The Crisis of World Order and the Constitutive Regime of the International System

Statespersons, scholars, and commentators of every political persuasion agree that we are currently witnessing a crisis of world order. It is widely assumed that the so-called Liberal World Order that the United States constructed in the post-World War II years is collapsing. This Article interrogates and challenges this claim. This Article examines what it means to speak of world order. It argues that to understand the notion of world order, it is necessary to investigate the normative foundations of the international system. Therefore, this Article develops a theoretical construct that I call the Constitutive Regime of the International System to conceptualize the notion of world order. It argues that the international system is predicated on and governed by a Constitutive Regime that embodies a grand worldview-i.e., a theory of world order-that prescribes policies, practices, and rules of international law that are considered necessary for maintaining global order and stability. This regime, which is designed by the Great Powers of each historical epoch, shapes international and domestic politics. It determines the criteria and preconditions of statehood, thereby affecting how societies are organized and governed. It promotes certain methods for the conduct of world politics, and it establishes mechanisms for international lawmaking, thus providing the constitutive foundation of international law. A crisis of world order occurs when these basic normative assumptions about the nature of the international system and the processes of global governance are challenged. Having provided a conceptual framework for understanding the notion of world order, this Article then challenges the claim that the post-World War II Liberal World Order is currently in a period of crisis. It argues that, beginning in the 1970s, the Liberal World Order of the post-World War II era was replaced by a neoliberal world order-in other words, a neoliberal Constitutive Regime. This Article shows how this neoliberal Constitutive Regime shaped virtually every aspect of world politics and provided the normative foundation ofglobalization during the closing decades of the twentieth century. This Article concludes with a discussion of the origins of the current crisis of world order and a reflection on the future of world order in an era of increased Great Power competition

The Unruly World of Tax: A Proposal for an International Tax Cooperation Forum

International cooperation in tax policy is deeply fractured. Inconsistencies, loopholes, and ineffective mechanisms—which could be avoided if real collaboration among countries existed—have created significant inefficiency losses for decades. This Article focuses on the institutional infrastructure underlying international cooperation in tax issues and argues that the current forums in which such cooperation is encouraged do not provide an adequate platform in which countries with similar interests can effectively make a collaborative effort. To facilitate cooperation, this Article proposes to create a new institution currently missing from the international tax policy-setting arena: an informal forum for coordination among countries that share similar interests in tax policy, inspired by the model of “Like Minded Groups” in international organizations. This forum will enable countries that share similar interests to cooperate and reach understandings about necessary policy adaptations. We identify two major projects that this forum could promote—efforts to curtail tax evasion and efforts to harmonize various aspects of tax policy. We argue that this model might have significant advantages in promoting cooperation, reducing the “competitiveness” threat, advocating coordinated policies, and overcoming external and domestic pressures. In light of the current challenges in the field of tax policy, and the difficulties in forming international cooperation within the current institutional framework, the proposed model is worth serious discussion and consideration

Implementation of breast cancer continuum of care in low- and middle-income countries during the COVID-19 pandemic

Breast cancer is the most common malignancy among women worldwide. The current COVID-19 pandemic represents an unprecedented challenge leading to care disruption, which is more severe in low- and middle-income countries (LMIC) due to existing economic obstacles. This review presents the global perspective and preparedness plans for breast cancer continuum of care amid the COVID-19 outbreak and discusses challenges faced by LMIC in implementing these strategies. Prioritization and triage of breast cancer patients in a multidisciplinary team setting are of paramount importance. Deescalation of systemic and radiation therapy can be utilized safely in selected clinical scenarios. The presence of a framework and resource-adapted recommendations exploiting available evidence-based data with judicious personalized use of current resources is essential for breast cancer care in LMIC during the COVID-19 pandemic

Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1

The rise in multidrug resistant (MDR) cases of tuberculosis (TB) has led to the need for the development of TB drugs with different mechanisms of action. The genome sequence of Mycobacterium tuberculosis (Mtb) revealed twenty different genes coding for cytochrome P450s. CYP121A1 catalyzes a C-C crosslinking reaction of dicyclotyrosine (cYY) producing mycocyclosin and current research suggests that either mycocyclosin is essential or the overproduction of cYY is toxic to Mtb. A series of 1,4-dibenzyl-2-imidazol-1-yl-methylpiperazine derivatives were designed and synthesised as cYY mimics. The derivatives substituted in the 4-position of the phenyl rings with halides or alkyl group showed promising antimycobacterial activity (MIC 6.25 μg/mL), with the more lipophilic branched alkyl derivatives displaying optimal binding affinity with CYP121A1 (iPr KD = 1.6 μM; tBu KD = 1.2 μM). Computational studies revealed two possible binding modes within the CYP121A1 active site both of which would effectively block cYY from binding

THE POWER OF INTEGRATION TOWARDS SUSTAINABLE PERFORMANCE: A MODEL TO MINIMIZE TECHNOSTRESS AMONG FRONTLINE RESTAURANT EMPLOYEES BY COMBINING JOB AND EMPLOYEE RESOURCES

