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Heat stress illnesses, including heat stroke and heat exhaustion, represent a serious, persistent, and growing public health threat to military and civilian populations. Global climate change, due primarily to increased greenhouse gas concentrations in the atmosphere, has resulted in measured increases in temperature and humidity. Climate models project warming trends to continue in the future with very high confidence, resulting in more dangerous mean and extreme heat conditions. The associations between environmental heat indicators and observed adverse health outcomes have been increasingly studied for mortality endpoints and among elderly populations. This dissertation aimed to expand this investigation to heat illness morbidity outcomes among active-duty military servicemembers while assessing a range of heat indices. This is an assumed healthy, working-age population that is regularly exposed to outdoor heat in combination with high levels of exertion. Comparable civilian populations, in some respects, include athletes and outdoor laborers such as construction workers or farmers. In Chapter 2, we assessed annual rates of ambulatory encounters, hospitalizations, and reportable events among active-duty soldiers at ten US Army installations from 1991 to 2018 to produce rate ratios for estimation of future climate change impacts. In this chapter, we identified positive long-term associations between annual heat indices and heat stress illness hospitalization and reportable event outcomes. Chapter 3 assessed incident active-duty US military heat stress illness cases at 24 installations between 1998 and 2019 on a daily-scale, resulting in odds ratio exposure-lag-response curves applicable to near-term risk assessment. The daily-scale relationships betweenheat indices and case-defined heat stress illnesses were non-linear, with increasing odds ratios starting from mild temperature ranges, and displayed short-term delayed effects. Finally, Chapter 4 described demographic and body composition risk factor trends in the US military from 1998 to 2019. In this assessment, we identified a null trend for body mass index among heat stress illness subjects over the study period. Overall, our findings demonstrate a connection between temperature and humidity indicators and observed heat stress illness morbidity outcomes among multiple sets of indices and timescales. This dissertation highlights an urgent need for vigilant heat stress prevention and control measures to protect health and maintain performance in hot and humid environments.

Background: Stress-Related Exhaustion (SE) has increased in the last 10 years. Examination is key for good care, but research on body examinations for SE is lacking. Clinically, autonomic stress response with affected respiratory patterns can be observed in SE.  Global Body Examination (GBE) can be used to evaluate autonomic stress responses. GBE has a respiratory domain (rGBE) that has been tested for validity, but not for its intra-rater reliability. Moreover, its’ association with SE symptom severity is unknown. Aim: To examine intra-rater reliability of rGBE in SE, and concurrent validity between rGBE and symptom severity in SE, measured with the self-reported outcome measure Shirom-Melamed Burnout Questionnaire (SMBQ). Method: Test-retest and cross-sectional design was used in the study, with a sample of convenience. Intra-rater reliability was analyzed with ICC, standard error of measurement (SEM) and agreement through a Bland-Altman plot. Spearman’s rho was used to analyze correlation between SMBQ and rGBE. Result: Sample size was 25. Intra-rater reliability was very high (ICC: 0.94, 95% CI: 0.86-0.97, p<0.01). Bland-Altman plot revealed no systematic errors. Mean of rGBE: 7.51 (SD2.14) with SEM: 0.56. Correlation between rGBE and SMBQ was low, Spearman’s rho=0.48,95% CI: 0.09-0.74, p=0,02, with 22% shared variance. Conclusion: rGBE shows good intra-rater reliability and seems suitable for examining SE symptoms. However, its use in diagnostic and to determinate symptom severity in SE remains uncertain due to the wide CI. Beyond SE, rGBE might be useful for other disorders