The increased prevalence of chronic kidney disease (CKD) has become a major global health burden. This increase in CKD burden parallels the increase in hypertension prevalence. In addition, increasing evidence suggest that genetics play a strong role in the susceptibility for renal disease. Inbred mouse strains C57BL/6 and 129S6SvEv differ in their susceptibility to kidney disease when subjected to hypertension using the DOCA/salt uninephrectomy model of hypertension. Similar to others, we found the 129S6SvEv mice to be susceptible to develop severe glomerulosclerosis, whereas the C57BL/6 mice are comparatively resistant. To identify new candidate genes that are involved in the pathogenesis of glomerular disease, we used microarray technology to compare the glomerular transcriptome of both strains and determine changes in glomerular gene expression when subjected to the DOCA/salt uninephrectomy model of systemic hypertension. This approach was accompanied with ultrastructural analysis and glomerular stiffness measurements to identify corresponding structural changes. Here, we have identified novel genes associated with strain differences and hypertension, and we used immunohistochemistry to validate their expression in podocytes and glomerular arterioles in murine and human kidneys. The increased understanding of the molecular mechanisms underlying hypertension-associated podocyte injury and glomerular damage which will result from these studies, will ultimately lead to identification of novel pharmacologic targets or therapeutic strategies for patients with hypertension and renal disease. / 2017-11-02T00:00:00Z

Yes / Objectives: To explore experienced physiotherapists’ attitudes, beliefs and experiences regarding their personal role in contributing to effective therapeutic relationships when working with people with chronic musculoskeletal pain. Design: Descriptive qualitative design using semi-structured interviews. Setting: Within physiotherapy departments in two National Health Service acute secondary care trusts in the North West of England. Participants: Six experienced physiotherapists working with people with chronic musculoskeletal pain. Data Analysis: Thematic coding analysis of transcribed interview recordings Main outcomes: Four overarching themes emerged from the data: Listening to the person; a caring understanding of the person’s situation; engaging the person and coming together; and moving forwards. Results: Participants emphasized the importance of building effective therapeutic relationships when working with people with chronic pain, seeking to create these by engaging with the person, to promote a strong collaborative partnership. Participants highlighted the themes of listening to the person’s story and showing a caring understanding of their situation through empathy and belief with validation. The final theme of moving forward emphasized how positive therapeutic relationships aid the rehabilitation process in enabling people to make positive changes in their lives. Conclusions: A clearer understanding of how physiotherapists engender positive therapeutic relationships has the potential to improve training and service development priorities for physiotherapists working in the area of chronic musculoskeletal pain. Future studies should seek to further define the core dimensions impacting therapeutic relationships, from the perspectives of both physiotherapists and people with chronic musculoskeletal pain. / Health Education Yorkshire and the Humber

A silent pandemic, chronic, non-healing wounds are a major cause of morbidity, with treatment and management representing significant health burdens. The opportunistic pathogens Staphylococcus aureus and Pseudomonas aeruginosa are the most common species isolated from chronic wounds. Polydimethylsiloxane (PDMS), a biocompatible and, inexpensive to fabricate polymer, can undergo various modifications. The ability of the produced polymers to attract S. aureus and P. aeruginosa, either from the planktonic state, or while sessile in biofilms on ex vivo skin, was investigated using flat (FL) or patterned (PT) PDMS with or without 1% or 10% triclosan Patterned PDMS + 10% triclosan (PT 10%) attracted significantly more live S. aureus and P. aeruginosa, as determined using Colony Forming Unit (CFU) analysis (*p<0.01), Scanning Electron Microscopy (SEM) (*p<0.01) and Confocal Scanning Laser Microscopy (CSLM) (*p<0.01). The released triclosan was not cytotoxic against either bacteria or primary cultures of human dermal fibroblasts using Water Soluble Tetrazolium Salts (WST-1) assay. High performance liquid chromatography analysis highlights low level of triclosan release from the PDMS. Bacterial infection in co-culture using the Boyden chamber assay increased fibroblast viability in the presence of PDMS (*p<0.05). PT 10% demonstrated superior biofilm transfer from epidermis (*p<0.05), in comparison to all other analysed polymers. In summary, the unique topography of PDMS combined with triclosan attracted bacteria most efficiently. This promising data suggests potential for engineering a patterned polymer to physically transfer biofilms from wounds, and importantly lacks bactericidal properties which is vital in the quest to combat antimicrobial resistance.

