During the COVID-19 pandemic, the US Environmental Protection Agency and numerous states offered regulated facilities flexibility in adhering to some monitoring and compliance requirements of ...environmental regulations. These temporary enforcement discretion (TED) policies provide a recent example of how environmental federalism works in practice in the United States. We examine the relationship between state sociodemographic and political characteristics and the timing and similarity of state-level TED policies. To analyze policy similarity, we use natural language processing tools. Thus, this policy brief illustrates how such techniques can be meaningfully applied to answer questions of relevance to environmental policy.
Endometriosis is a polygenic, estrogen-dependent, inflammatory disorder of uncertain aetiology associated with pain, infertility and reduced quality of life. While the positive association between ...endometriosis and estrogen is established, a suite of recent studies has demonstrated an inverse association between the presence of endometriosis lesions and levels of testosterone both prenatally and postnatally. The following narrative review provides new insights into the roles of testosterone in the aetiology, diagnosis, and management of endometriosis and associated symptoms, especially pain. A relatively short anogenital distance (AGD) is indicative of lower levels of testosterone during fetal development. A shorter AGD has recently been correlated with both a higher risk of developing endometriosis in adult life, and with known correlates of endometriosis including earlier onset of reproductive cycling, lower ovarian follicle number, lower postnatal testosterone, and premature ovarian insufficiency. During adult life, lower levels of testosterone are positively associated with key comorbidities of endometriosis, including days per month of pelvic pain and increased pain sensitivity. Biochemically, lower levels of testosterone are associated with higher levels of pro-inflammatory IL-1β and lower levels of β-endorphin. In rodents, prenatal administration of testosterone to females reduces their pain sensitivity in adulthood. The emerging convergent links of endometriosis with low prenatal and postnatal testosterone provide evidence of a centrally mediated effect beginning in early prenatal development, and persisting through adult life, with notable effects on pain sensitivity. They generate a novel conceptual framework for understanding, studying and treating this disorder, whereby endometriosis is mediated by a combination of high estrogen in endometrial tissue with low systemic and ovarian testosterone.
Bütz, Evans, and Webber-Dereszynski (2009) proposed that disorders such as factitious disorder by proxy (FDBP) ". . . may collectively be a forerunner of the more sophisticated practice of wedding ...individual diagnoses and group, social, family, and legal dynamics together into an integrated, coded conceptualization" (p. 37). This article expands this recommendation, offering the term interrelated multidimensional diagnoses (IMDs) to better describe phenomenon such as FDBP and parental alienation (PA). In turn, this article articulates a definition for IMDs and makes the argument that FDBP and PA are examples of more sophisticated next generation diagnoses, which integrate the characteristics, interactions, and symptoms of individuals and systems dimensionally with greater explanatory power than other diagnoses alone. Implications for clinical and forensic identification and practice are discussed.
Public Significance Statement
For well over forty years practitioners in the field of behavioral health and other professionals in legal as well as medical settings have struggled to understand and identify complex interactions between people, families and institutions. In this article the term Interrelated Multidimensional Diagnosis (IMD) has been proposed to capture these complex interactions and offer a new diagnostic framework to describe phenomena such as Munchausen's Syndrome by Proxy, Factitious Disorder by Proxy, and Parental Alienation. IMDs describe how individuals and systems interact to create pathological dynamics that prove harmful and even lethal to children.
•High-precision relative locations of seismicity induced by the Basel EGS.•Many earthquakes form clusters of similar events lasting several days.•Cluster dimensions can amount to several 100m.•Good ...coincidence between hypocenter distribution and focal mechanisms.•Results reveal a complex internal structure of the stimulated flow paths.
High-precision relative location procedures of the stronger seismic events (0.7≤ML≤3.4), based on cross-correlations of signals recorded by a six-sensor borehole network and numerous surface stations in the immediate epicentral area, show that clustering of hypocenters on different spatial scales is a dominant feature of the microseismicity induced by the stimulation of enhanced geothermal reservoir in Basel. In line with the fact that many of the observed earthquakes form clusters of similar events, several focal mechanisms are also nearly identical to each other. A comparison between the high-precision relative locations of the events within each cluster and the focal mechanisms often shows a good coincidence of the hypocentral distribution with one of the nodal planes of the focal mechanism. In some cases, the spatial extent of the individual clusters is limited to a few meters, which suggests that the corresponding events represent repeated slip with partial stress drop as pore pressures increase with time. In other cases, that include some of the stronger events (ML>2), the dimension of the individual clusters can amount to several 100m, and the activity within these clusters can extend over several days. Given that the orientation of many fault segments identified in this way deviates significantly from the overall orientation of the seismic cloud, these results reveal a complex internal structure of the flow paths in the rock volume stimulated by the water injection.
The seven-transmembrane G protein-coupled receptors activated by leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B(4) or the cysteinyl ...leukotrienes (LTC(4), LTD(4), and LTE(4)). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT(1) and BLT(2) receptors and CysLT(1) and CysLT(2) receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research.
This article illustrates the complex sociocultural components in the forensic psychological assessment of a young Ethiopian woman's claim for political asylum due to a well-founded fear of ...persecution and for relief under the Convention Against Torture. It draws attention to the subtle social and cultural influences in the practice of forensic psychological assessment with an emphasis of reflective practice, which is contextualized in the interpersonal theory of Sullivan. In the interpersonal approach, the essential work of the assessor is to pay careful attention to the microinteractions between the client and the assessor as reflections of the interpersonal (meaning social and cultural) processes, eschewing the illusion of objectivity.
