Unknown Rectal Lesions: A Case of Severe Proctitis Secondary to Mpox in the Setting of Concomitant HIV, Syphilis, HSV, and Chlamydia

Introduction: Mpox emerged as a public health crisis with limited research describing co-occurring HIV and sexually transmitted infections (STIs). We present a case of severe proctitis secondary to Mpox with concomitant HIV (Human Immunodeficiency Virus), syphilis, HSV (Herpes Simplex Virus), and chlamydia and review presentation, diagnosis, treatment, and prevention of Mpox with concurrent STIs. Case Presentation: 34-year-old male living with HIV (LWH) presenting with worsening rectal pain, multiple anal papules, and fever. His laboratory workup revealed simultaneous positive results for orthopoxvirus, chlamydia, and HSV-1 PCR. We initiated tecovirimat due to rectal involvement and uncontrolled pain. He subsequently developed lesions on hands as rectal pain improved. He completed tecovirimat treatment and the lesions cleared by outpatient follow-up. Discussion: Among published studies of Mpox patients, 40% were LWH, and a significant percent were found to have co-occurring gonorrhea (23%), chlamydia (20%), syphilis (8%), and HSV (1%) with presentations including fever (62%), lymphadenopathy (49%), malaise (39%), and rectal pain (25%). We recommend Mpox and full STI diagnostic testing for unknown anogenital lesions and early treatment should be considered. Early initiation of Tecovirimat treatment should be considered in severe disease, immune deficiency, or those at high-risk for serious sequelae, in accordance with CDC guidelines. Learning Points: Identify the differential diagnosis for unknown rectal lesions Describe the clinical presentation of Mpox Summarize the diagnostic approach and interpretation of diagnostic results Identify treatment options and considerations by patient populations Review preventative strategies and high-risk populations for Mpox transmissio

Pulmonary endothelial HIF2α\alpha-arginase axis plays an essential role in the development of hypoxia pulmonary hypertension

This is the author accepted manuscript. The final version is available from the Proceedings of the National Academy of Sciences (PNAS) via https://doi.org/10.1073/pnas.1602978113Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodelling. The hypoxia-inducible transcription factors (HIFs), HIF-1$\alpha$ and HIF-2$\alpha$ are known to contribute to the process of hypoxic pulmonary vascular remodelling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2$\alpha$ is a critical regulator of hypoxia-induced pulmonary arterial hypertension (PAH). The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2$\alpha$ deletion. The RVSP of mice lacking HIF-2$\alpha$ in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic wild type (WT) mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1$\alpha$ exposed to hypoxia. Endothelial HIF-2$\alpha$ deletion also protected mice from hypoxia remodelling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2$\alpha$, likewise attenuated many of the pathophysiological symptoms associated with HPH. We propose a mechanism whereby chronic hypoxia enhances HIF-2$\alpha$ stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2$\alpha$ in regulating the pulmonary vascular response to hypoxia.This study was funded by The Wellcome Trust, Papworth Hospital NIHR Cambridge Biomedical Research Centre

A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension.

BACKGROUND AND PURPOSE: Apelin is an endogenous vasodilatory and inotropic peptide that is down-regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein-biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β-arrestin-mediated receptor internalisation with chronic use. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated. KEY RESULTS: MM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline-induced changes in cardiac structure and function, including right ventricular end-systolic and end-diastolic volumes, ejection fraction, and left ventricular end-diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline-induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro. CONCLUSION AND IMPLICATIONS: Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.the Medical Research Council MC_PC_14116 [to APD] Wellcome Trust [107715/Z/15/Z to APD], Programme in Metabolic and Cardiovascular Disease [096822/Z/11/Z to PY; 203814/Z/16/A to TLW], Parke Davis Fellowship [to PY], British Heart Foundation [FS/14/59/31282 to CR] and in part by the National Institute for Health Research Cambridge Biomedical Research Centre

Efficacy of a Single Image-Guided Corticosteroid Injection for Glenohumeral Arthritis

Background There is limited data available on the efficacy of cortisone injection for glenohumeral osteoarthritis (GHOA). The amount and longevity of pain relief provided by a single cortisone injection is unclear. Additionally, it remains uncertain how the severity of radiographic GHOA and patient reported function and pain levels impact the efficacy of injection. Therefore, we sought to describe relief provided by a single, image guided glenohumeral injection for patients with GHOA. Additionally, we hypothesized that patients with more severe radiographic GHOA and poorer baseline shoulder function would require earlier secondary intervention. Methods Patients with symptomatic GHOA who elected to receive a corticosteroid injection for pain relief were prospectively enrolled. A phone interview was conducted to record baseline OSS and VAS scores prior to the injection, as well as at months 1, 2, 3, 4, 6, 9, and 12. Endpoints were designated when patients required a second injection, progressed to surgery, or reached month 12. Patients were grouped by their respective baseline OSS (mild, moderate/severe) and Samilson-Prieto radiographic classification (mild, moderate, severe) for analysis. Results Thirty shoulders (29 patients) were analyzed. 52% of patients were male. The average age of 66.1 years. No significant difference was seen in overall survival (defined as no additional intervention) between groups based on either OSS or Samilson-Prieto grades. Additionally, OSS and VAS scores at each follow-up were compared to baseline. For the entire cohort, a clinically significant difference was seen between baseline and months 1-4 for OSS and between baseline and months 1-4, 6,9, and 12 for VAS. Discussion This study aimed to determine the efficacy of corticosteroid injections for GHOA. There were no differences in the need for secondary interventions in this population based on severity of either the OSS or the Samilson-Prieto radiographic classification. However, patients with more severe shoulder dysfunction based on OSS did experience a statistically significant greater symptomatic relief compared with patients with milder dysfunction. Additionally, following a single injection, patients in this cohort experienced statistically and clinically relevant improvements in shoulder function and pain up to 4 months post-injection

HIF2α-arginase axis is essential for the development of pulmonary hypertension.

