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Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of [p21.sup.+] cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of [p21.sup.+] cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, [p21.sup.+] cell clearance did not alter bone loss due to aging; conversely, [p16.sup.+] cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, [p21.sup.+] neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while [p21.sup.+] OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was [p21.sup.+] and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of [p21.sup.+] versus [p16.sup.+] senescent/ senescent-like cells that may be leveraged for therapeutic opportunities., Introduction At the cellular level, aging is characterized by several hallmarks, including cellular senescence (1), which is driven by an increase in the cyclin-dependent kinase inhibitors Cdknla (p21) and/or Cdknla [...]

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging., Introduction The aging population and life expectancy continue to increase (1), and while unlikely to reverse course, this trend of more people living longer creates challenges that society remains poorly [...]

In Bostock v. Clayton County, one of the blockbuster cases from its 2019 Term, the Supreme Court held that federal antidiscrimination law prohibits employment discrimination on grounds of sexual orientation and gender identity. Unsurprisingly, the result won wide acclaim in the mainstream legal and popular media. Results aside, however, the reaction to Justice Neil Gorsuch's majority opinion, which purported to ground the outcome in a textualist approach to statutory interpretation, was more mixed. The great majority of commentators, both liberal and conservative, praised Justice Gorsuch for what they deemed a careful and sophisticated--even 'magnificent' and 'exemplary'--application of textualist principles, while a handful of critics, all conservative, agreed with the dissenters that textualism could not deliver the outcome that the decision reached. This Article shows that conservative critics of the majority's reasoning were correct--up to a point. Specifically, it argues that Title VII's ban on discrimination 'because of' an employee's 'sex' does not cover discrimination because of their sexual orientation as a matter of 'plain' or 'ordinary' meaning. Further, it demonstrates that Justice Gorsuch's effort to establish that result as a matter of 'legal' meaning wholly fails because it depends upon a fatally flawed application of the 'but-for' test for causation, one that flouts bedrock principles of counter/actual reasoning. It follows that if a textualist approach to statutory interpretation is correct or warranted, then Bostock was wrongly decided. However, if Bostock was rightly decided, then it must follow that textualism is wrong or misguided. This Article endorses the latter possibility, explaining that the dominant American approach to statutory interpretation is neither textualist nor purposivist but pluralist. It concludes by drawing powerful but previously unnoticed support for pluralism from Justice Samuel Alito 's principal dissent., INTRODUCTION 68 I. BOSTOCK IN BRIEF 73 A. The Decisions Below 71 B. The Supreme Court Resolves 76 II. TORTURED TEXTUALISM 79 A. Ordinary Meaning 80 1. A First Pass [...]

Background Implementing evidence into clinical practice is a key focus of healthcare improvements to reduce unwarranted variation. Dissemination of evidence-based recommendations and knowledge brokering have emerged as potential strategies to achieve evidence implementation by influencing resource allocation decisions. The aim of this study was to determine the effectiveness of these 2 research implementation strategies to facilitate evidence-informed healthcare management decisions for the provision of inpatient weekend allied health services. Methods and findings This multicentre, single-blinded (data collection and analysis), 3-group parallel cluster randomised controlled trial with concealed allocation was conducted in Australian and New Zealand hospitals between February 2018 and January 2020. Clustering and randomisation took place at the organisation level where weekend allied health staffing decisions were made (e.g., network of hospitals or single hospital). Hospital wards were nested within these decision-making structures. Three conditions were compared over a 12-month period: (1) usual practice waitlist control; (2) dissemination of written evidence-based practice recommendations; and (3) access to a webinar-based knowledge broker in addition to the recommendations. The primary outcome was the alignment of weekend allied health provision with practice recommendations at the cluster and ward levels, addressing the adoption, penetration, and fidelity to the recommendations. The secondary outcome was mean hospital length of stay at the ward level. Outcomes were collected at baseline and 12 months later. A total of 45 clusters (n = 833 wards) were randomised to either control (n = 15), recommendation (n = 16), or knowledge broker (n = 14) conditions. Four (9%) did not provide follow-up data, and no adverse events were recorded. No significant effect was found with either implementation strategy for the primary outcome at the cluster level (recommendation versus control [beta] 18.11 [95% CI -8,721.81 to 8,758.02] p = 0.997; knowledge broker versus control [beta] 1.24 [95% CI -6,992.60 to 6,995.07] p = 1.000; recommendation versus knowledge broker [beta] -9.12 [95% CI -3,878.39 to 3,860.16] p = 0.996) or ward level (recommendation versus control [beta] 0.01 [95% CI 0.74 to 0.75] p = 0.983; knowledge broker versus control [beta] -0.12 [95% CI -0.54 to 0.30] p = 0.581; recommendation versus knowledge broker [beta] -0.19 [-1.04 to 0.65] p = 0.651). There was no significant effect between strategies for the secondary outcome at ward level (recommendation versus control [beta] 2.19 [95% CI -1.36 to 5.74] p = 0.219; knowledge broker versus control [beta] -0.55 [95% CI -1.16 to 0.06] p = 0.075; recommendation versus knowledge broker [beta] -3.75 [95% CI -8.33 to 0.82] p = 0.102). None of the control or knowledge broker clusters transitioned to partial or full alignment with the recommendations. Three (20%) of the clusters who only received the written recommendations transitioned from nonalignment to partial alignment. Limitations include underpowering at the cluster level sample due to the grouping of multiple geographically distinct hospitals to avoid contamination. Conclusions Owing to a lack of power at the cluster level, this trial was unable to identify a difference between the knowledge broker strategy and dissemination of recommendations compared with usual practice for the promotion of evidence-informed resource allocation to inpatient weekend allied health services. Future research is needed to determine the interactions between different implementation strategies and healthcare contexts when translating evidence into healthcare practice. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12618000029291., Author(s): Mitchell N. Sarkies 1,2,3,*, Lauren M. Robins 3, Megan Jepson 3, Cylie M. Williams 3, Nicholas F. Taylor 4,5, Lisa O'Brien 6, Jenny Martin 7, Anne Bardoel 8, Meg [...]

