Regrets Associated with Providing Healthcare: Qualitative Study of Experiences of Hospital-Based Physicians and Nurses

Regret is an unavoidable corollary of clinical practice. Physicians and nurses perform countless clinical decisions and actions, in a context characterised by time pressure, information overload, complexity and uncertainty

Host Immune Response to Mosquito-Transmitted Chikungunya Virus Differs from That Elicited by Needle Inoculated Virus

Mosquito-borne diseases are a worldwide public health threat. Mosquitoes transmit viruses or parasites during feeding, along with salivary proteins that modulate host responses to facilitate both blood feeding and pathogen transmission. Understanding these earliest events in mosquito transmission of arboviruses by mosquitoes is essential for development and assessment of rational vaccine and treatment strategies. In this report, we compared host immune responses to chikungunya virus (CHIKV) transmission by (1) mosquito bite, or (2) by needle inoculation.Differential cytokine expression was measured using quantitative real-time RT-PCR, at sites of uninfected mosquito bites, CHIKV-infected mosquito bites, and needle-inoculated CHIKV. Both uninfected and CHIKV infected mosquitoes polarized host cytokine response to a TH2 profile. Compared to uninfected mosquito bites, expression of IL-4 induced by CHIKV-infected mosquitoes were 150 fold and 527.1 fold higher at 3 hours post feeding (hpf) and 6 hpf, respectively. A significant suppression of TH1 cytokines and TLR-3 was also observed. These significant differences may result from variation in the composition of uninfected and CHIKV-infected mosquito saliva. Needle injected CHIKV induced a robust interferon-gamma, no detectable IL-4, and a significant up-regulation of TLR-3.This report describes the first analysis of cutaneous cytokines in mice bitten by CHIKV-infected mosquitoes. Our data demonstrate contrasting immune activation in the response to CHIKV infection by mosquito bite or needle inoculation. The significant role of mosquito saliva in these earliest events of CHIKV transmission and infection are highlighted

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis. © 2018, The Author(s)

Borrelia burgdorferi has minimal impact on the lyme disease reservoir host Peromyscus leucopus

The epidemiology of vector-borne zoonotic diseases is determined by encounter rates between vectors and hosts. Alterations to the behavior of reservoir hosts caused by the infectious agent have the potential to dramatically alter disease transmission and human risk. We examined the effect of Borrelia burgdorferi, the etiological agent of Lyme disease, on one of its most important reservoir hosts, the white-footed mouse, Peromyscus leucopus. We mimic natural infections in mice using the vector (Black-legged ticks, Ixodes scapularis) and examine the immunological and behavioral responses of mouse hosts. Despite producing antibodies against B. burgdorferi, infected mice did not have elevated white blood cells compared with uninfected mice. In addition, infected and uninfected mice did not differ in their wheel-running activity. Our results suggest that infection with the spirochete B. burgdorferi has little impact on the field activity of white-footed mice. Lyme disease transmission appears to be uncomplicated by pathogen-altered behavior of this reservoir host

Signatures of immune dysfunction predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

Background and methods: The functional and transcriptional features of immune effector senescence and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). Results: We show that senescent-like bone marrow CD8+ T cells were impaired in killing autologous AML blasts, and that their proportion negatively correlated with overall survival (OS). We defined new immune effector dysfunction (IED) signatures using two gene expression profiling platforms and report that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or leukemia stem cell (LSC17) scores. IED expression signatures also identified an ICB-unresponsive tumor microenvironment and predicted significantly worse OS. Conclusion: The newly described IED scores provided improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit

Dermatologic Changes Induced by Repeated Ixodes scapularis Bites and Implications for Prevention of Tick-Borne Infection

Previous studies in rodents and people have demonstrated that repeated tick exposure is associated with reduced Borrelia burgdorferi transmission but the mechanism of prevention remains unclear. We examined the acute histopathologic reactions to initial and repeated Ixodes scapularis bites in BALB/c mice and in people. Skin biopsies of BALB/c mice infested for the first time by I. scapularis nymphs revealed vascular dilatation and an accumulation of inflammatory cells adjacent to the bite site but absent at the site of tick attachment. Such changes would enhance tick-borne pathogen transmission. Mice reexposed to I. scapularis nymphs experienced a decrease in vascular dilatation and a marked increase in inflammatory cells at the site of tick attachment. Skin biopsies of people with attached I. scapularis nymphs revealed similar histologic patterns. These results indicate that cellular changes at the tick-dermal interface following I. scapularis attachment are likely to allow for successful transmission of tick-borne pathogens in non-tick-immune hosts and to inhibit tick-borne pathogen transmission in hosts that have developed tick immunity