodulatory class (aOR, 3.07; 95% CI, 1.54-6.12), oral route of administration (aOR, 1.70; 95% CI, 1.11-2.60), and FDA approval before 1990 (aOR, 2.02; 95% CI, 1.40-2.94) were attributes of drugs that were more likely to be associated with a 50% or more price increase in a calendar year after adjusting for by initial price. Price increases of 25% or more were most common in 2014, and price increases of 50% or more were most common in 2013. Conclusions and Relevance: Price increases among sole-source, off-patent drugs are common, and policy interest in this practice is warranted. These findings should inform state drug pricing legislation.

Risk adjusting for Medicaid participation in Medicare Advantage.

OBJECTIVES: Determining appropriate capitated payments has important access implications for dual-eligible Medicare Advantage (MA) members. In 2017, MA plans began receiving higher capitated payments for beneficiaries with full vs partial Medicaid when payments started being risk adjusted for level of Medicaid benefits instead of any Medicaid participation. This approach could favor MA plans in states with more generous Medicaid programs where more beneficiaries qualify for full Medicaid and thus a higher capitated payment. To understand this issue, we examined adjusted Medicare spending for dual-eligible beneficiaries across states with differing Medicaid eligibility criteria. STUDY DESIGN: Retrospective analysis of 2007-2015 traditional Medicare data for dual-eligible beneficiaries 65 years and older. METHODS: We compared predicted per-beneficiary spending levels after adjusting for any Medicaid participation and for level of Medicaid benefits across states with varying Medicaid eligibility requirements. RESULTS: States with the most generous Medicaid requirements had more dual-eligible beneficiaries with full Medicaid compared with the most restrictive states (median, 82% vs 55%). Nationally, Medicare spending levels were 1.3 times greater for full vs partial Medicaid participants (range across states, 0.8-1.7). When per-beneficiary spending was adjusted for level of Medicaid benefits, rather than any Medicaid participation, states with more generous Medicaid eligibility had larger gains in predicted spending per dual-eligible beneficiary than states with less generous Medicaid coverage (1.7% vs 1.3% increase). CONCLUSIONS: Distinguishing between partial and full Medicaid in MA payments may disproportionately increase MA payments in states that have more full Medicaid beneficiaries due to more generous Medicaid eligibility.

Trends in Postacute Care Spending Growth During the Medicare Spending Slowdown.

Issue: Over the past decade, traditional Medicare's per-beneficiary spending grew at historically low levels. To understand this phenomenon, it is important to examine trends in postacute care, which experienced exceptionally high spending growth in prior decades. Goal: Describe per-beneficiary spending trends between 2007 and 2015 for postacute care services among traditional Medicare beneficiaries age 65 and older. Methods: Trend analysis of individual-level Medicare administrative data to generate per-beneficiary spending and utilization estimates for postacute care, including skilled nursing facilities, home health, and inpatient rehabilitation facilities. Key Findings and Conclusions: Per-beneficiary postacute care spending increased from $1,248 to $1,424 from 2007 to 2015. This modest increase reflects dramatic changes in annual spending and utilization growth rates, including a reversal from positive to negative spending growth rates for the skilled nursing facility and home health sectors. For example, the average annual spending growth rate for skilled nursing facility services declined from 7.4 percent over the 2008­11 period to ­2.8 percent over the 2012­15 period. Among beneficiaries with inpatient use, growth rates for postacute care spending and utilization slowed, but more moderately than observed among all beneficiaries. Reductions in hospital use, as well as reduced payment rates, contributed to declines in postacute spending.

The association between Medicare accountable care organization enrollment and breast, colorectal, and prostate cancer screening.

