In this book, the author examines the legal theoretical foundations of international tax law and situates the arguments raised in contemporary discourse within the spectrum between legal positivism, ...realism and naturalism.
Use the guidance in this comprehensive field guide to gain the support of your top executives for aligning a rational cybersecurity plan with your business. You will learn how to improve working ...relationships with stakeholders in complex digital businesses, IT, and development environments. You will know how to prioritize your security program, and motivate and retain your team. Misalignment between security and your business can start at the top at the C-suite or happen at the line of business, IT, development, or user level. It has a corrosive effect on any security project it touches. But it does not have to be like this. Author Dan Blum presents valuable lessons learned from interviews with over 70 security and business leaders. You will discover how to successfully solve issues related to: risk management, operational security, privacy protection, hybrid cloud management, security culture and user awareness, and communication challenges. This open access book presents six priority areas to focus on to maximize the effectiveness of your cybersecurity program: risk management, control baseline, security culture, IT rationalization, access control, and cyber-resilience. Common challenges and good practices are provided for businesses of different types and sizes. And more than 50 specific keys to alignment are included. What You Will Learn Improve your security culture: clarify security-related roles, communicate effectively to businesspeople, and hire, motivate, or retain outstanding security staff by creating a sense of efficacy Develop a consistent accountability model, information risk taxonomy, and risk management framework Adopt a security and risk governance model consistent with your business structure or culture, manage policy, and optimize security budgeting within the larger business unit and CIO organization IT spend Tailor a control baseline to your organization’s maturity level, regulatory requirements, scale, circumstances, and critical assets Help CIOs, Chief Digital Officers, and other executives to develop an IT strategy for curating cloud solutions and reducing shadow IT, building up DevSecOps and Disciplined Agile, and more Balance access control and accountability approaches, leverage modern digital identity standards to improve digital relationships, and provide data governance and privacy-enhancing capabilities Plan for cyber-resilience: work with the SOC, IT, business groups, and external sources to coordinate incident response and to recover from outages and come back stronger Integrate your learnings from this book into a quick-hitting rational cybersecurity success plan Who This Book Is For Chief Information Security Officers (CISOs) and other heads of security, security directors and managers, security architects and project leads, and other team members providing security leadership to your business
To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies ...are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 95% confidence interval 1.195, 1. 268, 1.268 1.231, 1.305 and 1.411 1.331, 1.495 for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 1.293, 1.480 for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 1.072, 1.791 for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 1.442, 21.080 for HLA-DRB1 and 3.640 1.574, 8.416 for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.
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Latrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom of Latrodectus spiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates ...(α-latrotoxin (α-LTX)), five specialized on insects (α, β, γ, δ, ε- latroinsectotoxins (LITs), and one on crustaceans (α-latrocrustatoxin (α-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca
-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear. Here, we report cryoEM structures of the α-LCT monomer and the δ-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel α-helices. Both domains are flexibly linked via an N-terminal α-helical domain and a small β-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant α-LCT and δ-LIT form channels in artificial membrane bilayers, that are stabilized by Ca
ions and allow calcium flux at negative membrane potentials. Our comparative analysis between α-LCT and δ-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family.