In this case study, I illustrate the particular cultural dilemmas for client and assessor in conducting a forensic assessment of psychological trauma, including cross-cultural, gender, and legal difficulties in arriving at an informed, objective, and compassionate assessment of an individual seeking asylum after an especially brutal experience of torture. I argue that collaborative therapeutic assessment methods adapted for forensic practice offer an approach to assessment of psychological trauma that provides more accurate and compassionate assessment than so-called neutral standard forensic assessment practice.
Abstract
Background
Mammogram risk scores based on texture and density defined by different brightness thresholds are associated with breast cancer risk differently and could reveal distinct ...information about breast cancer risk. We aimed to investigate causal relationships between these intercorrelated mammogram risk scores to determine their relevance to breast cancer aetiology.
Methods
We used digitised mammograms for 371 monozygotic twin pairs, aged 40–70 years without a prior diagnosis of breast cancer at the time of mammography, from the Australian Mammographic Density Twins and Sisters Study. We generated normalised, age-adjusted, and standardised risk scores based on textures using the Cirrus algorithm and on three spatially independent dense areas defined by increasing brightness threshold: light areas, bright areas, and brightest areas. Causal inference was made using the Inference about Causation from Examination of FAmilial CONfounding (ICE FALCON) method.
Results
The mammogram risk scores were correlated within twin pairs and with each other (
r
= 0.22–0.81; all
P
< 0.005). We estimated that 28–92% of the associations between the risk scores could be attributed to causal relationships between the scores, with the rest attributed to familial confounders shared by the scores. There was consistent evidence for positive causal effects: of Cirrus, light areas, and bright areas on the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively); and of light areas and bright areas on Cirrus (accounting for 37% and 28%, respectively).
Conclusions
In a mammogram, the lighter (less dense) areas have a causal effect on the brightest (highly dense) areas, including through a causal pathway via textural features. These causal relationships help us gain insight into the relative aetiological importance of different mammographic features in breast cancer. For example our findings are consistent with the brightest areas being more aetiologically important than lighter areas for screen-detected breast cancer; conversely, light areas being more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. These findings highlight the utility of ICE FALCON and family data in decomposing the associations between intercorrelated disease biomarkers into distinct biological pathways.
Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and ...Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1mg/kg, but did not induce significant emetic reflexes at doses <30mg/kg. Overall, the pharmacological effects of apremilast are consistent with those of a targeted PDE4 inhibitor, with selective effects on innate immune responses and a wide therapeutic index compared to its gastrointestinal side effects.
•The current analyses studied the pharmacodynamic properties of apremilast.•Apremilast activates the CREB/ATF-1 pathway and does not bind to human cereblon.•Apremilast does not affect B/T-cell expansion or immunoglobulin production.•Effects of apremilast on innate immunity are greater than on adaptive immunity.•Apremilast is a selective inhibitor of PDE4 that regulates inflammatory mediators.
ABSTRACT
We consider a scenario in which Sgr A* is in a massive black hole binary (MBHB) with an as-of-yet undetected supermassive or intermediate-mass black hole companion. Dynamical encounters ...between this MBHB and single stars in its immediate vicinity would eject hypervelocity stars (HVSs) with velocities beyond the Galactic escape velocity of the Galaxy. In this work, we use existing HVS observations to constrain for the first time the existence of a companion to Sgr A*. We simulate the ejection of HVSs via the ‘MBHB slingshot’ scenario and show that the population of HVSs detectable today depends strongly on the companion mass and the separation of the MBHB. We demonstrate that the lack of uncontroversial HVS candidates in Gaia Data Release 3 places a firm upper limit on the mass of a possible Sgr A* companion. Within one milliparsec of Sgr A*, our results exclude a companion more massive than $2000 \, \mathrm{M_\odot }$. If Sgr A* recently merged with a companion black hole, our findings indicate that unless this companion was less massive than $500 \, \mathrm{M_\odot }$, this merger must have occurred at least 10 Myr ago. These results complement and improve upon existing independent constraints on a companion to Sgr A* and show that large regions of its parameter space can now be ruled out.
Deformation monitoring between 2004 and 2011 at the rock slope instability above Randa (Switzerland) has revealed an intriguing seasonal trend. Relative dislocation rates across active fractures ...increase when near‐surface rock temperatures drop in the fall and decrease after snowmelt as temperatures rise. This temporal pattern was observed with different monitoring systems at the ground surface and at depths up to 68 m, and represents the behavior of the entire instability. In this paper, the second of two companion pieces, we interpret this seasonal deformation trend as being controlled by thermomechanical (TM) effects driven by near‐surface temperature cycles. While Part 1 of this work demonstrated in a conceptual manner how TM effects can drive deep rock slope deformation and progressive failure, we present here in Part 2 a case study where temperature‐controlled deformation trends were observed in a natural setting. A 2D discrete‐element numerical model is employed, which allows failure along discontinuities and successfully reproduces the observed kinematics of the Randa instability. By implementing simplified ground surface temperature forcing, model results were able to reproduce the observed deformation pattern, and TM‐induced displacement rates and seasonal amplitudes in the model are of the same order of magnitude as measured values. Model results, however, exhibit spatial variation in displacement onset times while field measurements show more synchronous change. Additional heat transfer mechanisms, such as fracture ventilation, likely create deviations from the purely transient‐conductive temperature field modeled. We suggest that TM effects are especially important at Randa due to the absence of significant groundwater within the unstable rock mass.
Key Points
Displacement monitoring at Randa exhibit increased rates in winter
Temporal behavior at Randa is not related to ground water
Thermomechanical effects drive progressive failure at Randa
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