Risk of skin cancer after neonatal phototherapy : retrospective cohort study

Peer reviewedPostprin

The Real Combination Problem : Panpsychism, Micro-Subjects, and Emergence

Panpsychism harbors an unresolved tension, the seriousness of which has yet to be fully appreciated. I capture this tension as a dilemma, and offer panpsychists advice on how to resolve it. The dilemma, briefly, is as follows. Panpsychists are committed to the perspicuous explanation of macro-mentality in terms of micro-mentality. But panpsychists take the micro-material realm to feature not just mental properties, but also micro-subjects to whom these properties belong. Yet it is impossible to explain the constitution of a macro-subject (like one of us) in terms of the assembly of micro-subjects, for, I show, subjects cannot combine. Therefore the panpsychist explanatory project is derailed by the insistence that the world’s ultimate material constituents (ultimates) are subjects of experience. The panpsychist faces a choice of abandoning her explanatory project, or recanting the claim that the ultimates are subjects. This is the dilemma. I argue that the latter option is to be preferred. This needn’t constitute a wholesale abandonment of panpsychism, however, since panpsychists can maintain that the ultimates possess phenomenal qualities, despite not being subjects of those qualities. This proposal requires us to make sense of phenomenal qualities existing independently of experiencing subjects, a challenge I tackle in the penultimate section. The position eventually reached is a form of neutral monism, so another way to express the overall argument is to say that, keeping true to their philosophical motivations, panpsychists should really be neutral monists.Peer reviewedFinal Accepted Versio

Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD:a Post Hoc Analysis of the TONADO® Trials

Introduction Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting beta(2)-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naive patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID. Methods Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 mu g or tiotropium 5 mu g (delivered via Respimat(R)) in two replicate, 52-week, parallel-group, double-blind studies (TONADO(R) 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID. Results Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P <0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P <0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P <0.0001) and maintenance-naive patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030). Conclusion In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naive patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy. PLAIN LANGUAGE SUMMARY COPD is a complicated disease that deteriorates over time. Worsening of COPD is associated with the lungs working less effectively, a fall in quality of life and a rise in sudden flare-ups of the disease. In this study, we looked at lung function, quality of life and flare-ups together using a measure called "clinically important deterioration" (CID). We looked at 2055 people with COPD to compare the effects of taking two bronchodilators (tiotropium and olodaterol) against taking one bronchodilator (tiotropium alone). Bronchodilators are a type of inhaled medication that relax the muscles in the lungs and widen airways, making it easier to breathe. They have also been shown to reduce sudden flare-ups of COPD. Across a wide range of people with COPD, we found that treatment with tiotropium/olodaterol reduced the risk of a CID compared with tiotropium alone. This includes in those patients at an early stage of disease, who may benefit from finding the best treatment option for them as early as possible

Personhood, consciousness, and god : how to be a proper pantheist

© Springer Nature B.V. 2018In this paper I develop a theory of personhood which leaves open the possibility of construing the universe as a person. If successful, it removes one bar to endorsing pantheism. I do this by examining a rising school of thought on personhood, on which persons, or selves, are understood as identical to episodes of consciousness. Through a critique of this experiential approach to personhood, I develop a theory of self as constituted of qualitative mental contents, but where these contents are also capable of unconscious existence. On this theory, though we can be conscious of our selves, consciousness turns out to be inessential to personhood. This move, I then argue, provides resources for responding to the pantheist’s problem of God’s person.Peer reviewedFinal Accepted Versio

Origins of the Qualitative Aspects of Consciousness: Evolutionary Answers to Chalmers' Hard Problem

According to David Chalmers, the hard problem of consciousness consists of explaining how and why qualitative experience arises from physical states. Moreover, Chalmers argues that materialist and reductive explanations of mentality are incapable of addressing the hard problem. In this chapter, I suggest that Chalmers’ hard problem can be usefully distinguished into a ‘how question’ and ‘why question,’ and I argue that evolutionary biology has the resources to address the question of why qualitative experience arises from brain states. From this perspective, I discuss the different kinds of evolutionary explanations (e.g., adaptationist, exaptationist, spandrel) that can explain the origins of the qualitative aspects of various conscious states. This argument is intended to clarify which parts of Chalmers’ hard problem are amenable to scientific analysis

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling

Rationale: Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae caninvade themyocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia. Objectives: We sought to determine whether S. pneumoniae can (1) translocate the heart, (2) induce cardiomyocyte death, (3) causeMACE, and (4) induce cardiac scar formation after antibiotic treatment during severe pneumonia using a nonhuman primate (NHP) model. Methods: We examined cardiac tissue from six adult NHPs with severe pneumococcal pneumonia and three uninfected control animals. Three animals were rescued with antibiotics (convalescent animals). Electrocardiographic, echocardiographic, and serum biomarkers of cardiac damage were measured (troponin T, N-terminal pro-brain natriuretic peptide, and heart-type fatty acid binding protein). Histological examination included hematoxylin and eosin staining, immunofluorescence, immunohistochemistry, picrosirius red staining, and transmission electron microscopy. Immunoblots were used to assess the underlying mechanisms. Measurements and Main Results: Nonspecific ischemic alterations were detected by electrocardiography and echocardiography. Serum levels of troponin T and heart-type fatty acid binding protein were increased (P,0.05) after pneumococcal infection in both acutely ill and convalescent NHPs. S. pneumoniae was detected in the myocardium of all NHPs with acute severe pneumonia. Necroptosis and apoptosis were detected in the myocardium of both acutely ill and convalescent NHPs. Evidence of cardiac scar formation was observed only in convalescent animals by transmission electron microscopy and picrosirius red staining. Conclusions: S. pneumoniae invades the myocardium and induces cardiac injury with necroptosis and apoptosis, followed by cardiac scarring after antibiotic therapy, in anNHP model of severe pneumonia

Selective Uncoupling of Individual Mitochondria within a Cell Using a Mitochondria-Targeted Photoactivated Protonophore

Depolarization of an individual mitochondrion or small clusters of mitochondria within cells has been achieved using a photoactivatable probe. The probe is targeted to the matrix of the mitochondrion by an alkyltriphenylphosphonium lipophilic cation and releases the protonophore 2,4-dinitrophenol locally in predetermined regions in response to directed irradiation with UV light via a local photolysis system. This also provides a proof of principle for the general temporally and spatially controlled release of bioactive molecules, pharmacophores, or toxins to mitochondria with tissue, cell, or mitochondrion specificity

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Modelling distributions of Aedes aegypti and Aedes albopictus using climate, host density and interspecies competition.

Florida faces the challenge of repeated introduction and autochthonous transmission of arboviruses transmitted by Aedes aegypti and Aedes albopictus. Empirically-based predictive models of the spatial distribution of these species would aid surveillance and vector control efforts. To predict the occurrence and abundance of these species, we fit a mixed-effects zero-inflated negative binomial regression to a mosquito surveillance dataset with records from more than 200,000 trap days, representative of 53% of the land area and ranging from 2004 to 2018 in Florida. We found an asymmetrical competitive interaction between adult populations of Aedes aegypti and Aedes albopictus for the sampled sites. Wind speed was negatively associated with the occurrence and abundance of both vectors. Our model predictions show high accuracy (72.9% to 94.5%) in validation tests leaving out a random 10% subset of sites and data since 2017, suggesting a potential for predicting the distribution of the two Aedes vectors