BACKGROUND: Despite the rapid diffusion of accountable care organizations (ACOs), the effect of ACO enrollment on cancer diagnosis, treatment, and survivorship remains unknown. The objective of this study was to determine whether Medicare Shared Savings Program (MSSP) ACO enrollment was associated with changes in screening for breast, colorectal, and prostate cancers. METHODS: The authors built a cohort of Medicare beneficiaries from 2006 through 2014 comprising 39,218,652 person-years of observation before and 17,252,345 person-years of observation after MSSP enrollment. The Centers for Medicare & Medicaid Services attribution methodology was recapitulated; and screening services were identified for breast, colorectal, and prostate cancer, implementing both sensitive and specific definitions of cancer screening. Adjusted difference-in-differences analyses were performed using linear regression to characterize changes in annual screening rates after ACO enrollment relative to contemporaneous changes in a non-ACO control group of Medicare beneficiaries. RESULTS: Medicare beneficiaries attributed to ACO-enrolled providers had higher rates of breast, colorectal, and prostate cancer screening before enrollment. A 1.8% relative reduction in breast cancer screening was observed among women attributed to ACO providers (P < .0001), a 2.4% relative increase was observed in colorectal cancer screening (P = .0259), and a 3.4% relative reduction was observed in prostate cancer screening among men attributed to ACO providers (P = .0025) compared with contemporaneous changes in non-ACO controls. CONCLUSIONS: Small-magnitude reductions were observed in breast and prostate cancer screening rates, and a small increase was observed in colorectal cancer screening associated with ACO enrollment. Although ACO enrollment does not appear to drive wholesale changes in cancer screening, small differences may map to meaningful changes in the epidemiology of screen-detected cancers among Medicare beneficiaries.

Trends In Medicare Fee-For-Service Spending Growth For Dual-Eligible Beneficiaries, 2007-15.

Cost containment for dual-eligible beneficiaries (those enrolled in Medicare and Medicaid) is a key policy goal, but few studies have examined spending trends for this population. We contrasted growth in Medicare fee-for-service per beneficiary spending for those with and without Medicaid in the period 2007-15. Relative to Medicare-only enrollees, dual-eligible beneficiaries consistently had higher overall Medicare spending levels; however, they experienced steeper declines in spending growth over the study period. These trends varied across populations of interest. For instance, dual-eligible beneficiaries ages sixty-five and older went from having annual spending growth rates that were 1.8 percentage points higher than Medicare-only beneficiaries in 2008 to rates that were 1.1 percentage points lower in 2015. Across population groups, long-term users of nursing home care had some of the highest spending growth rates, averaging 1.7-4.1 percent annually depending on age group and Medicaid participation. These findings have implications for value-based payment and other Medicare policies aimed at controlling spending for dual-eligible beneficiaries.

MicroRNA­665 suppresses the growth and migration of ovarian cancer cells by targeting HOXA10.

Ovarian cancer is the most lethal gynecological cancer and its metastasis leads to a poor prognosis. The present study was designed to elucidate how microRNA (miR)­665 regulates the proliferation and migration of ovarian tumor cells. Reverse transcription­polymerase chain reaction (RT­PCR) demonstrated that miR­665 expression was decreased in ovarian cancer tissues. Increased expression of miR­665 suppressed the growth and migration of ovarian cancer cells, whereas the downregulated expression of miR­665 led to the opposite results. Bioinformatics tools identified homeobox A10 (HOXA10) as a target of miR­665. Following miR­665 overexpression, HOXA10 protein expression was significantly reduced. A dual luciferase assay revealed that miR­665 bound to the 3'­untranslated region of HOXA10. Immunohistochemistry and RT­PCR revealed that the expression of HOXA10 was negatively correlated with the expression of miR­665. It was concluded that miR­665 targets HOXA10 and may act as a tumor­suppressing gene in ovarian cancer. This pathway may be involved in the development and metastasis of ovarian cancer.

Earlier smoking after waking and the risk of asthma: a cross-sectional study using NHANES data.

BACKGROUND: Recent research shows that nicotine dependence conveys additional health risks above and beyond smoking behavior. The current study examines whether smoking within 5 min of waking, an indicator of nicotine dependence, is independently associated with asthma outcomes. METHODS: Data were drawn from five pooled cross-sectional waves (2005-14) of NHANES, and the final sample consisted of N = 4081 current adult smokers. Weighted logistic regressions were run examining the relationship between smoking within 5 min of waking and outcomes of lifetime asthma, past-year asthma, and having had an asthma attack in the past year. Control variables included demographics, smoking behavior, family history of asthma, depression, obesity, and secondhand smoking exposure. RESULTS: After adjusting for smoking behavior, smoking within 5 min was associated with an approximately 50% increase in the odds of lifetime asthma (OR = 1.46, p = .008) and past-year asthma (OR = 1.47, p = .024), respectively. After additionally adjusting for demographics and other asthma risk factors, smoking within 5 min of waking was associated with a four-fold increase in the odds of lifetime asthma (OR = 4.05, p = .015). CONCLUSIONS: Smoking within 5 min of waking, an indicator of nicotine dependence, is associated with a significantly increased risk of lifetime asthma in smokers. These findings could be utilized in refining risk assessment of asthma among smokers.