Suppose that we disagree about a matter of constitutional law. Say that one of us contends, and the other denies, that transgender persons have constitutional rights to be treated in accord with their gender identity. It appears that we disagree about 'what the law is.' And, most probably, we disagree about what the law is on this matter because we disagree about what generally makes it the case that our constitutional law is this rather than that. Constitutional theory should provide guidance. Theorists should try to explain what gives our constitutional rules the contents that they have, or what makes true constitutional propositions true; they should aim to provide what I will call a 'constitutive theory' of constitutional law. It is obvious that we do not all share a constitutive theory. It is less obvious, and strikingly underappreciated, that we have precious few candidates to choose from. Few of our many prescriptive theories regarding how judges should exercise the power of judicial review have straightforward constitutive implications. This Article presents an original constitutive theory of American constitutional law (and of law generally), founded on the familiar distinction between two types of constitutional norms: 'principles' and 'rules.' It argues: first, that rules are determined by the interaction of principles, in a manner that can be loosely modeled as force addition; and second, that the principles are 'grounded' in mental states, speech-acts, and behaviors of persons who make up the constitutional community, much as rules of fashion or of billiards are grounded in behaviors of persons who make up their normative communities. In short: social facts determine constitutional principles, and constitutional principles determine constitutional rules. I call the account 'principled positivism.' It is positivist, pluralist, and dynamic. Principled positivism maintains that we can come to know our constitutional rules by discerning the contents, contours, and weights of our constitutional principles. Accordingly, the Article offers a preliminary and partial inventory of our constitutional principles--principles concerning the legal significance of what the enacted text says and what its authors intended; principles about the force of judicial precedents and of extra-judicial practices; principles of popular sovereignty, the distribution of governing power, and the demands of liberty and equality. It then puts the principles to work, illustrating how they operate in diverse constitutional controversies, from same-sex marriage to the scope of Congress's commerce power., INTRODUCTION 1328 I. A BRIEF HISTORY OF AMERICAN CONSTITUTIONAL THEORY 1335 A. Prescriptive Pluralism: A Whirlwind Tour 1337 B. Originalism and the Constitutive Turn 1340 1. Prescriptive Originalism 1340 2. [...]

A MATTER OF INTERPRETATION: FEDERAL COURTS AND THE LAW. By Antonin Scalia. Princeton and Chichester: Princeton University Press. 1997. Pp. xiii, 149. $18.95. INTRODUCTION Justice Antonin Scalia died last February, [...]

REFLECTIONS ON JUDGING. By Richard A. Posner. Cambridge and London: Harvard University Press. 2013. P. 366. $29.95. INTRODUCTION The world is complex, Richard Posner (1) observes in his most recent [...]

