FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / INTRODUÃÃO: ReaÃÃes adversas a medicamentos - RAM constituem causa de morbi-mortalidade em pacientes hospitalizados, pÃem em risco a vida do paciente e representam aumento no tempo de internaÃÃo e nos custos hospitalares. OBJETIVOS: Determinar a incidÃncia de reaÃÃes adversas a medicamentos no Hospital UniversitÃrio Walter CantÃdio - HUWC, investigar quais os fatores que podem estar associados a esses eventos e propÃr medidas de prevenÃÃo ou reduÃÃo do impacto negativo dessas reaÃÃes. MÃTODOS: Estudo observacional, analÃtico, prospectivo, com monitorizaÃÃo intensiva de pacientes, determinaÃÃo da incidÃncia acumulada de RAM e avaliaÃÃo exploratÃria de seus determinantes. Eram incluÃdos no estudo, todos os pacientes internados nas clÃnicas mÃdicas do HUWC, de 01 de setembro de 2000 a 28 de fevereiro de 2001, os quais foram acompanhados desde o momento da internaÃÃo atà a alta hospitalar ou Ãbito, para a detecÃÃo e acompanhamento de reaÃÃes adversas. Foram realizadas visitas diÃrias Ãs clÃnicas mÃdicas do HUWC, registrando os medicamentos utilizados e investigaÃÃo sobre a ocorrÃncia de RAM. Os casos em que os pacientes apresentavam RAM eram avaliados seguindo a metodologia recomendada pela OrganizaÃÃo Mundial de SaÃde. As reaÃÃes eram classificadas conforme imputabilidade, gravidade e tipo. Os medicamentos foram classificados de acordo com o Anatomical-Therapeutical-Chemical â ATC, Classification Index e as reaÃÃes adversas atravÃs do WHO-ART tambÃm recomendado pela OrganizaÃÃo Mundial da SaÃde. RESULTADOS: Foram internados nas clÃnicas mÃdicas do HUWC um total de 970 pacientes destes, 54% eram mulheres e 46% homens, com idade variando de 9 meses a 97 anos. Todos os pacientes fizeram uso de medicamentos durante a internaÃÃo, variando de 1 a 20 medicamentos/paciente. Os grupos de medicamentos mais utilizados, (1 nÃvel ATC) foram medicamentos que atuam no sistema nervoso central (19,0%), medicamentos que atuam sobre o trato alimentar e metabolismo (17,0%), medicamentos que atuam no sistema cardiovascular (16,7%). Do total, oito (0,8%) tiveram como diagnÃstico de internaÃÃo alguma reaÃÃo adversa a medicamento. Durante o perÃodo do estudo foram verificadas 30 novas ocorrÃncias de RAM em pacientes hospitalizados. As manifestaÃÃes das reaÃÃes adversas compreendiam principalmente afecÃÃes da pele (65,0%) e distÃrbios do estado geral (25,0%). Quanto à gravidade, as reaÃÃes foram na sua maioria classificadas como moderadas (79,0%), seguidas das reaÃÃes leves (19,0%). A relaÃÃo de causalidade foi considerada provÃvel em 58,0% dos casos e definida em 24,5%. Os grupos farmacolÃgicos mais envolvidos foram antibiÃticos de uso sistÃmico (66,4%), seguido por medicamentos que atuam no sistema nervoso (7,7%), antineoplÃsicos e agentes imunomoduladores (7,7%). A incidÃncia de RAM entre os pacientes hospitalizados nÃo està associada ao sexo nem à idade. O nÃmero de dias de internaÃÃo interferiu na ocorrÃncia de RAM. CONCLUSÃO: Foram identificadas ocorrÃncias de reaÃÃes adversas como causa de internaÃÃo e durante a internaÃÃo hospitalar. Todos os pacientes admitidos com RAM apresentaram manifestaÃÃes dermatolÃgicas. Os antibiÃticos, principalmente a cefalotina, foram os medicamentos mais envolvidos com a ocorrÃncia de RAM em pacientes internados. / INTRODUCTION: Adverse drug reactions (ADR) constitute cause of morbidity in hospitalized patients, represent a risk for patients and an increase in the period patients stay in hospitals and the costs. OBJECTIVES: To determine the incidence of adverse drug reactions in the Walter CantÃdio University Hospital (WCUH), investigate what factors may be associated with these events and propose measures to prevent or reduce the negative impact of those reactions. METHODS: An observational, analytical, and prospective study, with intensive monitoring of patients, analysis of the cumulative incidence of ADR and an exploratory evaluation of its determinants. The study included all inpatients in the medical clinics of WCUH from September 1st, 2000 to February 28th 2001, which were assisted from admission until discharge or death, to detection and monitoring of adverse reaction. Daily calls were made to the clinics WCUH in order to register the use of drugs and the occurrence of ADR. Cases in which patients had ADRs were assessed according to the methodology proposed by the World Health Organization. The reactions were classified based on liability, severity and type. Drugs were classified according to the Anatomical-Therapeutical-Chemical (ATC), Classification Index and adverse reactions through the WHO-ART also recommended by the World Health Organization. RESULTS: 970 patients were admitted to the medical clinics of HUWC. Of those, 54% were women and 46% were men, ranging in age from 09 months to 97 years. All patients received medication during hospitalization, ranging from 1 to 20 drugs / patient. The most commonly used drug groups (1st level ATC) are drugs that act on central nervous system (19.0%), drugs that act on the digestive tract and metabolism (17.0%), and drugs that act on the cardiovascular system (16.7%). Of the total, in eight (8%) the diagnosis for admission was an adverse reaction to medication. During the study, 30 new cases of ADRs in inpatients were registered. The results of adverse reactions comprised mainly skin disorders (65.0%) and general disturbances (25.0%). About gravity, the reactions were mostly classified as moderate (79.0%), followed by mild reactions (19.0%). The relation of causality was considered probable in 58.0% of cases and set at 24.5%. Most involved pharmacological groups were antibiotics for systemic use (66.4%), followed by drugs that act on the nervous system (7.7%), antineoplastic and immunomodulating agents (7.7%). The incidence of ADR among inpatients is not associated with age or gender. The number of days of hospital admission interfered with the occurrence of RAM. CONCLUSION: Adverse reactions as cause of admission were identified. All inpatients with ADRs have skin manifestations. Antibiotics, especially cephalosporins, were drugs commonly involved with the occurrence of ADRs in inpatients.

Abstract Radiotherapy is used in the treatment of breast cancer in order to reduce local recurrence rate. However, radiation is known to cause both acute and delayed side-effects on normal tissues. A common late complication of radiotherapy is fibrosis of skin and other organs. Fibrosis has been described as excessive accumulation of extracellular matrix components, especially collagens. Collagens are a group of extracellular matrix proteins that provide connective tissues with tensile strength. Type I and III collagens are the major structural proteins in skin. Alterations in collagen synthesis occur in various pathological conditions, during ageing and in association with diverse medical therapies. Collagens are degraded by matrix metalloproteinase enzymes (MMPs). The activity of MMPs is restrained by their specific tissue inhibitors (TIMPs). Elastic fibres constitute about 2–4% of skin dry weight. Despite their low quantity, elastic fibres are responsible for the resilient and elastic properties of skin. Dermal elastic fibres may be affected by intrinsic ageing, by extrinsic reasons such as photodamage and in several connective tissue diseases. The effect of radiotherapy on human skin type I and III collagen synthesis was investigated in a group of women who had been treated for breast cancer surgically and with radiotherapy. The levels of MMP-9, MMP-2/TIMP-2 complex, TIMP-1 and TIMP-2 in irradiated skin were also analysed. The effect of radiotherapy on elastic fibres was analysed using skin samples. The physio-mechanical properties of radiotherapy-treated skin were studied using ultrasound and elastometer devices, and compared with those of non-treated skin. In addition, skin samples were stained for haematoxylin-eosin, tenascin and mast cells. Factor VIII immunostaining was performed to visualize dermal blood vessels. Wound regeneration in irradiated skin was also studied using suction blister as a model. The synthesis of type I and III collagens was markedly increased as a result of radiotherapy. An increased amount of cross-linked type I collagen was detected in irradiated skin, and collagen turnover was also increased in irradiated skin. No difference in the amount or structure of the elastic fibres could be found between radiotherapy-treated and non-treated skin. A slight increase of skin thickness and stiffness was found in irradiated skin compared to non-treated skin. Increased tenascin expression was found in irradiated skin. The number of dermal blood vessels visualized by FVIII immunostaining was slightly higher in irradiated than in control skin. The amount of mast cells positive for tryptase, Kit receptor and chymase was increased in the upper dermis of irradiated skin. No difference in epidermal regeneration was found between irradiated and non-treated skin. The results of this study suggest that alteration of collagen metabolism contributes to dermal side effects of therapeutic irradiation.