Synthesis of novel quinolinomatrine derivatives and their insecticidal/acaricidal activities.

In continuation of our program to discover natural product-based pesticidal agents, a series of new quinolinomatrine derivatives were prepared. Especially three-dimensional structures of five compounds were unambiguously determined by single-crystal X-ray diffraction. Among them, 21-chloroquinolinomatrine exhibited good insecticidal and acaricidal activities against two crop-threatening insect pests, Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed.

Medicare Accountable Care Organization Enrollment and Appropriateness of Cancer Screening.

Importance: Despite rapid diffusion of Accountable Care Organizations (ACOs), whether ACO enrollment results in observable changes in cancer screening remains unknown. Objective: To determine whether Medicare Shared Savings Program (MSSP) ACO enrollment changes the appropriateness of screening for breast, colorectal, and prostate cancers. Design, Setting, and Participants: For this population-based analysis of Medicare beneficiaries, we used Medicare data from 2007 through 2014 and evaluated changes in screening associated with ACO enrollment using differences-in-differences (DD) analyses. We then performed difference-in-difference-in-differences (DDD) analyses to determine whether observed changes in cancer screening associated with ACO enrollment were different across strata of appropriateness, defined using age (65-74 years vs ≥75 years) and predicted survival (top vs bottom quartile). Main Outcomes and Measures: Rates of breast, colorectal, and prostate cancer screening measured yearly as a proportion of eligible Medicare beneficiaries undergoing relevant screening services. Results: Among Medicare beneficiaries, comprising 39 218 652 person-years before MSSP enrollment and 17 252 345 person-years after MSSP enrollment, breast cancer screening declined among both ACO (42.7% precontract, 38.1% postcontract) and non-ACO (37.3% precontract, 34.1% postcontract) populations. The adjusted rate of decline (DD) in the ACO population exceeded the non-ACO population by 0.79% (P < .001). This decline was most pronounced among elderly women (-2.1%), with minimal observed change among younger women (-0.26%). Baseline colorectal cancer screening rates were lower than those for breast cancer among both ACO (10.1% precontract, 10.3% postcontract) and non-ACO (9.2% precontract, 9.1% postcontract) populations. We observed an adjusted 0.24% (P = .03) increase in screening associated with ACO enrollment, most pronounced among younger Medicare beneficiaries (0.36%). For breast and colorectal cancer, we observed statistically significant differences in estimates of effect between age strata, suggesting that the ACO effect on cancer screening is mediated by age (DDD for both P < .001). Prostate cancer screening declined among ACO (35.1% precontract, 28.5% postcontract) and non-ACO (31.2% precontract, 25.7% postcontract) populations. The adjusted rate of decline in the ACO population exceeded that of the non-ACO population by 1.2%. We observed no difference in estimate of effect between age strata, suggesting that the ACO-mediated changes in prostate cancer screening are similar among younger and elderly men. Results characterizing appropriateness with predicted survival mirrored those when stratified by age. Conclusions and Relevance: Medicare Shared Savings Program ACO enrollment is associated with more appropriate breast and colorectal screening, although the magnitude of the observed ACO effect is modest in the early ACO experience.

Time-Varying Effects of Parental Alcoholism on Depression.

