Background: Hospital malnutrition is a prevalent issue with critically ill pediatric patients being at increased risk for nutritional loss. Nutritional risk screening has been associated with increased documentation of nutrition diagnosis and positive clinical outcomes, however, is not mandatory in developing countries. A nutrition screening tool that uses subjective examination of loss of subcutaneous fat and muscle tissue may be an efficient way to identify nutritional risk in hospitalized critical care pediatric patients. Objective: To determine whether loss of subcutaneous fat and muscle tissue in specific body locations was associated with moderate or severe malnutrition determined by SGA in pediatric critical care hospital units, and if loss of subcutaneous fat and muscle tissue differs by gender, age, or disease. Methods: Pediatric in-patients (n = 203), aged 1 month to 18 years old, in tuberculosis, burn, oncology, high dependency (HDU) and intensive care units (ICU) in two tertiary hospitals in Malawi were assessed for nutritional status using Subjective Global Assessment (SGA), Mid-upper arm circumference (MUAC), and weight for age Z-score (WAZ). The SGA form included four questions on weight, appetite, tolerance to food and fluids, and dietary intake, as well as a nutrition-focused physical exam. The nutrition-focused physical exam consisted of assessments of subcutaneous fat loss in two locations (below the eye, triceps/biceps) and eight locations for muscle tissue loss (temple, clavicle, shoulder, scapula, interosseous, knee, quadriceps, and calf). The analysis was focused on the assessment of loss of subcutaneous fat and muscle tissue in relation to malnutrition score determined by SGA. Results: The mean age and standard deviation of the study population was 5.32 years ± 4.80, with just over 55% of participants being male. Determined by SGA, moderate malnutrition prevalence was 70.9% and severe malnutrition prevalence was 13.8%. SGA alone identified more malnutrition (84.7%) than MUAC (20.5%) and WAZ (43%). Patients with cancer (100%) and organ-related disease (93.76%) had the highest rates of moderate and severe malnutrition. Loss of subcutaneous fat and muscle tissue in all body locations assessed were associated with moderate and severe malnutrition (p-value Conclusions: A nutritional screening tool that is efficient, valid, and allows for the screening of a large patient population in a short amount of time, is needed in Malawi. Although loss of subcutaneous fat and muscle tissue were significantly associated with moderate and severe malnutrition, moderate loss of muscle tissue in the quadriceps and calf had the highest odds of malnutrition. These results indicate that pediatric patients with moderate loss of muscle tissue in their quadriceps and calf should be treated with a high index of suspicion for malnutrition. While loss of subcutaneous fat and muscle were not significantly worse by gender, age, or disease, particular attention should be paid in patients of the male sex, aged 6 to 10 years old, and with cancer. These findings support increasing dietetic services to prevent and treat hospital malnutrition using simple screening tools, such as the one used in this sub-analysis.

<p>Long-acting injectables (LAI) offer many practical benefits for patients in improving drug adherence to therapies for chronic diseases. LAI, administered either subcutaneously (SC) or intramuscularly (IM), can improve drug bioavailability, and reduce frequency of administration as well as regimen complexity. SC also has additional benefits over IM injections as being safer, less painful, and able to be administered at home. However, development and translation of these products into the clinic is often limited because of physiological complexity at injection site, such that absorption rate mechanisms are not well understood. Common predictive and correlative methods used in oral formulations, such as <em>in vitro-in vivo </em>correlations, are not well suited for SC physiology and are only capable of measuring a few parameters at a time, meaning relationships between parameters cannot be discriminately measured.</p> <p><br></p> <p>This project seeks to address this gap in knowledge by using computation to bridge the gap between suboptimal preclinical testing methods and human pharmacokinetic data. A Multiscale framework was developed by integrating a first-principles Multiphysics model of the SC space to experimental plasma concentration profiles using simulated absorption rates. First, our lab’s previous framework for lymphatic absorption of monoclonal antibodies (mAbs) was converted into small molecule absorption into the capillaries. Drug and formulation critical quality attributes (CQA) were determined for a solution injection of methotrexate, and a nanocrystal formulation of medroxyprogesterone acetate (MPA, Depo-SubQ Provera). Two dissolution models were incorporated to compare the difference between using average particle size (Noyes-Whitney) and particle size distributions (Population Balance Model, PBM) as CQA for nanocrystal LAI specifically. Absorption rates were validated using compartmental pharmacokinetic models, and sensitivity analyses were conducted to determine model parametric sensitivity. Overall, the modeling framework was able to determine the importance of and discriminate the effect of parameters on SC absorption rates. </p>

No description available.

