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Responding to global standards and legislative updates in Canada, including Bill S-5 (2023), toxicity testing is shifting towards more ethical, in vitro methods. Traditional two-dimensional (2D) monolayer cell cultures, limited in replicating the complex in vivo environment, have prompted the development of more relevant three-dimensional (3D) spheroidal hepatocyte cultures. This study introduces the first 3D spheroid model for McA-RH7777 cells, assessing xenobiotic receptor activation, cellular signaling, and toxicity against dexamethasone and naphthenic acid (NA)-fraction components; NAFCs. Our findings reveal that 3D McA-RH7777 spheroids demonstrate enhanced sensitivity and more uniform dose–response patterns in gene expression related to xenobiotic metabolism (AhR and PPAR) for both single compounds and complex mixtures. Specifically, 3D cultures showed significant gene expression changes upon dexamethasone exposure and exhibited varying degrees of sensitivity and resistance to the apoptotic effects induced by NAFCs, in comparison to 2D cultures. The optimization of 3D culture conditions enhances the model's physiological relevance and enables the identification of genomic signatures under varied exposures. This study highlights the potential of 3D spheroid cultures in providing a more accurate representation of the liver's microenvironment and advancing our understanding of cellular mechanisms in toxicity testing. [ABSTRACT FROM AUTHOR]

Changes in the dynamics of prescription drug markets have raised issues regarding whether the United States Bureau of Labor Statistics' (BLS') Prescription Drug Consumer Price Index (CPI‐Rx) has adequately kept up with the evolving marketplace. The CPI‐Rx limits its sampling frame to retail outpatient outlets and excludes prescription pharmaceuticals dispensed in non‐retail settings such as hospitals, physician/clinic outpatient facilities, and nursing homes. Thus, the CPI‐Rx overlooks the increasingly important specialty pharmaceuticals dispensed in non‐retail settings, whose transactions are instead captured in the overall hospital and professional services component of the medical care CPI. Specialty drugs now account for about 55% of all U.S. drug spending, double the share of a decade earlier. To the extent specialty drug price growth differs from that of traditional pharmaceuticals, the CPI‐Rx could provide an inaccurate measure of overall drug price inflation. We calculate a chained Laspeyres CPI using data from the Merative™ MarketScan® Databases for the years 2010–2019 and IQVIA‐designated specialty drugs and offer evidence showing that by not sampling specialty drugs in non‐retail settings, the CPI‐Rx has understated overall U.S. prescription drug inflation by just under 75 basis points annually. We discuss implications for health care policy and suggest the BLS examine the feasibility of publishing an overall pharmaceutical price index incorporating both traditional and specialty pharmaceuticals dispensed in retail and non‐retail settings. [ABSTRACT FROM AUTHOR]

Amid the global opioid crisis, the volume of drug trade via darknet markets has risen to an all-time high. The steady increase can be explained by the reliable operation of darknet markets, affected by community-building trust factors reducing the risks during the process of the darknet drug trade. This study was designed to explore the risk reduction efforts of the community of a selected darknet market and therefore contribute to the harm assessment of darknet markets. We performed Latent Dirichlet Allocation topic modelling on customer reviews of drug products (n = 25,107) scraped from the darknet market Dark0de Reborn in 2021. We obtained a model resulting in 4 topics (coherence score = 0.57): (1) feedback on satisfaction with the transaction; (2) report on order not received; (3) information on the quality of the product; and (4) feedback on vendor reliability. These topics identified in the customer reviews suggest that the community of the selected darknet market implemented a safer form of drug supply, reducing risks at the payment and delivery stages and the potential harms of drug use. However, the pitfalls of this form of community-initiated safer supply support the need for universally available and professional harm reduction and drug checking services. These findings, and our methodological remarks on applying text mining, can enhance future research to further examine risk and harm reduction efforts across darknet markets. [ABSTRACT FROM AUTHOR]

Certified community behavioral health centers (CCBHCs) were established under section 223 of the Protecting Access to Medicare Act of 2014. CCBHCs had the goal of expanding access to care for people with behavioral health needs "regardless of ability to pay and place of residence." The authors used descriptive tables and a heat map to compare the geographic distribution of CCBHCs with county-level rates of mental illness, poverty, and population density. Regression models were employed to determine which county-level characteristics are most strongly associated with the establishment of a CCBHC. The authors found that population density is a stronger predictor of CCBHC presence than are rates of poverty or serious mental illness. Holding all other local characteristics constant, the authors observed that going from the population density typical of the most rural counties to that of the most urban counties was associated with an approximately 28-percentage-point increase (from 7% to 35%) in the likelihood of being served by a CCBHC. Expanding CCBHC services to areas with lower population densities likely requires an approach that is different from the current method of allocation of grant funds by the Substance Abuse and Mental Health Services Administration (SAMHSA). Two features of the program might be modified. The first would build on flexibilities incorporated into the most recent round of SAMHSA grantmaking, which explicitly aim to build infrastructure and capacity to develop a CCBHC. A second modification might seek to identify which certification requirements are essential to supporting CCBHC quality and access and eliminate nonessential requirements. [ABSTRACT FROM AUTHOR]