Lipopolysaccharide (LPS), a Gram-negative endotoxin, has been well-established as the trigger for the effects of sepsis and septic shock through its binding with the innate immune receptor, Toll-like receptor 4 (TLR4). High doses of LPS signal through TLR4 to produce a massive release of pro-inflammatory cytokines including IL-6, TNFα, and other. Additionally, several recent publications have demonstrated severe metabolic alterations after LPS challenge, suppressing lipid oxidation and concurrently up-regulating glucose oxidation. Unfortunately, this switch in metabolism is inefficient for the great energy demands of the host during a systemic microbial infection which can result in vital organ failure. Meanwhile, a novel concept in several chronic disease pathologies also implicates LPS, although at very low doses. The presence of subclinically elevated circulating endotoxin levels has been termed metabolic endotoxemia and is beginning to be investigated in disease pathologies including insulin resistance and type II diabetes, atherosclerosis, cancer metastasis and Parkinson's disease. These disease phenotypes all possess a component of chronic inflammation whose source has not largely been understood, but examining the effects of very low doses of LPS may provide vital information in understanding their etiologies. However, most information on LPS signaling has been obtained using high doses of LPS (10-200ng/ml) while little to no studies have been published regarding the effects of very low doses of LPS (1pg-100pg/ml) on inflammatory and metabolic alterations. Thus, we use in vivo and in vitro models to determine that both IRAK1 and JNK are critical points of crosstalk downstream of TLR4 for the metabolic and inflammatory alterations associated with metabolic endotoxemia. Additionally, we observed significant down-regulation of nuclear receptors responsible for fatty acid metabolism, including PGC1α, PPARα, and PPARγ after very low dose LPS challenge. Further, we observe phenotypic changes in fatty acid oxidation and glucose oxidation, as well as subsequent changes in cytosolic acetyl-CoA levels and acetylation of pro-inflammatory transcription factor ATF2. Overall our studies point to several mechanisms of cross-talk between metabolism and inflammation and offer significant support to the concept of metabolic endotoxemia in the development of chronic disease. / Ph. D.

Encephalitozoon cuniculi, Toxoplasma gondii and Sarcocystis neurona are intracellular parasites that infect a wide range of mammalian host species including domestic cats. The prevalence of antibodies to these parasites in cats was examined using an indirect immunofluorescence antibody assay. E. cuniculi targets the kidneys of rabbits but the prevalence of disease in cats is unknown. Chronic kidney disease (CKD) is a common cause of illness in cats. T. gondii is a widespread parasite of cats; however, it is not considered a major causative agent of CKD. The first hypothesis was that E. cuniculi and T. gondii are unrecognized causes of chronic kidney disease in domestic cats. Serum and plasma samples were examined for protozoal antibodies from 232 feline patients at the VMRCVM Teaching Hospital. Thirty-six of the 232 samples met the IRIS criteria for CKD. Antibodies to E. cuniculi were found in 15 samples, 4 of which came from cats with CKD. Antibodies to T. gondii were found in 63 samples; 10 cats of the 63 had CKD. These were not significantly different from cats with no CKD and the null hypothesis was rejected. Domestic cats, armadillos, raccoons and skunks are intermediate hosts (IH) for S. neurona while opossums are the definitive host (DH). The seroprevalence of S. neurona was examined in domestic cats from Virginia and Pennsylvania. The second hypothesis was that domestic cats are important IH for S. neurona transmission. A low seroprevalence was found in 32 of the 441 cats and the null hypothesis was rejected. / Master of Science in Life Sciences