Diabetes is a leading cause of death and disability in the United States. Diabetes requires a lifetime medical treatment. Some diabetes drugs could be taken orally, while others require daily injection or inhalation to maximize bioavailability and minimize toxicity. Parenteral delivery is a group of delivery routes which bypass human gastrointestinal track. Among all the parenteral methods, we chose subcutaneous implant based on its fast act and high patient compliance. When using subcutaneous implant, drug release needs to be strictly controlled. There are three major groups of controlled release methods. Solvent controlled system is already used as osmotic implant. Matrix controlled system is used in Zoladex® implant to treat cancer. Membrane controlled systems is widely used in coating tablets, but not that popular as an implant. Based on the research reported by previous scientists, we decided to build a hybrid system using both matrix and membrane control to delivery human insulin and other small molecule drugs. Subcutaneous environment is different from human GI track. It has less tolerance for external materials so many polymers cannot be used. From the FDA safe excipient database, we selected albumin as our primary polymer and gelatin as secondary choice. In our preliminary insulin diffusion study, we successfully found that insulin mixed with albumin provided a slower diffusion rate compared with control. In addition, we added zinc chloride, a metal salt that can precipitate albumin. The insulin diffusion rate is further reduced. The preliminary study proved that matrix control using albumin is definitely feasible and we might add zinc chloride as another factor. In order to fabricate an implant with appropriate size, we use lyophilisation technology to produce uniformly mixed matrix. Apart from albumin and human insulin, we added sucrose as protectant and plasticizer. The fine powder after freeze-dry was pressed as a form of tablet. The tablets were sealed in Falcon® cell culture insert. Cell culture insert provide a cylinder shape and 0.3 cm2 surface area for drug release. Insulin release study provided a zero order kinetics from prototypes with zinc chloride or 0.4 micron pore size membrane. Caffeine was used as a model drug to investigate the releasing mechanism. Three pore size membranes (0.4, 3 and 8 micron) were tested with same formulation. While 0.4 micron prototypes provided the slowest release, 3 micron ones surprisingly released caffeine faster than 8 micron implants. We calculated the porosity with pore size and concluded that the percentage of open area on a membrane is the key point to control caffeine release. 0.4 micron membranes were used for future research. We increased the percentage of albumin in our excipient, and achieved a slower caffeine release. However, the zero order release could only last for 3 days. After we replaced sucrose with gelatin, a 5 day zero order release of caffeine was achieved. With all the results, we proposed our “Three Phase” drug release mechanism controlled by both membrane and matrix. Seven other small molecule drugs were tested using our prototype. Cloudy suspension was observed with slightly soluble drugs. We updated our “Three Phase” drug release mechanism with the influence of drug solubility. Data shows that releasing rate with same formulation and membrane follows the solubility in pH 7.4. This result proves that our prototype might be used for different drugs based on their solubility. Finally, with all the information of our prototype, we decided to build a “smart insulin implant” with dose adjustment. We proposed an electrical controlled implant with different porosity membranes. Solenoid was used as the mechanical arm to control membrane porosity. 3-D printing technology was used to produce the first real prototype of our implant. Finally, insulin implant with clinically effective insulin release rate was achieved. / Pharmaceutical Sciences