A growing body of evidence indicates that poor health early in life can leave lasting scars on adult health and economic outcomes. While much of this literature focuses on childhood experiences, mechanisms generating these lasting effects—recurrence of illness and interruption of human capital accumulation—are not limited to childhood. In this study, we examine how an episode of depression experienced in early adulthood affects subsequent labor market outcomes. We find that, at age 50, people who had met diagnostic criteria for depression when surveyed at ages 27–35 earn 10% lower hourly wages (conditional on occupation), work 120–180 fewer hours annually, and earn 24% lower annual wage incomes. A portion of this income penalty (21%–39%) occurs because depression is often a chronic condition, recurring later in life. But a substantial share (25%–55%) occurs because depression in early adulthood disrupts human capital accumulation, by reducing work experience and by influencing selection into occupations with skill distributions that offer lower potential for wage growth. These lingering effects of early depression reinforce the importance of early and multifaceted intervention to address depression and its follow‐on effects in the workplace. [ABSTRACT FROM AUTHOR]

The article discusses Medicaid's crucial role in financing Substance Use Disorder (SUD) care, highlighting its significance for low-income individuals and underscoring progress in expanding coverage and services, including medications and post-release care. Challenges remain, notably in Medicaid expansion, coverage limitations, and reimbursement rates, urging coordinated advocacy efforts to ensure equitable, high-quality SUD care for Medicaid enrollees nationwide.

Historically, pandemics had inevitably produced demonization and scapegoating, and the COVID-19 pandemic has been no exception. Some individuals and groups have attempted to weaponize and exploit the pandemic, to use it as a means of spreading their extremist ideologies and to radicalize others to their causes. Segmented regression analyses of seven online extremist forums revealed that posting behavior on violent right-wing extremist and incel forums increased significantly following the declaration of the pandemic. The same was not true of left-wing or jihadist forums. These unequal effects likely reflect the particular grievance-based and online nature of right-wing and incel extremism. [ABSTRACT FROM AUTHOR]

Although many law enforcement and intelligence agencies are concerned about online communities known to facilitate violent right-wing extremism, little is empirically known about the presence of extremist ideologies, expressed grievances, or violent mobilization efforts that make up these spaces. In this study, we conducted a content analysis of a sample of postings from two of the most conspicuous right-wing extremist forums known for facilitating violent extremism, Iron March and Fascist Forge. We identified a number of noteworthy posting patterns within and across forums that may assist law enforcement and intelligence agencies in identifying credible threats online. [ABSTRACT FROM AUTHOR]

Despite decades of research, there is no consensus as to the core correlates of national-level voter turnout. We argue that this is, in part, due to the lack of comprehensive, systematic empirical analysis. This paper conducts such an analysis. We identify 44 articles on turnout from 1986 to 2017. These articles include over 127 potential predictors of voter turnout, and we collect data on seventy of these variables. Using extreme bounds analysis, we run over 15 million regressions to determine which of these 70 variables are robustly associated with voter turnout in 579 elections in 80 democracies from 1945 to 2014. Overall, 22 variables are robustly associated with voter turnout, including compulsory voting, concurrent elections, competitive elections, inflation, previous turnout, and economic globalization. [ABSTRACT FROM AUTHOR]

Mild and moderate mental illnesses can hinder labor force participation, lead to work interruptions, and hamper earning potential. Targeted interventions have proven effective at addressing these problems. But their potential depends on labor protections that enable people to take advantage of these interventions while keeping jobs and income. [ABSTRACT FROM AUTHOR]

In a pilot study, electron‐density (ED) and ED Laplacian distributions were reconstructed for the challenging case of CaB6 (Pearson symbol cP7) with conceptually fractional B—B bonds from quantum‐chemically calculated structure‐factor sets with resolutions 0.5 Å–1 ≤ [sin(θ)/λ]max ≤ 5.0 Å–1 by means of Fourier‐synthesis techniques. Convergence of norm deviations of the distributions obtained with respect to the reference ones was obtained in the valence region of the unit cell. The QTAIM (quantum theory of atoms in molecules) atomic charges, and the ED and ED Laplacian values at the characteristic critical points of the Fourier‐synthesized distributions have been analysed for each resolution and found to display a convergent behaviour with increasing resolution. The presented method(exponent) (ME) type of Fourier‐synthesis approach can qualitatively reconstruct all characteristic chemical bonding features of the ED from valence‐electron structure‐factor sets with resolutions of about 1.2 Å–1 and beyond, and from all‐electron structure‐factor sets with resolutions of about 2.0 Å–1 and beyond. Application of the ME type of Fourier‐synthesis approach for reconstruction of ED and ED Laplacian distributions at experimental resolution is proposed to complement the usual extrapolation to infinite resolution in Hansen–Coppens multipole model derived static ED distributions. [ABSTRACT FROM AUTHOR]