Background Disinvestment (removal, reduction, or reallocation) of routinely provided health services can be difficult when there is little published evidence examining whether the services are effective or not. Evidence is required to understand if removing these services produces outcomes that are inferior to keeping such services in place. However, organisational imperatives, such as budget cuts, may force healthcare providers to disinvest from these services before the required evidence becomes available. There are presently no experimental studies examining the effectiveness of allied health services (e.g., physical therapy, occupational therapy, and social work) provided on weekends across acute medical and surgical hospital wards, despite these services being routinely provided internationally. The aim of this study was to understand the impact of removing weekend allied health services from acute medical and surgical wards using a disinvestment-specific non-inferiority research design. Methods and findings We conducted 2 stepped-wedge cluster randomised controlled trials between 1 February 2014 and 30 April 2015 among patients on 12 acute medical or surgical hospital wards spread across 2 hospitals. The hospitals involved were 2 metropolitan teaching hospitals in Melbourne, Australia. Data from n = 14,834 patients were collected for inclusion in Trial 1, and n = 12,674 in Trial 2. Trial 1 was a disinvestment-specific non-inferiority stepped-wedge trial where the 'current' weekend allied health service was incrementally removed from participating wards each calendar month, in a random order, while Trial 2 used a conventional non-inferiority stepped-wedge design, where a 'newly developed' service was incrementally reinstated on the same wards as in Trial 1. Primary outcome measures were patient length of stay (proportion staying longer than expected and mean length of stay), the proportion of patients experiencing any adverse event, and the proportion with an unplanned readmission within 28 days of discharge. The 'no weekend allied health service' condition was considered to be not inferior if the 95% CIs of the differences between this condition and the condition with weekend allied health service delivery were below a 2% increase in the proportion of patients who stayed in hospital longer than expected, a 2% increase in the proportion who had an unplanned readmission within 28 days, a 2% increase in the proportion who had any adverse event, and a 1-day increase in the mean length of stay. The current weekend allied health service included physical therapy, occupational therapy, speech therapy, dietetics, social work, and allied health assistant services in line with usual care at the participating sites. The newly developed weekend allied health service allowed managers at each site to reprioritise tasks being performed and the balance of hours provided by each professional group and on which days they were provided. Analyses conducted on an intention-to-treat basis demonstrated that there was no estimated effect size difference between groups in the proportion of patients staying longer than expected (weekend versus no weekend; estimated effect size difference [95% CI], p-value) in Trial 1 (0.40 versus 0.38; estimated effect size difference 0.01 [-0.01 to 0.04], p = 0.31, CI was both above and below non-inferiority margin), but the proportion staying longer than expected was greater with the newly developed service compared to its no weekend service control condition (0.39 versus 0.40; estimated effect size difference 0.02 [0.01 to 0.04], p = 0.04, CI was completely below non-inferiority margin) in Trial 2. Trial 1 and 2 findings were discordant for the mean length of stay outcome (Trial 1: 5.5 versus 6.3 days; estimated effect size difference 1.3 days [0.9 to 1.8], p < 0.001, CI was both above and below non-inferiority margin; Trial 2: 5.9 versus 5.0 days; estimated effect size difference -1.6 days [-2.0 to -1.1], p < 0.001, CI was completely below non-inferiority margin). There was no difference between conditions for the proportion who had an unplanned readmission within 28 days in either trial (Trial 1: 0.01 [-0.01 to 0.03], p = 0.18, CI was both above and below non-inferiority margin; Trial 2: -0.01 [-0.02 to 0.01], p = 0.62, CI completely below non-inferiority margin). There was no difference between conditions in the proportion of patients who experienced any adverse event in Trial 1 (0.01 [-0.01 to 0.03], p = 0.33, CI was both above and below non-inferiority margin), but a lower proportion of patients had an adverse event in Trial 2 when exposed to the no weekend allied health condition (-0.03 [-0.05 to -0.004], p = 0.02, CI completely below non-inferiority margin). Limitations of this research were that 1 of the trial wards was closed by the healthcare provider after Trial 1 and could not be included in Trial 2, and that both withdrawing the current weekend allied health service model and installing a new one may have led to an accommodation period for staff to adapt to the new service settings. Stepped-wedge trials are potentially susceptible to bias from naturally occurring change over time at the service level; however, this was adjusted for in our analyses. Conclusions In Trial 1, criteria to say that the no weekend allied health condition was non-inferior to current weekend allied health condition were not met, while neither the no weekend nor current weekend allied health condition demonstrated superiority. In Trial 2, the no weekend allied health condition was non-inferior to the newly developed weekend allied health condition across all primary outcomes, and superior for the outcomes proportion of patients staying longer than expected, proportion experiencing any adverse event, and mean length of stay. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001231730 and ACTRN12613001361796, Author(s): Terry P. Haines 1,2,*, Kelly-Ann Bowles 3, Deb Mitchell 1,2, Lisa O'Brien 2,4, Donna Markham 5, Samantha Plumb 6, Kerry May 5, Kathleen Philip 7, Romi Haas 1,2, Mitchell [...]

ABSTRACT The partial defense of provocation provides that a person who kills in the heat of passion brought on by legally adequate provocation is guilty of manslaughter rather than murder. [...]

A study was conducted to evaluate and compare the efficacy of peginterferon Alfa-2b against Alfa-2a with ribavirin for the treatment of patients with hepatitis C infection. Results indicated that there was not much significant difference in treatment with any of these regimens.

