Introdução: A varfarina é um dos anticoagulantes orais (ACO) mais utilizados na atenção primária a saúde. Com janela terapêutica estreita, exibe grande variabilidade de resposta farmacológica, e maior suscetibilidade de eventos adversos, como sangramentos e tromboembolismo venoso. Entre os fatores que influenciam na variabilidade de dose destaca-se as interações tanto com medicamentos, como com a dieta e o polimorfismo genético. Objetivos: Estimar a incidência de eventos adversos relacionados ao uso de varfarina e descrever o itinerário do usuário pelo sistema público de saúde para resolução dos problemas. Métodos: trata-se de uma coorte prospectiva realizada por um período de 18 meses com usuários do serviço público de saúde, em uso de varfarina, do município de Ijuí/RS. Os dados foram coletados por entrevistas mensais nas residências e complementados com informações médicas obtidas na atenção primária e terciária. As interações medicamentosas foram checadas em bases de dados e os hábitos alimentares conforme metodologia validada. A estatística utilizada para associar sangramento e Time in Therapeutic Range (TTR) e os fatores de risco foi teste de Poison. O projeto foi aprovado no Comitê de Ética em Pesquisa da UFRGS, com parecer número 336.259/2013. Resultados: Foram entrevistados e acompanhados 69 pacientes, sendo que 64 concluíram o acompanhamento e 5 faleceram durante o estudo, 55,1% eram do sexo feminino, com idade média de 64,3 ±13,7 anos. O tempo médio de uso de varfarina foi de 5,5 anos, a dose média semanal foi de 30,69±15,19mg e o principal motivo para uso de varfarina foi prótese valvular (39,7%). A média de medicamentos utilizados por usuário foi de 9,6±4,5. Quanto aos eventos, os sangramentos tiveram incidência de 37,7/100 pacientes/ano, o tromboembolismo de 4,8/100 pacientes/ano e de óbitos de 4,8/100 pacientes/ano. Os sangramentos apresentaram associação com possuir mais que três interações medicamentosas com a varfarina (p=0,048) e com uso de medicamentos por automedicação (p=0,030). Já para o TTR houve associação com a idade inferior a 65 anos (p=0,032). E 67 usuários estavam suscetíveis a interações medicamentosasas com varfarina, com predomínio das moderadas, sendo a média de interações com este medicamento de 2,91±1,52. A maioria das interações agiam sobre o efeito anticoagulante da varfarina, aumentando a probabilidade de sangramento. Entre as interações que os usuários apresentavam, no momento do sangramento, as mais frequentes foram com: omeprazol, sinvastatina e paracetamol. A maioria dos entrevistados apresentou consumo baixo de vitamina K. Verificou-se que sangramentos e tromboembolismos venosos foram mais frequentes nos pacientes em início de tratamento. E todos os pacientes que foram a óbito durante o acompanhamento (5) eram pacientes com mais de um ano de uso de varfarina. Para a resolução de eventos adversos na maioria dos casos o paciente realizou cuidado domiciliar (53,4%), seguido por busca pela Unidades Básicas de Saúde, 7 pacientes buscaram o serviço de emergência e 5 realizaram internação hospitalar. Observou-se que aproximadamente metade dos pacientes não mostrou seus exames de INR (Razão Normalizada Internacional) ao médico. E na falta de varfarina na rede pública de saúde do município, que ocorreu entre os meses 13 e 16, entre 24,9 a 43,5%, deixaram de usar o medicamento. Os resultados do polimorfismo demonstram que 47 (71,2%) não apresentam polimorfismo ao genótipo CYP2C9, e 24 (36,4%) ao genótipo VKORC1. Avaliando os dois genótipos associados, verifica-se que 17 (25,8%) não apresentam polimorfismo a nenhum destes. Não foi observada associação estatística do polimorfismo com sexo e raça. Observou-se diferença significativa entre a dose utilizada para os diferentes polimorfismos (p=0,013). Da mesma forma, para o VKORC1, houve diferença significativa entre a dose e o