affecting the autonomic balance, as well as diseases that affect respiration. / Bakgrund: Utmattningssyndrom har ökat i samhället de senaste 10 åren. Undersökning är viktig för god rehabilitering men forskning gällande kroppsundersökningar saknas på utmattningssyndrom. Kliniskt har bland annat påverkat respirationsmönster observerats, som ett kroppsligt uttryck på autonom uppvarvning. Global Body Examination (GBE) är en undersökningsmetod som kartlägger autonom uppvarvning. GBE har en respirationsdomän (rGBE) som har testats för validitet, men inte för intrabedömarreliabilitet. Om ett samband föreligger mellan rGBE och besvärsgrad vid utmattningssyndrom är också okänt. Syfte: Att undersöka intrabedömarreliabilitet hos rGBE, samt den samtidiga validiteten mellan rGBE och självskattad besvärsgrad enligt Shirom-Melamed Burnout Questionnaire (SMBQ) hos individer med utmattningssyndrom. Metod: Test-retestdesign och tvärsnittsdesign användes i studien. Bekvämlighetsurval utfördes. Intrabedömarreliabilitet analyserades med ICC, standardmätfel och överenstämmelse via en Bland-Altman analys. Korrelationen mellan rGBE och SMBQ analyserades med Spearman’s rho. Resultat: Deltagarantalet blev 25. Intrabedömarreliabiliteten var mycket hög; ICC=0.94, 95% konfidensintervall 0.86-0.97, p<0.01. Bland-Altman analys visade inga systematiska mätfel. Medelvärde av rGBE blev 7.51 (SD 2.14) med standardmätfel på 0.56. Sambandet mellan rGBE och SMBQ var lågt; Spearmans's rho=0.48, 95% konfidensintervall 0.09-0.74, p=0.02. Samvariationen blev 22%. Slutsats: rGBE visar god intrabedömarreliabilitet och kan vara en lämplig undersökningsmetod för att observera utmattningssymtom. Inga säkra slutsatser kan dras gällande rGBEs användbarhet vid diagnostik eller besvärsgradering av utmattningssyndrom då konfidensintervallet blev brett. Utöver utmattningssyndrom kan rGBE troligen vara användbar vid besvär som påverkar den autonoma balansen, såväl som besvär som påverkar respirationen.

This study examined the extent of job-related burnout among Dallas County Community College Administrators. The levels of burnout among the participants were assessed with the Maslach Burnout Inventory (MBI). This questionnaire seeks to measure the frequency and intensity of the three components of burnout—emotional exhaustion, depersonalization and lack of a sense of personal accomplishment.

In brownfield regeneration models, extraction sites are often left out of the question because of degradation, severe contamination, or economic viability and are usually abandoned, after the minimal remediations. These exhaustions not only impact the environment and economy in spatial relations but also influence the growth of the communities cultured by them. With millions of abandoned sites around the globe, there is a demand for building a vision that develops - the ideas of emergence and diversification over time and space, as a base framework for similar towns and communities before they disappear. Underpinning the urgent need and evolving theme of ecologies, 'Reclaiming Kiruna' is an investigation of a vision for a post-exhaustion site of Kiruna mine, which is the world's largest underground mine, by developing landscape ecologies in the present framework that builds and adapts with time and space before the mine gets exhausted. The project reveals the concept of landscape as an amalgamation of production and recreation ecologies, synergizing with the existing potentials of nature, resources, and society. The work focuses on translating the knowns and unknowns of three time periods, synced with proposed plans of the New Kiruna settlement area, through programs of care and thinking that involve, engage, and encourage people (of Kiruna) in redefining the image of Kiruna beyond just a mine. The project unfolds new prospects offered by planned urban transformations, mining systems, and changing climate, which are integrated into building new economies and relations. The project is limited by the uncertainty of the future but attempts to initiate a dialogue in finding new positions as urban designers to contest with the present frameworks in building alternatives of change and novelty, for a sustainable future.