The research and development program and qualification of the toroidal field (TF) coil conductor are discussed. The first test results are considered sufficient to initiate strand procurement actions with the domestic agencies and the conductor layout option II is expected to wider the range of strand suppliers.

The assembly and final installation of the toroidal field (TF) coils in the ITER machine are analyzed. The procedure and tooling required for the TF coils final installation and the feasibility of fulfilling the accuracy needed by the maximum acceptable error fields induced by the TF coils fabrication tolerances and misalignments are analyzed.

The ITER coils are all designed by using superconducting conductors with a high current capability. The electrical design philosophy of the coils has included recovery options in the event of electrical faults internal to the coils.

The design of the ITER Toroidal Field coils and structures, the main critical design and manufacturing issues and the status of the procurement arrangements are described. The qualification and research and development work that are still needed for the preparation of the manufacture of these coils are discussed.

The main design features and drivers for the ITER magnets are discussed. The most critical technical issue, the performance of the [Nb.sub.3]Sn superconductor, is overcome and the fabrication routes allowing the TF coils to be produced within schedule and budget are being identified.

The article presents the THELMA analysis of the effects of current non-uniformity on the DC performance of the Good Joint (GJ) conductor. Results suggest that the reduction of the performance with the chopped joint is an effect of the increasingly unbalanced current distribution.

The predictive analysis of the International Thermonuclear Experimental Reactor (ITER) Poloidal Field Conductor Insert (PFCI) test program is presented. PFCI is the first insert coil based on NbTi and is aimed at bridging the extrapolation gap between its full-size short sample and the ITER Poloidal Field (PF) coils.

A study is conducted to measure the current sharing temperature T(sub cs) in the Toroidal Field Conductor Insert (TFCI) coil. The results indicate that some factors in the fabrication, cool-down or electromagnetic loading are responsible for the reduction of the critical current strands and their n-value.

The tests of the Toroidal Field Model Coil (TFMC) are completed in the TOSKA facility of Forschungszentrun Karlsruhe. The TFMC isolated strand is characterized at different applied uniaxial strain, and preliminary results indicate a stronger reduction of carrying capacity compared to the extrapolation from summers scaling used in the analysis.

Cable-in-conduit conductors (CICC) consisting of about 1000 Nb(sub 3)Sn strands with an outer diameter of bout 0.8 is designed for the TF and CS coils of the ITER. The test results indicate that both joint types are stable and could be used for applications to the full size ITER coils.

The ITER Central Solenoid, which was 12 m high and 4 m in diameter, consists of a stack of 6 electrically independent modules to allow control of plasma shape. The CS model coil and insert coil test results indicate that the conductor design must be modified to achieve an operation margin.

The choice of stability criteria for near steady state operation presents a problem n the design of CIC conductors using NbTi or Nb(sub 3)Sn strands cooled with supercritical He. The main parameters affected by the choice of stability criteria are temperature margin and Cu:nonCu ratio, both of which strongly affect cable cost and overall current density.

Tests of the International Thermonuclear Experimental Reactor (ITER) Toroidal Field (TF) Insert and Central Solenoid Model Coil (CSMC) are evaluated.

Performance of the NbAl Insert and the International Thermonuclear Experimental Reactor (ITER) Central Solenoid Model Coil (CSMC) are discussed.

Possible causes for a premature voltage gradient of the International Thermonuclear Experimental Reactor's (ITER) Central Solenoid (CS) insert coil are examined.

The International Thermonuclear Experimental Reactor's (ITER) Central Solenoid Model Coil (CSMC) project is described and discussed. All of the project's goals were successfully achieved.

Research describing some characteristics of cable-in-conduit conductors is presented. In particular an analytical model is developed based on current distribution and heat flow to study the effects of joined strands and copper.

Research is presented describing the Nb3Sn and NbTi cable-in-conduit conductors used in the International Thermonuclear Experimental Reactor project, and cooled by a supercritical helium forced flow. The design of the conductors, and non-uniform distribution between superconducting strands, are discussed.

The International Thermonuclear Experimental Reactor central solenoid model coil conductors were studied to determine predicted thermohydraulic performance.

The ITER toroidal field model coil is considered in terms of its manufacture, assembly and QA methods.

An evidentiary theory of blackmail may solve theoretical questions regarding the criminalization of the legal act of disclosing embarrassing personal information. The theory rests on the tenet that seeking enrichment for silence is prima facie evidence of morally blameworthy intent to injure another person. Society ultimately is correct in prohibiting specific motivations intended to cause harmful consequences.

Performance simulations were conducted on the International Thermonuclear Experimental Reactor-Central Solenoid coil. Operational considerations included the influence of ramp rate limitation. The non-uniform distribution is believed to be caused by the flux loops between the strands or cable substages. The effects of parameters on the coil's stability limit were also measured through simulations.