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Introduction: Improvements in the delivery of intensive care have led to a growing number of children with chronic medical conditions at significant risk of recurrent and prolonged critical illness. These patients are increasingly described as having pediatric chronic critical illness (CCI). To date, pediatric CCI is without an accepted consensus case definition. Objective: To evaluate how pediatric CCI has been defined in the current literature, including the concept of prolonged PICU admission, and describe the methodologies used to develop any existing definitions. Secondary aims included describing patient characteristics and outcomes evaluated in included studies. Methods: We searched four electronic databases for studies evaluating children identified with “CCI.” We also searched for studies describing prolonged PICU admission, as this concept is related to pediatric CCI. We developed a hybrid crowdsourcing and machine-learning (ML) methodology to complete citation screening. Screening and data abstraction were performed by two reviewers, independently and in duplicate. We completed data abstraction including details of population definitions, demographic and clinical characteristics of children with CCI, and outcomes evaluated. Results: Twenty-eight reviewers from 11 countries performed citation screening, with a mean sensitivity of 92%. Of 24,729 unique citations assessed for eligibility, 453 full-texts were reviewed and 67 studies were included. Of these, 12 studies (18%) defined CCI, most commonly by a prolonged PICU length of stay (LOS), either in isolation or in addition related to medical complexity patient characteristics and/or readmissions rate. The concept of prolonged PICU admission was defined in an additional 55 (82%) studies by a median of 14 days (range, 1 day-6 weeks). Conclusion: To our knowledge, this scoping review provides the most comprehensive epidemiologic evidence addressing pediatric CCI. Our results suggest a uniform consensus definition is needed in order to advance this emerging and important area of pediatric critical care research. / Thesis / Master of Science (MSc)

This dissertation is comprised of three essays, the goals of which are to provide an empirical understanding of how the income-health relationship evolves with child age and the underlying mechanisms. Previous research, conducted in US and Canadian settings, has found a positive association between household income and child health, which strengthens with age. One reason for this relationship may be that low-income children are more likely to suffer from chronic conditions than high-income children. While US research has controlled for the effects of parental health when examining the gradient, Canadian work has not. In Chapter 1, we seek to determine whether the Canadian findings persist after controlling for parental health status. Our results show that this adjustment reduces the size of the gradient in childhood and, importantly, indicates that it does not increase with age. In Chapter 2, we contribute to this literature by applying more flexible estimation techniques, namely nonparametric models, to understand the gradient in childhood. Our results provide evidence that our nonparametric model is closer to the true data generating process than the parametric model. Furthermore, our estimates confirm that the gradient does not increase with age, regardless of whether we control for parental health. In Chapter 3, we examine the relationship between family income, chronic conditions and child health. Generally, our results suggest that income does not have a significant impact on chronic conditions. Furthermore, we do not find the effect of chronic conditions on the probability of being in poor health differs by income levels, with the exception of asthma and mental handicap. / Thesis / Doctor of Philosophy (PhD)