Cancer immunotherapy has gained attention in recent years for its successes in potentiating immune responses that can elicit tumor control. In particular, adoptive cell therapy (ACT), which involves the autologous/allogeneic transplant of ex vivo-cultivated tumor-specific T lymphocytes, can mediate potent tumor recognition and killing; however, durable clinical responses are often difficult to obtain in solid tumors. Solid tumors and their unique microenvironments have the capacity to evade and suppress antitumor immune responses and represent significant hurdles for effective ACT. Recently, we have discovered that chemical inhibition of histone deacetylases via MS-275 (Entinostat) during ACT can subvert tumor resistance to foster potent, broad-spectrum antitumor immunity. Overall, the work described supports the efficacy of ACT in the treatment of immunosuppressive, solid tumors; however, consistency in durable clinical outcomes can only be achieved through the concurrent therapeutic targeting of tumor resistance mechanisms. This thesis uses pre-clinical models to describe how tumor resistance to ACT can manifest, and demonstrates that concurrent MS-275 delivery drives extensive immunomodulation to promote sustained tumor clearance. This includes: 1) The polarization of tumor-infiltrating myeloid cells into cytotoxic effectors with the ability to reject immune escape variants 2) The inflammatory remodeling of the tumor microenvironment to potentiate epitope spreading against secondary tumor antigens 3) The transcriptional reprogramming of adoptively transferred T cells to overcome tumor-burden-dependent exhaustion We expect that the results will help facilitate the development of next-generation ACT platforms that will feature strategies for multi-mechanistic perturbation of tumor resistance. / Thesis / Doctor of Philosophy (PhD) / The host immune system has the ability to recognize and destroy tumor cells. Therapeutic platforms that leverage antitumor immune cells, specifically T cells, have shown potency in the elimination of cancer. In the clinic, cancer immunotherapies have demonstrated early success against hematological malignancies; however, are unreliable in the treatment of solid tumors. Solid tumors utilize intrinsic and adapted mechanisms of resistance to mitigate the effectiveness of cancer immunotherapy. This thesis pursues research questions aimed at understanding how tumors resist immunotherapy, what mechanisms are utilized, and how to overcome these obstacles. We anticipate that these results will contribute to the development and incorporation of strategies to subvert tumor resistance and potentiate T cells against solid tumors.

Les interactions neuro-immunitaires entre les systèmes sensoriels et immunitaires ont été abondamment étudiées; cependant, leur rôle dans la régulation des cancers est encore mal connu. Les interactions croisées entre les cytokines, les facteurs de croissance et les neuropeptides peuvent promouvoir la progression des tumeurs. Les neuropeptides libérés par les nocicepteurs peuvent affecter la polarisation, la chimiotaxie et l'activité du système immunitaire acquis. Étant donné que les neurones sensoriels libèrent localement des neuropeptides qui modulent l'activité des lymphocytes, nous faisons l'hypothèse que les nocicepteurs sécrètent des neuropeptides qui induisent l'épuisement des cellules T CD8 et la croissance tumorale. L’épuisement des lymphocytes T CD8 est un phénomène observé dans le cadre d’infections chroniques et de cancers. Elle est définie comme une perte de la fonction effectrice des lymphocytes T CD8 (diminution de la production d'IFN-γ, de TNF-α et d'IL-2) ainsi qu'une expression élevée de récepteurs inhibiteurs tels que PD-1 (protéine 1 de mort cellulaire