The rise in illicit drug trafficking on darknet markets (DNMs) was boosted by those restrictions imposed due to the COVID-19 pandemic. This study aims to put this trend into context by exploring the characteristics of vendors' services and reputations and understand how products are advertised and what customers tend to value. Qualitative content analysis was conducted on a sample (n = 100) randomly selected from 6,357 product descriptions and a sample (n = 500) randomly selected from 34,619 reviews. Both samples are from products found in the drug category of the darknet market Dark0de Reborn. On the supply side, vendors tended to provide basic information on the drugs, a mention of their high quality, the speed and stealth of delivery, their availability for responding to messages, the effects of the drugs, and sometimes even instructions for use. Regarding the demand side, customers usually praised the quality of the product, mentioned the speed and stealth-secure packaging of delivery as essentials, and expressed only a small number of issues. These results support the applicability of Norbert Elias' social figuration theory in which the interdependencies of the actors are fueled by trust. This theoretical frame sheds light on the social value of the community of DNMs. Furthermore, the findings formulate a robust hypothesis for future research about the previously undervalued role of delivery providers. [ABSTRACT FROM AUTHOR]

Mental illnesses affect roughly 20 percent of the US population. Like other health conditions, mental illnesses impose costs on individuals; they also generate costs that extend to family members and the larger society. Care for mental illnesses has evolved quite differently from the rest of health care sector. While medical care in general has seen major advances in the technology of treatment this has not been the case to the same extent for the treatment of mental illnesses. Relative to other illnesses, the cost of care for mental illnesses has grown more slowly and the social cost of illness has grown more rapidly. In this essay we offer evidence about the forces underpinning these patterns and emphasize the challenges stemming from the heterogeneity of mental illnesses. We examine institutions and rationing mechanisms that affect the ability to make appropriate matches between clinical problems and treatments. We conclude with a review of implications for policy and economic research. [ABSTRACT FROM AUTHOR]

Lack of accountability contributes to the gap between best practices and potential outcomes. Few mental health providers routinely practice evidence-based care. In fact, within the mental health field, there is significant controversy over the use of evidence-based practices. Lack of accountability affects individuals receiving care at the patient level, provider level, and systems level. The authors identify several impediments to accountability in behavioral health care. These include failure to develop a diverse, well-trained workforce; challenges in measurement; misalignment of payment incentives; and misguided regulations. Accountability arrangements typically consist of several elements: a clear articulation of goals, objectives, or standards; metrics so that progress toward achieving goals can be tracked; and consequences for insurers, providers, and professionals for achieving or failing to achieve objectives. To advance system goals, the full complement of accountability tools should be consistently applied to all sources of behavioral health care and supports. The authors focus on three sets of accountability tools—performance metrics, payment incentives, and regulatory standards—that when implemented thoughtfully can help move the field toward more positive outcomes in behavioral health. [ABSTRACT FROM AUTHOR]

Despite the ongoing need for researchers, practitioners, and policymakers to identify and assess the online activities of violent extremists prior to their engagement in violence offline, little is empirically known about their online behaviors generally or differences in their posting behaviors compared to non-violent extremists who share similar ideological beliefs particularly. In this study, we drew from a unique sample of violent and non-violent right-wing extremists to compare their posting behaviors within a sub-forum of the largest white supremacy web-forum. Analyses for the current study proceeded in three phases. First, we plotted the average posting trajectory for users in the sample, followed by an assessment of the rates at which they stayed active or went dormant in the sub-forum. We then used logistic regression to examine whether specific posting behaviors were characteristic of users' violence status. The results highlight a number of noteworthy differences in the posting behaviors of violent and non-violent right-wing extremists, many of which may inform future risk factor frameworks used by law enforcement and intelligence agencies to identify credible threats online. We conclude with a discussion of the implications of this analysis, its limitations and avenues for future research. [ABSTRACT FROM AUTHOR]

The "Taxonomy of Artificial Intelligence for Medical Services and Procedures" became part of the Current Procedural Terminology (CPT®) code set effective January 1, 2022. It provides a framework for discrete and differentiable CPT codes which; are consistent with the features of the devices' output, characterize interaction between the device and the physician or other qualified health care professional, and foster appropriate payment. Descriptors include "Assistive", "Augmentative", and "Autonomous". As software increasingly augments the provision of medical services the taxonomy will foster consistent language in coding enabling patient, provider, and payer access to the benefits of innovation. [ABSTRACT FROM AUTHOR]

International reference prices (IRP), also called external reference prices, are widely used across developed nations. IRP uses the prices paid in other countries to either inform negotiations with the pharmaceutical industry or as a cap on market prices. The authors review the application of IRP to cap the prices of negotiated outcomes in the context of US proposals for changing the way prescription drug prices are established for the Medicare program. They examine the economic, political, and administrative issues associated with the use of IRP, and they summarize the evidence on the impacts of IRP. [ABSTRACT FROM AUTHOR]

There is an ongoing need for researchers, practitioners, and policymakers to detect and assess online posting behaviors of violent extremists prior to their engagement in violence offline, but little is empirically known about their online behaviors generally or the differences in their behaviors compared with nonviolent extremists who share similar ideological beliefs particularly. In this study, we drew from a unique sample of violent and nonviolent right-wing extremists to compare their posting behaviors in the largest White supremacy web-forum. We used logistic regression and sensitivity analysis to explore how users' time of entry into the lifespan of an extremist sub-forum and their cumulative posting activity predicted their violence status. We found a number of significant differences in the posting behaviors of violent and nonviolent extremists which may inform future risk factor frameworks used by law enforcement and intelligence agencies to identify credible threats online. [ABSTRACT FROM AUTHOR]

