Impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and adverse events of special interest in patients with rheumatoid arthritis or spondyloarthritis: a systematic analysis of the literature and meta-analysis.

OBJECTIVES: To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state. MATERIALS AND METHODS: A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies. RESULTS: Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (- 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups. CONCLUSION: We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.

Essential competencies in prescribing: A first european cross-sectional study among 895 final-year medical students.

European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.

Feeding frequency and growth performance of juvenile pink shrimp ([farfantepenaeus paulensis) / Frequência de oferta alimentar e desempenho zootécnico de juvenis do camarão rosa (farfantepenaeus paulensis)

It is generally believed that increasing feeding frequency has immediate benefits, including reduced nutrient leaching and increased shrimp growth. In this context, the aim this work was to evaluate the effect of feeding frequency in growth performance of Farfantepenaeus paulensis. Juveniles of Farfantepenaeus paulensis were grown for 30 days in pen enclosures, at a stocking density of 5 shrimp/m2. The shrimp were fed on feeding trays at a rate of 8% of their biomass per day, with treatments of one, two, three and four times per day, with four replicates each. The results showed no differences (5% probability) in biomass gain of F. paulensis when feed was offered two, three or four times per day. However, it was observed that the once a day frequency had a negative influence on weight gain for this species of shrimp. We conclude that the supply of food with 35% crude protein twice a day is sufficient for the growth of F paulensis. Feeding frequency of three or four times can provide increased spending in the cultivation of juveniles of this species.

Acredita-se que uma frequência maior de alimentação traz benefícios imediatos, incluindo a redução da lixiviação de nutrientes e o aumento do crescimento do camarão. Nesse contexto, o objetivo do presente trabalho foi avaliar o efeito de diferentes frequências de oferta de alimento sobre o crescimento de Farfantepenaeus paulensis. Juvenis de Farfantepenaeus paulensis foram criados por 30 dias em tanques-rede, na densidade de estocagem de cinco camarões/m 2. Os camarões foram alimentados em comedouros com 8% da sua biomassa/dia, ofertados em parcelamentos de uma, duas, três e quatro vezes ao dia, com quatro repetições para cada tratamento. Os resultados mostraram que não ocorreram diferenças (5% de probabilidade) no ganho de biomassa de F. paulensis quando a frequência alimentar foi de duas, três ou quatro vezes ao dia. No entanto, os dados indicam que a frequência alimentar de uma vez ao dia interferiu negativamente no ganho de peso dessa espécie. Conclui-se que o fornecimento de ração com 35% de proteína bruta duas vezes ao dia é suficiente para o crescimento de F paulensis. O fornecimento de alimento três ou quatro vezes ao dia poderia acarretar maiores gastos no manejo de juvenis dessa espécie.

A randomised double blind clinical trial to compare surgical field bleeding during endoscopic sinus surgery with clonidine-based or remifentanil-based hypotensive anaesthesia.

BACKGROUND: Significant bleeding during functional endoscopic naso-sinusal surgery (FESS) impairs recognition of anatomical references and may negatively affect surgical outcome. Anaesthesia including clonidine as an adjuntive hypotensive agent may reduce intraoperative bleeding. METHODS: A randomised comparison of clonidine-based vs remifentanil-based hypotensive anaesthetic regimen was conducted in patients undergoing FESS. The main assessment was the proportion of subjects with Boezaart scores of surgical field bleeding, as blindly assessed from video recordings by a third surgeon not involved in patient care. RESULTS: A total of 47 subjects underwent FESS and were randomised to clonidine or remifentanil. A significantly lower proportion of patients in the clonidine arm had blindly-assessed Boezaart scores higher than 2, with significantly lower mean blind Boezaart scores at 60 minutes and at 120 minutes. Similar findings were reported by the operating surgeon, and when Wormald and VAS scores were used. Objective estimates of bleeding and the duration of surgery and anaesthesia did not differ between groups. CONCLUSION: The use of clonidine- based controlled hypotensive anaesthesia achieves lower surgical field bleeding during FESS.

Natural breeding sites of phlebotomine sand flies (Diptera: Psychodidae) on Marambaia Island, Rio de Janeiro State, Brazil.