programmée), LAG-3 (gène 3 d'activation des lymphocytes) et TIM-3 (protéine 3 d'immunoglobuline des lymphocytes T et de contenant du domaine mucine). Nous avons utilisé le modèle murin de mélanome pour tester cette hypothèse et avons observé que les cellules malignes de cancer de la peau B16F10 interagissent avec les nocicepteurs pour promouvoir la croissance des neurites, la sensibilité aux ligands activateurs et la libération de neuropeptides. En conséquence, le peptide lié au gène de la calcitonine (CGRP), qui est libéré par les nocicepteurs, augmente directement l'épuisement des cellules T CD8 et réduit leur capacité à éliminer les cellules du mélanome. L'ablation génétique des neurones sensoriels, leur inhibition pharmacologique ou le blocage du récepteur au CGRP (RAMP1) suffisent à limiter l'épuisement des lymphocytes infiltrés dans la tumeur et la croissance tumorale. De plus, l'injection de CGRP recombinant dans des souris dépourvues de neurones sensoriels réduit l'épuisement des cellules T CD8. Les cellules T CD8 RAMP1-/- montrent aussi moins d'épuisement que leurs homologues sauvages lorsqu'elles sont co-transplantées dans des souris immunodéficientes Rag1-/- portant une tumeur. En résumé, réduire la libération de CGRP en bloquant localement les nocicepteurs associés à la tumeur limite les effets immunomodulateurs de CGRP sur les cellules T cytotoxiques CD8 et représente une stratégie d'intérêt pour protéger l'immunité antitumorale. / Neuroimmune crosstalk between the nervous and the immune systems has been widely studied; however, their modulating roles are largely unknown in cancer. Bilateral interactions of cytokines, growth factors and neuropeptides may support tumor progression. Nociceptor-released neuropeptides can affect polarization, chemotaxis and adaptive immune system activity. Since sensory neurons locally release neuropeptides that modulate the activities of lymphocytes, we hypothesized that nociceptors might secrete neuropeptides leading to CD8+ T-cell exhaustion and tumor growth. CD8 T cell exhaustion is a phenomenon observed in the context of chronic infections and cancer. It is defined as loss of effector function of CD8 T cells (decreasing the production of IFN-γ, TNF-α, and IL-2) as well as high expression of inhibitory receptors such as PD-1 (programmed cell death protein 1), LAG-3 (lymphocyte-activation gene 3), and TIM-3 (T-cell immunoglobulin and mucin domain-containing protein 3). We used the mouse model of melanoma cancer to test this hypothesis and found that malignant B16F10 skin cancer cells interacted with nociceptors to expand neurite outgrowth, responsiveness to noxious ligands, and neuropeptide release. Consecutively, neuropeptide calcitonin gene-related peptide (CGRP), which is released by nociceptors, directly increased the exhaustion of cytotoxic CD8+ T cells and reduced their ability to eliminate melanoma cells. Genetic ablation of sensory neurons, local pharmacological silencing, and antagonism of the CGRP receptor (RAMP1) were all able to limit the exhaustion of tumor-infiltrating lymphocytes (TIL) and tumor growth. Moreover, treatment with recombinant CGRP in sensory neuron- depleted mice reduced the exhaustion of CD8+ T cells. Compared with wild-type cells, RAMP1-/- CD8+ T cells were rescued to go under exhaustion when co-transplanted into tumor-bearing Rag1-/- deficient mice. In summary, reducing CGRP release by local silencing of tumor-associated nociceptors, limits the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells and represents an ideal strategy to protect anti-tumor immunity.

