Análise de custo-efectividade da terapêutica de ressincronização cardíaca : avaliação da selecção baseada na dessincronia mecânica

RESUMO - A Terapêutica de Ressincronização Cardíaca (TRC) apresenta benefícios significativos na classe funcional, função ventricular, hospitalização e mortalidade. É uma técnica com custos elevados e, com os actuais métodos de selecção de doentes, a taxa de não-respondedores ronda os 30%. Objectivo: Compreender se a inclusão da dessincronia mecânica (DM) na selecção de doentes para TRC contribui para a sua relação custo-efectividade, na perspectiva do Serviço Nacional de Saúde português. Metodologia: Estudo prospectivo baseado em coortes histórias de 12 meses de dois grupos submetidos a TRC com desfibrilhador, o grupo de intervenção com doentes seleccionados com inclusão da DM (n=133) e o de controlo com selecção baseada exclusivamente nas recomendações internacionais (n=71). Reuniram-se dados clínicos e de custos nos 12 meses subsequentes à implantação, para cálculo do rácio custo-efectividade incremental (RCEI). Resultados: O grupo de intervenção apresentou uma sobrevivência de 91% e o de controlo de 93%, aos 12 meses (p=0,335). O grupo de intervenção apresentou 60 re-internamentos e o de controlo 46 re-internamentos por qualquer causa aos 12 meses (p=0,032), com RCEI=6.886,09€/re-internamento evitado. O grupo de intervenção apresentou 19 re-internamentos e o de controlo apresentou 31 re-internamentos por Insuficiência Cardíaca (IC) descompensada aos 12 meses (p<0,001), com RCEI=2.686,26€/re-internamento por IC descompensada evitado. Relativamente à melhoria da classe funcional e da fracção de ejecção não foi possível estabelecer associações com custos (p>0,05). Conclusão: É seguro afirmar que recomendar a selecção com inclusão da DM, nos hospitais com capacidade instalada, é um passo positivo na redução de custos com re-internamentos de doentes com TRC.

Life cycle and reproductive patterns of Triatoma rubrovaria (Blanchard, 1843) (Hemiptera: Reduviidae) under constant and fluctuating conditions of temperature and humidity

The aim of this study was to evaluate the temperature and relative humidity influence in the life cycle, mortality and fecundity patterns of Triatoma rubrovaria. Four cohorts with 60 recently laid eggs each were conformed. The cohorts were divided into two groups. In the controlled conditions group insects were maintained in a dark climatic chamber under constant temperature and humidity, whereas triatomines of the ambiental temperature group were maintained at room temperature. Average incubation time was 15.6 days in the controlled conditions group and 19.1 days in the ambiental temperature. In group controlled conditions the time from egg to adult development lasted 10 months while group ambiental temperature took four months longer. Egg eclosion rate was 99.1% and 98.3% in controlled conditions and ambiental temperature, respectively. Total nymphal mortality in controlled conditions was 52.6% whereas in ambiental temperature was 51.8%. Mean number of eggs/female was 817.6 controlled conditions and 837.1 ambiental temperature. Fluctuating temperature and humidity promoted changes in the life cycle duration and in the reproductive performance of this species, although not in the species mortality.

Undrestanding postoperative cognitive dysfunction: novel insights

ABSTRACT: Background: Sleep is integral to biological function and sleep disruption can result in both physiological and psychological dysfunction. The acute cognitive consequences of sleep loss has been an active field of recent investigation, evidence suggests that sleep disruption in critically ill older adults can result in acute decrements in cognitive functioning. Surgery activates the innate immune system, inducing neuroinflammatory changes that interfere with cognition. The fact that patients with sleep disorders have an increased likelihood of exhibiting postoperative delirium encourages us to investigate the contribution of perioperative SF to the neuroinflammatory and cognitive responses of surgery. Methods: The effects of 24h sleep fragmentation (SF) and surgery were explored on adult C57BL/6J male mice. SF procedure started at 7 am with the home-cages being placed on a large platform orbital shaker cycled every 120 seconds (30 sec on/90 sec off). This procedure lasted for 24h. Stabilized tibia fracture was performed either before or after the 24h SF procedure. Separate cohorts of mice were tested for systemic and hippocampal inflammation and cognition. Results: Twenty-four hours of SF induced non-hippocampal memory dysfunction and increase in systemic IL-6. SF and surgery caused hippocampal-dependent memory impairment, although memory impairment was not exacerbated by combining SF with surgery. One day after either SF or surgery there was a significant increase in IL6 mRNA and TNF-alpha mRNA. These increments were more pronounced when either pre or post operative SF was combined with surgery. Conclusions: We show that while SF and surgery can independently produce significant memory impairment, perioperative SF significantly increased hippocampal inflammation without further cognitive impairment. The dissociation between neuroinflammation and cognitive decline may relate to our use of a sole memory paradigm that does not capture other aspects of cognition, especially learning.