To develop a model that integrates restaurant and employee resources to overcome technostress and achieve sustainable performance. This qualitative study is based on twenty-two semi-structured interviews with restaurant managers and frontline employees (FLEs) to comprehensively understand how restaurant resources and personnel can be employed to combat technostress and achieve sustainable performance. Restaurant FLEs experience technostress from multiple sources, including unclear work-life boundaries, complex new systems, job insecurity, and the frequent use of new technologies. In addition, restaurant managers and FLEs concur that integrating restaurant and FLE resources is an effective model for reducing technostress and achieving FLEs' sustainable performance. The study expands the JD-R model to address the challenges faced by FLEs in managing technology-induced job demands, offering a comprehensive solution that benefits restaurants and employees. This approach considers the role of both employers and employees in managing technostress, leading to a supportive work environment and improved sustainable performance

Alterations in the transcriptome and antibiotic susceptibility of Staphylococcus aureus grown in the presence of diclofenac

<p>Abstract</p> <p>Background</p> <p>Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has been shown to increase the susceptibility of various bacteria to antimicrobials and demonstrated to have broad antimicrobial activity. This study describes transcriptome alterations in <it>S. aureus </it>strain COL grown with diclofenac and characterizes the effects of this NSAID on antibiotic susceptibility in laboratory, clinical and diclofenac reduced-susceptibility (Dc^RS) <it>S. aureus </it>strains.</p> <p>Methods</p> <p>Transcriptional alterations in response to growth with diclofenac were measured using <it>S. aureus </it>gene expression microarrays and quantitative real-time PCR. Antimicrobial susceptibility was determined by agar diffusion MICs and gradient plate analysis. Ciprofloxacin accumulation was measured by fluorescence spectrophotometry.</p> <p>Results</p> <p>Growth of <it>S. aureus </it>strain COL with 80 μg/ml (0.2 × MIC) of diclofenac resulted in the significant alteration by ≥2-fold of 458 genes. These represented genes encoding proteins for transport and binding, protein and DNA synthesis, and the cell envelope. Notable alterations included the strong down-regulation of antimicrobial efflux pumps including <it>mepRAB </it>and a putative <it>emrAB/qacA</it>-family pump. Diclofenac up-regulated <it>sigB </it>(σ^B), encoding an alternative sigma factor which has been shown to be important for antimicrobial resistance. <it>Staphylococcus aureus </it>microarray metadatabase (SAMMD) analysis further revealed that 46% of genes differentially-expressed with diclofenac are also σ^B-regulated. Diclofenac altered <it>S. aureus </it>susceptibility to multiple antibiotics in a strain-dependent manner. Susceptibility increased for ciprofloxacin, ofloxacin and norfloxacin, decreased for oxacillin and vancomycin, and did not change for tetracycline or chloramphenicol. Mutation to Dc^RSdid not affect susceptibility to the above antibiotics. Reduced ciprofloxacin MICs with diclofenac in strain BB255, were not associated with increased drug accumulation.</p> <p>Conclusions</p> <p>The results of this study suggest that diclofenac influences antibiotic susceptibility in <it>S. aureus</it>, in part, by altering the expression of regulatory and structural genes associated with cell wall biosynthesis/turnover and transport.</p

Alterations In the Transciptome and Antibiotic Susceptibility of \u3ci\u3eStaphylococcus aureus\u3c/i\u3e Grown In the Presence of Diclofenac

Background Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) which has been shown to increase the susceptibility of various bacteria to antimicrobials and demonstrated to have broad antimicrobial activity. This study describes transcriptome alterations in S. aureus strain COL grown with diclofenac and characterizes the effects of this NSAID on antibiotic susceptibility in laboratory, clinical and diclofenac reduced-susceptibility (DcRS) S. aureus strains. Methods Transcriptional alterations in response to growth with diclofenac were measured using S. aureus gene expression microarrays and quantitative real-time PCR. Antimicrobial susceptibility was determined by agar diffusion MICs and gradient plate analysis. Ciprofloxacin accumulation was measured by fluorescence spectrophotometry. Results Growth of S. aureus strain COL with 80 μg/ml (0.2 × MIC) of diclofenac resulted in the significant alteration by ≥2-fold of 458 genes. These represented genes encoding proteins for transport and binding, protein and DNA synthesis, and the cell envelope. Notable alterations included the strong down-regulation of antimicrobial efflux pumps including mepRAB and a putative emrAB/qacA-family pump. Diclofenac up-regulated sigB (σB), encoding an alternative sigma factor which has been shown to be important for antimicrobial resistance. Staphylococcus aureus microarray metadatabase (SAMMD) analysis further revealed that 46% of genes differentially-expressed with diclofenac are also σB-regulated. Diclofenac altered S. aureus susceptibility to multiple antibiotics in a strain-dependent manner. Susceptibility increased for ciprofloxacin, ofloxacin and norfloxacin, decreased for oxacillin and vancomycin, and did not change for tetracycline or chloramphenicol. Mutation to DcRS did not affect susceptibility to the above antibiotics. Reduced ciprofloxacin MICs with diclofenac in strain BB255, were not associated with increased drug accumulation. Conclusions The results of this study suggest that diclofenac influences antibiotic susceptibility in S. aureus, in part, by altering the expression of regulatory and structural genes associated with cell wall biosynthesis/turnover and transport

Design and synthesis of imidazole and triazole pyrazoles as mycobacterium tuberculosis CYP121A1 inhibitors

The emergence of untreatable drug‐resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert‐butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H‐bond acceptors/H‐bond donors 4/0, number of rotatable bonds 5–6, molecular volume >340 Å3, topological polar surface area <40 Å2

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020