The extraction of bitumen from surface mining in the Athabasca Oil Sands Region (AOSR) produces large quantities of oil sands process‐affected water (OSPW) that needs to be stored in settling basins near extraction sites. Chemical constituents of OSPW are known to impair bone health in some organisms, which can lead to increased fracture risk and lower reproductive fitness. Naphthenic acid fraction components (NAFCs) are thought to be among the most toxic class of compounds in OSPW; however, the effect of NAFCs on osteoblast development is largely unknown. In this study, we demonstrate that NAFCs from OSPW inhibit osteoblast differentiation and deposition of extracellular matrix, which is required for bone formation. Extracellular matrix deposition was inhibited in osteoblasts exposed to 12.5–125 mg/L of NAFC for 21 days. We also show that components within NAFCs inhibit the expression of gene markers of osteoblast differentiation and function, namely, alkaline phosphatase (Alp), osteocalcin, and collagen type 1 alpha 1 (Col1a1). These effects were partially mediated by the induction of glucocorticoid receptor (GR) activity; NAFC induces the expression of the GR activity marker genes Sgk1 (12.5 mg/L) and p85a (125 mg/L) and inhibits GR protein (125 mg/L) and Opg RNA (12.5 mg/L) expression. This study provides evidence that NAFC concentrations of 12.5 mg/L and above can directly act on osteoblasts to inhibit bone formation and suggests that NAFCs contain components that can act as GR agonists, which may have further endocrine disrupting effects on exposed wildlife. Surface mining in the Athabasca Oil Sands Region (AOSR) produces large quantities of oil sands process‐affected water (OSPW), constituents of which are known to impair bone health in some organisms. Naphthenic acid fraction components (NAFCs) are thought to be responsible for most of the toxic effect of OSPW, but their effects on bone are unknown. In this study, we demonstrate that NAFCs extracted from the AOSR inhibit osteoblast differentiation and may act via the glucocorticoid receptor. [ABSTRACT FROM AUTHOR]

Many researchers, practitioners, and policymakers are concerned about online communities that are known to facilitate violent right-wing extremism, but little is empirically known about these digital spaces in general and the developmental posting behaviors that make up these spaces in particular. In this study, group-based trajectory modeling—derived from a criminal career paradigm—was used to identify posting trajectories found in the open-access sections of the Iron March and Fascist Forge forums, both of which have gained notoriety for their members' online advocacy of violence and acts of violence carried out by them. Multinomial logistic regression and analysis of variance were then used to assess whether posters' time of entry into the violent forums predicted trajectory group assignment. Overall, the results highlight a number of similarities and differences in posting behaviors within and across platforms, many of which may inform future risk factor frameworks used by law enforcement and intelligence agencies to identify credible threats online. We conclude with a discussion of the implications of this analysis, followed by a discussion of study limitations and avenues for future research. [ABSTRACT FROM AUTHOR]

Disinformation attacks that make use of social media platforms, e.g., the attacks orchestrated by the Russian "Internet Research Agency" during the 2016 U.S. Presidential election campaign and the 2016 Brexit referendum in the UK, have led to increasing demands from governmental agencies for AI tools that are capable of identifying such attacks in their earliest stages, rather than responding to them in retrospect. This research undertaken on behalf of the Canadian Armed Forces and Department of National Defence. Our ultimate objective is the development of an integrated set of machine-learning algorithms which will mobilize artificial intelligence to identify hostile disinformation activities in "near-real-time." Employing The Dark Crawler, the Posit Toolkit, TensorFlow (Deep Neural Networks), plus the Random Forest classifier and short-text classification programs known as LibShortText and LibLinear, we have analysed a wide sample of social media posts that exemplify the "fake news" that was disseminated by Russia's Internet Research Agency, comparing them to "real news" posts in order to develop an automated means of classification. [ABSTRACT FROM AUTHOR]

Critical infrastructures (CI) are connecting their systems to the internet at an increasing rate, providing the opportunity for malicious actors to attack these systems using cyber-weapons. Compromised systems then pose issues for the affected company, and may disrupt the broader population. The purpose of the current study was to analyze IP addresses collected from discussion forums, with a specific interest in which Canadian CIs could potentially be at risk of a cyber-attack. Overall, 897,524 IP addresses were extracted from 47,134,503 posts across 20 discussion forums, 39,164 of which were associated with Canadian CI. Of all Canadian CI sectors, the majority of IP addresses were found to belong to the information and technology sector. A thematic analysis of posts containing IP addresses was conducted, revealing that the majority of posters were sharing large lists of IP addresses with no context given. Lastly, a keyword search was employed on the forums in an attempt to understand discussions surrounding CI. A thematic analysis was employed on a random sample of posts containing keywords, revealing two major themes: Potential threat and threat information. Findings from this study reveal that information useful for conducting cyber-attacks against CI is being shared within these online forums. [ABSTRACT FROM AUTHOR]