Prevalence of hepatitis A virus infection: the paradoxical example of isolated communities in the western Brazilian Amazon region

This study evaluated the prevalence of hepatitis A virus infection in the rural area of Lábrea, in the western Brazilian Amazon region. Communities and households were selected randomly. Serum samples were analyzed by means of the immunoenzymatic method for the presence of total antibodies against HAV. The study included 1,499 individuals. The prevalence of anti-HAV was 74.6% (95% CI 72.3-76.8). Univariate analysis showed associations with age (chi-square for linear trend = 496.003, p < 0.001), presence of outside toilet (p < 0.001), history of hepatitis (p < 0.001) and family history of hepatitis (p = 0.05). After adjusting for age, HAV infection also showed an association with the number of people in the family (p = 0.03). The overall prevalence rates were high, but not more than 60% of the children under the age of ten years had already been infected. Very high prevalence was detected only within older cohorts, thus paradoxically defining this as a region with intermediate endemicity, even under the conditions of poverty encountered.

Predição precoce de risco de Pré-eclâmpsia na doença hipertensiva e diabetes na gravidez: Papel de fatores angiogénicos

RESUMO: A pré-eclâmpsia tem elevada morbi-mortalidade materna e perinatal. A sua etiologia multi-fatorial tem sido objeto de investigação, não sendo ainda totalmente conhecida. Não se conhece também a razão da diferente suscetibilidade individual e das diferentes expressões da doença. A hipertensão crónica e a diabetes são fatores de risco reconhecidos, e o adiamento da maternidade contribui para que estas duas patologias sejam atualmente mais prevalentes entre as mulheres grávidas. Uma vez que o seu quadro fisiopatológico precede em meses o quadro clínico, tem-se investigado a possibilidade de serem encontrados marcadores precoces e indicadores de risco. Em Portugal, os estudos relativos à hipertensão na gravidez são escassos, bem como a investigação sobre fatores de risco e marcadores para a mesma. No sentido de avaliar possíveis marcadores de risco para o desenvolvimento de préeclâmpsia ou complicações hipertensivas foi colhida, para esta dissertação, uma amostra de 1215 mulheres que frequentaram a consulta de Hipertensão ou de Diabetes na gravidez de um centro terciário, entre 2004 e 2013. Optou-se pela realização de três estudos independentes, abrangendo os dois primeiros um leque temporal de 9 e de 2 anos respetivamente. O primeiro, centrado na hipertensão, pesquisou, em 521 mulheres com hipertensão na presente ou em anterior gravidez, fatores de risco capazes de influenciar a progressão para pré-eclâmpsia. O segundo, direcionado para a diabetes gestacional, considerou uma amostra de 334 grávidas, parte das quais tinha também hipertensão crónica e procurou identificar fatores que contribuíram para o aparecimento de complicações hipertensivas. O terceiro estudo, realizado em 2012 e 2013, em três coortes de grávidas com hipertensão crónica, com diabetes gestacional, e sem estas patologias - procurou avaliar no 1º trimestre o comportamento de dois marcadores placentares obtidos no 1º trimestre - proteína plasmática A associada à gravidez (PAPP-A) e o fator de crescimento placentar (PlGF) - e o seu papel, quer como bio-marcadores isolados, quer em associação aos fatores de risco encontrados nos anteriores estudos, na construção de um modelo preditivo de préeclâmpsia. No primeiro estudo, a nuliparidade, a hipertensão gestacional, a fluxometria das artérias uterinas com IP superiores ao P95 entre as 20-22 semanas e a existência de restrição de crescimento fetal, foram os fatores que contribuíram para a construção de um modelo preditivo de pré-eclâmpsia. No segundo estudo, a coexistência de diabetes e hipertensão crónica agravou o prognóstico, associando-se as complicações hipertensivas à multiparidade, obesidade, idade materna e etnia negra. No terceiro estudo verificou-se uma redução da PlGf e da PAPP-A no 1º trimestre nas duas primeiras coortes, comparativamente à coorte sem patologia; na análise separada de cada coorte, quando se verificaram complicações hipertensivas ou pré-eclâmpsia, as concentrações de PlGf e PAPP-A também foram inferiores. Contudo, na elaboração de um modelo preditivo de pré-eclâmpsia, em conjunto com marcadores encontrados, apenas a PlGf pode ser integrada no modelo preditivo, o que se verificou na coorte com hipertensão crónica. Os marcadores bioquímicos em estudo tiveram valores inferiores nas coortes com patologia hipertensiva, demonstrando uma deficiente produção destas proteínas placentares nestas situações, podendo ser importante a sua pesquisa. Contudo, neste estudo, apenas na coorte de hipertensão crónica a PlGf teve participação como fator de risco, na construção de um modelo preditivo de pré-eclâmpsia.