Spinal tumor metastases are secondary tumors in the bone of the vertebral column that arise from primary cancers from other areas of the body. Metastatic neoplasms in the spine have significant implications for the overall quality of life of patients with all cancer types. Bone is one of the most common sites for metastases to develop, and the spine is the most common osseous site for metastatic disease. Accurate and early diagnosis is critical in order to prevent irreversible spinal cord damage. MRI is the standard for diagnostic imaging, and various techniques to employ key imaging findings are discussed. Treating spinal tumor metastases requires an interdisciplinary approach involving close collaboration between oncologists, neurosurgeons, radiologists and orthopedic surgeons. The Neurological, Oncological, Mechanical instability and Systemic disease (NOMS) decision-making framework has been developed to assess these four pillars in order to facilitate complex decision-making across specialties to improve treatment for secondary spinal tumors. One of the major advantages of NOMS is its ability to incorporate the most recent clinical data available in the decision framework. Each component of NOMS has various methods for standardizing prognostication and recommending treatment options, but the reliability of these methods is questioned by the literature. Standardized prognostication and treatment planning have high potential for improving treatment outcomes, but more research on their accuracy is imperative for optimal application. Creating a common language across medical disciplines can help streamline the treatment process and prevent unnecessary complications. As the revolutionary advancements in cancer treatment continue to unfold and more cancer patients achieve long term survival, the incidence of spinal tumor metastases will increase for patients with advanced metastatic cancers. This thesis will discuss the utility of current diagnostic standards, assess the value of prognostic scoring systems, and evaluate the decision-making framework used to synthesize treatment recommendations based on diagnostic and prognostic data.

Study purpose: The objectives of the study were to measure external and internal load and recovery status of junior semi-professional rugby union players (n = 36) during the u/19 Currie Cup campaign. Methods: The monitoring period covered 280 days (July – October) and included phases divided into off-season, pre-season and competition. Twelve league matches were played during the competition phase. The variables associated with external and internal load and recovery status were summarised for each player and also compared to each other to establish relationships between these variables. Data were collected either daily (training load, subjective fatigue and recovery) or weekly (recovery heart rate) or during matches (mechanical load, physiological load and training load). Injuries were also recorded throughout the season. Results: The primary finding of this study was that the players' loads (arbitrary units; AU) (605293 AU), fatigue (4.51.3 AU) and recovery (14.12.3 AU) did not change significantly throughout the different phases of the season. Also, recovery heart remained similar throughout the different phases of the season supporting the pattern of the subjective data. There was no clear predictive relationship between training load, subjective fatigue and recovery prior to sustaining an injury (both soft tissue and musculoskeletal). Conclusion: This study questions the usefulness of a wearable device to measure training load (internal/external), particularly since the session rating of perceived effort(sRPE) is cost effective, quick and easy to implement and provides accurate information. Subjective training load and subjective fatigue did not predict injury in this cohort of players. However, these variables can be used as markers to guide training to ensure the conditioning status of the players remains similar throughout the season. In particular they enable individualised decisions to be made about each player, ensuring that load and fatigue in response to the load remain steady.

Tuberculosis (TB) disease, caused by the pathogen Mycobacterium tuberculosis (Mtb), remains a major global health problem claiming 1.5-2 million lives annually. One of the major factors contributing towards Mtb's success as a pathogen is its unique cell wall and its ability to counteract various arms of the host's immune response. Understanding these survival mechanisms will help us develop new therapeutic interventions that can enhance the capacity of the immune system to kill the pathogen. A recent genome scale study profiled a list of candidate genes that are predicted to be essential for Mtb survival of host mediated responses. One candidate was ftsEX, a protein complex comprised of an ATP binding domain, FtsE, and a transmembrane domain, FtsX. FtsEX functions through interaction with a periplasmic hydrolase, RipC. FtsEX homologs in other bacteria have been linked to a key role in regulation of PG hydrolysis during elongation and division. Using M. smegmatis as a model, we hypothesised that FtsEX and RipC are required in the regulation of PG hydrolysis during normal cell wall elongation and division under stressful conditions in vitro. Antibiotic sensitivity was confirmed using Alamar blue MIC determination assays, which showed that ftsEX and ripC had increased sensitivity to chloramphenicol and not to rifampicin, isoniazid and ethambutol. Our growth curve analysis showed that ftsEX and ripC are not essential for survival in normal growth conditions. However, ftsEX and ripC are conditionally essential for M. smegmatis in low salt media. Growth defects in this condition were characterized by short and bulgy cells, as well as elongated filamentous cells with visible chaining. Major morphological changes were seen under nitrosative stress. A higher proportion of cells struggled to divide normally and formed chains. Lateral branching was also observed in ΔftsE, ΔftsX and ΔftsEX but not in ΔripC. The protein complex was also required for survival in media containing rifampicin. Treatment with the drug exacerbated growth defects of all the mutants, which were much shorter than WT cells, indicating impairment in the elongation process. Collectively, mutants are much shorter in length with an exception of a few extremely lengthy cells, suggesting that ftsEX and ripC are required for both normal cell elongation and division and ultimately for survival in stressful conditions.