Bakgrund: Långvarig smärta innebär stort lidande för individen. Multimodal rehabilitering har positiv påverkan på långvarig smärta, men det är ej känt vilken multimodal rehabilitering som är effektivast. Ökad kunskap om vilka delar i smärtrehabilitering som gör nytta är viktigt för att kunna optimera vården. Syfte: Syftet med studien var att undersöka kroppsmedvetenhet, tilltro till egen förmåga att vara fysiskt aktiv och självskattad fysisk aktivitetsnivå för personer med långvarig smärta samt att undersöka om dessa variabler förändrades av multimodal smärtrehabilitering. Syftet var även att undersöka korrelationen mellan kroppsmedvetenhet och tilltro till egen förmåga att vara fysiskt aktiv. Metod: Studien hade en deskriptiv, korrelerande kvasiexperimentell design. Patienter med långvarig smärta som vårdades inneliggande för ett 4 veckors långt multimodal smärtrehabiliteringsprogram besvarade direkt före och efter rehabiliteringen frågeformulären Multidimensional Assessment of Interoception Awareness (MAIA) och Exercise Self-efficacy Scale (S-ESES) samt Socialstyrelsens indikatorfrågor för fysisk aktivitet. Resultat: Tjugofem personer deltog i studien. Interventionen ökade vissa dimensioner av kroppsmedvetenhet samt tilltron till egen förmåga att vara fysiskt aktiv. Den självskattade fysiska aktivitetsnivån var låg och ökade ej efter interventionen. Korrelationen mellan MAIA och S-ESES var statistiskt signifikant efter interventionen. Konklusion: Multimodal smärtrehabilitering kan öka kroppsmedvetenhet och tilltro till egen förmåga att vara fysiskt aktiv för personer med långvarig smärta. / Background: Chronic pain implies a big suffering for individuals. Multimodal rehabilitation has a positive impact on chronic pain, but it is unknown which rehabilitation that is the most effective. Increased knowledge of which parts in pain rehabilitation that are effective is important to be able to optimize the care of these individuals. Purpose: The purpose of this study was to investigate interoception, exercise self-efficacy and level of self-assessed physical activity in people suffering from chronic pain and explore if these variables are changed by multimodal pain rehabilitation. The purpose was also to investigate the correlation between interoception and execise self-efficay. Method: The study had a descriptive, correlating experimental within-group design. Patients with chronic pain that were enrolled for inpatient care 4 weeks of multimodal pain rehabilitation answered the questionnaires Multidimensional Assessment of Interoception Awareness (MAIA) and swedish version of Exercise Self-Efficacy Scale (S-ESES) and the Swedish social welfare boards indicator questions of level of physical activity before and after the intervention. Results: Twenty five persons participated in the study. The intervention increased some dimensions of interoception and the exercise self-efficacy. The self-assessed level of physical activity was low and did not increase. The correlation between MAIA and S-ESES was strengthened by the intervention. Conclusion: Multimodal pain rehabilitation can for people with chronic pain increase interoception and exercise self-efficacy.

Dysregulation of low-voltage-activated calcium channels (CaV3.1-CaV3.3) underlies diseases including chronic pain, autism, and hypertension. As a major determinant of protein half-life, the ubiquitin-proteasome system (UPS) may not only cause abnormal CaV3 expression but also be targeted to control channel levels for therapy. There are >600 E3 ubiquitin ligases that catalyse the final step in ubiquitination. A crucial aspect of harnessing the UPS is knowing which E3 ligases regulate a given substrate, and whether their actions are redundant. We report that CaV3.1 and CaV3.2 are distinctively regulated by two NEDD4 family E3 ligases – NEDD4L and Smurf1. Reconstituted CaV3.1 currents were robustly suppressed by Smurf1 but not NEDD4L, whereas CaV3.2 was inhibited by both NEDD4L and Smurf1, concomitant with diminished channel surface density and expression. FRET experiments revealed NEDD4L and Smurf1 interact with distinct loci in CaV3.1 and CaV3.2. Nanobody-mediated targeting of NEDD4L or Smurf1, but not WWP1, HECT domains to CaV3.1 and CaV3.2 strongly suppressed currents through both channels. shRNA knockdown of either NEDD4L or Smurf1 in dorsal root ganglion (DRG) neurons substantially increased both low-voltage and high-voltage-activated calcium channel currents. The results reveal non-redundant regulation of CaV3 channels by NEDD4L and Smurf1; introduce Smurf1 as a potent determinant of ion channel expression; suggest a new mechanism for CaV3.2 up-regulation in chronic pain; and advance leveraging the UPS to control CaV3 expression for therapy.

Opioid misuse and addiction constitute a significant public health challenge in the 21st century, with opioids involved in the majority of drug overdose deaths since 1999. A vigorously researched area that contributes substantially to the opioid misuse and addiction challenge is pain. The impact of pain, however, on important health outcomes for individuals in recovery from opioid use is less well understood. The effects of pain on substance use and mental health outcomes was investigated among individuals in recovery from opioid use disorder. Two studies are reported. First, the relationships between pain status and severity on substance use, treatment utilization, and mental health outcomes (e.g., depressive symptoms) was characterized cross-sectionally. Second, subgroups of OUD recovery defined by depression, opioid withdrawal, and pain were identified. Relationships between recovery subgroups, OUD symptoms, remission, opioid use, and quality of life were assessed. Finally, transitions among subgroups across 4 years of recovery were characterized. The present findings support pain as a key dimension of opioid use disorder recovery, highlighting the distinction between acute and chronic pain, the dynamic nature of opioid use disorder recovery, and emphasizing the necessity of integrating pain into opioid use disorder treatment. / Doctor of Philosophy / Misuse of and addiction to opioids is a significant health challenge. Pain has played a central role in facilitating the opioid epidemic in the United States, but the impact of pain on substance use and mental health outcomes for individuals in recovery from opioid use is less well understood. The following two studies investigated how pain affects substance use and mental health outcomes among individuals in recovery from opioid use disorder. Study 1 examined how different types of pain (chronic pain, acute pain, no pain) affect substance use, treatment use, and mental health measures (e.g., depression, quality of life). Study 2 investigated the role that depression, opioid withdrawal, and pain have in defining different groups in opioid recovery. Together these studies support pain as an important factor in OUD recovery, highlight the distinction between acute and chronic pain, emphasize the importance of integrating treatment for opioid use disorder and pain, and demonstrate that opioid use disorder recovery is a dynamic process with individuals transitioning among different recovery groups over time.