Exposure to exogenous estrogens such as synthetic 17α-ethinyl estradiol (EE) occurs via multiple sources (i.e. hormonal contraceptives, environmental contamination, hormone replacement therapy). The natural estrogen, 17β-estradiol (E2), is a well-studied immunomodulatory hormone at both environmental and pharmacologic levels. Conversely, little data exist regarding the immune effects of EE at either environmentally-relevant exposure levels or at pharmacological levels. Further, EE is delivered to patients in a clinical setting via different routes of exposure (e.g. subcutaneous or oral). Many key questions in relation to potential immunological effects of EE are unanswered. Important variables in estrogen-modulation of the immune system include: (i) dose, (ii) age, (iii) gender, and (iv) route of exposure. Thus, pertinent questions emerge. Does exposure to EE at low concentrations for a subacute duration affect the immune or reproductive systems? Are the effects similar in both hormones and between sexes? Are these effects similar in juvenile and aged mice? How do the effects compare across two common routes of exposure (subcutaneous versus oral)? To address these questions, three separate studies were performed. In the first study, we investigated whether very low, but environmentally relevant, doses of EE, E2 (10 ng/kg body weight), or vehicle orally administered every other day for 21 days to young (6 week-old) and aged (>15 month-old) C57BL/6 mice had immunomodulatory effects. As expected, significant gender and age-related differences were noted with regard to thymus weight, thymocyte recovery, spleen weight, and splenocyte recovery. However, low dose treatment of either E2 or EE had no marked effects on the thymus or spleen organ to body weight ratios, cell numbers, or lymphocyte subsets. Low dose oral estrogens did not alter the ability of activated splenocytes to induce interferon-γ or nitric oxide. No effects on male reproductive organ to BW ratios of young or aged mice were found. Similarly, with the exception of E2-stimulating effects on the female reproductive tract of young mice, there were no pronounced effects in females. In separate studies, intact juvenile female and male C57BL/6 mice were given daily subcutaneous (second study) or oral (third study) doses of either EE or E2 (0.04, 0.4, or 4.0 μg per 25 g BW) for 21 days. In the subcutaneous exposure study, both EE and E2 morphologically altered uterine and seminal vesicle weights. However, EE had a more pronounced effect compared to E2, especially in males, even at the lowest dose administered. Additionally, like E2, EE induced thymic atrophy in both sexes. In female mice, thymic atrophy and thymic cellularity were significantly decreased by subcutaneous EE and E2 at doses of 0.4 and 4.0 μg/25 g body weights. EE elicited significantly more pronounced thymic atrophy-inducing effects compared to E2 at the 4.0 μg/25g dose. In males, thymocyte cellularity was decreased by both subcutaneous EE and E2 only at the highest dose tested (4.0 μg/25 g body weight), whereas only 4.0 EE significantly decreased thymus to body weight ratios. Neither splenic weights, splenic cellularity, nor splenic cell phenotype were affected by either estrogenic compound regardless of route of exposure. Oral exposure of EE or E2 did not induce marked immunological effects. Collectively, these data demonstrate that select thymic and reproductive endpoints are significantly altered following a 21-day subcutaneous exposure to either EE or E2 and that the thymus is a more sensitive target than the spleen with regard to subacute exposure to EE. In addition, EE at a comparable dose was more potent than E2 at exerting thymic and reproductive organ morphological alterations. Furthermore, route of administration is critical, as subcutaneous exposure induced far more dramatic thymic and reproductive morphological alterations than did oral administration. Future studies need to address the precise mechanism through which EE induces thymic atrophy and diminished thymus cellularity. Are these effects mediated directly through the thymus, perhaps through estrogen-induced increased thymocyte apoptosis or alterations to thymic epithelial cells? Or could EE be mediating alterations via bone marrow stem cells targeted for distribution to the thymus? Our novel findings regarding EE-induced effects on the thymus are of health significance and set the stage for future work. / Master of Science

Damage to dura mater may occur during intracranial or spinal surgeries, which can result in cerebrospinal fluid leakage as well as other potentially fatal physiological changes. As a result, biological scaffolds derived from xenogeneic materials are typically used to repair and regenerate dura mater post intracranial or spinal surgeries. In this study we explore the mechanics, structure, and immunological capacity of xenogeneic dura mater to be considered as a replacement for human dura. A comparative analysis is done between native porcine dura and a commercially available bovine collagen-based dura graft. Native porcine dura mater was decellularized and subjected to mechanical and histological analysis. Our decellularized porcine dura was able to maintain the overall morphological/structural integrity and held an increased extensibility without sacrificing strength, which provides a solid foundation as a functional grafting material. The histological observations showed that the orientation of fibers was maintained after decellularization. We investigated the biocompatibility of native and decellularized porcine dura reseeded with fibroblast cells for in vitro study. Cell proliferation, cell viability, and mechanical properties of dural grafts were evaluated post reseeding on days 3, 7, and 14. Live-dead staining and resazurin salts quantified cell viability and cell proliferation, respectively. This in vitro study showed that the acellular porcine dural graft provided a favorable environment for rat fibroblast cell infiltration. The results of micro indentation testing show that the cell-seeded porcine dural graft provides a favorable environment for rat fibroblast cell infiltration. The mechanics and biocompatibility results provide promising insight for the potential use of porcine dura in future cranial dura mater graft applications. Lastly, a subcutaneous in vivo study of dura graft compared with the market available Lyoplant®. Grafts were evaluated for inflammation by evaluating macrophage and leukocyte invasion on 3, 7, and 14 days post implantation. Histological analysis of both implants revealed macrophage (and leukocyte infiltration, supporting reabsorption, and thus encouraging the regeneration at 14 days. Cell markers also revealed that inflammation and leukocytes decreased as the number of days increased. Future work will involve a long-term subcutaneous implantation up to 30 days and 60 days to determine the long-term immune response.

