The darker side of travel Sharpley, Richard; Stone, Philip R
2009., 2009, 2009-08-25, Volume:
41
eBook
This book is a contemporary and comprehensive analysis of dark tourism. Drawing on existing literature, numerous examples and introducing new conceptual perspectives, it develops a theoretically ...informed foundation for examining the demand for and supply of dark tourism experiences.
Liposomal amphotericin B (AmBisome(®); LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB ...has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.
Objective
The interleukin‐6 pathway is up‐regulated in giant cell arteritis (GCA), Takayasu arteritis (TA), and polymyalgia rheumatica (PMR). We retrospectively assessed the outcomes of 10 patients ...with relapsing/refractory GCA, TA, or PMR treated with tocilizumab (TCZ).
Methods
Patients with GCA (n = 7), TA (n = 2), and PMR (n = 1) received TCZ. Seven subjects had failed at least 1 second‐line agent. The outcomes evaluated were symptoms of disease activity, inflammatory markers, ability to taper glucocorticoids, and cross‐sectional imaging when indicated clinically.
Results
The mean followup time of this cohort since diagnosis was 27 months (range 16–60 months). The patients were treated with TCZ for a mean period of 7.8 months (range 4–12 months). Before TCZ therapy, the patients experienced an average of 2.4 flares/year. All patients entered and maintained clinical remission during TCZ therapy. The mean daily prednisone dosages before and after TCZ initiation were 20.8 mg/day (range 7–34.3 mg/day) and 4.1 mg/day (range 0–10.7 mg/day), respectively (P = 0.0001). The mean erythrocyte sedimentation rate declined from 41.5 mm/hour (range 11–68 mm/hour) to 7 mm/hour (range 2.2–11.3 mm/hour; P = 0.0001). The adverse effects of TCZ included mild neutropenia (n = 4) and transaminitis (n = 4). One patient flared 2 months after TCZ discontinuation. An autopsy on 1 patient who died from a postoperative myocardial infarction following elective surgery revealed persistent vasculitis of large and medium‐sized arteries.
Conclusion
TCZ therapy led to clinical and serologic improvement in patients with refractory/relapsing GCA, TA, or PMR. The demonstration of persistent large‐vessel vasculitis at autopsy of 1 patient who had shown a substantial response requires close scrutiny in larger studies.
In last few years, there have been significant advances in our understanding of a newly recognized condition known as IgG4-related systemic disease. This review will focus on IgG4-related systemic ...disease as a cause of thoracic aortitis, inflammatory abdominal aortic aneurysm or periaortitis, and retroperitoneal fibrosis.
A significant fraction of thoracic lymphoplasmacytic aortitis cases, about 40% of inflammatory abdominal aortic aneurysms/abdominal periaortitis cases, and a portion of retroperitoneal fibrosis cases are all caused by IgG4-related systemic disease. Assessing pathologic specimens for the fraction of plasma cells that express IgG4 is useful in identifying patients with this disorder. Recently reported data may indicate IgG4-related aortic disease to be more common than widely realized.
IgG4-related systemic disease is a newly recognized disorder that may manifest as thoracic aortitis, inflammatory abdominal aortic aneurysm or retroperitoneal fibrosis. IgG4-related systemic disease should be considered in any patient found to have aortitis or periaortitis. Further studies into diagnostic criteria, disease prevalence, prognosis, therapeutic interventions, and differentiating possible localized hypersensitivity reactions from systemic disease are areas of active investigation. Criteria are presented for the pathologic diagnosis of IgG4-related aortitis.
Objective
IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. ...This work was undertaken to develop and validate an international set of classification criteria for IgG4‐RD.
Methods
An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included.
Results
A 3‐step classification process was developed. First, it must be demonstrated that a potential IgG4‐RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4‐RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4‐RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval 95% CI 97.2–99.8%) and a sensitivity of 85.5% (95% CI 81.9–88.5%). In the second, the specificity was 97.8% (95% CI 93.7–99.2%) and the sensitivity was 82.0% (95% CI 77.0–86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds.
Conclusion
ACR/EULAR classification criteria for IgG4‐RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.
