The accumulation of pro-inflammatory macrophages in the inflamed vascular wall is a critical step in atherogenesis. The mechanism of macrophage retention within the site of inflammation is not understood yet. High adhesion that prevents macrophage migration is one of the potential mechanisms. Previous research in our laboratory showed that integrin αDβ2 is upregulated on pro-inflammatory macrophages, promotes macrophage retention, and contributes to atherogenesis. However, a key ligand for αDβ2 within the tissue is yet to be identified, since αDβ2 does not interact with major ECM proteins, collagens, and laminins. We recently found that during acute inflammation, the oxidation of docosahexaenoic acid (DHA) leads to the generation of end product carboxyethylpyrrole (CEP), which forms an adduct with fibrinogen and albumin via ε-amino group of lysines. There is evidence that macrophages adhere to CEP-modified albumin in αDβ2-dependent manner. We continued the advancement of the proposed hypothesis that non-conserved, basic amino acids of integrin αDβ2 located near the MIDAS site of the I-domain are responsible for binding to CEP. αD I-domain and generated I-domain mutants: H272(D), K297(Q) and K309(N) were used to map the ligand binding site between integrin and CEP. Using site-directed mutagenesis, mutant αD I-domains were generated with minimal amino acid substitutions. Protein-protein binding reveals that the generated mutation of K297(Q) on the I-domain demonstrates the strong reduction of binding, while H272(D) and K309(N) did not have a significant effect on integrin binding properties. Therefore, lysine 297 located in I-domain of integrin αD, is a critical amino acid for αDβ2 binding to CEP-modified proteins. The identification of a binding site for CEP-modified proteins within αDβ2 will help to develop a blocking reagent for the treatment of the inflammatory component of atherosclerosis.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The risks for women increase at the onset of menopause. A central feature in CVD patients is excessive sympathetic stimulation of beta-adrenergic receptors (β-ARs). Both clinical and animal studies show that estrogen loss and age exacerbate cardiac β-AR signaling and contractile function. We, therefore, examined the hypothesis that prolonged estrogen deficiency followed by chronic sympathetic injury worsens left ventricular cardiac function in the aged female heart. Bilateral ovariectomy (OVX) or SHAM surgery was performed in female mice at 2.5 months of age and infused with Isoproterenol (ISO; 400μg/kg/h) at 12 months (12M) post OVX for 3 days to induce chronic sympathetic stimulation. Transthoracic two-dimensional M-mode echocardiography was used to measure left ventricular (LV) wall thickness and left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), percent fractional shortening (%FS), and ejection fraction (EF). Animal body weight was measured to calculate the heart-body ratio, followed by the removal of the heart, left lung, and uterus during euthanasia. Tissue samples were treated with wheat germ agglutinin staining to measure cardiac myocyte cross-sectional area (hypertrophy). Results show that prolonged ovariectomy increased mortality in mice treated with ISO post-ovariectomy (OVX +ISO) compared to the SHAM+ISO group. Echocardiography imaging demonstrated a smaller systolic diameter and increased contractility in the ISO and ISO+OVX groups. OVX, ISO, and ISO+OVX treatment had a significant decrease in LVESD versus SHAM and OVX groups. The LVEDD resulted in a significant decrease with ISO treatment compared to the SHAM group, and no significant difference was observed between the OVX and ISO+OVX groups compared to the SHAM. Percent FS presented a significant increase in cardiac function in OVX, ISO, and ISO+OVX groups compared to the SHAM. There was an increased %FS in the ISO+OVX compared to the OVX group, and no significant difference between the ISO+OVX and ISO treatment groups. Percent EF significantly increased in the OVX, ISO, and ISO+OVX treatment groups from the SHAM and OVX group, and no significant difference between the ISO+OVX and ISO treatment groups. OVX increased left ventricular mass compared to SHAM. While ISO treatment did not increase LV mass ISO+OVX treatment group significantly increased in LV mass when compared to the ISO treatment group. There was no significant difference in the left ventricular mass between the ISO+OVX vs. OVX group. There was no significant difference in cardiac myocyte cross-sectional area in the SHAM, OVX vs ISO groups. There was however a significant increase in myocyte cross-sectional area in the ISO+OVX group compared to OVX treatment and ISO groups. The results presented here show that estrogen loss impairs left ventricular cardiac function and increases remodeling in response to β-AR stimulation and that prolonged estrogen loss may blunt the sympathetic response in the heart. These results highlight the importance of the long-term effects of estrogen loss during menopause in the treatment and management of heart disease.