Immature phlebotomine sand flies develop in soils with essential and ideal characteristics for their life cycle, such as organic matter, humidity, temperature and low levels of light. Information regarding the potential breeding places of these dipterans is fundamental to understand the epidemiology and ecology of leishmaniasis, in addition to its importance to control them. In the present study, we aimed to find natural breeding sites of sand flies on Marambaia Island with the aid of emergence traps and direct search of immature forms using the flotation technique with saturated sugar solution in organic substrates of the region. Both methods were effective, with a total of 42 specimens of six different species - including some species that participate in the transmission cycle of American Tegumentary Leishmaniasis - collected by the emergence traps, and five immature forms obtained by floatation technique. However, further studies are still necessary, mainly with respect to the ecology and biology of immature sandfly stages, so that control measures focused on breeding sites can produce positive sustainable results in natural environments.

Hypotensive anaesthesia and bleeding during endoscopic sinus surgery: an observational study.

Significant bleeding during functional endoscopic naso-sinusal surgery (FESS) impairs recognition of anatomical references and may negatively affect surgical outcome. Through their hypotensive effect, adjuvant anaesthetic agents may influence intraoperative bleeding. The present study compared intraoperative bleeding in patients undergoing FESS administered a clonidine-based anaesthetic regimen and in patients receiving other an anaesthetic combination with higher acquisition costs. Prospective observational study included 37 subjects undergoing FESS in 2011. Assessment of intraoperative bleeding was according to type of anaesthesia (clonidine vs. opioid derivatives). Patients receiving clonidine (N = 11; 29.7%) presented significantly lower surgical field bleeding scores than those receiving opioid derivatives (N = 26; 70.3%) [mean (SD) Boezaart scores 1.91 (0.53) vs. 2.92 (0.79), p < 0.0001]. The multivariate analysis including baseline characteristics and risk factors related to bleeding intensity showed that the type of drug used for controlled hypotensive anaesthesia was the best predictor of bleeding during FESS, with an OR of 0.03 for clonidine based vs. opioid based anaesthesia (p = 0.014). The anaesthetic combination including clonidine for controlled hypotensive anaesthesia produces lower levels of surgical field bleeding during FESS. Compared with other hypotensive anaesthetics, clonidine is inexpensive and associated with better surgical conditions during FESS. If confirmed through randomized clinical trials, the use of clonidine during FESS can reduce surgical time and improve surgical results through a less bloody field, resulting in lower patient morbidity and improvement of operating room resources.

Effects of long-term periodized resistance training on body composition, leptin, resistin and muscle strength in elderly post-menopausal women.

AIM: Objective of the study was to determine the effects of a periodized resistance training program on body composition, plasmatic levels of leptin and resistin, and muscle strength in elderly post-menopausal women. METHODS: Twenty-three post-menopausal women (age= 63.02±4.42 years; height 1.55±0.06 m; body mass 67.56±2.26 kg) were submitted to 12 months of periodized resistance training twice a week. The training program consisted of 3 sets of 6-14 repetitions maximal (RM). Body composition (DXA), muscle strength (bench press, leg press 45º and arm curl), plasmatic levels of resistin and leptin (ELISA method) were assessed before and after the training program. Paired Student's t test was used for comparison between pre- and post-training values. RESULTS: There was a significant increase in muscle strength and lean body mass; decrease in body mass, body fat percentage and fat mass after 12 months of resistance training, a part from the decrease in leptin and resistin levels. CONCLUSION: Long-term periodized resistance training prevents aging sarcopenia, decreases body fat and systemic markers of inflammation in postmenopausal elderly women.

Association of Bartonella spp bacteremia with Chagas cardiomyopathy, endocarditis and arrythmias in patients from South America

Infection with Bartonella spp may cause cardiac arrhythmias, myocarditis and endocarditis in humans. The aim of the present study was to evaluate a possible association between Bartonella spp bacteremia and endocarditis, arrhythmia and Chagas cardiomyopathy in patients from Brazil and Argentina. We screened for the presence of bacterial 16S rRNA in human blood by PCR using oligonucleotides to amplify a 185-bp bacterial DNA fragment. Blood samples were taken from four groups of subjects in Brazil and Argentina: i) control patients without clinical disease, ii) patients with negative blood-culture endocarditis, iii) patients with arrhythmias, and iv) patients with chronic Chagas cardiomyopathy. PCR products were analyzed on 1.5% agarose gel to visualize the 185-bp fragment and then sequenced to confirm the identity of DNA. Sixty of 148 patients (40.5%) with cardiac disease and 1 of 56 subjects (1.8%) from the control group presented positive PCR amplification for Bartonella spp, suggesting a positive association of the bacteria with these diseases. Separate analysis of the four groups showed that the risk of a Brazilian patient with endocarditis being infected with Bartonella was 22 times higher than in the controls. In arrhythmic patients, the prevalence of infection was 45 times higher when compared to the same controls and 40 times higher for patients with Chagas cardiomyopathy. To the best of our knowledge this is the first report of the association between Bartonella spp bacteremia and Chagas disease. The present data may be useful for epidemiological and prevention studies in Brazil and Argentina.