Includes abstract. / Includes bibliographical references. / Recently, behavioural (motor precision) differences were reported between isometric wrist flexion and extension. Neurophysiological as well as clinical differences have also been reported between these antagonistic movements. Corticomuscular coherence (CMC), i.e. the frequency specific temporal coupling between the electroencephalogram (EEG) and electromyogram (EMG) recorded during isometric force production, reflects the functional connectivity between cortex and muscle. A single muscle (flexor digitorum superficialis) study suggests a positive correlation between 15-35 Hz (beta) CMC and motor precision of the muscle. Yet, no study has simultaneously compared CMC and motor precision between wrist flexion and extension. Task perceived difficulty, which is a perceptual variable, may influence both motor precision and CMC, but has not been studied yet. The main aim of the present study was to investigate the interaction between CMC, motor precision and perceived difficulty in isometric wrist flexion and extension tasks.

Purpose Sternal wound infection (SWI) is associated with significant morbidity and mortality in postoperative cardiac patients. We aimed to describe the burden, risk factors and outcomes of SWI in post-operative paediatric cardiac patients at a tertiary children's hospital. Methods We conducted a retrospective record review of cardiac surgeries via median sternotomy over a five-year period to identify cases of SWI. Results Between 2012-16, 1319 patients underwent median sternotomy. Thirty-four (2.6%) patients developed SWI; eighteen (1.4%) patients developed deep sternal wound infection (DSWI), and sixteen (1.2%) developed superficial sternal wound infections (SSWI). Twenty-two (1.6%) of SWIs were apparent within a week post-surgery before discharge, the remaining were re-admitted post-discharge. Seven (0.5%) patients died from complications. Conclusion Significant morbidity was associated with SWI. Furthermore, with a mortality rate of 20 % in the case of DSWI. We strongly support quality improvement procedures such as the Sternal Wound Prevention Bundle (SWPB) that was introduced in late 2014. However, the rate of SWI implies that ongoing monitoring and evaluation of the SWPB is necessary and more stringent adherence to the protocol may result in better outcomes.

Background:Tuberculous pericarditis includes the spectrum of pericarditis caused by Mycobacterium tuberculosis manifesting with pericardial effusion, cardiac tamponade, effusive-constrictive and constrictive pericarditis. In patients with pericardial tuberculosis, co-infection with human immunodeficiency virus (HIV) is associated with increased incidence of haemodynamic instability, electrocardiographic (ECG) ST elevation and mortality, suggesting an aggressive myopericarditis. However, little is known about myocardial involvement in patients with pericardial tuberculosis. Cardiovascular magnetic resonance (CMR) can assess non-invasively cardiac function, myocardial oedema, inflammation and fibrosis. Objectives: To assess cardiac and pericardial structure and function in patients with TBPC with and without HIV co-infection and to assess the relationship of left ventricular (LV) function with other imaging biomarkers. Methods: 72 patients with TBPC (37 male (51.3%), mean age 40 ± 14.3) were included in the study. Of these, 35 were HIV infected (17 male (48.6%), mean age 34 ± 8) and 37 were HIV uninfected (20 male (54.1%), mean age 51 ± 16). Assessments included clinical examination, ECG, echocardiography, serum and pericardial biomarkers and CMR (biventricular volumes and function, oedema, and late gadolinium enhancement - LGE). Results: HIV infected TBPC patients were younger (p<0.001), had lower serum haemoglobin (p<0.001) and were more likely to have NYHA class III and IV symptoms (p<0.001). There were no differences on ECG and echocardiography between HIV infected and uninfected TBPC patients. There were also no differences in global systolic function between HIV infected and uninfected TBP patients. Focal fibrosis on LGE was found more commonly in those with HIV infection (p<0.001). Pericardial effusions were frequent (>50%) in both groups of TBPC patients. Determinants of LV ejection fraction in TBPC included heart rate, LV size, E/A ratio, pericardial LGE and pericardial thickness (all p<0.01). Conclusions: HIV co-infection is associated with increased focal myocardial fibrosis in TBPC patients suggesting increased myocardial inflammation in those with HIV co-infection. In the future, it will be important to assess the prognostic significance of these findings.