Magister Public Health - MPH / Chronic non-communicable diseases (NCDs) have not received adequate attention in Eswatini (formerly Swaziland) due to the high burden of HIV/AIDS, tuberculosis and other communicable diseases. However, in 2019, NCDs were estimated to account for 45.86% of all deaths in the country with cardiovascular diseases, diabetes mellitus and chronic respiratory conditions amongst the top ten causes of death. Persistent shortages of medicines in public health facilities in Eswatini have been observed resulting in patients purchasing their medicines from private retail pharmacies.

Thesis advisor: Susan Roberts / The young adult fiction classification features a number of novels that center on the experience of chronic illness in children. This thesis examines the subgenre known as “sick-lit” and its use of illness and gender as themes. Through this study, a repetitive narrative of a beautiful teenage girl falling ill becomes clear. When examined in context, this trope can be traced through several of the most popular “sick-lit” publications. This project is comprised of four chapters, each of which focuses on a specific work, series, or author: Little Women, The Baby-Sitters Club, Lurlene McDaniel, and The Fault in Our Stars. Fleet argues that the representation of these characters is a complex narrative that does not align with the lived experience of chronically ill girlhood while still containing a degree of truth. / Thesis (BA) — Boston College, 2022. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: English.

Background: There are many individuals living with chronic illness and therefore follow one or more prescribed drug therapies. It is shown that over 50 percent of these are not adherent to their prescriptions and that low adherence is a growing problem across the world. Earlier research indicates that low adherence leads to decreased health and reduced quality of life. Aim: The aim was to find factors affecting adherence among individuals with chronic illness. Method: A literature study based on empirical qualitative research. The articles were analysed in accordance with Friberg's five step model. Results: Four categories emerged from the analysis of the articles; personal factors, social factors, health care factors and therapy related factors. Individuals' adherences depend on different internal and external factors. Individuals' own ability to follow routines were the most appearing factor for high adherence. Lack of trust in health professionals was the most appearing factor because of low adherence. Other appearing and affecting factors were social support, trust in healthcare and severe side effects. Conclusion: Adherence is a common and complex issue. There are many facilitators and barriers affecting adherence. Increased awareness of different factors can help health professionals to promote high adherence among individuals with chronic illness. / Många personer i världen lever med en eller flera kroniska sjukdomar och behandlas därför med läkemedel. Definitionen av adherence innebär i vilken utsträckning en person är följsam till sin läkemedelsbehandling. Tidigare forskning påvisar att endast 50 procent är följsamma till förskrivna ordinationer. Låg följsamhet är ett växande problem inom Sverige, men även globalt. I resultatet påvisades att en persons motivation, kunskap och förmåga att kunna ta eget ansvar över sin behandling var viktiga faktorer för långvarig och hög följsamhet. Ett socialt stöd från familj och närstående var betydande för hög följsamhet. Religiösa traditioner och stigmatisering i samhället visade sig ofta ha en negativ påverkan på följsamhet. Vårdrelaterade faktorer som påverkade följsamhet var exempelvis information, kommunikation, förtroende för vårdpersonal och behandling samt vårdtillgänglighet. Läkemedelsrelaterade biverkningar var ett bekymmer för upprätthållandet av följsamhet. I analysen som gjordes enligt Fribergs femstegsmodell framkom att faktorer som påverkar följsamhet inte skiljer sig märkbart över världen. Ökad kunskap hos personer och vårdpersonal om hur följsamhet till läkemedelsbehandling påverkas av olika faktorer kan främja följsamhet. Hög följsamhet bidrar till förbättrad hälsa och ökad livskvalitet hos personer med kronisk sjukdom. Det leder även till färre sjukdomsrelaterade komplikationer och färre vårdtillfällen på sjukhus. I resultatdiskussionen framkom att 'förmåga till följsamhet' och 'tillit till vård och behandling' visade sig vara betydelsefulla faktorer som påverkade följsamhet.

