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This paper examines the relationship between therapeutic progress and the patient's family or residential situation with reference to the intensive treatment of an adolescent boy who had a severe learning disability and moved placement five times within four years. The idea is explored that the capacity to be thoughtful about emotional distress and to be engaged in learning about one's own mental processes is dependent in part on the human context surrounding the individual. It is illuminated by detailed clinical material using in particular Winnicott's concept of the facilitating environment and Sinason's concept of secondary handicap. The paper also discusses the dilemma for the therapist of whether a thoughtful state of mind and emotional connectedness are always in the interest of the patient's mental health when the external context is so at odds with this and whether retreating into psychic "suspended animation" may sometimes be an adaptive response. Despite this, the author hopes that the paper will contribute to a growing understanding of the potential of psychoanalytic psychotherapy as an intervention for children and young people with severe learning disabilities. (Contains 2 notes.)

Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2′-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations.Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

Abstract The COVID-19 pandemic triggered the resurgence of synthetic RNA vaccine platforms allowing rapid, scalable, low-cost manufacturing, and safe administration of therapeutic vaccines. Self-amplifying mRNA (SAM), which self-replicates upon delivery into the cellular cytoplasm, leads to a strong and sustained immune response. Such mRNAs are encapsulated within lipid nanoparticles (LNPs) that act as a vehicle for delivery to the cell cytoplasm. A better understanding of LNP-mediated SAM uptake and release mechanisms in different types of cells is critical for designing effective vaccines. Here, we investigated the cellular uptake of a SAM-LNP formulation and subsequent intracellular expression of SAM in baby hamster kidney (BHK-21) cells using hyperspectral coherent anti-Stokes Raman scattering (HS-CARS) microscopy and multiphoton-excited fluorescence lifetime imaging microscopy (FLIM). Cell classification pipelines based on HS-CARS and FLIM features were developed to obtain insights on spectral and metabolic changes associated with SAM-LNPs uptake. We observed elevated lipid intensities with the HS-CARS modality in cells treated with LNPs versus PBS-treated cells, and simultaneous fluorescence images revealed SAM expression inside BHK-21 cell nuclei and cytoplasm within 5 h of treatment. In a separate experiment, we observed a strong correlation between the SAM expression and mean fluorescence lifetime of the bound NAD(P)H population. This work demonstrates the ability and significance of multimodal optical imaging techniques to assess the cellular uptake of SAM-LNPs and the subsequent changes occurring in the cellular microenvironment following the vaccine expression.

Continued population growth, increased demands for water and declining water availability are statewide water concerns in Texas. The development and movement of water from where it is to where it is needed brings with it benefits to the receiving area and concerns for the area of origin. The Vista Ridge project serves as an on-point example and case study of such concerns and processes that can mitigate, in part, negative impacts that are informative to other Texans who will soon be facing similar pressures.. Impacts on the water levels in existing wells made the Vista Ridge Project a focus of significant public discussion in 2022, including Texas House and Senate interim session hearings. This paper spotlights groundwater management issues prominent in the Vista Ridge Project that will likely be of concern with other Texas groundwater projects in the near future. These issues involve well mitigation, significant impacts from groundwater production across groundwater conservation district boundaries, meaningful consideration of nine factors in Texas Water Code §36.108(d), the balance between limiting groundwater production, development of fair share doctrines, the role of the Texas Water Development Board in the

89 sexually active men from four fraternities were surveyed concerning their sexual behavior and condom use. Significantly associated with frequency of condom use were high school sex education, preferred method of birth control, partner's attitude toward use of condoms, and feelings that condoms were inconvenient, uncomfortable, or limiting.

Abstract The leadership role can be demanding and depleting. Using self-regulation and social exchange theory as a framework, we developed a three-step sequential mediation model that explains how feelings of depletion can degrade leaders’ own performance level, via the reciprocating behavior of their employees. Specifically, we hypothesized that leader depletion is negatively related to their trust beliefs. This lack of trust is expected to be reciprocated by employees in such a way that they display less citizenship behaviors towards their leader. These lowered citizenship behaviors are, in turn, predicted to negatively impact leader performance. Additionally, we hypothesized that these negative effects of feeling depleted are more pronounced for leaders who believe that their willpower is limited. Studies 1 and 2 illustrated that leader depletion indirectly influences their own performance level through leaders’ trust beliefs and employees’ leader-directed citizenship behaviors. Study 3 extended these findings from the inter-individual to the intra-individual level, and demonstrated the predicted moderating role of belief in limited willpower. Together, our studies provide new and useful insights in the broader, more distal implications of leader depletion, which have not yet been considered in existing self-regulation models.