Association of Bartonella spp bacteremia with Chagas cardiomyopathy, endocarditis and arrhythmias in patients from South America.

Infection with Bartonella spp may cause cardiac arrhythmias, myocarditis and endocarditis in humans. The aim of the present study was to evaluate a possible association between Bartonella spp bacteremia and endocarditis, arrhythmia and Chagas cardiomyopathy in patients from Brazil and Argentina. We screened for the presence of bacterial 16S rRNA in human blood by PCR using oligonucleotides to amplify a 185-bp bacterial DNA fragment. Blood samples were taken from four groups of subjects in Brazil and Argentina: i) control patients without clinical disease, ii) patients with negative blood-culture endocarditis, iii) patients with arrhythmias, and iv) patients with chronic Chagas cardiomyopathy. PCR products were analyzed on 1.5% agarose gel to visualize the 185-bp fragment and then sequenced to confirm the identity of DNA. Sixty of 148 patients (40.5%) with cardiac disease and 1 of 56 subjects (1.8%) from the control group presented positive PCR amplification for Bartonella spp, suggesting a positive association of the bacteria with these diseases. Separate analysis of the four groups showed that the risk of a Brazilian patient with endocarditis being infected with Bartonella was 22 times higher than in the controls. In arrhythmic patients, the prevalence of infection was 45 times higher when compared to the same controls and 40 times higher for patients with Chagas cardiomyopathy. To the best of our knowledge this is the first report of the association between Bartonella spp bacteremia and Chagas disease. The present data may be useful for epidemiological and prevention studies in Brazil and Argentina.

Effects of resistance training on matrix metalloproteinase-2 activity and biomechanical and physical properties of bone in ovariectomized and intact rats.

The purpose of this study was to investigate the influence of resistance training on the activity of matrix metalloproteinase (MMP)-2 and bone biomechanical properties in ovariectomized and intact rats. Forty-eight female rats were divided into two distinct groups, ovariectomized (OVX) and intact (Int), which were subdivided into three similar subgroups: sedentary, acute exercise and chronic exercise. Rats performed a resistance training for 12 weeks in which animals climbed a vertical ladder of 1.1 m with weights attached to their tails. Sessions were performed with an interval of 3, 4-9 and 8-12 days scaled dynamic movements of climbing. Biomechanical and physical analyses were performed using a universal testing machine, and MMP-2 activity analysis by zymography. Bone density (BD), mineral density (MD), maximum load and fracture load was reduced in sedentary and acute exercise OVX groups compared with the sedentary intact group (P<0.05); in contrast, chronically trained groups (OVX and Int) showed a significant increase in BD, MD and fracture load compared with all the other groups. MMP-2 activity in chronically trained groups also showed a significant increase, while the sedentary OVX group showed a decrease in MMP-2 activity compared with the intact sedentary group (P<0.05). Our results suggest that the resistance training proposed in our work was efficient in reverting the deleterious effects of ovariectomy on bone tissue, and also produced modeling effects in intact rats. On the other hand, ovariectomy reduced the activity of MMP-2 and produced deleterious effects on bone tissue, mimicking menopause intrinsically.

Suboptimal survival of male germ-cell tumors in southern Portugal--a population-based retrospective study for cases diagnosed in 1999 and 2000.