>Magister Scientiae - MSc / Healthcare professionals (HCPs) have a primary role to play in the detection, assessment and spontaneous reporting of adverse drug reactions (ADRs). An improvement of their related knowledge, attitude and practice concerning pharmacovigilance and ADR reporting is vital. The objective of the study was to determine whether or not pharmacovigilance training, provided by a Pharmaceutical Company, would improve HCP’s perceptions and adherence to pharmacovigilance and ADR reporting. A quasi-experimental research design was used. A total of 44 HCPs participated in the study. Participants were divided into two groups: an experimental group that received pharmaceutical training intervention; and a control group that did not receive any training. Using a self-administered questionnaire before and after the training intervention assessed the knowledge, attitudes, and practice of pharmacovigilance and ADR reporting displayed amongst the HCPs.

Class of 2005 Abstract / Objectives: The purpose of this retrospective investigation is to compare the quantity, importance, and associated cost implications of drug-related problems identified (and ultimately resolved) through order entry/verification versus other clinical activities of a decentralized critical care pharmacist. Methods: The data from this study was collected by one decentralized pharmacist assigned to a surgical intensive care unit. A standard form was used to document all interventions during the period of this observation. For the purposes of this retrospective evaluation the following data will be extracted from the existing database: amount of time spent performing various clinical activities, how drug-related problems were identified (e.g., order entry verification versus chart reviews), the time it took to identify and resolve drug-related problems, a general description of interventions, the importance of the intervention, and the estimated economic impact associated with interventions. Results: In only a 41⁄2 month period, 111 patients would have likely experienced an adverse drug event had the ICU pharmacist not intervened. This equals a cost avoidance to the institution of anywhere from $200,000 to $280,000 for as little on average of 15-30 minutes of the pharmacist time. Implications: As previous studies have shown, the presence of a pharmacist in an ICU is crucial to lowering the incidence of adverse drug events. Our results have proven the interventions pharmacist make during team rounding and chart review are not only cost effective, but substantially improve patient care.

Background: Adverse events are poor health outcomes caused by medical care rather than the underlying disease process. Voluntary reporting is a key component to adverse event reduction; however, incident reporting systems contain many limitations. The Patient Safety Learning System (PSLS) is an electronic incident reporting system with several unique features that were designed to address the weaknesses of previous systems, including a process for physician assessment of reported events to determine their significance. The primary objectives for this study were to determine the positive predictive value of the PSLS for identifying adverse events. Secondary objectives were to identify event, patient, and system-level factors associated with true events, and to assess event rates over time. Methods: I performed a retrospective cohort study using electronic health care data collected data from the Ottawa Hospital, between April 1 2010 and September 30, 2011. We Included all reported patient safety events if they occurred in adults aged 18 and older, admitted to an inpatient ward at the Civic, General, or Heart Institute campus. Events that occurred on Psychiatry, Rehabilitation services, were excluded due to data restrictions. A Clinical Reviewer manually reviewed each event to distinguish true events from non-events. For each hospital program, we used a generalized linear mixed model (GLIMMIX) to predict true events, using the role of the reporter as a random effect. Results: Over the study period, there were 2,569 events reported by hospital staff and physicians. Of these, 660 were rated as adverse events and 1,909 were rated as near misses. This yielded an overall positive predictive value of the PSLS system of 63% (95% CI 62-65%). The variance between reporters was not significant for Critical Care, Heart Institute, Nephrology, Obstetrics and Gynecology, Surgery and Periops, therefore I used a traditional logistic regression model with a common intercept. Number of months the PSLS was available was the only significant covariate found in all programs; the direction of the