Bakgrund Digital vård är ett växande fenomen trots en begränsad forskningsbas. Det tycks finnas en kunskapslucka när det gäller upplevelsen av digifysisk och digital fysioterapi vid psykisk ohälsa i allmänhet och vid utmattningssyndrom i synnerhet. Det finns riktlinjer om användning av personcentrerad vård och kommunikation i vården för att skapa en god upplevelse av vård. Syftet med studien var att från ett patientperspektiv undersöka upplevelsen av digifysisk fysioterapi under ett rehabiliteringsprogram för utmattningssyndrom. Metod En kvalitativ innehållsanalys användes i studien. Tio personer rekryterades genom strategiskt urval. De hade alla fått diagnosen utmattningssyndrom och behandlats multidisciplinärt och delvis digitalt på en klinik i Stockholm. Semistrukturerade intervjuer genomfördes och analyserades med kvalitativ innehållsanalys. Resultat Analysen resulterade i fem kategorier, som i korthet lyder: Digital fysioterapi underlättade deltagandet, De fysiska mötena var en förutsättning för digital fysioterapi, Faktorer som påverkade digitala möten med fysioterapeut, Digitala verktyg/IT i rehabilitering - utmaningar och fördelar, Kombinationen av digital och fysisk fysioterapi uppskattades och upplevdes ha god effekt. I kategorierna framkom elva underkategorier som visade olika aspekter av de övergripande kategorierna. Slutsats Digital fysioterapi ihop med fysiska besök upplevdes positivt av deltagarna trots låga förväntningar på behandlingsformen inledningsvis. I digitala möten är värdet av fysioterapeutens bemötande och närvaro av stor vikt vilket underlättades av att förtroende skapades i de fysiska gruppbesöken. Vidare var fysiska gruppbesök av stor vikt för erfarenhetsutbyte, kommunikation och stöttning. För ökad användarvänlighet ses behov av att förenkla och utveckla tekniska lösningar och att möjliggöra digitala gruppbesök. / Background Digital care is a growing phenomenon despite a limited research base. There seems to be aknowledge gap regarding the experience of digi-physical and digital physiotherapy for mental illness in general and for exhaustion disorder in particular. There are guidelines on the use of person-centered care and communication in care to create a good experience of care. The purpose of the study is, from a patient perspective, to examine the experience of digi-physical physiotherapy during a rehabilitation program for exhaustion disorder. Method Qualitative research method with content analysis was used in this study. Ten persons were recruited through strategic sampling. They were all diagnosed with exhaustion disorder and treated multidisciplinary and partly digital at a clinic in Stockholm. Semi structured interviews were conducted and analyzed. Results The analysis resulted in five categories, that in short are: Digital physiotherapy facilitated participation, The physical meetings were a prerequisite for digital physiotherapy, Factors that influenced digital meetings with physiotherapist, Digital tools/IT in rehabilitation -challenges and benefits, The combination of digital and physical physiotherapy was appreciated and perceived to have good effect. In the categories, eleven subcategories emerged that showed different aspects of the overall categories. Conclusion Digital physiotherapy can be valuable in combination with physical meetings to patients with exhaustion disorder despite low expectations initially. In digital meetings, the value of the physiotherapist's treatment and presence is of great importance, which was created at physicalgroup visits. The physical group visits were of great importance for the exchange of experience, communication and support. For increased user-friendliness, there is a need to simplify technical solutions and to enable group visits digitally.