Some existing human trafficking research has examined how trafficking laws and regulations deter traffickers. This research, however, has paid little attention to how states' freedom-of-movement policies influence human trafficking. Existing policy debates suggest two possible effects. Europe's experiences with open borders have led to claims that freedom of movement decreases the likelihood that traffickers are detected, thus making human trafficking in and out of states more likely. By contrast, movement restrictions could create an environment in which people become more vulnerable to traffickers. We use data from 182 countries from 2001 to 2017 to test whether freedom of movement increases or decreases human trafficking flows. We find that it is necessary, theoretically and empirically, to consider freedom of foreign movement both locally and in a state's neighborhood, because freedom of movement increases human trafficking when the local and neighborhood practices diverge from each other. [ABSTRACT FROM AUTHOR]

Many developing countries have implemented social health insurance programmes to protect their citizens against the financial risks of seeking healthcare. While many studies have explored how individual insurance enrolments affect catastrophic health spending (CHS) in the short term, there is a lack of evidence on the long-term macro-level effects of social health insurance on CHS in low- and middle-income countries. This study examines the long-term effects of Basic Medical Insurance (BMI) on individual CHS in China, a middle-income country that has witnessed one of the highest worldwide increases in CHS rates despite its remarkable achievement of universal health insurance coverage. Specifically, we used existing longitudinal data from 1989 to 2015, therein assessing BMI policy effects by constructing two macro-level indicators, including the year of BMI presence at the prefectural level and number of years relative to BMI introduction. We employed a three-level difference-in-differences approach for the estimation. There were two main findings. First, BMI policy did not significantly reduce the probability of incurring CHS for BMI enrollees over time. Years after BMI was introduced, the policy even predicted a significant increase in the probability of incurring CHS for individuals who shifted their enrolments from traditional insurance to BMI. Second, BMI policy had spillover effects on the increase in the probability of incurring CHS for non-BMI individuals a few years after its inception. We believe there are three possible explanations for these findings: (1) shrinking BMI service coverage compared to pre-existing government-funded insurance schemes, (2) a profit-driven hospital reform that induces the overuse of expensive medicines and diagnostic tests and (3) the absence of strategic purchasing among local BMI agencies. We also discuss how relevant policy interventions may alleviate insurance-driven financial risks. [ABSTRACT FROM AUTHOR]

Our study evaluated whether exposure to naphthenic acid fraction compounds (NAFCs) extracted from oil sands process–affected waters (OSPW) has adverse effects on fish embryos that persist into later life. We exposed fathead minnow (Pimephales promelas) embryos to concentrations of NAFCs found in OSPW (2.5–54 mg/L) for 7 days (1 day postfertilization to hatch), then raised surviving larvae in outdoor mesocosms of uncontaminated lake water for 1 month. Embryos exposed to NAFCs were more likely to exhibit malformations (by up to 8‐fold) and had slower heart rates (by up to 24%) compared to controls. Fish raised in uncontaminated lake water following exposure to NAFCs as embryos, were 2.5‐fold less likely to survive during the larval stage than control fish. These fish also showed up to a 45% decrease in swim activity and a 36% increase in swim burst events during behavioral tests relative to controls. We conclude that exposure to NAFCs during the embryonic stage can have lasting effects on fish survival, physiology, and behavior that persist at least through the larval stage. These findings of delayed mortalities and persistent sublethal effects of embryonic NAFC exposure are relevant to informing the development of regulations on treated OSPW releases from mining operations. Environ Toxicol Chem 2022;41:1319–1332. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Biologics accounted for roughly $145 billion in spending in 2018. They are also the fastest growing segment of the pharmaceutical industry. The Biological Price Competition and Innovation Act (BPCIA) of 2010 created an abbreviated pathway for biosimilar products to promote price competition in the market for biological drugs. There was great anticipation that the BPCIA would lead to a moderation in drug prices driven by market competition. The observed levels of competition and the accompanying savings have not reached those expected levels. We investigate the early impacts of biosimilar competition on the use and pricing of biological products. We focus especially on the ways in which altered market structures stemming from the implementation of the BPCIA have affected the prices for biological products subject to biosimilar competition. We do so by studying seven products that have recently faced biosimilar competition. We estimate fixed effects and Instrumental Variables models to estimate the impact of market competition on prices. Our results indicate that in the range of one to three entrants each additional marketed product results in a reduction in weighted average market prices of between 5.4% and 7% points. These are the result of a combination of reductions in originator prices and shifting in demand to biosimilar products. [ABSTRACT FROM AUTHOR]