relationship was the same across all programs, and showed a decrease in true events reported over time. Other common covariates included: time from admission to event, severity of illness, and admission type. All models achieved a good calibration, yet discrimination was poor (c <0.70) in all models except Heart Institute. Discrimination ranged from 65% in Critical Care to 77% in the Heart Institute. Overall, the rate of patient safety events reported for inpatients was 6.39 per 1000 patient days. After an initial learning period, from April 2010-January 2011, in which rates were low, reporting rates increased and stabilized; remaining constant from month to month. The rate of true patient safety event reporting fluctuated greatly from April 2010-January 2011, after which they began to steadily decline. Trends in reporting were similar across hospital campus, reporter, and program. The majority of patient safety events were reported by nurses (44%), and laboratory staff (42%). The remaining 14% of events were reported by the classification ‘Other,’ which included all other hospital staff, such as technicians, physicians, and administrative staff. Only 7 physicians reported events to the PSLS during my study period, therefore, they were categorized under ‘Other’. Conclusions: Despite the many unique advantages of the PSLS, the proportion of true events reported has remained low. The overall utility of statistical models to predict patient safety events is limited. The traditional patient and system-level covariates, which are used to predict risk of adverse outcomes with high accuracy, did not help us discriminate between true patient safety events from non events. It is possible that many different individual and institutional barriers are influencing reporting and perhaps reviewing behavior, which in turn leads to non-clinical variability in what gets reported and classified as a patient safety event.

Background Previous measurements of preventable death in hospital do not account for the uncertainty of preventability ratings. Objective To determine the proportion of deaths in hospital that a have high probability of being prevented with high quality care. Methods We created summaries for every death at a tertiary care hospital over 4-months. Four reviewers assigned preventability ratings to each death and latent class analysis was used to classify deaths into high and low preventability categories. Results There were 480 decedents with mean age of 73.9. Inter-rater reliability was poor with an intra-class correlation of 0.14. The best latent class model found that 6.2% (95% CI 0.00 – 15.2%) of deaths had a 31.0% probability of being rated more likely preventable than not by each reviewer. In contrast, 93.8% (95% CI 84.8 - 100.0%) of deaths had a 0.8% probability of being rated more likely preventable than not by each reviewer. The incidence of truly preventable deaths is less than the 6.2% that are deemed possibly preventable. xi Conclusion Very few deaths in hospital are preventable. The low incidence of preventable deaths and low inter-rater reliability means that peer review methodology is only sensitive to large differences in preventable death rate.

The role of cholesterol-rich diet and of high protein supplement on the development of a glomerular lesion was studied in male guinea pigs. The possible pathogenesis of lipid-induced glomerulosclerosis was investigated. Four experiments were carried out. Four groups of guinea pigs were used in experiment I: CONT group was kept on normal guinea pig chow for 70 days; HC group was kept on 2% cholesterol diet for 70 days; HP group was kept on 50% casein diet for 70 days, and HCHP group received 2% cholesterol diet for 30 days and 2% cholesterol/50% casein diet for another 40 days. In experiment II two groups were used: CONT group and acetyl phenylhydrazine (APH)-treated group in which haemolytic anaemia was induced. In the third experiment the same dietary regimens as described in experiment I were used. In experiment IV three groups, namely CONT, HC, and HCHP, were employed. The animals in experiment IV were sacrificed after 5, 10, and 30 days. The first experiment explored the role of high cholesterol - and high cholesterol/high protein diet in the development of glomerulosclerosis. The other three experiments were designed to learn about the possible mechanism of lipid-induced glomerulosclerosis. Lipid analyses of plasma, erythrocytes and kidney tissue as well as complete blood count, erythrocyte osmotic fragility and blood cell morphology studies were performed. Kidney histology, histochemistry, immunohistochemistry, electron microscopy, morphometry, and renal and liver function