從「迷樓」的敘事研究可投射出「享樂」與「匠藝」的兩大圖像。本論文的論述分成兩個層次，一個層次從唐宋期間各種不同類型的文本和文體來探討「迷樓」典故中的欲望與當時的話語現象的關係，涵蓋唐宋時二元對立的一系列價值如節制／放縱、儉／奢、自然／人工。另一個層次則是以「迷樓」的欲望與技術，來比擬文學創作意識中的欲望與技巧的問題，後者觸及詩學中的自然風格與人工技術或「工巧」之間的辯證關係。 迷樓不見於任何官方正史及私家撰述的史籍，它主要見於詩、詞、賦、小說逸史、方志和筆記或札記。根據方志，揚州被認為位於揚州，但在文學作品中，卻有迷樓位在揚州、長安、洛陽之說，本文認為，從唐宋詩詞的空間意象來看，迷樓其實更近於一種散佈於汴淮流域的想像空間，顯見「迷樓」有傳聞異辭的性質。雖然這篇論文有探究方志與文學文本中迷樓地點所在的問題，然而目的並非志在斷定迷樓「實體」存在與否、或存在於何處，而是在提供一種背景來理解唐宋時期人們對迷樓所在的認同差異與相關的空間敘述。 根據小說《迷樓記》的敘述，迷樓是煬帝所建的一座結構宛若迷宮的宮殿，它也是一個承載「極樂」想像的空間。「極樂」在宋代的養身論與主張節制的話語之中是需被抑制的一種禁忌。故此，有關「迷樓」中的「極樂」敘述是在尋回如同拉康所言的某種早已被排除出去的「愛欲」或原初已經失落的「歡爽」，人們對這種「極樂」的境界充滿想像，對於「極樂」的渴求威脅著主體賴以生存的經濟制度與權力體制乃至耗竭個人的身體。在此也參考巴塔耶的色情史理論，來說明主體也會渴求某種迷失自我的欲望。本文也將隋煬帝在迷樓內「浪費的技術」（即同時耗損自身精氣、浪費「發明」的技能、揮霍國家的財富）也延伸到詩學裡詩歌藝術裡一種創作技術上的魅力，來回扣宇文所安《迷樓：詩與欲望的迷宮》中以迷樓作為論述結構的「比擬」。本文也試圖以「迷樓」來「比擬」唐宋期間勾連自然與技巧的文學觀念，詩人為此心搖神馳，對文學技巧追求完美的「欲望」，使得欲望從現實空間「逃遁」到文學空間裡來，追求天工般技巧所造的詩境。 中國人傾向於將政權興亡與自然現象互比相連，使得興、亡循環成為必然發生且無可避免的現象，這種對於興亡循環有其必然性的觀念反而削弱了諷喻文學規勸帝王的實質功能。這正是迷樓作為諷喻的典故所盤結的重重矛盾與衝突之所在。意識到「諷喻」在啟悟他人功能上的侷限，詩歌作為高度創作與獨立自足的藝術性質更受重視，如唐宋詩學中有頗多詩話與詩評大量闡述詩歌創作的理想，崇尚以不鑿痕跡的技巧，來達到完美「自然」的詩境。 在唐宋兩代，可以發現在歷史處境的衝擊下，迷樓典故亦有所衍異，並被詩人加以部署以訴說個人的生命情境。唐宋兩代旅人在揚州岸外的長江與運河水道上曲曲折折的移動經驗，這種移動經驗也賦予迷樓遺址特殊的意象，無論是在遠離或接近揚州，蜀岡上的迷樓遺址都被包裹在迂回曲折的路線地圖裡，從迂迴到昇華，迷樓成為想像中登高地點的所在。在有意託諷之下，迷樓的敘事並不純粹只是過往歷史的回顧，同時也是當代歷史的指涉。 除了作為社會性敘事的諷喻功能之外，本論文最後也在兩個層次上回扣宇文所安以迷樓作為文學論述與詩學上的「比擬」：一、迷樓作為個體欲望縷織下與群體相隔離的藝術空間；二、傳聞中迷樓是一座在技術上巧奪天工的宮殿，在詩歌中「迷樓」經常被強調作為一種人工成果，與自然對立。通過這種自然──天工對比的論述，本文也嘗試指出迷樓足可比擬文學裡透過崇尚自然風格征服人工鑿痕的觀念。 / Through the variety of texts and genres from Tang to Sung, the narration of “Milou” had projected the figure of pleasure and exquisite craftwork. The inquisitions of this essay consist of two layers. First, to addresses the relation of the desire and the discursive phenomena at the time of Tang to Sung, especially on the binary aspect of temperance and pleasure, frugality and luxury, nature and craftsmanship. Secondly, to mate the dazzling craftwork of Milou correspondent with the desire and pleasure of the attentive craftwork in literary world, in which the dialectical relation between the Nature and craftsmanship was deeply concerned. Neither the official nor the private historical texts have any record on Milou. However, the allusion and narration of Milou was found in variety of texts including poets, rhapsodies, lyrics, novels, geographical documents and notes. According to the novel “The Tales of Milou”(Milou Ji, 迷樓記), Milou was a labyrinthine palace built by Shui Yang Ti, a space loaded with the imagination of “utmost enjoyment”(Ji Le, 極樂). The utmost enjoyment had been known as a forbidden state in the discourse on regimen, it was also considered as a dangerous force which threatening to the nation. The inquisition of “utmost enjoyment” has been linked to the “technique of waste”, which provoke the exhaustion of the King’s body, and also the waste of accumulative wealth of the kingdom, and brought huge chaos and doom to the dynasty. My argument of the “technique of waste” has extended to the discussion of creative technique involved in literary writing, which had been gaining a lot of attention in late-Tang and Sung, poets were aware of the poor efficacy of “critical allegory” (feng yu諷喻) due to the paradox of flourish and fading which had been seen as nature mechanism, as has been pointed out by Stephen Owen. Poetry had gained its own sovereignty; poetic commentators had discussed the technique of creation enthusiastically and pursued for the perfect poetic scene(境). There are two layers of discussion which closely interrelated with each other: 1. Milou was a symbol of pleasure and crafty achievement, and thus contradictory to the Nature. 2. This essay has further elaborated the relation of the crafty image of Milou with the “clever technique” (巧工) in the poetic notion from Tang to Sung. However, to achieve perfect work for poetry that look like the work of nature(天工), it definitely had to be created through superb technique that can smooth away any crafty traces.