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia

Estimation of gestational age from fundal height: a solution for resource-poor settings

Many women in resource-poor settings lack access to reliable gestational age assessment because they do not know their last menstrual period; there is no ultrasound (US) and methods of newborn gestational age dating are not practised by birth attendants. A bespoke multiple-measures model was developed to predict the expected date of delivery determined by US. The results are compared with both a linear and a nonlinear model. Prospectively collected early US and serial symphysis-pubis fundal height (SFH) data were used in the models. The data were collected from Karen and Burmese women attending antenatal care on the Thai–Burmese border. The multiple-measures model performed best, resulting in a range of accuracy depending on the number of SFH measures recorded per mother (for example six SFH measurements resulted in a prediction accuracy of ±2 weeks). SFH remains the proxy for gestational age in much of the resource-poor world. While more accurate measures should be encouraged, we demonstrate that a formula that incorporates at least three SFH measures from an individual mother and the slopes between them provide a significant increase in the accuracy of prediction compared with the linear and nonlinear formulae also using multiple SFH measures

Reciprocity as a foundation of financial economics

This paper argues that the subsistence of the fundamental theorem of contemporary financial mathematics is the ethical concept ‘reciprocity’. The argument is based on identifying an equivalence between the contemporary, and ostensibly ‘value neutral’, Fundamental Theory of Asset Pricing with theories of mathematical probability that emerged in the seventeenth century in the context of the ethical assessment of commercial contracts in a framework of Aristotelian ethics. This observation, the main claim of the paper, is justified on the basis of results from the Ultimatum Game and is analysed within a framework of Pragmatic philosophy. The analysis leads to the explanatory hypothesis that markets are centres of communicative action with reciprocity as a rule of discourse. The purpose of the paper is to reorientate financial economics to emphasise the objectives of cooperation and social cohesion and to this end, we offer specific policy advice

Mechanisms Underlying Hypoxia Tolerance in Drosophila melanogaster: hairy as a Metabolic Switch

Hypoxia-induced cell injury has been related to multiple pathological conditions. In order to render hypoxia-sensitive cells and tissues resistant to low O2 environment, in this current study, we used Drosophila melanogaster as a model to dissect the mechanisms underlying hypoxia-tolerance. A D. melanogaster strain that lives perpetually in an extremely low-oxygen environment (4% O2, an oxygen level that is equivalent to that over about 4,000 m above Mt. Everest) was generated through laboratory selection pressure using a continuing reduction of O2 over many generations. This phenotype is genetically stable since selected flies, after several generations in room air, survive at this low O2 level. Gene expression profiling showed striking differences between tolerant and naïve flies, in larvae and adults, both quantitatively and qualitatively. Up-regulated genes in the tolerant flies included signal transduction pathways (e.g., Notch and Toll/Imd pathways), but metabolic genes were remarkably down-regulated in the larvae. Furthermore, a different allelic frequency and enzymatic activity of the triose phosphate isomerase (TPI) was present in the tolerant versus naïve flies. The transcriptional suppressor, hairy, was up-regulated in the microarrays and its binding elements were present in the regulatory region of the specifically down-regulated metabolic genes but not others, and mutations in hairy significantly reduced hypoxia tolerance. We conclude that, the hypoxia-selected flies: (a) altered their gene expression and genetic code, and (b) coordinated their metabolic suppression, especially during development, with hairy acting as a metabolic switch, thus playing a crucial role in hypoxia-tolerance

25 Years of Self-organized Criticality: Concepts and Controversies

Introduced by the late Per Bak and his colleagues, self-organized criticality (SOC) has been one of the most stimulating concepts to come out of statistical mechanics and condensed matter theory in the last few decades, and has played a significant role in the development of complexity science. SOC, and more generally fractals and power laws, have attracted much comment, ranging from the very positive to the polemical. The other papers (Aschwanden et al. in Space Sci. Rev., 2014, this issue; McAteer et al. in Space Sci. Rev., 2015, this issue; Sharma et al. in Space Sci. Rev. 2015, in preparation) in this special issue showcase the considerable body of observations in solar, magnetospheric and fusion plasma inspired by the SOC idea, and expose the fertile role the new paradigm has played in approaches to modeling and understanding multiscale plasma instabilities. This very broad impact, and the necessary process of adapting a scientific hypothesis to the conditions of a given physical system, has meant that SOC as studied in these fields has sometimes differed significantly from the definition originally given by its creators. In Bak’s own field of theoretical physics there are significant observational and theoretical open questions, even 25 years on (Pruessner 2012). One aim of the present review is to address the dichotomy between the great reception SOC has received in some areas, and its shortcomings, as they became manifest in the controversies it triggered. Our article tries to clear up what we think are misunderstandings of SOC in fields more remote from its origins in statistical mechanics, condensed matter and dynamical systems by revisiting Bak, Tang and Wiesenfeld’s original papers