tests were also carried out. De novo cholesterol synthesis was assessed by measuring HMG COA reductase activity and incorporation of tritiated water into cholesterol in the kidneys. Cholesterol-fed animals showed decreased weight gain, increased cholesterol concentration in plasma, erythrocytes, and kidney tissue. Haemolytic anaemia was documented after 70 days on this dietary regimen. Glomerular proliferation lesion was first noted at day 30 and progressed by day 70. Moderate proteinuria and haematuria were observed at day 70. Addition of protein to the high cholesterol diet led to a further decrease in weight gain. It also increased the mortality rate to 40% by day 70. The glomerular lesion, proteinuria and haematuria, and possibly haemolysis were more marked in the HCHP group. No causal relationship was found between liver function, immune complexes, haemolysis and glomerulosclerosis. Serum phosphate levels did not differ among the groups. The lipid found in the kidney of both HC and HCHP groups was mostly of plasma origin, since the kidney cholesterol de novo synthesis was suppressed in these two groups compared to the CONT group. There was a concommitant increase in the lipid content of kidney tissue and the mesangial expansion (MA/GTA) at day 30. No significant increase in the intraglomerular monocyte/macrophage was found at day 30 in the HCHP group compared to the HC group. However, a significant correlation (r=0.678, p 0.001) was found between the number of these cells and MA/GTA ratio among the four experimental groups at day 70. These data indicate that lipid deposits in kidney tissue may induce a glomerulosclerotic lesion in the absence of monocytes. However, these cells likely augment the proliferation of mesangial cells. We postulate that high protein diet could worsen the lipid-induced glomerular lesion by increasing delivery of abnormal lipoproteins to the kidney which could trigger mesangial cellular proliferation directly and indirectly by a macrophage-mediated process. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Introduction. The high cost and concern of adverse events, particularly infections, limit the use of biologic disease-modifying anti-rheumatic (bDMARD) therapies. We undertook this retrospective study to document their use for immune-mediated diseases (IMDs) and explore the efficacy, safety, adherence and screening practices prior to initiating bDMARDs in a tertiary referral hospital. Methods. A folder review of all adult and paediatric patients treated for IMDs with bDMARDs at Groote Schuur and Red Cross Hospitals between January 2013 and December 2019. Clinico-demographic particulars, details of bDMARD therapy, and adverse events were collated. Changes in disease activity were measured by diseasespecific tools at 6, 12, 24-months and at the last available visit, and patient adherence to bDMARDs was explored by folder and pharmacy record review. Results. We studied 151 folders, with 182 bDMARDs uses (29 patients used more than 1 bDMARD). Patients were from rheumatology (n= 38: 13 rheumatoid arthritis; 10 spondyloarthritis, 5 Systemic Lupus Erythematosus (SLE) , 5 inflammatory myositis and 5 other conditions); gastroenterology (n=31; 26 Crohn`s and 5 Ulcerative Colitis), dermatology (n=9; psoriasis), neurology (n=4, ophthalmology (n= 25; 6 scleritis, 18 uveitis, 1 optic neuritis), and paediatrics (n= 45, 26 juvenile idiopathic arthritis , 12 SLE, 7 other conditions). The bDMARDs used were TNF inhibitors (112), rituximab (55), tocilizumab (10), anakinra (3), abatacept (1), and tofacitinib (1). The vast majority of patients had an excellent response and were in low disease activity or remission at their last available visit. Adverse events included severe infection (4), tuberculosis (TB) (2), mild infection (4), severe allergic reaction (3), mild skin reaction (14), elevated liver enzymes (2), and worsening interstitial lung disease ILD (1). bDMARD Therapy was discontinued in 18 patients, most commonly due to adverse reaction (9), lack of response (3), poor adherence (2), or remission (1). bDMARD Therapy was changed to alternative therapy in 29 patients, most commonly because of poor response (14), or adverse effects (9) or poor adherence (3). Poor adherence or patients lost to follow-up was noted in 18/182 (9.9%). Complete latent TB infection screening with chest x-ray and TB skin test was performed in only 55 (36.4 %) but INH prophylaxis was given to 51/88 (57.9%) of patients prescribed TNFi therapy. Hepatitis B screening performed in 93 (61.6 %) patients, but most patients (72.2 %) were not tested for Hepatitis B core ab. Hepatitis C screening was performed in 81 (53.6 %) patients. Only 88 (58.3%) patients had a recent HIV test. The majority (17.2%) received the influenza vaccine, but only 24 (15.8 %) received pneumococcal vaccination. Discussion and Conclusion. bDMARD therapy was an effective treatment, and the most common adverse effect was infection (7.2%), with 2 TB infections. Vaccination and screening for TB, viral hepatitis and HIV was suboptimal. Of concern, poor adherence to bDMARDs was frequently encountered.