INTRODUCTION: Children of alcoholic parents are at increased risk for lifetime depression. However, little is known about how this risk may change in magnitude across age, especially in mid-adulthood and beyond. METHODS: We used a nationally representative sample (N = 36,057) of US adults from the National Epidemiologic Survey on Alcohol and Related Conditions, wave III. After adjusting for demographic characteristics, we examined the relationship between parental alcoholism and outcomes of 1) major depressive disorder, Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) and 2) DSM-5 persistent depressive disorder. To examine continuous moderation of this relationship across participants' age, we used time-varying effect models. RESULTS: Parental alcoholism was associated in general with a higher risk for both major depressive disorder (odds ratio [OR], 1.98, 95% confidence interval [CI], 1.85-2.11; P < .001) and persistent depressive disorder (OR, 2.28, 95% CI, 2.04-2.55; P < .001). The association between parental alcoholism and major depressive disorder was stable and positive across age, but the association with persistent depressive disorder significantly declined among older adults; respondents older than 73 years old were not at increased risk for persistent depressive disorder. CONCLUSIONS: Findings from this study show that the risk of parental alcoholism on depression is significant and stable among individuals of a wide age range, with the exception of a decline in persistent depressive risk among older adults. These findings highlight the importance of screening for depression among adults with parental alcoholism.

Acetylcholinesterase: A Primary Target for Drugs and Insecticides.

BACKGROUND: Acetylcholinesterase is a serine hydrolase that terminates the action of the neurotransmitter acetylcholine by hydrolyzing it into acetic acid and choline. OBJECTIVE: The enzyme, containing an ellipsoidal structure, possesses three binding sites such as active site (with catalytic anionic and esteratic subsites), aromatic gorge and peripheral anionic site, where the inhibiting compounds interact. The acetylcholinesterase inhibitors bind to the enzyme and interfere with the breakdown of acetylcholine, leading to the deposition of acetylcholine in the nerve synapses and causing disrupted neurotransmission. Based on this principle of action, many therapeutic drugs for the treatment of different diseases, pesticides and chemical warfare agents have been synthesized targeting the actylcholinesterase. CONCLUSION: The present review summarizes the current knowledge about acetylcholinesterase, its structure, function and biosynthesis, its inhibitors, and mode of action of inhibitors on it. Besides, the review also presents an overview about the resistance mechanism that the organisms develop due to the over-application of acetylcholinesterase inhibitors.

Time to First Cigarette, a Proxy of Nicotine Dependence, Increases the Risk of Pulmonary Impairment, Independently of Current and Lifetime Smoking Behavior.

INTRODUCTION: Cigarette smoking is the largest known risk factor for chronic obstructive pulmonary disease (COPD), but little is known about the role of time to first cigarette (TTFC), an indicator of nicotine dependence (ND). This study examines whether daily TTFC is associated with pulmonary outcomes, independently of smoking behavior. METHODS: A cross-sectional sample of 1461 current adult smokers were drawn from the National Health and Nutrition Examination Survey (NHANES), 2007-2010. The relationships of daily TTFC with outcomes of spirometry-defined pulmonary impairment and self-reported respiratory symptoms (coughing, bringing up phlegm, and wheezing) were examined (1) at the unadjusted level, (2) after adjusting for smoking heaviness and duration, and (3) after also adjusting for environmental exposure and demographics. RESULTS: In fully-adjusted weighted regressions, those reporting TTFC ≤ 5 minutes were three times as likely to have COPD (confidence interval [CI] = 1.30-8.77), had a 3% lower forced vital capacity expired in the first second (FEV1/FVC) (CI = -0.051 to -0.009), were seven times as likely to report coughing (CI = 1.96-26.41), and 16 times as likely to report bringing up phlegm (CI = 3.43-74.82), relative to those reporting TTFC > 60 minutes. Similar associations were often found when comparing TTFC between 5 to 30 minutes and TTFC between 30 to 60 minutes with TTFC > 60 minutes. CONCLUSIONS: "Addicted" smoking, as measured by earlier TTFC, is associated with a markedly increased risk of spirometry-measured obstructive pulmonary impairment, and of reporting symptoms of coughing and phlegm, even after controlling for smoking behavior and other risk factors for COPD. TTFC may prove valuable in more precisely assessing smokers' risk of pulmonary impairment. IMPLICATIONS: This study shows that smoking sooner after waking, a reliable indicator of ND, substantially increases the risk of spirometry-defined pulmonary impairment and self-reported symptoms, independently of lifetime and current smoking behavior. This study adds to a small body of literature examining health outcomes associated with higher ND, including outcomes of COPD. The current study overcomes important shortcomings of these existing studies in at least two ways: controlling for other known risk factors for COPD, and using empirical, spirometry-defined outcomes pulmonary function rather than self-reported COPD outcomes.