Explore the vast range of titles available.

Abstract Purpose The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs). Methods In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures. Results Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience. Conclusions OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

PurposeBio-based recycling systems and agricultural production using recycled materials are often evaluated separately. This study performs an environmental and socio-economic life cycle assessment (LCA) of a food waste treatment and spinach farming system in Japan. The environmental and economic tradeoffs of introducing a recycling system and the net environmental benefit of the substitution of market fertilizer considering operation changes are also examined.MethodsThree scenarios were developed and compared. In the conventional (CV) scenario, food waste is collected, incinerated, and disposed of in landfill, and the farmer uses market organic fertilizer. The on-site composting (OC) scenario processes food waste using an on-site garbage disposer and transports compost to a nearby spinach farmer. Food waste in the centralized composting (CC) scenario is transported to a centralized composting facility and resultant compost is sent to the farm. Primary data were obtained from field experiments and interviews. Non-greenhouse gas (GHG) emissions from the field and nitrogen leaching to water systems were simulated using the denitrification–decomposition (DNDC) model.The environmental LCA targeted climate change, eutrophication, and waste landfill. An input–output analysis estimated socio-economic indicators, namely gross added value and employment inducement effect.Results and discussionThe scenario with the lowest impact is the CC scenario. Climate change and eutrophication impacts are highest in the OC scenario and waste landfill impacts are most significant in the CV scenario. The weighted impact by LIME2 can be reduced by 47% in the CC scenario and 17% in the OC scenario due to the recycling of food waste instead of dumping in the landfill. The difference in socio-economic indicators between the scenarios was relatively small, although the CV scenario encouraged more employment. The substitution effect of composting, as well as the environmental impact reduction of replacing market organic fertilizer with compost, will result in 28.7% of the avoided impacts in GHG emissions.ConclusionsBoth composting scenarios are feasible from an environmental and socio-economic perspective when compared with conventional organic production, although there is a tradeoff between waste landfill and GHG emissions for the on-site composting system. However, the OC scenario needs to save electricity to improve its environmental competitiveness with the CV scenario. When considering the substitution effect of composting, it is recommended to take into account that agricultural operation also changes.

Background Harvested wood products (HWPs) mitigate climate change through carbon storage, material substitution, and energy substitution. We construct a model to assess the overall climate change mitigation effect (comprising the carbon storage, material substitution, and energy substitution effects) resulting from HWPs in regions of Japan. The model allows for projections to 2050 based on future scenarios relating to the domestic forestry industry, HWP use, and energy use. Results Using the production approach, a nationwide maximum figure of 2.9 MtC year −1 for the HWP carbon storage effect is determined for 2030. The maximum nationwide material substitution effect is 2.9 MtC year −1 in 2050. For the energy substitution effect, a nationwide maximum projection of 4.3 MtC year −1 in 2050 is established, with at least 50 % of this figure derived from east and west Japan, where a large volume of logging residue is generated. For the overall climate change mitigation effect, a nationwide maximum projection of 8.4 MtC year −1 in 2050 is established, equivalent to 2.4 % of Japan’s current carbon dioxide emissions. Conclusions When domestic roundwood production and HWP usage is promoted, an overall climate change mitigation effect is consistently expected to be attributable to HWPs until 2050. A significant factor in obtaining the material substitution effect will be substituting non-wooden buildings with wooden ones. The policy of promoting the use of logging residue will have a significant impact on the energy substitution effect. An important future study is an integrated investigation of the climate change mitigation effect for both HWPs and forests.

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306). Test of therapeutic mosaic vaccines in HIV-infected individuals shows no control of virus after treatment interruption.

Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200–800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, “high” vs “low”), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80–125%) in the analysis population. This study is registered with ClinicalTrials.gov\\, number NCT01713777. Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98–103, Cmax 90% CI 99–105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

This empirical study seeks to identify determinants of the underground economy in the U.S. in the form of aggregate federal personal income tax evasion over the period 1975-2008, with a specific focus upon the impact of higher federal income tax rates on tax evasion. In this study, we use the most recent data available on aggregate personal income tax evasion, data that are derived from the General Currency Ratio Model and measured in the form of the ratio of unreported AGI to reported AGI. Most other studies of federal income tax evasion for the U.S. do not use data this current. It is found that the impact of increases in the federal income tax rate on aggregate personal income tax evasion may, on balance, be ambiguous, possibly suggesting that the income effect is negative and outweighs the positive substitution effect for the representative taxpayer. It is also found that the degree of aggregate personal income tax evasion may be an increasing function of the percentage of federal personal income tax returns characterized by itemized deductions and a decreasing function of the Tax Reform Act of 1986 (during the first two years of implementation), the ratio of the tax free interest rate yield on high grade municipals to the interest rate yield on ten year Treasury notes, and higher audit rates of filed federal income tax returns (as a measure of risk from tax evasion) by IRS personnel. Finally, unpopular wars may provide a secondary benefit for and therefore act as an inducement for greater tax evasion.