genótipo (p=0,018). Conclusão: Estes resultados demonstram a necessidade de uma maior assistência a estes pacientes, buscando melhores resultados clínicos, com menos eventos adversos. / Introduction: Warfarin is an oral anticoagulant (OAC) most used in primary health care. With narrow therapeutic window, shows great variability in drug response, and greater susceptibility to adverse events such as bleeding and venous thromboembolism. Among the factors that influence the amount of variability highlights the interactions with both drugs, as with diet and genetic polymorphism. Objectives: To estimate the incidence of adverse events related to warfarin use and describe the user journey through the public health system to the problems. Methods: This is a prospective cohort study conducted over a period of 18 months with users of the public health service in the use of warfarin, the city of Ijuí/RS. The data were collected monthly interviews in homes and complemented with medical information obtained in primary and tertiary care. Drug interactions were checked in databases and eating habits as validated methodology. The statistics used to associate bleeding and Time in Therapeutic Range (TTR) and the risk factors was Poison test. The project was approved by the Research Ethics Committee of UFRGS, with opinion number 336259/2013. Results: We interviewed and followed 69 patients, 64 completed the follow-up and 5 died during the study, 55.1% were female, mean age 64.3 ± 13.7 years. The mean duration of warfarin use was 5.5 years, the average weekly dose was 30.69 ± 15,19mg and the main reason for warfarin use was valvular prosthesis (39.7%). The average per user used medications was 9.6 ± 4.5. As for events, the bleeding had incidence of 37.7 / 100 patients / year, thromboembolism of 4.8 / 100 patients / year and deaths of 4.8 / 100 patients / year. Bleeds were associated with having more than three drug interactions with warfarin (p = 0.048) and use of self-medication by drugs (p = 0.030). As for the TTR was no association with age less than 65 years (p = 0.032). And 67 users were susceptible to medicamentosasas interactions with warfarin, with a predominance of moderate, with an average of interactions with this drug of 2.91 ± 1.52. Most interactions acting on the anticoagulant effect of warfarin, increasing the probability of bleeding. Among the interactions that users had, at the time of bleeding, the most common were with: omeprazole, simvastatin and acetaminophen. Most respondents showed low consumption of vitamin K. It was found that bleeding and venous thromboembolism were more frequent in patients starting treatment. And all patients who died during follow-up (5) were patients with more than one year of warfarin use. For adverse event resolution in most cases the patient underwent home care (53.4%), followed by search for the Basic Health Units, 7 patients sought emergency services and 5 held hospitalization. It was observed that approximately half of the patients showed their INR test (International Normalized Ratio) to the doctor. And in the absence of warfarin in public municipal health, which occurred between the months 13:16, from 24.9 to 43.5% stopped using the drug. The polymorphism results demonstrate that 47 (71.2%) did not have the polymorphism CYP2C9 genotype, and 24 (36.4%) the VKORC1 genotype. Evaluating the two genotypes associated, it is found that 17 (25.8%) did not show any polymorphism thereof. There was no statistical association of the polymorphism with gender and race. A significant difference between the dose for different polymorphisms (p = 0.013). Likewise, for the VKORC1, a significant difference between the dose and genotype (p = 0.018). Conclusion: These results demonstrate the need for further assistance to these patients, looking for better clinical outcomes, with fewer adverse events.