In order to efficiently manage and operate industrial-level production, an increasing number of industrial devices and critical infrastructure (CI) are now connected to the internet, exposed to malicious hackers and cyberterrorists who aim to cause significant damage to institutions and countries. Throughout the various stages of a cyber-attack, Open-source Intelligence (OSINT) tools could gather data from various publicly available platforms, and thus help hackers identify vulnerabilities and develop malware and attack strategies against targeted CI sectors. The purpose of the current study is to explore and identify the types of OSINT data that are useful for malicious individuals intending to conduct cyber-attacks against the CI industry. Applying and searching keyword queries in four open-source surface web platforms (Google, YouTube, Reddit, and Shodan), search results published between 2015 and 2020 were reviewed and qualitatively analyzed to categorize CI information that could be useful to hackers. Over 4000 results were analyzed from the open-source websites, 250 of which were found to provide information related to hacking and/or cybersecurity of CI facilities to malicious actors. Using thematic content analysis, we identified three major types of data malicious attackers could retrieve using OSINT tools: indirect reconnaissance data, proof-of-concept codes, and educational materials. The thematic results from this study reveal an increasing amount of open-source information useful for malicious attackers against industrial devices, as well as the need for programs, training, and policies required to protect and secure industrial systems and CI. [ABSTRACT FROM AUTHOR]

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Since the advent of the Internet, right-wing extremists and those who subscribe to extreme right views have exploited online platforms to build a collective identity among the like-minded. Research in this area has largely focused on extremists' use of websites, forums, and mainstream social media sites, but overlooked in this research has been an exploration of the popular social news aggregation site Reddit. The current study explores the role of Reddit's unique voting algorithm in facilitating "othering" discourse and, by extension, collective identity formation among members of a notoriously hateful subreddit community, r/The_Donald. The results of the thematic analysis indicate that those who post extreme-right content on r/The_Donald use Reddit's voting algorithm as a tool to mobilize like-minded members by promoting extreme discourses against two prominent out-groups: Muslims and the Left. Overall, r/The_Donald's "sense of community" facilitates identity work among its members by creating an environment wherein extreme right views are continuously validated. [ABSTRACT FROM AUTHOR]

Generic drug prices have received a great deal of attention in the past few years. Many agencies have conducted investigations into the pricing patterns for generic drugs. Price spikes for several specific generic drugs have also been widely reported in the media. Today, 90% of all retail prescriptions sold in the United States are generic drugs. Thus, these prices affect affordability of prescription drugs. We construct two Laspeyres chained price indexes for generic prescription drugs. The first reflects direct out-of-pocket payments by consumers to pharmacies for dispensing generic prescription drugs. The second measures the total price received by the pharmacy (the direct out-of-pocket payment plus the price paid to the pharmacy by the insurer). The chained direct out-of-pocket consumer price index we construct shows a roughly 50% decline for generic prescription drugs between 2007 and 2016. The total consumer price index for generic prescription drugs fell by nearly 80%. [ABSTRACT FROM AUTHOR]

Policy PointsMuch concern about generic drug markets has emerged in recent policy debates.Important changes in regulations, the structure of purchasing, and the length of the drug supply chain have affected generic drug markets.Effective price competition remains the rule in generic markets for large‐selling drugs. Smaller markets and those for injectable products often have less price competition and are more susceptible to supply disruptions. Context: The image of generic drugs as a commodity sold in competitive markets is an oversimplification, as evidenced by increasing accounts of price spikes, sustained high price‐cost margins, and market disruptions. The mismatch between the canonical economic model of generic drug markets and reality motivated our empirical project. Methods: To explore recent changes in those factors impacting the supply and demand for generic drugs, we studied, from a variety of sources, the data on price, competition, supply disruptions and recalls, changes to the supply chain, and buy‐side concentration. We examined quarterly data through 2018 for a cohort of 77 molecules that lost patent protection during the so‐called patent cliff between 2010 and 2013. Findings: On the supply side, we found that for large‐market oral solids, generic entry and price declines were consistent with past studies showing a significant number of market entrants and substantial reductions in the average price of a molecule. In smaller markets for oral solids and injectable products, we observed fewer entrants, higher rates of exit, smaller price reductions, and, in some cases, considerable price instability. The number of reported shortages increased across all generic market types over time, with the rate of shortage increases especially pronounced in markets for injectable products. The number of product recalls also rose over our study period. Although we did not estimate causal effects, we did find several changes in the market environment for generic drugs that may contribute to these phenomena. The demand side for generics has become more concentrated. Supply chains rely more on producers outside the United States (particularly from China and India). Contracting practices have undergone changes that may inhibit competition in product supply. FDA regulatory scruitiny has increased. Conclusions: Competition in generic drug markets varies widely by market size and product form. Recent changes in demand‐side market structure imply more downward pressure on prices stemming from buy‐side concentration. The FDA's greater regulatory oversight puts upward pressure on costs, and the lengthening of the supply chain increases production uncertainty for producers. Demand and supply‐side changes point to further market instabilities across all generic markets due to producers' changing economic position. [ABSTRACT FROM AUTHOR]