The goal of this study was to utilize a multimodal magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging approach to assess the local innate immune response in skeletal muscle and draining lymph node following vaccination in rats using two different vaccine platforms (AS01 adjuvanted protein and lipid nanoparticle (LNP) encapsulated Self-Amplifying mRNA (SAM)). MRI and 18FDG PET imaging were performed temporally at baseline, 4, 24, 48, and 72 hr post Prime and Prime-Boost vaccination in hindlimb with Cytomegalovirus (CMV) gB and pentamer proteins formulated with AS01, LNP encapsulated CMV gB protein-encoding SAM (CMV SAM), AS01 or with LNP carrier controls. Both CMV AS01 and CMV SAM resulted in a rapid MRI and PET signal enhancement in hindlimb muscles and draining popliteal lymph node reflecting innate and possibly adaptive immune response. MRI signal enhancement and total 18FDG uptake observed in the hindlimb was greater in the CMV SAM vs CMV AS01 group (↑2.3 – 4.3-fold in AUC) and the MRI signal enhancement peak and duration were temporally shifted right in the CMV SAM group following both Prime and Prime-Boost administration. While cytokine profiles were similar among groups, there was good temporal correlation only between IL-6, IL-13, and MRI/PET endpoints. Imaging mass cytometry was performed on lymph node sections at 72 hr post Prime and Prime-Boost vaccination to characterize the innate and adaptive immune cell signatures. Cell proximity analysis indicated that each follicular dendritic cell interacted with more follicular B cells in the CMV AS01 than in the CMV SAM group, supporting the stronger humoral immune response observed in the CMV AS01 group. A strong correlation between lymph node MRI T2 value and nearest-neighbor analysis of follicular dendritic cell and follicular B cells was observed (r=0.808, P

We consider a $2$-dimensional ordinary differential equation (ODE) depending on a parameter $\epsilon$. If the ODE is autonomous the supercritical Andronov–Hopf bifurcation theory gives sufficient conditions for the genesis of a repeller–attractor pair, made up by a critical point and a stable limit cycle respectively. We give assumptions that enable us to reproduce the analogous phenomenon in a non-autonomous context, assuming that the coefficients of the system are subject to fast oscillations, and have very weak recurrence properties, e.g. they are almost periodic (in fact we just need that the associated base flow is uniquely ergodic). In this context the critical point is replaced by a trajectory which is a copy of the base and the limit cycle by an integral manifold. The dynamics inside the attractor becomes much richer and, if one asks for stronger recurrence assumptions, e.g. the coefficients are quasi periodic, it can be (partially) analyzed by the methods of [M. Franca, R. Johnson, V. Muñoz-Villarragut, Discrete Contin. Dyn. Syst. Ser. S 9(2016), No. 4, 1119–1148]. The problem is in fact studied as a two parameters problem: we use $\epsilon$ to describe the size of the perturbation and $1/\mu$ to describe the speed of oscillations, but the results allows to set $\epsilon=\mu$.

Advanced LIGO and Advanced Virgo are monitoring the sky and collecting gravitational-wave strain data with sufficient sensitivity to detect signals routinely. In this paper we describe the data recorded by these instruments during their first and second observing runs. The main data products are gravitational-wave strain time series sampled at 16384 Hz. The datasets that include this strain measurement can be freely accessed through the Gravitational Wave Open Science Center at http://gw-openscience.org, together with data-quality information essential for the analysis of LIGO and Virgo data, documentation, tutorials, and supporting software.

The National Coastal Property Model (NCPM) simulates flood damages resulting from sea level rise and storm surge along the contiguous U.S. coastline. The model also projects local-level investments in a set of adaptation measures under the assumption that these measures will be adopted when benefits exceed the costs over a 30-year period. However, it has been observed that individuals and communities often underinvest in adaptive measures relative to standard cost-benefit assumptions due to financial, psychological, sociopolitical, and technological factors. This study applies an updated version of the NCPM to incorporate improved cost-benefit tests and to approximate observed sub-optimal flood risk reduction behavior. The updated NCPM is tested for two multi-county sites: Virginia Beach, VA and Tampa, FL. Sub-optimal adaptation approaches slow the implementation of adaptation measures throughout the 100-year simulation and they increase the amount of flood damages, especially early in the simulation. The net effect is an increase in total present value cost of $1.1 to $1.3 billion (2015 USD), representing about a 10% increase compared to optimal adaptation approaches. Future calibrations against historical data and incorporation of non-economic factors driving adaptation decisions could prove useful in better understanding the impacts of continued sub-optimal behavior.