Objetivo: O objetivo deste estudo foi avaliar clínica e hitologicamente a reação do material de preenchimento em dois sítios diferentes. Método: Vinte e duas femêas de ratos Wistar (Rattus novergicus) foram submetidas a aplicação de PMMA testando duas técnicas: subcutânea e transmuscular. Passados 3 meses do ato cirúrgico os ratos foram eutanasiados e as áreas injetadas foram excisadas, submetidas a técnica de inclusão em parafina e coloração por hematoxilina e eosina. As lâminas foram analisadas observando-se a resposta local à injeção do corpo estranho quanto ao grau de inflamação. Resultados: Foi encontrada diferença significativamente estatística entre os sítios muscular e subdérmico quanto a formação de granuloma (p<0,05), sendo que o grupo subdérmico obteve melhores resultados. Conclusão: A aplicação de materiais de preenchimento, que provoca maior trauma e sangramento nos tecidos, é a casusa de reações adversas. / Objective: The objective of this study was to evaluate clinical and hitopathology the reaction of the fill material at two different sites. Method: Twenty-two female Wistar rats (Rattus norvegicus) submitted the application of PMMA testing two techniques: subcutaneous and trans. After 3 months of surgery, the rats were euthanized and the injected areas were excised, subjected to paraffin embedding technique and stained with hematoxylin and eosin. The slides were analyzed by observing the local response to injection of foreign body in the degree of inflammation. Results: We found statistically significant differences between sites and subdermal muscle as granuloma formation (p <0.05), and the subdermal group achieved better results. Conclusion: The application of filling materials, which causes more injury and bleeding in the tissues, is Casusa of adverse reactions.

Background: There are approximately 12 million statin users in the United Kingdom. Reports of statin intolerance occurs between 7 and 29% of users, manifesting as muscle ache, fatigue or more seriously, muscle breakdown leading to myopathy. Creatine phosphokinase (CK) levels are used as a biomarker of statin-induced muscle damage. Non-adherence or discontinuation of therapy is a common result of intolerance and can result in negative cardiovascular disease-related outcomes. Aim: This thesis attempts to identify trends in record-linked medical data in a Scottish Caucasian cohort (GoDARTS) that best represent statin intolerance in order to study associated genetic factors. Methods: Prescribing trends such as switching or discontinuation of statin therapy were examined, and thresholds created to select true cases of intolerance. Information on CK levels was gathered from medical records and appropriate test results were utilized. Genotypic data was gathered for the variants and genetic regions of interest using a variety of methods including chip-based genotyping followed by imputation, TAQMAN genotyping, and exome sequencing. Subsequently hypothesis-based association analyses were conducted, including linear and logistic regressions, followed by meta-analyses, regional GWAS followed by a regional meta –analysis. Results: The phenotypes of statin intolerance were validated both internally and externally. Previously reported missense variants in LILRB5 (Asp247Gly) and CKM (Glu83Gly) were replicated and shown to be associated with CK levels irrespective of statin usage in the GoDARTS cohort and the clinical trial setting (JUPITER). Further, the CKM variant was also associated with inducibility of CK at times of tissue injury. The Asp247 genotype in LILRB5 was associated with increased risk of statin intolerance, and was replicated in associations with non-compliance to statin therapy and the development of myalgia in the JUPITER trial. The association with myalgia showed a stratified effect based on therapy (statin or placebo), with those on placebo showing the genotype effect. Further, the variant was also associated with increased risk of statin-induced myositis, cases of which had been clinically adjudicated and exome sequenced for the PREDICTION-ADR consortium. Further exploration of the LILR gene region showed an association with variants in LILRB2 (His20Arg and Val235Met) which were in strong LD with each other but were not in linkage with the variant in LILRB5. Stratified analysis revealed that the risk for carriers of the LILRB2 variants was increased depending on the genotype carried at the LILRB5 variant. Conclusions: This study characterises novel genetic factors associated with statin intolerance impacting adherence. The findings point to the immunomodulatory effects of statins. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a possible role for the immune system in their development. The findings encourage further investigation into the immune-physiology of statin-induced muscle damage and identifies genetically susceptible groups who are more likely to be statin intolerant.