Yes / Non-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology’s suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use. / University of Bradford

<p>Biotherapeutic compounds such as monoclonal antibodies help millions of people worldwide.  Currently, one of the most popular ways to deliver these compounds is via subcutaneous (SC)  injection. While it is understood that SC drug delivery does change with respect to injection  location, it is not understood why, as how the composition of SC changes as a function of location  is unknown. In this study, liquid chromatography mass spectrometry was used to understand and  describe how the SC tissue space changes on a molecular level. SC tissue from three different  locations, belly, breast, and behind the ear, of Yucatan minipigs was harvested and analyzed to  understand if and how SC tissue changes when anatomical location changes. It was determined  that there were distinct differences between the proteins identified in the three anatomical  locations. These differences included differences in relative cell populations, indicating that  different anatomical locations of SC tissue have different functions. Additionally, an ex vivo human SC tissue model was used to identify a core human proteome, as well as determine  compositional differences between female and male SC tissues. This model was also compared to  the Yucatan minipig model to determine compositional similarities between all groups. Finally,  proteomics were also used to ascertain whether the mass of SC tissue used affected the proteomic  results of the sample. These results indicated that human SC identifies the same number of proteins  down to samples of 10mg. This information can be used to design a proteomic experiment that  uses core needle biopsies to determine what gauge needle should be used in a wide scale clinical  study characterizing the human SC proteome. </p>

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / The role of enzyme‐assisted subcutaneous fluid administration (EASFA) in treating mild to moderate dehydration in pediatrics, geriatrics, and palliative care has been studied in developed countries. However, it has historically been underutilized due to widely available health care and alternative treatments, namely peripheral intravenous (IV) fluid administration. Fluid infusions in the subcutaneous tissue have a low risk of infection, are easy to administer, and have wide potential use. The use of EASFA in low resource settings to treat those with difficult IV access or where skilled healthcare workers are not as readily available could prove to be a live saving measure in many situations, including the care of patients in remote areas of the world, mass casualty events, or other disasters. Our objective was to determine if EASFA is a valid and appropriate technique to utilize in pediatric and elderly patients, and evaluate if it could be a safe and efficient way to provide fluid resuscitation in low resource settings. For this systematic review MEDLINE and Cochrane Library were searched from January 1950 to December 2015 to recover all available literature relevant to this topic. Studies that met the inclusion criteria were analyzed using Cohen’s D. This was calculated using the mean difference between intervention and control divided by the pooled standard deviation. For dichotomous outcome of the placement success rate the odds ratios were calculated with 95% confidence intervals. In reviewing 7 articles using Cohen’s D to compare mean differences to determine effect size, we found that catheter placement success rates and infusion rates were similar between EASFA and peripheral intravenous fluid administration. Additionally, it was found that the odds of correct initial needle placement was 7.19 times higher in EASFA versus intravenous administration. EASFA is a comparable alternative to intravenous fluid administration when delivering fluids to pediatric and elderly patients with mild to moderate dehydration. While infusion rates and total volume of fluids administered were similar, the high rate of success with placement of the subcutaneous catheter proves it to be more useful in some situations. Venous cannulation is difficult, even for a trained healthcare provider, and the ease of placement of subcutaneous catheters makes training lay people to administer subcutaneous fluids a possibility. Additionally, this type of fluid administration may lead to less psychological trauma to a child from multiple needle sticks, while still achieving a similar outcome of effective volume replacement. Based on the results of this study, further research is needed to evaluate the effectiveness of utilizing EASFA in low resource settings.