Abstract Background A hospital culture that promotes and insures patient safety is a critical aspect for the effective delivery of hospital services and patient care. Yet there are significant patient health and safety issues in hospitals worldwide. This study aims to investigate doctors’ and nurses’ attitudes toward patient safety in the emergency departments (ED) of two Saudi hospitals. Method A cross-sectional survey using a validated Safety Attitudes Questionnaire (SAQ) was used. Total of 503 ED doctors and nurses completed SAQ. Correlation analysis, using Spearman’s Rho, was performed between the number of incidents reported and each dimension of the SAQ. Results The mean score of each SAQ dimension was

Background: Ecological models of physical activity posit that social and physical environmental features exert independent and interactive influences on physical activity, but previous research has focussed on independent influences. This systematic review aimed to synthesise the literature investigating how features of neighbourhood physical and social environments are associated with physical activity when both levels of influence are simultaneously considered, and to assess progress in the exploration of interactive effects of social and physical environmental correlates on physical activity. Methods: A systematic literature search was conducted in February 2016. Articles were included if they used an adult (≥15 years) sample, simultaneously considered at least one physical and one social environmental characteristic in a single statistical model, used self-reported or objectively-measured physical activity as a primary outcome, reported findings from quantitative, observational analyses and were published in a peer-reviewed journal. Combined measures including social and physical environment items were excluded as they didn’t permit investigation of independent and interactive social and physical effects. Forty-six studies were identified. Results: An inconsistent evidence base for independent environmental correlates of physical activity was revealed, with some support for specific physical and social environment correlates. Most studies found significant associations between physical activity and both physical and social environmental variables. There was preliminary evidence that physical and social environmental variables had interactive effects on activity, although only 4 studies examined interactive effects. Conclusions: Inconsistent evidence of independent associations between environmental variables and physical activity could be partly due to unmeasured effect modification (e.g. interactive effects) creating unaccounted variance in relationships between the environment and activity. Results supported multiple levels of environmental influence on physical activity. It is recommended that further research uses simultaneous or interaction analyses to gain insight into complex relationships between neighbourhood social and physical environments and physical activity, as there is currently limited research in this area.

Introduction: Safety attitudes have been investigated in a number of countries across different hospital departments, however there are few studies including Emergency Departments. Aim: To investigate doctors’ and nurses’ attitudes towards patient safety in Emergency Department in an Australian hospital. Materials and Methods: A cross-sectional research design was used. The participants included 51 doctors and nurses who completed a Safety Attitudes Questionnaire (SAQ) and reported the number of errors they had witnessed over the last year. Multivariate and univariate analysis was used to compare mean subscale scores of safety attitudes between doctors vs. nurses. Results: The findings showed doctors had comparatively positive safety attitudes compared to nurses, who rated teamwork climate, safety climate, unit management and work conditions particularly low. Both doctors and nurses had low opinions of hospital management and working conditions. Doctors and nurses with longer tenures and those who reported a higher number of medical errors had good safety attitudes. Conclusion: This study provides an insight into the safety attitudes of doctors and nurses employed in an Emergency Department in an Australian hospital. Further investigation into the relationship between safety attitudes, error rates and reporting should be performed in future studies.

Summary: TFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. Using C. elegans and mammalian models, we report that the master metabolic modulator 5′-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK confers pathogen resistance via activation of TFEB/TFE3-dependent antimicrobial genes, whereas ablation of total AMPK activity abolishes this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages is observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status with innate immunity. : El-Houjeiri et al. show that loss of FLCN or pharmacological activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory cytokine expression and phagocytosis in macrophages and confers pathogen resistance in C. elegans. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status to innate immunity. Keywords: TFEB, TFE3, FLCN, AMPK, innate immune response, pathogen resistance, autophagy, lysosomal biogenesis, phagocytosis