This article elaborates a conceptual framework for assessing the character and effectiveness of immigration policies. It argues that, to a considerable extent, the public and academic controversy concerning this issue is spurious because of fuzzy definitions of policy effectiveness, stemming from confusion between (1) policy discourses, (2) policies on paper, (3) policy implementation, and (4) policy impacts. The article distinguishes three policy gaps: the discrepancy between public discourses and policies on paper (discursive gap); the disparity between policies on paper and implemented policies (implementation gap); and the extent to which implemented policies affect migration (efficacy gap). Although implemented policies seem to be the correct yardstick to assess policy effectiveness, in practice the (generally more pronounced) discourses are often used as a benchmark. This can lead to an overestimation of policy failure. Existing empirical studies suggest that policies significantly affect the targeted migration flows, but they crucially fail to assess the relative importance of policies in comparison to other migration determinants, including non-migration policies, as well as the hypothetical occurrence of unintended categorical, spatial, inter-temporal, and reverse flow \"substitution\" effects. Evidence on such effects is still scarce, showing the need for more empirically informed insights about the short- and long-term effects of migration policies.

This paper shows the existence of a net market expansion effect of news aggregators through which news outlets increase their number of visits. The impact of aggregators on news outlets is ambiguous. In particular, the existing theoretical literature highlights that, although aggregators create a market expansion effect when they bring visitors to news outlets, they also generate a substitution effect if some visitors switch from the news outlets to the aggregators. Using the shutdown of the Spanish edition of Google News in December of 2014 and difference-in-differences methodology, this paper empirically examines the relevance of these two effects. We show that the shutdown of Google News in Spain decreased the number of daily visits to Spanish news outlets between 8% and 14% and that this effect was larger in outlets with fewer overall daily visits and a lower share of international visitors. We also find evidence suggesting that the shutdown decreased online advertisement revenues and advertising intensity at news outlets. We then analyze the effect of the opt-in policy adopted by the German edition of Google News in October of 2014. Although such policy did not significantly affect the daily visits of all outlets that opted out, it reduced by 8% the number of visits of the outlets controlled by the publisher Axel Springer. Our results show the existence of a net market expansion effect through which news aggregators increase consumers' awareness of news outlets' contents, thereby increasing their number of visits.

[Purpose/Significance] The ongoing digital transformation has led to significant changes in public cultural services, particularly in content generation, communication channels, and modes of public participation. \"Accessibility,\" a key indicator of the extent to which citizens' cultural rights are realized, is typically assessed along four dimensions: availability, acceptability, accessibility, and adaptability. Previous research has focused primarily on the supply side of accessibility, examining how factors such as the distribution of cultural resources, infrastructure development, and policy support affect user engagement. However, with the widespread adoption of digital technologies, individuals' ability and willingness to access information, utilize services, and provide feedback - collectively referred to as \"digital literacy\" - has become an increasingly important variable influencing cultural participation. Consequently, this study seeks to explore the relationship between users' digital literacy and the accessibility of public cultural services from a demand-side perspective. It aims to provide a more systematic theoretical framework and practical approach to optimizing the effectiveness of public cultural services. [Methods/Process] This study assesses users' digital literacy by examining their level of digital access, Internet usage, and service availability based on data collected from the Beijing-Tianjin-Hebei region. A structured questionnaire yielded 892 valid responses. To analyze the relationship between users' digital literacy and the accessibility of public cultural services, the study applies a generalized ordered logit model. A generalized ordered logit model is employed to analyze the substitution and overlap effects between users' digital literacy and the various dimensions of service accessibility. [Results/Conclusions] There is currently a digital divide exists between different demographic groups. A significant substitution effect is observed between traditional public cultural accessibility and users' digital literacy, with limited overlap between the two. Digitization has driven the modernization of public cultural resources and services, particularly in terms of technology and service delivery. However, there remains a time lag between the users' digital literacy of users and the digital transformation of the public cultural supply side. This lag suggests that the digital needs of users and the availability of digital cultural services are not fully aligned, which negatively impacts the effectiveness of public cultural services. Therefore, enhancing users' digital literacy, especially improving their ability to adapt to digital cultural resources, is a crucial factor in transitioning public cultural services from \"accessibility\" to \"enjoyment\". In promoting the digital upgrading of public cultural services, greater emphasis should be placed on developing users' capabilities and anticipating their needs.

U.S. data reveal three facts: (1) the share of goods in total expenditure declines at a constant rate over time, (2) the price of goods relative to services declines at a constant rate over time, and (3) poor households spend a larger fraction of their budget on goods than do rich households. I provide a macroeconomic model with non-Gorman preferences that rationalizes these facts, along with the aggregate Kaldor facts. The model is parsimonious and admits an analytical solution. Its functional form allows a decomposition of U.S. structural change into an income and substitution effect. Estimates from micro data show each of these effects to be of roughly equal importance.