--------------------------------------------------------------------------------------------------ABSTRACT: Preeclampsia is associated with a great maternal and perinatal morbimortality. Its multifactorial etiology has been under investigation and is still insufficiently understood. The reason why there are differences in individual susceptibility and differences in expressions of the disease is still unknown. Chronic hypertension and diabetes are known risk factors for preeclampsia and maternity delay contributes to the great prevalence of these pathologies among pregnant women. As the physiopathological signs antedate by months the clinical course of the disease, early risk factors and biological markers are object of clinical research. In Portugal, scarce clinical studies were devoted to hypertension in pregnancy and to risk factors and markers of this pathology. This dissertation inquires 1215 pregnant women who were treated for hypertension or diabetes in a tertiary care center between 2004 and 2013, in order to find risk markers for hypertensive complications or preeclampsia. We conducted three independent studies for this purpose. In the first one we investigated which risk factors could influence the progression to preeclampsia in 521 pregnant women with present or past history of hypertension. The second one was conducted to find what factors were associated to hypertensive complications, with a sample of 334 pregnant women with gestational diabetes, some also with chronic hypertension, addressing the identification of the factors contributing to hypertensive complications. The third study was conducted between 2012 and 2013 with three cohorts of pregnant women, with chronic hypertension, gestational diabetes, and in the third one, pregnant women had a low risk pregnancy. The objective of the study was to evaluate the behavior of two placental markers – PAPP-A and PlGf – obtained in the first trimester, and the role of these markers as isolated biomarkers or in association with other risk factors, in order to define a predictive model of early preeclampsia. In the first study, nuliparity, gestational hypertension, uterine arteries doppler with PI above P95 between 20-22 weeks of gestation and the presence of fetal growth restriction were the markers involved in a predictive model for preeclampsia. In the second study the cohort with the coexistence of diabetes and hypertension had registered worse result and hypertensive complications were associated to multiparity, obesity, maternal age and black ethnicity. In the third study there was a reduction of the PlGf and a PAPP-A concentration for the first trimester in the two first cohorts comparatively to the low risk cohort; the separate analysis of each cohort showed that plGf and PAPP-A concentrations were reduced when hypertensive complications appeared. However, when trying to find a preeclampsia predictive model, only plGf gave significant results for being considered in the model and this was only possible in the chronic hypertension cohort. The biochemical markers investigated in this study were reduced in the cohorts when high blood pressure complications occurred, showing a defective production of these placenta proteins, and suggesting that they should be investigated as first trimester biomarkers. Nevertheless, for this research, in the cohort of chronic hypertension only PlGf had a significant result, when multivariate analysis of all the risk factors was considered for the construction of a preeclampsia predictive model.

Para uma pedagogia das literacias: das conceções e práticas docentes aos conceitos e competências discentes. Um estudo da aula de língua portuguesa no 2º ciclo do ensino básico

Tese de Doutoramento em Ciências da Educação (Especialidade em Literacias e Ensino do Português)

Neurocognitive profile and cognitive intervention in Alzheimer's disease

Tese de Doutoramento em Psicologia (Especialidade de Psicologia Clínica)

Reversibility of ventricular dysfunction: clinical experience in a medical office

OBJECTIVE - To describe clinical observations of marked improvement in ventricular dysfunction in a medical office environment under circumstances differing from those in study protocols and multicenter studies performed in hospital or with outpatient cohorts. METHODS - Eleven cardiac failure patients with marked ventricular dysfunction receiving treatment at a doctors office between 1994 and 1999 were studied. Their ages ranged from 20 and 66 years (mean 39.42±14.05 years); 7 patients were men, 4 were women. Cardiopathic etiologies were arterial hypertension in 5 patients, peripartum cardiomyopathy in 2, nondefined myocarditis in 2, and alcoholic cardiomyopathy in 4. Initial echocardiograms revealed left ventricular dilatation (average diastolic diameter, 69.45±8.15mm), reduced left ventricular ejection fraction (0.38±0.08) and left atrial dilatation (43.36±5.16mm). The therapeutic approach followed consisted of patient orientation, elimination of etiological or causal factors of cardiac failure, and prescription of digitalis, diuretics, and angiotensinconverting enzyme inhibitors. RESULTS - Following treatment, left ventricular ejection fraction changed to 0.63±0.09; left ventricular diameters changed to 57.18±8.13mm, and left atrium diameters changed to 37.27±8.05mm. Maximum improvement was noted after 16.9±8.63 (6 to 36) months. CONCLUSION - Patients with serious cardiac failure and ventricular dysfunction caused by hypertension, alcoholism, or myocarditis can experience marked improvement in ventricular dysfunction after undergoing appropriate therapy within the venue of the doctor's office.