1. Little work has been done on the response of regular haemodialysis patients to dynamic exercise. A systematic study of exercise capacity and the underlying mechanisms is of particular importance because these patients are encouraged to return to as normal a way of life as possible. Accordingly, a select group of healthy young male patients and a group of older males have been studied during submaximal cycling. The young male patients were compared to a closely matched sedentary control group. The 17 subjects discussed represent the fittest of 40 patients tested. 2. In both groups there was decreased work capacity associated with disproportionate tachycardia, which was not obvious at rest. Blood pressure was measured with a sphygmomanometer. During exercise there was a striking rise in the systolic blood pressure in about half the patients from currently acceptable resting levels. This occurred in the absence of any clinical circulatory overload. Mild hyperventilation and disproportionate lactic acidosis was seen towards peak exercise, probably because, in spite of the decreased work capacity, the patients were much closer to their maximum performance. However, the limiting factors were clearly circulatory and not respiratory. 3. A number of the younger male patients were more intensively studied to determine why some remained relatively 'normotensive' during exercise while others developed systolic hypertension. Total blood volume, total body water and plasma renin activity were measured at rest. It was found that the 'normotensive' patients had normal body volumes and normal to high plasma renin activity, while the hypertensive subgroup had increased volumes and normal to low plasma renin activity. Thus, in these patients the blood pressure responses to exercise were largely volume dependent, albeit at a subclinical level. 4. Cardiac output was measured at rest and during exercise. All patients developed a variable hyperkinetic circulation during exercise which was not apparent at rest. The patients were all anaemic and (xi) their cardiac output response was very like that described in patients with anaemia unassociated with renal disease. However, some patients with striking anaemia developed a less hyperkinetic circulation than others who were not so anaemic. When the body volume and the blood pressure response on exercise were considered, those patients who were normovolaemic and 'normotensive' developed a hyperkinetic circulation on exercise appropriate to their degree of anaemia. Those with subclinical volume overload and a hypertensive response to exercise developed a much less striking hyperkinetic circulation, suggesting that the blood pressure and volume excess was depressing the anticipated cardiac output response to their underlying anaemia. 5. One patient with an arteriovenous shunt was studied twice, initially when hypervolaemic with a haemoglobin of 9,1gm/100 ml and again after ultrafiltration when he was normovolaemic but his haemoglobin had risen to 12,5 gm/100 ml. On the first occasion his cardiac output response was moderately hyperkinetic but he developed increasing hypertension with a high calculated total peripheral resistance. On the second occasion his cardiac output response fell within the normal range, his blood pressure was lower but not normal and his calculated total peripheral resistance was even higher than before. Thus, the blood pressure of these volume dependent patients is due to a high total peripheral resistance, but may not simply be on the basis of 'waterlogging' of the peripheral vasculature. Some other factor, such as structural thickening, must be considered. 6. It is suggested that the combination of tachycardia and hypertension which develop on mild exertion and which may not be obvious at rest, is the most potent cause of the increased cardiovascular mortality seen in dialysis patients. Simple exercise testing will reveal those with subclinical volume overload who are most at risk. It was striking that in the two groups tested those who developed striking hypertension on exercise were usually older, between 35 and 50 years. This accelerated aging of their vascular tree would correspond with recent data showing that dialysis mortality increases with age, and is about a decade earlier than in the general population. It is suggested that a more aggressive policy be adopted towards blood pressure fluctuations and that the resting blood pressure should be kept below 140/90 mm Hg at all times, if necessary by complementing ultrafiltration with drug therapy and/or bilateral nephrectomy at an early stage. 7. Thus simple exercise testing with blood pressure recordings not only serves as a yardstick of physical rehabilitation and long-term follow-up, but may also reveal or magnify abnormalities not obvious at rest.

Hip fracture in older adults may be the sentinel event leading to functional decline, long-term disability, and death. For the substantial number of older persons who fracture a hip each year, the chances of full functional recovery remains relatively low. The purpose of this study was to examine the differences between older persons with hip fracture who recover fully and those individuals who do not fully recover. A chronic disease trajectory framework guided the theoretical design of the research. Data were collected from the medical records of 102 persons aged 60 years and older who sustained a proximal hip fracture from 1993 to 1998 at a medical center in North Carolina. Data included personal characteristics, prefracture health status, hospital factors, rehabilitation features, and functional outcomes. The analysis consisted of a two-step hierarchical logistic regression model with the control variables of age, prefracture ambulation status, and prefracture cognitive status entered first and the variables of type of therapy program, frequency of therapy, number of therapy provider organizations, and location of therapy at 4 weeks entered second. Significance of the final model was observed, Chi-Square(7, n = 99)=43.55, p < .05. Significant individual predictors (p < .05) in the model were prefracture ambulation status (43.56 odds ratio) and cognitive status (6.44 odds ratio). Post-hoc analysis of the cases revealed a substantial lack of stability in ambulation status from three months post-fracture to the six-month and one-year follow-up. Findings support other research studies that indicate prefracture personal characteristics of older persons who fracture a hip are the most influential factors in predicting successful recovery. Linkage of the findings to the chronic disease trajectory model suggests that intervention efforts should focus on prevention, health promotion, and policies that extend the ability of health care providers to assist older persons with hip fracture in managing their conditions. / Ph. D.