Immune checkpoint inhibitor therapy for malignancy has been associated with adverse events including myocarditis. It has been unclear if there are distinct pathologic grades of this myocarditis that ...are associated with distinct clinical outcomes. Cardiac tissue from ten patients with immune checkpoint inhibitor myocarditis (nine biopsies and one autopsy) were evaluated using immunohistochemistry for CD3, CD8, CD68, tryptase, PD-L1, and C4D. The immune checkpoint inhibitor myocarditis cases were classified as either high grade (>50 CD3
cells/hpf) or low grade (≤50 CD3
cells/hpf). The densities of macrophages, T cells, eosinophils, necrotic myocytes, and PD-L1
macrophages and myocytes were compared between the two groups and with 13 cases of grade 2R acute cellular allograft rejection. Three patients were classified as high-grade myocarditis and seven as low grade. There were higher densities of CD3
cells and CD8
cells in high-grade immune checkpoint inhibitor myocarditis and rejection compared with low-grade myocarditis. The number of CD68
macrophages was higher in high-grade myocarditis compared with low-grade myocarditis and rejection. For both grades of myocarditis, there was a higher CD68/CD3 ratio and a higher density of PD-L1
macrophages and myocytes compared with rejection. Clinically, there were trends toward higher serum troponin levels and shorter interval from first immune checkpoint inhibitor treatment in the high-grade myocarditis group compared with the low-grade group. All the patients with high-grade myocarditis died, while all the patients with low-grade myocarditis were still living. These data suggest that immune checkpoint inhibitor myocarditis occurs in two forms, a high-grade form with increased inflammatory cell infiltration and a more fulminant clinical course, and a low-grade form with a lower degree of inflammatory cell infiltration and a more indolent clinical course. Compared with acute cellular rejection, immune checkpoint inhibitor myocarditis is characterized by a more lymphohistiocytic inflammatory infiltrate with an increased CD68/CD3 ratio and increased PD-L1
macrophages and myocytes.
Abstract
Aims
Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement ...including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described.
Methods and results
In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.
Conclusions
In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.
We explore the dynamical response of dissipative Kerr solitons to changes in pump power and detuning and show how thermal and nonlinear processes couple these parameters to the frequency-comb degrees ...of freedom. Our experiments are enabled by a Pound-Drever-Hall (PDH) stabilization approach that provides on-demand, radio-frequency control of the frequency comb. PDH locking not only guides Kerr-soliton formation from a cold microresonator but opens a path to decouple the repetition and carrier-envelope-offset frequencies. In particular, we demonstrate phase stabilization of both Kerr-comb degrees of freedom to a fractional frequency precision below 10^{-16}, compatible with optical-time-keeping technology. Moreover, we investigate the fundamental role that residual laser-resonator detuning noise plays in the spectral purity of microwave generation with Kerr combs.
This book represents the first monograph in womanist theological ethics and pentecostalism from within Europe. Despite its designation as an 'embodied faith', this book argues that both historically ...and in the present, classical pentecostalism often fails to integrate the body with spirituality in ways which attend to the hierarchies which oppress certain bodies in the church and the wider world. Looking back to the African and Wesleyan roots of the movement to explore this tension, the book then draws on qualitative as well as textual research, to analyse classical progressive pentecostalism in Britain today which models an integrated pentecostal faith to an extent, but retains inconsistencies. Finally, a womanist pentecostal theology is being constructed, which calls attention to the Spirit and the body - especially the bodies of the oppressed - as a path towards a holistic understanding of the work of the Spirit and pentecostal faith and ministry.
We explore intrinsic thermal noise in soliton microcombs, revealing thermodynamic correlations induced by nonlinearity and group-velocity dispersion. A suitable dispersion design gives rise to ...control over thermal-noise transduction from the environment to a soliton microcomb. We present simulations with the Lugiato-Lefever equation (LLE), including temperature as a stochastic variable. By systematically tuning the dispersion, we suppress repetition-rate frequency fluctuations by up to 50 decibels for different LLE soliton solutions. In an experiment, we observe a measurement-system-limited 15-decibel reduction in the repetition-rate phase noise for various settings of the pump-laser frequency, and our measurements agree with a thermal-noise model. Finally, we compare two octave-spanning soliton microcombs with similar optical spectra and offset frequencies, but with designed differences in dispersion. Remarkably, their thermal-noise-limited carrier-envelope-offset frequency linewidths are 1 MHz and 100 Hz, which demonstrates an unprecedented potential to mitigate thermal noise. Our results guide future soliton-microcomb design for low-noise applications, and, more generally, they illuminate emergent properties of nonlinear, multimode optical systems subject to intrinsic fluctuations.
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