Cancer is the second leading cause of mortality in the United States today, and equally prevalent throughout the world. Traditional treatments such as chemotherapy and radiotherapy have thus far proven unable to treat the disease with high efficacy, with different cancer types often requiring different treatments providing a spectrum of results. Cancer types in the late stages often have no adequate treatment at all. Over the past two decades, research in the field of gene therapy has created new hope in finding a remedy for cancer that displays a high efficacy in treating many different types and stages. The p53 tumor suppressor gene has garnered a great deal of interest, as p53 mutation or inactivation is present in approximately 50% of all cancers. The loss of p53 activity can be attributed to several different causes, including mutation of the p53 gene or overexpression of p53 inhibitors. Research has illustrated that the p53 protein plays an important role in tumor suppression by inducing senescence, cell cycle arrest, or cell apoptosis. Studies have shown that reactivation of p53 in tumor cells leads to tumor cell apoptosis and overall tumor regression. The focus of p53 research has now shifted to strategies of reintroducing or reactivating the gene in tumor cells so that it may carry out its anti-tumor functions. Of the strategies proposed, the use of adenovirus to introduce p53 shows the most promise. Adenoviruses bind to and enter the cell, and, after escaping proteasomal degradation, travel to the nucleus where they inject their genetic material. By delivering wild-type p53 gene into tumor cells using adenovirus, large amounts of p53 protein are transcribed in the cell and initiate its antitumor properties. Many clinical trials using adenovirus-mediated p53 gene transfer (Ad-p53) have been performed with generally positive results across a variety of cancer types. Ad-p53 in combination with more traditional treatments like chemotherapy and radiotherapy has been especially promising. The engineering of both adenoviral vectors and the p53 gene to be delivered presents new options for further increasing the efficacy of this therapeutic approach. Both Onyx-015, a selectively replicating adenovirus, and Ad-p53vp, a p53 gene that avoids inhibition, have been used in clinical trials with success. As a whole the field of adenovirus-mediate p53 gene transfer is promising and holds many advantages to classical treatments, but is still in the early stages of research. Further research must be completed so this therapy may be widely approved and used. The specific combination of Ad-p53 and traditional therapies has proven highly effective and should be used in clinical settings immediately.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a head and neck cancer that is typically diagnosed in elderly patients. Because the incidence rates of OSCC increases by two-to-four fold in older age groups, age is considered one of the major risk factors. With aging, there is an accumulation of mutational changes that may initiate tumor formation and a growing population of senescent cells that can reprogram the microenvironment via soluble factors. The result of these changes can create a tumor permissive microenvironment. Although age is considered a risk factor in OSCC, there have not been many preclinical studies on the role of aging in the oral microenvironment. OBJECTIVE: To investigate the role of aging in modulating early oral lesions in the microenvironment by analyzing protein localization and alterations in cellular phenotypes. METHODS: Tongue sections from non-treated 12-week-old, non-treated aging 31-week-old, and 4NQO-treated 31-week-old mice were subjected to immunohistochemical analyses (IHC). The sections were incubated with antibodies against anti-𝛼-SMA, -PDGFRβ and -E-cadherin to observe changes in cellular morphology, staining intensity, localization and frequency of appearance. RESULTS: The membranous localization of E-cadherin significantly decreased from young and aging normal epithelia to severe dysplasia. 𝛼-SMA expression was observed in the cytoplasm and at the membrane of elongated and spindle-like epithelial cells in severe dysplasia. 𝛼-SMA and PDGFRβ expressions were localized to blood vessels/pericytes in the stroma for all tissue samples. In the stroma surrounding severe epithelial dysplasia, there was an increase in vascular structures. While no 𝛼-SMA-positive myofibroblasts were found in any of the stroma, PDGFRβ-positive stromal cells were found in the stroma of aging tissues from 4NQO-treated mice. CONCLUSIONS: This study provides evidence that aging has a role in modulating the microenvironment in the early pre-cancerous lesions. The appearance of myofibroblasts may have originated from senescent cell populations and the effects of the 4NQO carcinogen caused changes in the expression and localization of E-cadherin, 𝛼-SMA and PDGFRβ as well as in cellular phenotypes. The changes observed in the precancerous lesions may contribute to their progression to OSCC.