BACKGROUND: The outcome of germ-cell tumors (GCTs) is a hallmark of good-quality cancer care. In the Eurocare-4 study, the mean 5-year survival for patients diagnosed from 1995 to 1999 was 95.5%. PATIENTS AND METHODS: We carried out a population-based retrospective chart review study of male patients diagnosed with GCT in 1999 and 2000 in southern Portugal (2 119 065 males). RESULTS: There were 87 GCTs-79 testicular, 2 retroperitoneal, 3 mediastinal, 2 of the central nervous system and 1 of the stomach. For the 81 patients with testicular or retroperitoneal primaries, 35 had stage I, 13 stage II and 30 stage III at presentation (3 unknown). Classification by International Germ Cell Consensus Classification Group criteria, 17 belonged to the poor prognosis group (mediastinal primary 3, liver metastases 11 and very elevated markers 3). With median follow-up of 89 months, the 5-year absolute overall survival was 80% (100% for stage I, 92% for stage II and 53% for stage III disease). CONCLUSIONS: While GCT incidence was similar to neighboring Spain, the 5-year overall survival was lower than that of other European countries. This may result from delays in diagnosis, suggested by high proportion of high-stage and large-burden disease, and poor adherence to recommended treatment algorithms.

Exploratory factor analysis of the Brazilian OHIP for edentulous subjects.

The use of seven domains for the Oral Health Impact Profile (OHIP)-EDENT was not supported for its Brazilian version, making data interpretation in clinical settings difficult. Thus, the aim of this study was to assess patients' responses for the translated OHIP-EDENT in a group of edentulous subjects and to develop factor scales for application in future studies. Data from 103 conventional and implant-retained complete denture wearers (36 men, mean age of 69.1 +/- 10.3 years) were assessed using the Brazilian version of the OHIP-EDENT. Oral health-related quality of life domains were identified by factor analysis using principal component analysis as the extraction method, followed by varimax rotation. Factor analysis identified four factors that accounted for 63% of the 19 items total variance, named masticatory discomfort and disability (four items), psychological discomfort and disability (five items), social disability (five items) and oral pain and discomfort (five items). Four factors/domains of the Brazilian OHIP-EDENT version represent patient-important aspects of oral health-related quality of life.

Enfermedad de Whipple cerebral sin manifestaciones gastrointestinales / Cerebral Whipple disease without gastrointestinal symptoms

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Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer.

Inflammation plays a key role in the development of colorectal cancers. We have investigated the relationship between PTGS2 (COX2) polymorphisms and colorectal cancer risk in a hospital based case-control study. We recruited 292 patients with colorectal cancer and 274 controls from new patients admitted to Bellvitge Hospital, Barcelona, Spain, from 1996 to 1998. Subjects responded to a questionnaire on risk factors. Genotypes of the eight more frequent polymorphisms of PTGS2 were determined. Two polymorphisms are located in the promoter sequence, one in the untranslated region of exon 1, one in exon 3, one in intron 5, two in the untranslated region of exon 10, and one downstream of the last polyadenylation (poly-A) signal. Associations were analysed with logistic regression models assuming a dominant effect for rare variants to increase statistical power. An association was detected between colorectal cancer and a polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01. A nearby polymorphism downstream of the last poly-A signal also showed a nonsignificant increase in risk (OR 2.17, 95% CI 0.99-4.78, P=0.05). Analysis of haplotypes confirmed that individuals with these variants were at increased risk of colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97-4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti-inflammatory drugs and risk of colorectal cancer were also explored.

Comparison of the antihypertensive effects of the fixed dose combination enalapril 10 mg/nitrendipine 20 mg vs losartan 50 mg/hydrochlorothiazide 12.5 mg, assessed by 24-h ambulatory blood pressure monitoring, in essential hypertensive patients.

Fixed combinations of calcium channel blockers and angiotensin converting enzyme inhibitors represent an alternative to diuretic-based combination therapy. The aim of the present study was to compare the antihypertensive efficacy of the combination enalapril 10 mg/nitrendipine 20 mg (E/N) vs losartan 50 mg/hydrochlorothiazide 12.5 mg (L/H), assessed by 24-h ambulatory blood pressure monitoring. This multicentre, double-blind, parallel study included 97 hypertensive patients (office diastolic blood pressure (DBP) 90-109 mmHg and daytime DBP > 85 mmHg). After a 2- to 3-week period of single-blind placebo, they were randomized to receive double-blind treatment with E/N (n = 48) or L/H (n = 49) for a 4-week period. The primary outcome measure was the difference in 24-h DBP reduction between treatments from randomization to the end of the double-blind period. Secondary efficacy variables included differences in 24-h systolic (S) BP reduction, daytime, night-time and office SBP and DBP reduction, proportion of responders and controlled patients, trough-to-peak ratio and smoothness indexes. Safety was assessed by the proportion of patients with adverse events and the detection of laboratory abnormalities. No significant differences were observed in the primary outcome measure. The group receiving E/N tended to show greater reductions in most measures (24 h, daytime and office SBP and DBP) and higher BP control rates, but only the difference in the rate of office SBP control (< 140 mmHg) reached statistical significance (42.2 vs 22.4%; P = 0.048). The trough-to-peak ratios and smoothness indexes were similar in both groups. The incidence of adverse events related to the treatment was 27.1% (95% CI 14.5-39.6%) in E/N-treated patients and 14.3% (95% CI 4.5-45.8%) in the L/H group, but differences were not significant. The kind of event more frequently observed were flushing and headache in E/N, and dizziness and asthenia in L/H; all observed adverse events were mild. We conclude that E/N and L/H have a similar antihypertensive efficacy, assessed by office or ambulatory blood pressure monitoring. E/N achieved a significantly higher office SBP control rate, but this was accompanied by an apparently higher proportion of mild adverse events.