This study evaluated a brief sleep intervention designed to improve the sleep, mood, and cognitive performance of professional electronic sports (esports) athletes from three major esports regions ...(i.e., Asia, North America, and Oceania). Fifty-six esports athletes from South Korea (N = 34), the United States (N = 7), and Australia (N = 15) completed the study. Participants completed an initial 2-week pre-intervention phase to establish a baseline, followed by a 2-week intervention phase that involved a group sleep education class, 1:1 session with a trained clinical psychologist, and daily biofeedback. A wrist activity monitor and daily sleep diary were used to monitor sleep during both phases, while at pre- and post-intervention, participants completed a battery of sleep and mood questionnaires and underwent cognitive performance testing. Sleep knowledge increased from pre- to post-intervention (d = 0.83 95% CI −1.21, −0.43, p =< 0.001), while there were modest improvements in sleep diary estimates (i.e., sleep onset latency (Mdiff = −2.9 min, p = 0.02), sleep onset time (Mdiff = −12 min, p = 0.03), and sleep efficiency (Mdiff = 1.1%, p = 0.004)) and wrist activity monitor estimates (i.e., sleep onset time (Mdiff = −18 min, p = 0.01)). Insomnia severity scores decreased significantly (d = 0.47 95% CI 0.08, 0.84, p = 0.001), while sleepiness scores increased but not meaningfully (d = 0.23 95% CI −0.61, 0.14, p = 0.025). However, there was no significant change in mood (i.e., depression and anxiety) or cognitive performance scores (i.e., mean reaction time or lapses). Sleep interventions for esports athletes require further investigation. Future research should examine whether a stepped-care model, whereby increasing therapeutic input is provided as needed, can optimize sleep, mood, and cognitive performance outcomes.
To determine whether an intervention to reduce eveningness chronotype improves sleep, circadian, and health (emotional, cognitive, behavioral, social, physical) outcomes.
Youth aged 10 to 18 years ...with an evening chronotype and who were "at risk" in 1 of 5 health domains were randomized to: (a) Transdiagnostic Sleep and Circadian Intervention for Youth (TranS-C; n = 89) or (b) Psychoeducation (PE; n = 87) at a university-based clinic. Treatments were 6 individual, weekly 50-minute sessions during the school year. TranS-C addresses sleep and circadian problems experienced by youth by integrating evidence-based treatments derived from basic research. PE provides education on the interrelationship between sleep, stress, diet, and health.
Relative to PE, TranS-C was not associated with greater pre-post change for total sleep time (TST) or bed time (BT) on weeknights but was associated with greater reduction in evening circadian preference (pre-post increase of 3.89 points, 95% CI = 2.94-4.85, for TranS-C, and 2.01 points, 95% CI = 1.05-2.97 for PE, p = 0.006), earlier endogenous circadian phase, less weeknight-weekend discrepancy in TST and wakeup time, less daytime sleepiness, and better self-reported sleep via youth and parent report. In terms of functioning in the five health domains, relative to PE, TranS-C was not associated with greater pre-post change on the primary outcome. However, there were significant interactions favoring TranS-C on the Parent-Reported Composite Risk Scores for cognitive health.
For at-risk youth, the evidence supports the use of TranS-C over PE for improving sleep and circadian functioning, and improving health on selected outcomes.
Triple Vulnerability? Circadian Tendency, Sleep Deprivation and Adolescence. https://clinicaltrials.gov; NCT01828320.
Insulin resistance in diabetes mellitus has been associated with mitochondrial dysfunction. Defects at the level of mitochondria are also characteristic of heart failure. We assessed changes in ...cardiac insulin response and mitochondrial function in a model of pressure overload-induced heart failure.
Rats underwent aortic banding to induce pressure overload. At 10 weeks, rats showed cardiac hypertrophy and pulmonary congestion, but left ventricular dilatation and systolic dysfunction were only evident after 20 weeks. This contractile impairment was accompanied by mitochondrial dysfunction as shown by markedly reduced state 3 respiration of isolated mitochondria. Aortic banding did not affect systemic insulin response. However, insulin-stimulated cardiac glucose uptake and glucose oxidation were significantly diminished at 10 and 20 weeks, which indicates cardiac insulin resistance starting before the onset of mitochondrial and contractile dysfunction. The impaired cardiac insulin action was related to a decrease in insulin-stimulated phosphorylation of insulin receptor β. Consistently, we found elevated activity of protein tyrosine phosphatase 1B (PTP1B) at 10 and 20 weeks, which may blunt insulin action by dephosphorylating insulin receptor β. PTP1B activity was also significantly increased in left ventricular samples of patients with systolic dysfunction undergoing aortic valve replacement because of aortic stenosis.