O Cimento de Ionômero de Vidro (CIV) é um material restaurador utilizado na Odontologia Minimamente Invasiva pois, além de apresentar propriedade adesiva à estrutura dental, apresenta propriedades tais como liberação e absorção de íons flúor, compatibilidade biológica com os tecidos bucais e coeficiente de expansão térmica similar ao da dentina. No entanto, o CIV apresenta baixa resistência mecânica, alta suscetibilidade à perda e ao ganho de água nas primeiras 24 horas (sinérese e embebição), período prolongado de presa e polimento ruim. Apesar desse material ter sido introduzido na Odontologia há mais de 40 anos, sua fórmula original vem sofrendo alterações, com o objetivo principal de aprimorar as propriedades mecânicas e alcançar melhores resultados clínicos. Dentre os CIV convencionais, destaca-se o EQUIA&reg; Forte Fil (GC Corporation, Tokyo, Japan), material elaborado com o objetivo de aprimorar as características físicas e estéticas do seu antecessor EQUIA&reg; Fil. No entanto, até o momento não existem trabalhos biológicos avaliando o desempenho do EQUIA&trade; Forte e Ketac&trade; Universal Aplicap&trade;. O objetivo deste estudo foi avaliar a resposta do tecido conjuntivo subcutâneo de camundongos isogênicos após implante de diferentes cimentos de ionômero de vidro (EQUIA&reg; Forte Fil, EQUIA&reg; Fil e Ketac&trade; Universal Aplicap&trade;). Foram utilizados 87 camundongos isogênicos da linhagem BALB/c divididos em 12 grupos, sendo 9 experimentais (Ketac, E. Fil e E. Forte nos períodos de 7, 21 e 63 dias) e 3 controles (tubos de polietileno vazios, nos mesmos períodos). Decorridos os períodos experimentais, a porção do tecido conjuntivo subcutâneo circundante ao material implantado foi removida e submetida ao processamento histotécnico e à coloração com hematoxilina e eosina. Foi realizada a descrição da reação tecidual em contato com cada material, análise semi-quantitativa do fibrosamento e do infiltrado inflamatório e análise quantitativa da espessura do tecido reacional granulomatoso em contato com o material testado ou tubo de polietileno. Os dados foram analizados estatisticamente (&alpha;=0,05), utilizando o teste de Kruskal-Wallis, seguido pelo Pós-teste de Dunn. Inicialmente, o fibrosamento não foi diferente entre os materiais testados (p>0,05), porém passou a ser diferente aos 21 dias, com o controle apresentando o estágio mais avançado de fibrosamento, e chegando ao final do experimento com o Grupo EQUIA&reg; Forte Fil com estágio mais avançado de fibrosamento, em comparação ao grupo EQUIA&reg; Fil (p<0,05). O infiltrado inflamatório, por sua vez, não apresentou diferença entre os materiais testados ao longo dos períodos experimentais (p>0,05). A área do tecido reacional granulomatoso foi maior para o Grupo E. Forte, diferindo do controle em todos os períodos avaliados (p<0,05). De acordo com os resultados obtidos, concluiu-se que todos os cimentos à base de ionômero de vidro testados apresentaram compatibilidade tecidual, de acordo com os diferentes parâmetros avaliados / The Glass Ionomer Cement (GIC) is a restorative material used in Minimally Invasive Dentistry. Besides it presenting adhesive properties to the dental structure, GIC has properties such as release and absorption of fluoride ion, biological compatibility with buccal tissues and expansion coefficient similar to that of dentin. However, GIC presents low mechanical resistance, high susceptibility to loss and water gain in the first 24 hours (syneresis and imbibition), prolonged setting time and poor polishing. Although this material was introduced in Dentistry more than 40 years ago, its original formula has undergone changes, with the main objective of improving the mechanical properties and achieving better clinical results. Among the conventional GIC, we highlight EQUIA&reg; Forte Fil, a material developed with the aim of improving the physical and aesthetic characteristics of its predecessor EQUIA&reg; Fil. However, there are no biologic researches evaluating the performance of EQUIA&reg; Forte and Ketac&trade; Universal Aplicap&trade;. The aim of this study was to evaluate the subcutaneous connective tissue response of isogenic mice after implanting different glass ionomer cements (EQUIA&reg; Forte Fil, EQUIA&reg; Fil and Ketac&trade; Universal Aplicap&trade;). Eighty-seven isogenic mice of the BALB/c were divided into 12 groups, 9 were experimental (Ketac, E. Fil and E. Forte at 7, 21 and 63 days) and 3 controls (empty polyethylene tubes at the same experimental time). After the experimental periods, the portion of the subcutaneous connective tissue surrounding the implanted material was removed and subjected to histotechnical processing and staining with hematoxylin and eosin. A description of the tissue reaction in contact with each material, semi-quantitative analysis of f collagen fiber formation and inflammatory infiltrate and quantitative analysis of the tissue thickness of the granulomatous reaction tissue in contact with the tested material or polyethylene tube were performed. Data were analyzed statistically (&alpha;=0.05) using the Kruskal-Wallis test, followed by the Dunn Post test. Initially, the collagen fiber formation was not different between the tested materials (p>0.05), but it became different at 21 days, with the control presenting the most advanced stage of collagen fiber formation, and reaching the end of the experiment with the EQUIA&reg; Forte Fil group with a more advanced stage of collagen fiber formation, compared to the EQUIA&reg; Fil group (p<0.05). Inflammatory infiltrate, on the other hand, showed no difference between the materials tested during the experimental periods (p>0.05). The tissue thickness was larger for the EQUIA&reg; Forte Fil group, differing from the control group in all evaluated periods (p<0.05). According to the results obtained, it was concluded that all the glass ionomer - based cements tested showed tissue compatibility, according to the different parameters evaluated