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Movile Cave, situated in Romania close to the Black Sea, constitutes a distinct and challenging environment for life. Its partially submerged ecosystem depends on chemolithotrophic processes for its energetics, which are fed by a continuous hypogenic inflow of mesothermal waters rich in reduced chemicals such as hydrogen sulfide and methane. We sampled a variety of cave sublocations over the course of three years. Furthermore, in a microcosm experiment, minerals were incubated in the cave waters for one year. Both endemic cave samples and extracts from the minerals were subjected to 16S rRNA amplicon sequencing. The sequence data show specific community profiles in the different subenvironments, indicating that specialized prokaryotic communities inhabit the different zones in the cave. Already after one year, the different incubated minerals had been colonized by specific microbial communities, indicating that microbes in Movile Cave can adapt in a relatively short timescale to environmental opportunities in terms of energy and nutrients. Life can thrive, diversify and adapt in remote and isolated subterranean environments such as Movile Cave.
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Background: Despite better accessibility of the effective lipid-lowering therapies, only about 20% of patients at very high cardiovascular risk achieve the low-density lipoprotein cholesterol (LDL-C) goals. There is a large disparity between European countries with worse results observed for the Central and Eastern Europe (CEE) patients. One of the main reasons for this ineffectiveness is therapeutic inertia related to the limited access to appropriate therapy and suitable dosage intensity. Thus, we aimed to compare the differences in physicians' therapeutic decisions on alirocumab dose selection, and factors affecting these in CEE countries vs. other countries included in the ODYSSEY APPRISE study. Methods: ODYSSEY APPRISE was a prospective, single-arm, phase 3b open-label (≥12 weeks to ≤30 months) study with alirocumab. Patients received 75 or 150 mg of alirocumab every 2 weeks, with dose adjustment during the study based on physician's judgment. The CEE group in the study included Czechia, Greece, Hungary, Poland, Romania, Slovakia, and Slovenia, which we compared with the other nine European countries (Austria, Belgium, Denmark, Finland, France, Germany, Italy, Spain, and Switzerland) plus Canada. Results: A total of 921 patients on alirocumab were involved [modified intention-to-treat (mITT) analysis], including 114 (12.4%) subjects from CEE countries. Therapy in CEE vs. other countries was numerically more frequently started with lower alirocumab dose (75 mg) at the first visit (74.6 vs. 68%, p = 0.16). Since week 36, the higher dose was predominantly used in CEE patients (150 mg dose in 51.6% patients), which was maintained by the end of the study. Altogether, alirocumab dose was significantly more often increased by CEE physicians (54.1 vs. 39.9%, p = 0.013). Therefore, more patients achieved LDL-C goal at the end of the study (<55 mg/dl/1.4 mmol/L and 50% reduction of LDL-C: 32.5% vs. 28.8%). The only factor significantly influencing the decision on dose of alirocumab was LDL-C level for both countries' groups (CEE: 199.2 vs. 175.3 mg/dl; p = 0.019; other: 205.9 vs. 171.6 mg/dl; p < 0.001, for 150 and 75 mg of alirocumab, respectively) which was also confirmed in multivariable analysis (OR = 1.10; 95% CI: 1.07-1.13). Conclusions: Despite larger unmet needs and regional disparities in LDL-C targets achievement in CEE countries, more physicians in this region tend to use the higher dose of alirocumab, they are more prone to increase the dose, which is associated with a higher proportion of patients reaching LDL-C goals. The only factor that significantly influences decision whether to increase or decrease the dose of alirocumab is LDL-C level.
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Sulfidic cave ecosystems are remarkable evolutionary hotspots that have witnessed adaptive radiation of their fauna represented by extremophile species having particular traits. Ostracods, a very old group of crustaceans, exhibit specific morphological and ecophysiological features that enable them to thrive in groundwater sulfidic environments. Herein, we report a peculiar new ostracod species Pseudocandona movilaensis sp. nov. thriving in the chemoautotrophic sulfidic groundwater ecosystem of Movile Cave (Romania). The new species displays a set of homoplastic features specific for unrelated stygobitic species, e.g., triangular carapace in lateral view with reduced postero-dorsal part and simplification of limb chaetotaxy (i.e., loss of some claws and reduction of secondary male sex characteristics), driven by a convergent or parallel evolution during or after colonization of the groundwater realm. P. movilaensis sp. nov. thrives exclusively in sulfidic meso-thermal waters (21 °C) with high concentrations of sulphides, methane, and ammonium. Based on the geometric morphometrics-based study of the carapace shape and molecular phylogenetic analyses based on the COI marker (mtDNA), we discuss the phylogenetic relationship and evolutionary implication for the new species to thrive in groundwater sulfidic groundwater environments.
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Ecossistema , Extremófilos , Animais , Masculino , Filogenia , Romênia , Crustáceos , SulfetosRESUMO
Novel phenotypes can come about through a variety of mechanisms including standing genetic variation from a founding population. Cave animals are an excellent system in which to study the evolution of novel phenotypes such as loss of pigmentation and eyes. Asellus aquaticus is a freshwater isopod crustacean found in Europe and has both a surface and a cave ecomorph which vary in multiple phenotypic traits. An orange eye phenotype was previously revealed by F2 crosses and backcrosses to the cave parent within two examined Slovenian cave populations. Complete loss of pigmentation, both in eye and body, is epistatic to the orange eye phenotype and therefore the orange eye phenotype is hidden within the cave populations. Our goal was to investigate the origin of the orange eye alleles within the Slovenian cave populations by examining A. aquaticus individuals from Slovenian and Romanian surface populations and Asellus aquaticus infernus individuals from a Romanian cave population. We found orange eye individuals present in lab raised surface populations of A. aquaticus from both Slovenia and Romania. Using a mapping approach with crosses between individuals of two surface populations, we found that the region known to be responsible for the orange eye phenotype within the two previously examined Slovenian cave populations was also responsible within both the Slovenian and the Romanian surface populations. Complementation crosses between orange eye Slovenian and orange eye Romanian surface individuals suggest that the same gene is responsible for the orange eye phenotype in both surface populations. Additionally, we observed a low frequency phenotype of eye loss in crosses generated between the two surface populations and also in the Romanian surface population. Finally, in a cave population from Romania, A. aquaticus infernus, we found that the same region is also responsible for the orange eye phenotype as the Slovenian cave populations and the Slovenian and Romanian surface populations. Therefore, we present evidence that variation present in the cave populations could originate from standing variation present in the surface populations and/or transgressive hybridization of different surface phylogenetic lineages rather than de novo mutations.