Over 15 million contact sports players and military veterans are at risk for the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) that sometimes presents with parkinsonian motor symptoms, although very little is understood about how these individuals develop parkinsonism. CTE is characterized by accumulation of hyperphosphorylated tau protein (p-tau), and diagnosis requires the presence of neuronal tau in the form of neurofibrillary tangles at the depth of cortical sulci. We performed quantitative immunoassays for markers of neurovascular inflammation within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers were increased in CTE compared to RHI-exposed and -naïve controls. Markers increased with RHI exposure duration and were associated with increased microglial density and tau pathology. Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity. We next performed a cross-sectional analysis of all brain donors with CTE and without comorbid neurodegenerative disease (n=495) in the UNITE Brain Bank. Participants with parkinsonism (CTE-p, n=119) had a higher mean age at death (71.5 years (y)) than participants without parkinsonism (CTE-np, n=362, 54.1 y) and exhibited a higher rate of dementia than CTE-np participants. CTE-p participants had a more severe CTE stage and nigral pathology (NFTs, neuronal loss, and more frequent Lewy bodies), though the majority of cases were negative for nigral Lewy bodies. In American football players, simultaneous regression analysis demonstrated that nigral NFTs and neuronal loss mediate a connection between years of play and parkinsonism in CTE. In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation was associated with SN proteinopathy and neuronal loss, and these pathologies were associated with parkinsonism. Finally, in a postmortem cohort (n=392) of brain donors with CTE without comorbid neurodegenerative disease, we used linear regression modelling to analyze the associations between isodendritic core nuclei pathology (semiquantitative neurofibrillary tangles (NFTs), neurites, and neuronal loss scores) and CTE disease severity, RHI exposure duration (years of contact sport play), and informant-reported cognitive and daily function as assessed by the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ), respectively. Overall, isodendritic core (IC) NFT scores increase with disease stage, Initially in the locus coeruleus and finally in the median raphe nuclei. Neuronal loss occurred at later disease stages than NFT accumulation. RHI exposure was associated with p-tau pathology for all IC regions. NFTs and neuronal loss in the substantial nigra were associated with increased CDS scores (i.e., worse cognitive function), and neuronal loss in the substantia nigra and locus coeruleus were associated with increased FAQ scores (i.e., worse daily function). We are able to show CTE is similar in distribution of p-tau pathology to progressive supranuclear palsy (PSP), a disease that is thought to primarily affect subcortical regions, especially by end stage disease. These results demonstrate the vulnerability of the isodendritic core nuclei to p-tau pathology and neuronal loss in CTE, and suggest that their involvement contributes to cognitive and functional symptoms during life. This work highlights the possible linkage between neuroinflammation leading to nigral p-tau accumulation and neuron loss which likely underlies the development and progression of parkinsonian motor symptoms in CTE.

Gold nanoparticles (GNPs) are currently being intensely investigated for their potential use in biomedical applications. Nanotoxicity studies are urgently needed to validate their safety in clinical practice. The objective of this research was to assess the acute, subacute, and chronic effects of a single intravenous exposure to commercially available GNPs in two in vivo models, mice and rats. Gold nanoparticles were purchased and independently characterized. Animals were exposed to either 1000 mg GNPs/kg body weight (GNP group) or an equivalent volume of phosphate buffered saline (PBS group) intravenously via the tail vein. Subsets of animals were euthanized 1, 7, 14, 21, 28 days (female BALB/c mice and female F344 rats) or 20 weeks (female and male C57BL/6 mice) post-exposure and samples were collected for biochemistry, histopathology, electron microscopy, and atomic absorption spectrometry analysis. Independent characterization demonstrated that the physicochemical properties of the purchased GNPs were in good agreement with the information provided by the supplier. Important differences in GNP-induced immune responses were identified when comparing mice and rats 1 to 28 days post-exposure. Gold nanoparticles stimulated the formation of liver microgranulomas in mice, along with transiently increased serum levels of the proinflammatory cytokine interleukin-18. No such alterations were found in rats. Species differences in GNP biodistribution and excretion were also detected, with higher relative accumulation of GNPs in spleen and longer fecal excretion in rats. In the long-term (20 weeks after dosing), exposure to GNPs incited chronic inflammation in mice, characterized by the persistence of microgranulomas in liver, spleen, and lymph nodes, as well as further increased serum levels of interleukin-18. Impairment of body weight gain was also observed in the GNP-exposed group. No sex differences were detected. In conclusion, GNPs are not innocuous and have the ability to incite a robust macrophage response in mice. However, considering the mildness of the toxic effects identified despite the high dose selected for the study, GNPs continue to have great potential for biomedical uses. Further studies are needed in order to determine specific mechanisms of toxicity and the role of chronic inflammation in the development of adverse effects after co- or post-exposures. / Ph. D.