Elections are contentious by design, but contentious election outcomes—from democratic backsliding to widespread protests and violence—occur regularly and represent significant challenges to both domestic and international stability. This review essay explores three specific outcomes of contentious elections (i.e. failed democratization, democracy protests, and election violence) using three recent, influential books on these topics. It highlights several, overlapping causal mechanisms, including those focusing on structural characteristics, actor behavior, and election cycle dynamics. It also explores four cross-cutting themes (i.e. democratization, electoral history, structural constraints, and money in politics), as well as three areas for future research (i.e. overlooked actors, election integrity, and international factors). [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic is just one of two public health crises the new Biden administration will confront. The addiction crisis is the othen The opioid epidemic has already killed more Americans than World Wars 1 and 11 combined. And it is but the most visible sign of a broader population health challenge that includes methamphetamine, cocaine, benzodiazepines, and alcohol. This article presents practical legislative and executive actions that are required for addressing these challenges. The authors focus on two broad policy challenges: (1) improving financing and delivery of treatment for substance use disorders, and (2) reducing population exposure to addictive and lethal substances. Through both of these channels, a portfolio of well-implemented, evidence-informed policies can save many thousands of lives every year. [ABSTRACT FROM AUTHOR]

A major obstacle to mental health treatment for many Americans is accessibility: the United States faces a shortage of mental health providers, resulting in federally designated shortage areas. Although digital mental health treatments (DMHTs) are effective interventions for common mental disorders, they have not been widely adopted by the U.S. health care system. National and international expert stakeholders representing health care organizations, insurance companies and payers, employers, patients, researchers, policy makers, health economists, and DMHT companies and the investment community attended two Banbury Forum meetings. The Banbury Forum reviewed the evidence for DMHTs, identified the challenges to successful and sustainable implementation, investigated the factors that contributed to more successful implementation internationally, and developed the following recommendations: guided DMHTs should be offered to all patients experiencing common mental disorders, DMHT products and services should be reimbursable to support integration into the U.S. health care landscape, and an evidence standards framework should be developed to support decision makers in evaluating DMHTs. [ABSTRACT FROM AUTHOR]

The theoretical literature from criminology, social movements, and political sociology, among others, includes diverging views about how political outcomes could affect movements. Many theories argue that political defeats motivate the losing side to increase their mobilization while other established models claim the winning side may feel encouraged and thus increase their mobilization. We examine these diverging perspectives in the context of the extreme right online and recent presidential elections by measuring the effect of the 2008 and 2016 election victories of Obama and Trump on the volume of postings on the largest white supremacy web-forum. ARIMA time series using intervention modeling showed a significant and sizable increase in the total number of posts and right-wing extremist posts but no significant change for firearm posts in either election year. However, the volume of postings for all impact measures was highest for the 2008 election. [ABSTRACT FROM AUTHOR]

This is the story of the successful analysis of an experienced analyst being analyzed by an even more experienced analyst, told by means of prose, poetry and drawings. It is replete with attempts to be humorous, dramatic and ironic. It mixes up observations and commentary. Some have called it "transgressive," which is a bit of a surprise to me, because I didn't even realize it was irreverent while I was composing it. I didn't have a conscious intention for it to take the form it has. The desire, content and style flowed from the liberation and cultivation of my natural self-expression freed from painful inhibitions by my analysis. I am very grateful to my analyst Mel. [ABSTRACT FROM AUTHOR]

Workers with mental illness may be uniquely affected by the labor market impacts of the pandemic. The authors used data from the National Health Interview Survey (2016-2018) to categorize workers by employment in essential or nonessential industries and by the feasibility of working remotely. Workers with psychological distress prepandemic were less likely than those without psychological distress to have occupations where remote work was feasible. These individuals may face higher risk of exposure to the virus and, if they are nonessential workers, higher risk of unemployment. Efforts that facilitate safe, continued connection to the workforce may be of value to workers with preexisting mental illnesses. [ABSTRACT FROM AUTHOR]

Purpose: Impaired glucose metabolism is present in most patients with pancreatic ductal adenocarcinoma (PDAC). Whereas previous studies have focused on pre-treatment glycemic indices and prognosis in those with concomitant diabetes, the effects of glycemic control during chemotherapy treatment on prognosis, in patients with and without diabetes, have not been well characterized. We examined the relationship between early glycemic control and overall survival (OS) in a cohort of patients with advanced PDAC treated in a community setting. Patients and Methods: Seventy-three patients with advanced PDAC (38% with diabetes) receiving chemotherapy while participating in a biobanking clinical trial were included. Clinical characteristics and laboratory results during 1 year were obtained from the electronic medical record. Kaplan-Meier estimate, log-rank test and hazard ratios were computed to assess the effect of glycemic control on OS. The Cox proportional hazards regression model was applied to ascertain the significance of glycemic control with other survival variables. Results: One thousand four hundred eighteen random blood glucose (RBG) values were analyzed. In accord with previous findings, a 50% decline in the serum tumor marker CA 19-9 at any time was predictive of survival (P =0.0002). In univariate analysis, an elevated pre-treatment average RBG, 3-month average RBG (RBG-3) and the FOLFIRINOX regimen were associated with longer survival. Based on ROC analysis (AUC=0.82), an RBG-3 of 120 mg/dl was determined to be the optimal cutoff to predict 12-month survival. In multivariate analysis that included age, stage, BMI, performance status, presence of diabetes, and chemotherapy regimen, only RBG-3 maintained significance: an RBG-3 ≤120 mg/dl predicted for improved OS compared to >120 mg/dl (19 vs. 9 months; HR=0.37, P =0.002). In contrast, an early decline in CA 19-9 could not predict OS. Conclusion: Lower glucose levels during the first 3 months of treatment for advanced PDAC predict for improved OS in patients both with and without diabetes. These results suggest that RBG-3 may be a novel prognostic biomarker worthy of confirmation in a larger patient cohort and that studies exploring a possible cause and effect of this novel survival-linked relationship are warranted. [ABSTRACT FROM AUTHOR]