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / The goals of this research were to characterize suicidal behavior among a cohort of pregnant Peruvian women and identify risk factors for transitions between behaviors. The World Health Organization Composite International Diagnostic Interview suicide questionnaire was employed to assess suicidal behavior. Discrete-time survival analysis was used to study the cumulative age-of-onset distribution. The hazard function was calculated to assess the risk of onset of each suicidal behavior. Among 2062 participants, suicidal behaviors were endorsed by 22.6% of participants; 22.4% reported a lifetime history of suicidal ideation, 7.2% reported a history of planning, and 6.0% reported attempting suicide. Childhood abuse was most strongly associated with suicidal behavior, accounting for a 2.57-fold increased odds of suicidal ideation, nearly 3-fold increased odds of suicide planning, and 2.43-fold increased odds of suicide attempt. This study identified the highest prevalence of suicidal behavior in a population of pregnant women outside the USA. Diverse populations of pregnant women and their patterns of suicidal behavior transition must be further studied. The association between trauma and suicidal behavior indicates the importance of trauma-informed care for pregnant women. / Revisión por pares

Adverse childhood experiences (ACEs) are stressful or traumatic events that occur during childhood that impact health and wellbeing, thus having long-lasting effects. In the context of parenting, a history of ACEs can impact a caregiver’s ability to manage stress and interfere with their ability to provide sensitive and regulated caregiving. Thankfully, there are many ways that one can foster resilience in the face of past ACEs. This study aims to help mothers combat ACEs and parenting stress by experimentally investigating the benefits of two resilience-building programs. The first is an emotion-based program that focuses on emotion regulation, self-care, and attachment theory. The second is a behavior-based program that focuses on developmental milestones and general behaviorally based parenting practices (e.g. positive reinforcement, punishment). The present project uses a pre/post/follow-up design to assess parenting stress before and after engagement in the resilience-building programs. Mothers of 3-year-old children will complete the ACEs Questionnaire, which assesses how many and what specific ACEs participants have (pre-assessment), and the Parental Stress Scale (PSS), which assesses their parenting stress (pre, post, follow up). Although statistical analyses will be conducted to examine differences in PSS scores, the ACEs Questionnaire will only be used to ensure that the sample examined is mothers with ACEs, as participants who report no ACEs will be excluded from data analysis. In addition to self-report questionnaires, participants visit the Affect, Regulation, Coping, and Health (ARCH) lab to complete moderately stressful tasks while physiological data is obtained; data from lab visits will not be analyzed in this project but will be collected since this research is a part of a larger study called the 2Gen: Feeling Better Project (2Gen) that aims to examine emotion coregulation and physiological synchrony between mothers and their three-year-old children. After the pre-assessment, participants will be randomly assigned to one of the two 8-week programs (Emotion Curriculum, Behavior Curriculum) which will be provided through electronic links to brief videos. Participants also receive binders with the video scripts, handouts, resources, and reflection questions for each week’s content. Due to being at early stages in data collection, the present project will summarize the 2Gen protocol and will simulate data using mean parenting stress values from comparable studies. That simulated data will then be analyzed using JASP, an open-source statistics software. A 2x2 factorial ANOVA will be run to compare pre and post PSS scores for the emotion and behavior-based resilience-building programs. We hypothesize that parenting stress scores will decrease for all participants; however, we anticipate this change to be greater for those who receive the emotion-based program.