It has been well documented that Adverse Childhood Experiences (ACEs) lead to unfavorable outcomes in later life, especially with regard to health and psychological outcomes. Recent research has demonstrated the impact of early childhood adversity on the onset of aggression and illegal behavior. However, often those with mental illness diagnoses with comorbid behavioral problems exhibit trajectories that include both arrest and hospitalization. While some are arrested for their criminal behavior, others are hospitalized. This begs the question: are those with mental illness and behavioral problems more likely to be arrested, or hospitalized, for their early behavioral problems? In the current study, it was hypothesized that arrest precedes hospitalization for the majority of these offenders, and that specific diagnoses of a mental illness are related to outcome. It was also hypothesized that early exposure to environmental adversity, as measured by the age of earliest ACE and total ACE score, would significantly predict whether offenders were arrested or hospitalized first. Other socio-ecological factors were also studied. The data for this study were gathered from a sample of 182 adult psychiatric inpatients in a secure forensic facility. Data were archival and retrospective in nature. All participants had been hospitalized following acts of violence or aggression, exhibiting a history of both behavioral problems as well as mental illness. A series of logistic and linear regressions were used to examine the relationship between reason for first admission to a psychiatric facility, diagnosis of a mental disorder, and early childhood adversity to clarify whether early problematic behaviors resulted in initial arrest or psychiatric hospitalization. Results indicate that subjects were much more likely to be hospitalized initially than arrested (33.5% arrested first, 66.5% hospitalized first). A diagnosis of impulse control disorder was significantly related to whether initial incident led to arrest or hospitalization (p=0.030), while the diagnosis of ADHD neared significance (p=0.056). No significant relationship was found between incidence of initial arrest or hospitalization and age that drug/alcohol abuse began. Other findings and implications for future research will be discussed.

Medication therapy is the most prevalent and critical intervention of health delivery and the source of most errors in healthcare. Medication errors and associated adverse drug events (ADE) have serious health and economic ramifications, and in elderly patients ADE are the leading cause of morbidity and mortality. Medication reconciliation is the process of evaluating current medication treatment to manage the risk and optimize the outcomes of medication treatment by detecting, solving, and preventing ADEs. This education project answered the question whether education provided to long term care staff would improve knowledge of medication reconciliation and be retained over time. The education program was developed through results of a literature search to identify evidence-based standards for medication reconciliation. The guiding theory for program was Kurt Lewin's theory of planned change. The test was developed on the medication reconciliation content and arrangements made for each of the 30 participants who were RNs, LPNs, and CMAs to take the test before and after the education program and again at 30 and 45 days. Results showed statistically significant improvement (p < 0.05) with knowledge of medication reconciliation retained at 30- and 45-days post intervention. Positive social change is possible as nurses and CMAs in the long-term care facility use the knowledge of medication reconciliation to improve patient medication safety for the long-term care residences in the facility. Through appropriate reconciliation, medication errors and ADEs can be reduced or prevented and patient outcomes improved.

Alzheimer's disease (AD) is defined as a progressive neurodegenerative disorder and is characterized by a devastating mental decline. There are three pathological hallmarks of the disease necessary for its diagnosis, these are extracellular amyloid plaques comprised of the beta-amyloid (Aβ) protein, intracellular neurofibrillary tangles comprised of hyperphosphorylated tau protein, and marked neuronal loss. Active immunization against Aβ1-42 or passive immunization with monoclonal anti-Aβ antibodies has been shown to reduce amyloid deposition and improve cognition in transgenic mouse models of AD, aged beagles, and nonhuman primates. Unfortunately, due to cerebrovascular adverse events, both active and passive immunization strategies targeting Aβ have failed in clinical trials. It is, therefore, necessary to identify novel amyloid-clearing therapeutics that do not induce cerebrovascular adverse events. We hypothesized that neuroinflammatory modulation could be a potential novel target. Triggering receptor expressed on myeloid cells-2 (TREM2) is a lipid and lipoprotein binding receptor expressed exclusively in the brain by microglia. Homozygous TREM2 loss of function mutations cause early-onset progressive presenile dementia while heterozygous, function-reducing point mutations triple the risk of sporadic, late-onset AD. Heterozygous TREM2 point mutations, which reduce either ligand binding or cell surface expression, are associated with a reduction in the number of microglia surrounding amyloid plaques, microglial inability to phagocytose compact Aβ deposits and form a barrier between plaques and neurons, an increase in the number of phospho- tau-positive dystrophic neurites and increased tau in the cerebrospinal