Climate change is anticipated to raise overall temperatures in the twenty-first century and is likely to intensify population exposure to heat during the warm season and, as a result, increase the risk of heat-related illnesses and deaths. While earlier studies of heat exposure and related health impacts generally focused on the acute effects of short-term exposure indicated by high daily temperature or several days of very hot weather, recent research has suggested that small changes in seasonal average temperature over a long period of time is likely to pose significant health risk as well. Using downscaled climate projections under three Representative Concentration Pathways emission scenarios, high-spatial-resolution population data, and the latest population projections by the United Nations, we aim at projecting future changes in long-term population exposure to summer heat across China in the mid- and late-twenty-first century resulting from global climate change. As the impacts of population growth are often overlooked in projecting future changes in heat exposure, we estimated changes in population-weighted average temperature in the warmest quarter over two future 20-year time periods and compared them with changes in temperature only. Our analysis shows that, nationally, population-weighted average temperature in the warmest quarter is projected to increase by 2.2 °C relative to the current situation in the 2050s and by 2.5 °C in the 2070s, as the result of climate change and population growth. Despite the foreseeable population stabilization in China, changes in population-weighted temperature are projected to be higher than changes in temperature itself for the majority of the 33 provinces (ranging from 0.02 °C to 1.27 °C, or 1% to 126% higher in the 2050s and from 0.02 °C to 1.16 °C, or 1% to 73% higher in the 2070s), with the largest differences mainly occurring in Western China. The impact of urbanization is projected to be relatively insignificant. Our findings provide evidence of possible underestimation of future changes in long-term exposure to summer heat if the effect of population growth is not factored in.

Background: The opioid epidemic in the United States has been on the rise. Acute exacerbations of chronic pancreatitis (AECP) patients are at higher risk for Opioid Use Disorder (OUD). Evidence on OUD's impact on healthcare utilization, especially hospital re-admissions is scarce. We measured the impact of OUD on 30-day readmissions, in patients admitted with AECP from 2010 to 2014. Methods: This is a retrospective cohort study which included patients with concurrently documented CP and acute pancreatitis as first two diagnoses, from the National Readmissions Database (NRD). Pancreatic cancer patients and those who left against medical advice were excluded. We compared the 30-day readmission risk between OUD-vs.-non-OUD, while adjusting for other confounders, using multivariable exact-matched [(EM); 18 confounders; n = 28,389] and non-EM regression/time-to-event analyses. Results: 189,585 patients were identified. 6589 (3.5%) had OUD. Mean age was 48.7 years and 57.5% were men. Length-of-stay (4.4 vs 3.9 days) and mean index hospitalization costs ($10,251 vs. $9174) were significantly higher in OUD-compared to non-OUD-patients (p < 0.001). The overall mean 30-day readmission rate was 27.3% (n = 51,806; 35.3% in OUD vs. 27.0% in non-OUD; p < 0.001). OUD patients were 25% more likely to be re-admitted during a 30-day period (EM-HR: 1.25; 95%CI: 1.16–1.36; p < 0.001), Majority of readmissions were pancreas-related (60%), especially AP. OUD cases’ aggregate readmissions costs were $23.3 ± 1.5 million USD (n = 2289). Conclusion: OUD contributes significantly to increased readmission risk in patients with AECP, with significant downstream healthcare costs. Measures against OUD in these patients, such as alternative pain-control therapies, may potentially alleviate such increase in health-care resource utilization.