Chronic absenteeism is a growing concern nationwide. Millions of students are absent from school, with the number summing to one month's worth of absences per student per year. As a result of Every Student Succeed Act (ESSA), many states have included chronic absenteeism as part of their school quality indicator. For the 2018-2019 school year, attendance was included in standards of accreditation. Reducing chronic absenteeism has long been a goal for many public principals at each grade level nationwide. The purpose of this study was to identify what interventions and strategies principals were implementing to decrease chronic absenteeism. This study further identified principals' perceptions of the interventions and strategies with the greatest and least effect on decreasing chronic absenteeism. A qualitative research design was used with semi-structured interviews to determine principals' perceptions of interventions and strategies to decrease chronic absenteeism. Participants were principals from secondary schools in one urban school district, located in the Southeastern region of Virginia. Findings from the research revealed that principals in this district are implementing interventions and strategies that include: positive behavioral interventions and supports, parent contacts, community partnerships, district supports, and professional development to decrease chronic absenteeism. The findings also suggested that interventions and strategies that help build relationships between the school, students, and parents are being most effective in decreasing chronic absenteeism in this district. Implications for continued decrease in chronic absenteeism at all level of practice are recommended and suggestions for future research / Doctor of Education / The purpose of this study was to identify what interventions and strategies principals were implementing to decrease chronic absenteeism. This study further identified principals' perceptions of the interventions and strategies with the greatest and least effect on decreasing chronic absenteeism. The study included principals from secondary schools in one urban school district, located in the Southeastern region of Virginia. Principals were interviewed using interview questions designed by the researcher (see Appendix E). The research findings identified principals are implementing positive behavior interventions and supports in their schools to decrease chronic absenteeism. They are also implementing parent contacts, community partnerships, district supports, and professional development. The interventions and strategies principals find most effective in decreasing chronic absenteeism are interventions and strategies that help build relationships with students and parents. Future interventions and strategies should include additional efforts to contact parents, an increase in staff to make home visits and students being able to recover or buy back time lost from school due to absenteeism. Implications for practice in the continued decrease of chronic absenteeism are recommended, as well as suggestions for future research.

Yes / Background: The place of opioids in the management of chronic, non-cancer pain is limited. Even so their use is escalating, leading to concerns that patients are prescribed strong opioids inappropriately and alternatives to medication are under-used. We aimed to understand the processes which bring about and perpetuate long-term prescribing of opioids for chronic, non-cancer pain. Methods: We held semi-structured interviews with patients and focus groups with general practitioners (GPs). Participants included 23 patients currently prescribed long-term opioids and 15 GPs from Leeds and Bradford, United Kingdom (UK). We used a grounded approach to the analysis of transcripts. Results: Patients are driven by the needs for pain relief, explanation, and improvement or maintenance of quality of life. GPs’ responses are shaped by how UK general practice is organised, available therapeutic choices and their expertise in managing chronic pain, especially when facing diagnostic uncertainty or when their own approach is at odds with the patient’s wishes. Four features of the resulting transaction between patients and doctors influence prescribing: lack of clarity of strategy, including the risk of any plans being subverted by urgent demands; lack of certainty about locus of control in decision-making, especially in relation to prescribing; continuity in the doctor-patient relationship; and mutuality and trust. Conclusions: Problematic prescribing occurs when patients experience repeated consultations that do not meet their needs and GPs feel unable to negotiate alternative approaches to treatment. Therapeutic short-termism is perpetuated by inconsistent clinical encounters and the absence of mutually-agreed formulations of underlying problems and plans of action. Apart from commissioning improved access to appropriate specialist services, general practices should also consider how they manage problematic opioid prescribing and be prepared to set boundaries with patients. / National Institute for Health Research (NIHR) under its Research for Patient Benefit Programme (Grant Reference Number PB-PG- 1010–23041).

Yes / The international business literature has mainly focused on the impact of top managers' psychological attributes on firms' strategic decisions. However, the potential moderating influence of industry conditions such as competition has not been well explored. Deriving insights from the regulatory focus and upper echelons theories, this paper extends the international business and regulatory focus literature by investigating how the impact influence of CEOs' regulatory foci on firms' degree of internationalization depends on the intensity of competitive market conditions. Using primary data gathered from 289 small and medium-sized enterprises (SMEs) in Ghana, the findings of the study revealed when competition is intense in the domestic market, the potency of a CEO's promotion focus as a driver of internationalization is amplified. In addition, the research shows that intense domestic market competition weakens the negative influence of a CEO's prevention focus on a firm's degree of internationalization. These findings have important research and managerial implications for international business.