fluid. Heterozygous mutations also double the rate of brain atrophy and decrease the age of AD onset by 3-6 years. Although human genetics supports the notion that loss of TREM2 function exacerbates neurodegeneration, it is unclear whether activation of TREM2 in a disease state is beneficial. The work we present here characterizes a TREM2 agonizing antibody as a potential therapeutic for amyloid reduction. We found that its administration results in immune modulation, recruitment of microglia to the site of amyloid plaques, reduced amyloid deposition and improvement in spatial learning and novel object recognition memory in the 5xFAD model of AD. More specifically, we show that intracranial injection of TREM2 agonizing antibodies into the frontal cortex and hippocampus of 5xFAD mice leads to clearance of diffuse and compact amyloid. We also show that systemic injection of TREM2 agonizing antibodies weekly over a period of 14 weeks results in clearance of diffuse and compact amyloid as well as elevated plasma concentrations of Aβ1-40 and Aβ1-42. Furthermore, systemic administration of these antibodies led to immune modulation and enhanced cognitive performance on radial arm water maze and novel object recognition tests. Importantly, we show the TREM2 agonizing antibody does not induce the adverse cerebrovascular events known to accompany amyloid modifying therapies. Though systemic administration of both TREM2 agonizing and anti-Abantibodies does not further enhance amyloid clearance or cognitive performance, co-administration mitigates the adverse cerebrovascular events associated with anti-Aβ antibodies. Collectively, these data indicate TREM2 activators may be an effective therapeutic target for the treatment of AD.

As the healthcare industry continues to change, dental providers are concerned about the different types of adverse events that can occur if systemic diseases are not well understood when treating patients. The purpose of this study was to explore the level of understanding among dental care providers of the relationship between oral care and systemic diseases and how these are linked to adverse events. The theoretical foundation that was used for this study was the Swiss cheese model. The research questions were designed to address the level of understanding among dental care providers of the link between oral care and systemic diseases as well as their perceptions of adverse events in dentistry and why they occur. Using a qualitative phenomenological approach, interviews were conducted with 10 dental care providers who practice in the New Jersey area. As I reviewed the field notes and listened to the audio recording, themes were developed to gain a deeper understanding of the research. The research findings revealed that dental providers have moderate knowledge of systemic disease and that some dentists had encountered an adverse event when providing oral care to patients; this experience led participants to look at patients' overall health instead of only oral care. Positive social change could result from improved training and education for dental providers to gain a better understanding of systemic diseases and systems such as the Swiss cheese model for preventing adverse events in patients with systemic diseases. Dental providers should be more involved with community services by providing health fairs to educate the public about why taking care of their oral health is as important as their physical health.

Objective: To investigate the association between hospital investment in human resources variables and patient safety, specifically after surgery adverse events in Florida hospitals. We performed the analysis to identify the association of after surgery complication rates with full time equivalent employees (FTEs) per admission and per patient day, expenses per admission and per patient day and, the percent of total operating expense accounted for by payroll expenses. Design: A cross sectional analysis using inpatient hospital discharge data and financial data from seventy short-term general hospitals, both for-profit and not-for-profit. Methods: Discharge data from year 2000 was obtained from Agency for Health Care Administration (AHCA). This data was used to calculate Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators (PSIs) related to after surgery complications in 840,945 hospital discharge records from 70 short-term general hospitals across the state of Florida. The predictor variables include: payroll expenditures per admission, payroll expenditures per patient day, personnel (FTE) per admission, personnel (FTE) per patient day and payroll expense as a percent of total operating expenses. Main outcome measures: Nine patient safety indicators defined by AHQR and specific to after surgery complications: complications of anesthesia, foreign body left during procedure, postoperative hemorrhage or hematoma, postoperative physiologic and metabolic derangement, postoperative pulmonary embolism or deep vein thrombosis, postoperative respiratory failure, postoperative sepsis, postoperative wound dehiscence. Results: Patient safety indicator rate showed an inverse relationship with the percent of total operating expense represented by payroll, Personnel per patient day and personnel per admission. The patient safety indicators showing significant relationship with hospital human resource characteristics are postoperative hemorrhage or hematoma (p=0.0002), postoperative hip fracture (p<0.0001), and postoperative sepsis (p=0.0371). Conclusion: Human resource investment is positively related to favorable outcomes, although the effect varies across the type of outcomes.