OBJECTIVE: The overall goal of this study was to examine the relationship between preoperative, 1-year post-operative, and 2-year postoperative self-image in adolescents with idiopathic scoliosis undergoing spinal fusion surgery. In addition, a minor goal was to examine the relationship between pre-surgical mental health and post-surgical self-image and satisfaction. Additionally, spinal curvature and preoperative pain were explored in relation to the effect of pre-surgical mental health on post-surgical self-image. Analyses were performed in order to better understand the relationship of corrective surgery to self-image, and self-image's relationship to persistent postoperative pain, which has been recognized as a common clinically significant problem. METHODS: The Scoliosis Research Society Questionnaire-30 and Spinal Appearance Questionnaire were administered to 219 patients enrolled in the Prospective Pediatric Scoliosis study at pre-operative, 1-year post-operative, and 2-year post-operative time points. A subset (n=163) of these patients had complete data. The Scoliosis Research Society Questionnaire-30 includes pain and mental health subscales, which were examined preoperatively for the purpose of this study. Measurements of preoperative curve (Cobb) angle percentage correction were used in the analysis of this data, which were determined using operative notes. The Spinal Appearance Questionnaire (SAQ) includes self-image appearance and expectations subscales, which were examined at the preoperative, 1-year postoperative, and 2-year postoperative time points. RESULTS: There were significant improvements in self-image after surgical intervention in children with idiopathic scoliosis undergoing spinal fusion surgery. Cobb angle percentage correction, preoperative pain scores as determined by the SRS-30, and preoperative mental health scores as determined by the SRS-30 were not significant predictors of postoperative self-image as measured by the SAQ. There is little to no correlation between the preoperative measures and postoperative self-image. CONCLUSIONS: Prior studies have confirmed that pediatric persistent postsurgical pain is a significant health concern, and that presurgical mental health and self-image are factors that contribute to a pediatric patient's longitudinal experience with postsurgical pain. This study shows that there are clinically significant improvements in self-image after surgical intervention in patients with adolescent idiopathic scoliosis undergoing spinal fusion surgery. These findings suggest that preoperative pain, degree of spinal curvature correction, and preoperative mental health are not determinative of postoperative self-image in pediatric populations. Future studies should be conducted on more diverse populations, and take into account measures that may be predictors of poor postoperative self-image, specifically depression and anxiety. In summary it is important to explore the biological mechanisms pertaining to pediatric post-surgical chronic pain and their relation to differences in somatosensory phenotypes in this patient population.

OBJECTIVE: To examine how parent factors assessed at a multidisciplinary pain clinic evaluation predict child psychological and functional outcomes at four-month follow-up. After controlling for child baseline functioning, we predicted that parent distress and behavior would significantly predict child pain-related psychological and functional outcomes. METHODS: Among the 321 patients with chronic pain (ages 8-17) and their parents who presented for a multidisciplinary evaluation, 195 completed measures at baseline and at four-month follow-up via REDCap surveys. Patients completed measures of pain catastrophizing, pain-related fear and avoidance, generalized anxiety, depressive symptoms, functional disability, and somatic symptoms. Parents completed measures of pain catastrophizing, pain-related fear and avoidance, protective responses to pain, and child school functioning. Associations between parent and child distress and behavior were examined cross-sectionally at the time of the pain clinic evaluation, and longitudinally (i.e., parent at evaluation and child at follow-up). Lastly, using step-wise hierarchical regression analyses, we controlled for child baseline measures and examined the degree to which parent distress and behaviors predicted child outcomes at four-month follow-up. RESULTS: As hypothesized, parent distress and behavior was correlated with child distress and functioning at the time of evaluation with many of these associations persisting at four-month follow-up. For the regression analyses, after controlling for baseline child depressive symptoms, parent avoidance of activities (b = .24, p < .01) and parent helplessness (b = -.14, p < .10) reported at baseline significantly predicted child depressive symptoms at four-month follow-up. After controlling for baseline child pain catastrophizing, only parent pain-related fear reported at baseline (b = .15, p < .05) emerged as a significant predictor of child pain catastrophizing at four-month follow-up. Lastly after controlling for child school functioning at baseline, parent avoidance of activities (b = -.27, p < .01) and parent protective behavior (b = -.18, p < .05) reported at baseline emerged as significant predictors of child school functioning at four-month follow-up. Parent distress and behavior did not significantly predict child anxiety, pain-related fear, avoidance of activities, somatic symptoms, or functional disability at follow-up, after controlling for baseline functioning. CONCLUSIONS: Across parent factors, parent helplessness, avoidance of activities, pain-related fear, and protective behavior emerged as predictors of child outcomes four months after a multidisciplinary pain clinic evaluation. The results from this study provide initial data regarding the influence of parent emotions and behavior on child function over time. In addition, the results suggest potential targets for pain treatment interventions that go beyond the typical focus on child emotions and behaviors to include influential parent factors.