Pressure overload causes cardiac insulin resistance that precedes and accompanies mitochondrial and systolic dysfunction. Activation of PTP1B in the heart is associated with heart failure in both rats and humans and may account for cardiac insulin resistance. PTP1B may be a potential target to modulate insulin sensitivity and contractile function in the failing heart.
Technological adjuncts have been developed to improve the accuracy of fluid removal goals in maintenance dialysis recipients. We aimed to determine whether the introduction of these tools has been ...shown to impact clinical outcomes.
We performed a systematic review and meta-analysis of randomized controlled trials that compared fluid management guided by technological adjuncts to standard care in hemodialysis and peritoneal dialysis. The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular events, hospitalizations, intradialytic hypotension, blood pressure, symptoms, antihypertensive medications. and left ventricular mass index.
Of the 2940 citations retrieved, we identified a total of 12 eligible trials comprising 2406 participants. In the 10 studies (n = 2111) with data on mortality, the use of adjunct technologies was not associated with a reduction of mortality (rate ratio RR: 0.92; confidence interval CI: 0.57–1.51; I2 = 36%). The intervention conferred a reduction in systolic arterial pressure (mean difference: −3.14; CI: −5.89 to −0.38; I2 = 39%) but did not affect other outcomes. In a subgroup analysis, bioimpedance was associated with a reduced risk of hospitalization (RR: 0.68; CI: 0.46–0.99; I2 = 55%). The risk of bias was high or unclear in most studies and the quality of evidence was judged to be low.
Among maintenance dialysis recipients, technological adjuncts for fluid management did not improve survival. Trials mostly investigated the use of bioimpedance, whereas the evidence for use of other technologies remain very scarce. Future adequately powered trials should assess a broader array of promising technologies using meaningful clinical outcomes over a prolonged follow-up duration.
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Purpose:
Even in cases of medical emergency, mistreatment and negative experiences in life or in medical settings can deter trans patients from seeking necessary care. The purpose of this study was ...to identify factors associated with trans persons' emergency department (ED) avoidance in the mixed urban-rural Region of Waterloo, Ontario, Canada.
Methods:
The OutLook Study was a community-based partnership that created an online, cross-sectional questionnaire for lesbian, gay, bisexual, transgender, and other sexual and gender minority community members. Participants in this analysis were 16 years of age or older, lived, worked, or attended school in Waterloo Region, and identified as trans (
n
=112). Binary logistic regression was used to test associations between sociodemographic, resilience, and risk variables, and ED avoidance. Sociodemographic variables statistically significant at
p
<0.05 at the bivariate level were included as controls to explore different combinations of resilience and risk factor in multivariable models.
Results:
Participants reporting complete or partially complete medical transitions were more likely to report ED avoidance, compared to those who had not initiated medical transition. Elevated transphobia was associated with greater likelihood of avoidance. However, increasing levels of social support decreased the likelihood of avoidance. In multivariable models, social support, support from a special person, and transphobia were always significant, regardless of controlled variables.
Conclusion:
Transphobia—enacted in the contexts of everyday life and health care—can deter patients from seeking care. Patient-centered care requires careful attention to trans identity and health needs, especially in emergency settings. In the absence of structural changes, providers can take steps to mitigate the erasure and discrimination trans patients experience and anticipate when accessing EDs.
In nephrology, point-of-care ultrasound (POCUS) has multiple applications including the rapid evaluation of acute kidney injury, enhancing the initial evaluation of chronic kidney disease, direct ...evaluation of vascular access, and improved fluid balance management in acute and chronic settings 1, 2. Recently, the role of POCUS has been formally acknowledged by the American College of Physicians and curricula specific to nephrology have been proposed 3, 4. However, the integration of a novel clinical skill into a field comes with its unique set of challenges. Above all, most nephrologists in leadership roles within fellowship training programs lack POCUS experience, which represent a significant barrier for adequate exposure and teaching. Although educational curriculum centered on nephrology have been proposed, the optimal model to ensure adequate POCUS exposure considering the scarcity of expertise among educators is not known.
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