Rationale: The objective of this study was to identify unique chemical tracers of oil sands process-affected water (OSPW) to enable definitive discrimination of tailings pond seepage from natural bitumen-influenced waters from the Canadian Alberta McMurray formation. Methods: The approach involved comparing unknowns from an unprecedented sample set of OSPW (n = 4) and OSPW-affected groundwaters (n = 15) with natural bitumen-influenced groundwaters (n = 20), using high-performance liquid chromatography/electrospray ionisation high-resolution mass spectrometry (HPLC/ESI-HRMS) operated in both polarities. Results: Four unknown chemical entities were identified as potential tracers of OSPW seepage and subsequently subjected to structural elucidation. One potential tracer, tentatively identified as a thiophene-containing carboxylic acid [C15H23O3S]-, was only detected in OSPW and OSPW-affected samples, thereby showing the greatest diagnostic potential. The remaining three unknowns, postulated to be two thiochroman isomers [C17H25O3S]+ and an ethyl-naphthalene isomer [C16H21]+, were detected in one and two background groundwaters, respectively. Conclusions: We advanced the state of knowledge for tracers of tailings seepage beyond heteroatomic classes, to identifying diagnostic substances, with structures postulated. Synthesis of the four proposed structures is recommended to enable structural confirmations. This research will guide and inform the Oil Sands Monitoring Program in its efforts to assess potential influences of oil sands development on the Athabasca River watershed. [ABSTRACT FROM AUTHOR]

Objective: For individuals with serious mental illness, work can play an important role in improving quality of life and community integration. Since the 1960s, demand has shifted away from routine cognitive (e.g., clerical work) and manual skills (warehouse picking and packing) toward nonroutine analytical (computer coding), interpersonal (nursing), and manual skills (home health attendant). This study aimed to determine whether individuals with serious mental illness are likely to hold the types of jobs that are in decline and to assess their ability to compete for the types of jobs that have been in increased demand.Methods: Using data from the National Health Interview Survey and the Occupational Information Network database on occupational skills (N=387,240 person-year responses), this study explored changes in patterns of employment from 1997 to 2017 for people with mental illnesses.Results: Individuals with any mental health condition experienced a 10.9 percentage point decline in employment in jobs requiring routine cognitive or any manual skills. Much of this decline was offset by an increase in employment in jobs involving nonroutine cognitive skills. However, individuals with serious psychological distress experienced a 7.9 percentage point decline in employment in jobs requiring routine cognitive or any manual skills, and about 75% of this decline coincided with reduced levels of employment rather than a shift toward employment in nonroutine cognitive jobs. These patterns were more striking among men.Conclusions: Likely directions for interventions include renewed efforts at workplace accommodations, greater investment in evidence-based return-to-work programs, and efforts to popularize early intervention programs. [ABSTRACT FROM AUTHOR]

Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges fromthe widespread use of potent androgen receptortargeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency. [ABSTRACT FROM AUTHOR]

Effects‐directed analysis (EDA) is used to identify the principal toxic components within a complex mixture using iterative steps of chemical fractionation guided by bioassay results. Bioassay selection can be limited in EDA because of the volume requirements for many standardized test methods, and therefore, a reduced‐volume acute toxicity test that also provides whole‐organism responses is beneficial. To address this need, a static, 7‐d, water‐only, reduced‐volume method (50 mL, 10 organisms) was developed for Hyalella azteca that substantially decreases the volume requirements of standard‐volume acute test exposures (200–500 mL of test solution, 15–20 organisms) while maintaining water quality and meeting control survival criteria. Standard‐ and reduced‐volume methods were compared by conducting concurrent toxicity tests with 2 inorganic toxicants (KCl and CdCl2) and 2 organic mixtures of naphthenic acid fraction components (NAFCs) to evaluate test performance. There was no difference between methods when comparing the median lethal concentrations (LC50s) for KCl and both NAFC mixtures (p > 0.05). The LC50s for CdCl2 were statistically different (p = 0.0002); however, this was not considered biologically meaningful because the difference between LC50s was <2‐fold. In conclusion, the reduced‐volume H. azteca test method generated results comparable to standard‐volume test methods and is suitable for use in situations where limited testing material is available, such as when conducting EDA. Environ Toxicol Chem 2020;39:2221–2227. © Her Majesty the Queen in Right of Canada 2020. Reproduced with the permission of the Minister of Environment and Climate Change Canada. [ABSTRACT FROM AUTHOR]

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Summary: Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4–2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed. [ABSTRACT FROM AUTHOR]