La GVH chronique (cGVHD) est une complication fréquente de l’allogreffe de cellules souches hématopoïétiques (CSH) dont la physiopathologie demeure partiellement comprise. Les données disponibles ont établi le rôle des lymphocytes T (LT) et B (LB) au cours de la cGVHD, mais la qualité de leur interaction et les sous-types de LT impliqués restent à définir. L’interaction entre les LT et les LB se fait au niveau du centre germinatif (CG) aboutissant à la production de LB mémoires et de cellules productrices d’anticorps de haute affinité grâce aux signaux d’aide reçus par les LT folliculaires helpers (TFH) finement contrôlés par une population régulatrice (TFR). La possibilité d’interroger les évènements se déroulant au niveau du CG par l’analyse de leur contingent circulant (c) nous a permis de mieux comprendre la physiopathologie de la cGVHD. En effet, la signature phénotype des cTFH suggère un gain de fonction au cours de la cGVHD, confirmée par étude fonctionnelle, et corrélant avec le phénotype des LB observé. De plus, les mécanismes de régulation apparaissent défectueux au cours de la cGVHD, puisque les cTFR présentent un défaut numérique expliqué par un défaut de résistance à l’apoptose et de prolifération. D’autre part, nous avons analysé une population de LT CD4+CD146+CCR5+, leur conférant une capacité de migration au travers des structures endothéliales et vers les sites inflammatoires. Cette population est significativement augmentée au cours de la cGVHD, et les modèles murins de cGVHD recevant des splénocytes de souris CD146-/- voient leur score clinique amélioré. L’expression de CD146 est associée à une polarisation Th17 justifiant un traitement par TMP778 (inhibiteur de RORγt) améliorant la cGVHD chez la souris. L’analyse de ces populations révèle des anomalies de la balance effecteurrégulateur et de potentielles cibles thérapeutiques à évaluer en clinique. / Chronic GVHD (cGVHD) remains a major complication of allogeneic stem cell transplantation and its pathogenesis poorly understood. Previous reports established the role of T cells and B cells during cGVHD, but the quality of their interaction and T cell subsets involved remain to be defined. T cell – B cell crosstalk occurs in the germinal center generating memory B cells and high affinity antibody secreting cells consecutively to signals provided by T follicular helper cells (TFH) which are tightly controlled by a regulatory subset (TFR). The opportunity to interrogate events occurring in the germinal center through the analysis of their circulating contingent (c), allowed us to better understand cGVHD pathogenesis. cTFH phenotypic signature suggest an enhanced function during cGVHD, confirmed in functional studies, and correlating with observed B cell phenotype. In addition, regulatory mechanisms appeared defective during cGVHD, as cTFR showed a numerical deficiency, explained by a defect in resistance to apoptosis and low proliferative capacity. We also studied a T cell subset expressing CD4+CD146+CCR5+, giving the capacity to migrate through endothelial structures and toward inflammatory sites. This population is significantly increased during cGVHD, and cGVHD murine models receiving splenocytes from CD146-/- mice showed improved clinical score. CD146 expression is associated with a Th17 polarization justifying a treatment by TMP778 (RORγt inhibitor) improving cGVHD in mice. The analysis of these different populations revealed an abnormal effector-regulator balance and potential therapeutic targets to evaluate in clinic.