Chronic kidney disease (CKD) impacts millions of people in the world, and those diagnosed with cardiovascular disease (CVD) are at a higher risk of mortality. Accumulated uremic toxins increases the risks of CVD in CKD patients and symptoms of CVD include endothelial injury, inflammatory reaction, vessel calcification and occlusion, and blood clot. Calciphylaxis is a complication of CKD that is life-threatening; it is a uremic vascular disease in which calcified micro-vessels cause painful skin lesions, and there is currently no effective diagnosis nor treatment. CKD patients with calciphylaxis require hemodialysis to survive and the most effective approach is through arteriovenous fistula (AVF). AVF connects an artery and vein to increase the blood flow needed for hemodialysis treatment. However, complications, such as stenosis of AVF portends a bad prognosis for patients. This study focuses on the microarchitecture of AVF to observe the abnormal changes in structure of vessels. By identifying the specific changes in the AVF, possible therapeutics can be made to target mechanisms of calciphylaxis and AVF to provide patients with successful rates of hemodialysis and recovery. In this study, it is observed that smooth muscle cell proliferation, necrosis of muscle tissue, accumulation of proteoglycan in the intima, and scarring of collagen contribute to abnormalities observed in AVF. / 2023-11-22T00:00:00Z

BACKGROUND: Sickle Cell Disease (SCD) is the most common inherited blood disorder in the United States, causing red blood cells to take on a rigid “sickle” shape, leading to chronic hemolytic anemia and occlusion of blood vessels. SCD results in repeated vascular injury and inflammation, reduced immune functioning, and causes acute complications such as pain crises and Acute Chest Syndrome, as well as progressive damage to every organ system of the body. Given the tendency of hypoxia and other stressors to trigger sickling and SCD complications, it is likely that young individuals with SCD are at increased risk during COVID-19 illness. OBJECTIVES: To characterize complications of SARS-CoV-2 infection in children and adolescents with Sickle Cell Disease, and to determine if children with SCD have worse clinical outcomes than other Black and African American patients without SCD. METHODS: Surveillance for COVID-19 related complications was conducted across the United States from March 15, 2020 to January 31, 2021 as part of the CDC’s Overcoming COVID-19 public health registry. Hospitalized patients < 21 years of age, with positive SARS-CoV-2 test (reverse-transcriptase polymerase chain reaction ([RT-PCR]) and/or antibody test) or recent exposure without an alternate diagnosis were included in the registry. Clinicians reported data on patient demographics, baseline health status, clinical course, and outcomes in a standardized report form. A case series of patients with Sickle Cell Disease was identified in the registry, and illness and outcomes of Black and African American children and adolescents with and without SCD were analyzed in order to characterize disease course, complications, and outcomes in this population. RESULTS: Of 1,996 patients from 62 sites, 585 were Black or African American (54% male, median age 9.6 years), and 47 patients were reported with an underlying diagnosis of Sickle Cell Disease (45% male, median age 14.2 years). 43 (91%) of these patients were Black or African American, which was much higher than expected from the CDC’s estimate that 1 in 365 African American children have SCD. SCD patients came from 22 hospitals in 17 states, and were admitted between March 30 and December 8, 2020. Median hospital stay was 5 days (IQR 2.5-8), whereas for non-SCD Black patients it was 6 days (3-10). Overall, 65% (28/43) of Black SCD patients had at least one additional underlying condition, the most common of which was asthma (n=17, 40%). In comparison, 48% (262/542) of Black patients without SCD reported no underlying conditions, and 45% (n=245) reported two or more, of which obesity was the most common (n=99, 24%). The majority of patients with SCD had acute COVID-19, and only 19% (n=8) of patients with SCD were diagnosed with multisystem inflammatory syndrome in children (MIS-C), which is presumed to be a post-infectious complication, whereas 54% (n=285) of the comparison group had MIS-C. Overall, 35% (n=15) of the SCD patients were admitted to the ICU, compared to 67% (n=362) of patients without SCD. Median length of ICU stay was 4 days (2-7) in both the SCD and non-SCD groups. There were no deaths reported in patients with SCD, although one patient was transferred to a different hospital for a lung transplant, and death was rare in Black patients without SCD (n=9, 1.7%) w. Additionally, 30 patients (64%) presented with an SCD-related complication, including Acute Chest Syndrome (n=15, 32%) and vaso-occlusive pain crises (n=19, 40%). CONCLUSIONS: As a whole, Black children and adolescents with SCD did not display clinical outcomes more severe than Black children without SCD, however they were hospitalized at approximately 27 times the expected rate, suggesting that SCD may be a risk factor for hospitalization with COVID-19. COVID-19 may trigger SCD Complications, and some very severe cases show that SCD may be a risk factor for COVID-19 complications as well. / 2023-11-22T00:00:00Z