A Infância na latitude zero: as brincadeiras da criança 'global' africana

Tese de Doutoramento em Estudos da Criança (área de especialização em Sociologia da Infância).

Molt cycle of the natural population of Palaemonetes argentinus (Crustacea, Palaemonidae) from Los Padres Lagoon (Buenos Aires, Argentina)

The molt cycle of the natural population of Palaemonetes argentinus Nobili, 1901 from Los Padres Lagoon, Buenos Aires, Argentina, was studied in relation to age, sex, and environmental factors. A total of 1645 individuals (740 females, 539 males, and 366 juveniles) were collected and analyzed between December 1995 and December 1996. The results indicate that the sex ratio (males:females) remains around 1:1.4 throughout most of the year. The reproductive period extends from September until February (spring and summer), with maximum sexual activity in October and November. Two cohorts originated in the spring and in the summer were differentiated. Ovigerous females arrest their molt cycle during the intermolt period to restart it after oviposition. The duration of the intermolt period does not differ between adults and juveniles. Since the percentage of premolt individuals represents 60% of the total cycle, it was classified as a diecdysic cycle. Within the studied range of water temperatures, the observed variations in the span of the different stages, indicate that this factor does not alter the molt frequency. Like in the rest of decapods, the intermolt duration of P. argentinus is modified by ovarian maturation.

Population ecology of the multivoltine Neotropical gall midge Eugeniamyia dispar (Diptera, Cecidomyiidae)

Our understanding of the population ecology of insect gallers is largely built on examples from temperate zones, but tropical and subtropical gallers may present distinct patterns of abundance and distribution across time. Eugeniamyia dispar Maia, Mendonça & Romanowski, 1996 is a multivoltine Neotropical cecidomyiid that induces spongy leaf galls on Eugenia uniflora (Myrtaceae). Galls were censused in the urban area of Porto Alegre, southern Brazil on six plants at two sites, for two years, at roughly weekly intervals. Overall 9,694 eggs, galling attempts and galls were counted. New galls continuously appear on developing leaves, but galls with live inducers are absent from June to at least early August. Galls on a same shoot develop synchronically, thus the shoot is probably the unit for oviposition. Given the also synchronic appearance of galls on different plants on a site, it seems midges can disperse and attack close-by plants. Gall cohorts varied in abundance by two orders of magnitude; there were more galls during summer than for spring and autumn, in a wave-like pattern. Host plant leaf production was seasonal, with low production during winter and cyclic production during the rest of the year. Perhaps because of this very variable pattern, gall abundance did not follow leaf production: this galler is not synchronised with its host at least during most of the year. This multivoltine gall inducer with "labile" galls, short development time, partially overlapping generations and low host synchronisation differs from the commonly studied species of the temperate regions providing a subject for ecological comparisons.

Giant warts in a kidney transplant patient: regression with sirolimus.

Purpose: Recent reports have suggested that intraabdominal postoperative infection is associated with higher rates of overall and local recurrence and cancer-specific mortality. However, the mechanisms responsible for this association are unknown. We hypothesized that the greater inflammatory response in patients with postoperative intraabdominal infection is associated to an increase in local and systemic angiogenesis. Methods: We designed a prospective cohorts study with matched controls. Patients with postoperative intra-abdominal infection (abscess and/or anastomotic leakage) (group 1; n=17) after elective colorectal cancer resection operated on for cure were compared to patients with an uncomplicated postoperative course (group 2; n=17). IL-6 and VEGF levels were determined by ELISA in serum and peritoneal fluid at baseline, 48 hours and postoperative day 4 or at the time the peritoneal infection occurred. Results: No differences were observed in age, gender, preoperative CEA, tumor stage and location and type of procedure performed. Although there were no differences in serum IL-6 levels at 48 hours, this pro-inflammatory cytokine was higher in group 1 on postoperative day 4 (group 1: 21533 + 27900 vs. group 2: 1130 + 3563 pg/ml; p < 0.001). Serum VEGF levels were higher in group 1 on postoperative day 4 (group 1: 1212 + 1025 vs. group 2: 408 + 407 pg/ml; p < 0.01). Peritoneal fluid VEGF levels were also higher in group 1 at 48 hours (group 1: 4857 + 4384 vs. group 2: 630 + 461 pg/ml; p < 0.001) and postoperative day 4 (group 1: 32807 + 98486 vs. group 2: 1002 + 1229 pg/ml; p < 0.001). A positive correlation between serum IL-6 and VEGF serum levels was observed on postoperative day 4 (r=0.7; p<0.01). Conclusions: These results suggest that not only the inflammatory response but also the angiogenic pathways are stimulated in patients with intra-abdominal infection after surgery for colorectal cancer. The implications of this finding on long-term follow-up need to be evaluated.

Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Which screening strategy using BMD measurements would be most cost effective for hip fracture prevention in elderly women? A decision analysis based on a Markov model.

INTRODUCTION: Hip fractures are responsible for excessive mortality, decreasing the 5-year survival rate by about 20%. From an economic perspective, they represent a major source of expense, with direct costs in hospitalization, rehabilitation, and institutionalization. The incidence rate sharply increases after the age of 70, but it can be reduced in women aged 70-80 years by therapeutic interventions. Recent analyses suggest that the most efficient strategy is to implement such interventions in women at the age of 70 years. As several guidelines recommend bone mineral density (BMD) screening of postmenopausal women with clinical risk factors, our objective was to assess the cost-effectiveness of two screening strategies applied to elderly women aged 70 years and older. METHODS: A cost-effectiveness analysis was performed using decision-tree analysis and a Markov model. Two alternative strategies, one measuring BMD of all women, and one measuring BMD only of those having at least one risk factor, were compared with the reference strategy "no screening". Cost-effectiveness ratios were measured as cost per year gained without hip fracture. Most probabilities were based on data observed in EPIDOS, SEMOF and OFELY cohorts. RESULTS: In this model, which is mostly based on observed data, the strategy "screen all" was more cost effective than "screen women at risk." For one woman screened at the age of 70 and followed for 10 years, the incremental (additional) cost-effectiveness ratio of these two strategies compared with the reference was 4,235 euros and 8,290 euros, respectively. CONCLUSION: The results of this model, under the assumptions described in the paper, suggest that in women aged 70-80 years, screening all women with dual-energy X-ray absorptiometry (DXA) would be more effective than no screening or screening only women with at least one risk factor. Cost-effectiveness studies based on decision-analysis trees maybe useful tools for helping decision makers, and further models based on different assumptions should be performed to improve the level of evidence on cost-effectiveness ratios of the usual screening strategies for osteoporosis.

Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients.

BACKGROUND: The goal of antiretroviral therapy (ART) is to reduce HIV-related morbidity and mortality by suppressing HIV replication. The prognostic value of persistent low-level viremia (LLV), particularly for clinical outcomes, is unknown. OBJECTIVE: Assess the association of different levels of LLV with virological failure, AIDS event, and death among HIV-infected patients receiving combination ART. METHODS: We analyzed data from 18 cohorts in Europe and North America, contributing to the ART Cohort Collaboration. Eligible patients achieved viral load below 50 copies/ml within 3-9 months after ART initiation. LLV50-199 was defined as two consecutive viral loads between 50 and 199 copies/ml and LLV200-499 as two consecutive viral loads between 50 and 499 copies/ml, with at least one between 200 and 499 copies/ml. We used Cox models to estimate the association of LLV with virological failure (two consecutive viral loads at least 500 copies/ml or one viral load at least 500 copies/ml, followed by a modification of ART) and AIDS event/death. RESULTS: Among 17 902 patients, 624 (3.5%) experienced LLV50-199 and 482 (2.7%) LLV200-499. Median follow-up was 2.3 and 3.1 years for virological and clinical outcomes, respectively. There were 1903 virological failure, 532 AIDS events and 480 deaths. LLV200-499 was strongly associated with virological failure [adjusted hazard ratio (aHR) 3.97, 95% confidence interval (CI) 3.05-5.17]. LLV50-199 was weakly associated with virological failure (aHR 1.38, 95% CI 0.96-2.00). LLV50-199 and LLV200-499 were not associated with AIDS event/death (aHR 1.19, 95% CI 0.78-1.82; and aHR 1.11, 95% CI 0.72-1.71, respectively). CONCLUSION: LLV200-499 was strongly associated with virological failure, but not with AIDS event/death. Our results support the US guidelines, which define virological failure as a confirmed viral load above 200 copies/ml.