"April 1999." Includes bibliographical references (leaves 46-51). Aims to collect information about the numbers of dental workers who are sensitive or allergic to nickel and to help identify signs which might predict those people who are most likely to be sensitive to nickel. Uses a standard patch test to identify sensitive subjects.

Gestational diabetes (GDM) is a potentially serious disorder requiring timely diagnosis and management to prevent adverse maternal and fetal outcomes. Of increasing concern today, when treating the woman with GDM, is the need to provide every woman with an intensive management plan to optimise the likelihood of favourable pregnancy outcomes. Early identification of those women with GDM who require insulin therapy in addition to diet therapy would be beneficial in the planning and standardisation of clinical management protocols, to enhance pregnancy outcomes and increase cost benefits with improved allocation of resources. The aim of this study was to evaluate the ability of the fasting plasma glucose level (FPG) at diagnosis to predict an increased risk to the fetus and the need for insulin therapy in a pregnancy complicated by GDM. A prospective longitudinal study design and recruitment by convenience sample was used. Data were obtained from 327 women and their babies. Diagnosis of GDM was made by a 75 gram oral glucose tolerance test (OGTT) using Australasian Diabetes in Pregnancy Society (ADIPS) criteria with the exception of seven women diagnosed on a blood glucose level >11.1mmol/l. Following consent of the women data were collected by a self report questionnaire and the medical record system at three points; at first intervention, following delivery and at the postpartum OGTT. Demographic, social, medical, maternal and neonatal outcome data were collected. The management protocol was similar for all of the women. Following nutritional intervention any woman who could not meet the glycemic targets of <= 5mmol/l fasting and/or <= 6.5mmol/l two hours postprandial was commenced on insulin therapy. The women had a mean age of 32 years, body mass index (BMI) of 25.7 and parity of 2 (range 1-12). Diagnosis was made at an average of 30 weeks and 70 women required insulin therapy with a mean dose of 34 IU per day, commencing at a mean of 31 weeks gestation. Mean birthweight was 3400G. Of the babies 12% were >4000G. Congenital abnormalities occurred in 3%, neonatal morbidities in 2% and there was 1 death in utero. Logistic regression analysis found the following significant associations: Increasing maternal BMI was related to increasing FPG levels at diagnosis and the requirement of higher insulin doses. There was a negative linear relationship to weight gain. Ethnicity was associated with maternal BMI and ethnicity with BMI was associated with birthweight in the specific ethnic group. BMI with insulin therapy as a covariate and the FPG value at OGTT were predictive of persistent glucose intolerance in 14% of women postpartum. Each value of the OGTT was a significant predictor of the need for insulin therapy as a function of the week of gestation. The FPG level was the statistical model of best fit. A 50% probability for requiring insulin was reached with a FPG at diagnosis of 4.0 mmol/l if tested at 10 weeks gestation, 5.1mmol/l at 20 weeks and 6.1 mmol/l at 30 weeks (p<.001). These results support the substantive research aim of the study. The model has the power to predict the probability (risk) of requiring insulin therapy based on the maternal FPG level at the OGTT according to the week of gestation. The study results demonstrate that glucose intolerance is linked to a number of adverse maternal and fetal outcomes in a continuous and graded fashion. The degree of reversibility of maternal and fetal risk through therapeutic interventions such as nutrition therapy, blood glucose monitoring, exercise and active patient participation aimed at improving glucose tolerance is unknown. Therefore, the rationale for, and feasibility of, new treatment strategies such as the application of this statistical model as a management approach require large scale randomised intervention studies, oriented toward measuring maternal and fetal outcomes amongst different populations.