Worldwide deaths of children younger than 5 years reduced from 12.7 million in 1990 to 6.3 million in 2013. Much of this decline is attributed to an increase in the knowledge, skills, and abilities of child health professionals. In turn this increase in knowledge, skills, and abilities has been brought about by increased child-health-focused education available to child health professionals. Therefore child-health-focused education must be part of the strategy to eliminate the remaining 6.3 million deaths and to achieve the United Nations Millennium Development Goals. This article describes a child-health-focused program that was established in 1992 and operates in 20 countries: Australia, Bangladesh, Botswana, Cambodia, China, Ethiopia, Hong Kong, India, Kenya, Malawi, Mongolia, Myanmar, Sierra Leone, the Seychelles, the Solomon Islands, Tanzania, Tonga, Vanuatu, Vietnam, and Zimbabwe. The Diploma in Child Health/International Postgraduate Paediatric Certificate (DCH/IPPC) course provides a comprehensive overview of evidence-based current best practice in pediatrics. This includes all subspecialty areas from infectious diseases and emergency medicine through to endocrinology, respiratory medicine, neurology, nutrition, and dietetics. Content is developed and presented by international medical experts in response to global child health needs. Content is provided to students via a combination of learning outcomes, webcasts, lecture notes, personalized study, tutorials, case studies, and clinical practice. One hundred eleven webcasts are provided, and these are updated annually. This article includes a brief discussion of the value and focus of medical education programs; a description of the DCH/IPPC course content, approaches to teaching and learning, course structure and the funding model; the most recent evaluation of the DCH/IPPC course; and recommendations for overcoming the challenges for implementing a multinational child-health-focused program.

messenger RNA (mRNA)-based vaccines combine the positive attributes of both live-attenuated and subunit vaccines. In order for these to be applied for clinical use, they require to be formulated with delivery systems. However, there are limited in vivo studies which compare different delivery platforms. Therefore, we have compared four different cationic platforms: (1) liposomes, (2) solid lipid nanoparticles (SLNs), (3) polymeric nanoparticles (NPs) and (4) emulsions, to deliver a self-amplifying mRNA (SAM) vaccine. All formulations contained either the non-ionizable cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or dimethyldioctadecylammonium bromide (DDA) and they were characterized in terms of physico-chemical attributes, in vitro transfection efficiency and in vivo vaccine potency. Our results showed that SAM encapsulating DOTAP polymeric nanoparticles, DOTAP liposomes and DDA liposomes induced the highest antigen expression in vitro and, from these, DOTAP polymeric nanoparticles were the most potent in triggering humoral and cellular immunity among candidates in vivo.

This paper analyzes Kierkegaard’s scattered writings on communication to foreground the distinctively theological dimension of Kierkegaard’s rhetorical theory. “Indirect communication” needs to be understood as a strategy to address a specific theological problem, namely, the tendency for readers who think they are already Christian to dismiss or domesticate rhetoric that summons them to authentic Christian existence. Since Christianity is an “existence-communication,” the questions of what it means to be a Christian and how one can faithfully communicate Christianity are integrally linked for Kierkegaard. Contemporary apologists, activists, and preachers who rely on more direct modes of communication to express the Christian gospel have much to learn from Kierkegaard’s grappling with the illusions that beset Christian witness.

Despite growing interest in collective robotics over the past few years, analysing and debugging the behaviour of swarm robotic systems remains a challenge due to the lack of appropriate tools. We present a solution to this problem—ARDebug: an open-source, cross-platform, and modular tool that allows the user to visualise the internal state of a robot swarm using graphical augmented reality techniques. In this paper we describe the key features of the software, the hardware required to support it, its implementation, and usage examples. ARDebug is specifically designed with adoption by other institutions in mind, and aims to provide an extensible tool that other researchers can easily integrate with their own experimental infrastructure.

In the original published version of the article, Valerie Vancollie was mistakenly omitted from the list of members of the International Mouse Phenotyping Consortium. In addition, recognition of funding from Wellcome Trust grant WT098051 was mistakenly omitted from the Acknowledgements.The errors have been corrected in both the PDF and HTML versions of the paper.

Background: As a major zoonotic pathogen, characterization of the infectivity and pathogenicity of Coxiella burnetii is essential to understand Q-fever epidemiology. Objectives: We want to extend a recently published human dose response model based on experimental challenge of young adult males to include other age groups and both genders. Additionally, we can estimate the spatial distribution of exposure based on observed outbreak data. Methods: Dose response assessment based on human challenge, is extended by including outbreak data, using location of cases as a proxy for exposure. This allows estimation of the influence of age and gender on the probability of developing symptoms of acute respiratory illness. Results: In an outbreak in Switzerland, in 1983, exposure to C. burnetii was shown to depend strongly on distance from the source. The susceptibility of males to develop Q-fever decreases with age, while in females, middle-aged women appear to have the lowest risk. Conclusions: The published dose response model for Q-fever, based on experimental challenge of a small group of human volunteers, has been updated with data from a well studied outbreak. Infectivity estimates remain high, and even low doses (of 10 or fewer organisms) cause a high risk of illness.