[Theoretical model of a cost-effectiveness analysis of combined enalapril-nitrendipine therapy for treating hypertension]. / Modelo teórico de análisis coste-efectividad de la terapia combinada de enalapril-nitrendipino en el tratamiento de la hipertensión arterial.

OBJECTIVE: Cost-effectiveness analysis of combined enalapril-nitrendipine therapy (E/N), as second-line therapy for light or moderate hypertension. DESIGN: Theoretical model of cost-effectiveness, based on the norms of hypertension treatment in primary care, the considered view of a panel of experts and the direct costs of health resources and purchase of medication. SETTING: Spanish National Health system. PARTICIPANTS: Simulation of 1000 patients with hypertension, with a time horizon of one year. INTERVENTIONS: After a prior failure of the first-line treatment with either enalapril or nitrendipine, an evaluation was made of the possibilities of increasing dosage of the first-line treatment, changing the drug or administering the E/N combination. MAIN MEASUREMENT: The likelihoods, in the primary care context, of controlling diastolic pressure, of abandonment and of using the two strategies or not were measured, as were the use of health resources in each situation, and costs of resource use and of medication. RESULTS: The cost-effectiveness quotient of the combined E/N treatment was consistently more efficient than the increase in dose or change to another drug. This was so, whether the treatment was started with enalapril (301.06 euros vs 337.97 euros and 588.42 euros) or with nitrendipine (331.5 euros vs 469.88 euros and 579.76 euros). CONCLUSIONS: Combined therapy (E/N) is, on the basis of the assumptions made in the model, an efficient therapy option. Therefore, it can be recommended for prescription.

Modelo teórico de análisis coste-efectividad de la terapia combinada de enalapril-nitrendipino en el tratamiento de la hipertensión arterial / Theoretical model of a cost-effectiveness analysis of combined enalapril-nitrendipine therapy for treating hypertension

Objetivo. Análisis coste-efectividad de la terapia combinada de enalapril y nitrendipino (E/N), como terapia de segunda línea para la HTA leve o moderada. Diseño. Modelo teórico de coste-efectividad basado en las pautas de tratamiento habituales de la HTA en atención primaria, la opinión sistematizada de un panel de expertos y los costes directos de los recursos sanitarios y la adquisición de medicación. Emplazamiento. Sistema Nacional de Salud español. Participantes. Simulación de 1.000 pacientes hipertensos con un horizonte temporal de un año. Intervenciones. Tras un primer fracaso del tratamiento de primera línea con enalapril o con nitrendipino, se evalúan el incremento de la dosis del tratamiento de primera línea, el cambio de fármaco y la administración de la combinación enalapril/nitrendipino. Mediciones principales. Probabilidades de alcanzar o no el control de la presión arterial diastólica, de abandono y de aplicar una u otra estrategia en nuestro medio. Utilización de recursos sanitarios en cada situación. Costes asociados a la utilización de recursos y costes de adquisición de la medicación. Resultados. El cociente coste-efectividad de la terapia combinada con enalapril/nitrendipino es consistentemente más eficiente que el aumento de dosis o el cambio a otro fármaco, tanto si se inicia el tratamiento con enalapril (301,06 euros frente a 337,97 y 588,42) como con nitrendipino (331,5 euros frente a 469,88 y 579,76).Conclusiones. La terapia combinada (E/N) es una opción terapéutica eficiente, según los supuestos considerados en el modelo y, por tanto, recomendable para su prescripción (AU)