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Isópodes , Animais , Filogenia , Fenótipo , Variação Genética , Água Doce , CavernasRESUMO
Thiovulum spp. (Campylobacterota) are large sulfur bacteria that form veil-like structures in aquatic environments. The sulfidic Movile Cave (Romania), sealed from the atmosphere for ~5 million years, has several aqueous chambers, some with low atmospheric O2 (~7%). The cave's surface-water microbial community is dominated by bacteria we identified as Thiovulum. We show that this strain, and others from subsurface environments, are phylogenetically distinct from marine Thiovulum. We assembled a closed genome of the Movile strain and confirmed its metabolism using RNAseq. We compared the genome of this strain and one we assembled from public data from the sulfidic Frasassi caves to four marine genomes, including Candidatus Thiovulum karukerense and Ca. T. imperiosus, whose genomes we sequenced. Despite great spatial and temporal separation, the genomes of the Movile and Frasassi Thiovulum were highly similar, differing greatly from the very diverse marine strains. We concluded that cave Thiovulum represent a new species, named here Candidatus Thiovulum stygium. Based on their genomes, cave Thiovulum can switch between aerobic and anaerobic sulfide oxidation using O2 and NO3- as electron acceptors, the latter likely via dissimilatory nitrate reduction to ammonia. Thus, Thiovulum is likely important to both S and N cycles in sulfidic caves. Electron microscopy analysis suggests that at least some of the short peritrichous structures typical of Thiovulum are type IV pili, for which genes were found in all strains. These pili may play a role in veil formation, by connecting adjacent cells, and in the motility of these exceptionally fast swimmers.
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Cavernas , Epsilonproteobacteria , Cavernas/química , Enxofre/metabolismo , Epsilonproteobacteria/metabolismo , Romênia , FilogeniaRESUMO
So far, only members of the bacterial phyla Proteobacteria and Verrucomicrobia are known to grow methanotrophically under aerobic conditions. Here we report that this metabolic trait is also observed within the Actinobacteria. We enriched and cultivated a methanotrophic Mycobacterium from an extremely acidic biofilm growing on a cave wall at a gaseous chemocline interface between volcanic gases and the Earth's atmosphere. This Mycobacterium, for which we propose the name Candidatus Mycobacterium methanotrophicum, is closely related to well-known obligate pathogens such as M. tuberculosis and M. leprae. Genomic and proteomic analyses revealed that Candidatus M. methanotrophicum expresses a full suite of enzymes required for aerobic growth on methane, including a soluble methane monooxygenase that catalyses the hydroxylation of methane to methanol and enzymes involved in formaldehyde fixation via the ribulose monophosphate pathway. Growth experiments combined with stable isotope probing using 13C-labelled methane confirmed that Candidatus M. methanotrophicum can grow on methane as a sole carbon and energy source. A broader survey based on 16S metabarcoding suggests that species closely related to Candidatus M. methanotrophicum may be abundant in low-pH, high-methane environments.
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Ecossistema , Mycobacterium , Proteômica , Filogenia , Metano/metabolismo , Mycobacterium/genéticaRESUMO
Background and Objectives: Cancer and coronary artery disease (CAD) often coexist. Compared to quantitative coronary angiography (QCA), fractional flow reserve (FFR) has emerged as a more reliable method of identifying significant coronary stenoses. We aimed to assess the specific management, safety and outcomes of FFR-guided percutaneous coronary intervention (PCI) in cancer patients with stable CAD. Materials and Methods: FFR was used to assess cancer patients that underwent coronary angiography for stable CAD between September 2008 and May 2016, and were found to have ≥50% stenosis by QCA. Patients with lesions with an FFR > 0.75 received medical therapy alone, while those with FFR ≤ 0.75 were revascularized. Procedure-related complications, all-cause mortality, nonfatal myocardial infarction, or urgent revascularizations were analyzed. Results: Fifty-seven patients with stable CAD underwent FFR on 57 lesions. Out of 31 patients with ≥70% stenosis as measured by QCA, 14 (45.1%) had an FFR ≥ 0.75 and lesions were reclassified as moderate and did not receive PCI nor DAPT. Out of 26 patients with <70% stenosis as measured by QCA, 6 (23%) had an FFR < 0.75 and were reclassified as severe and were treated with PCI and associated DAPT. No periprocedural complications, urgent revascularization, acute coronary syndromes, or cardiovascular deaths were noted. There was a 22.8% mortality at 1 year, all cancer related. Patients who received a stent by FFR assessment showed a significant association with decreased risk of all-cause death (HR: 0.37, 95% CI 0.15−0.90, p = 0.03). Conclusions: Further studies are needed to define the optimal therapeutic approach for cancer patients with CAD. Using an FFR cut-off point of 0.75 to guide PCI translates into fewer interventions and can facilitate cancer care. There was an overall reduction in mortality in patients that received a stent, suggesting increased resilience to cancer therapy and progression.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Neoplasias , Intervenção Coronária Percutânea , Constrição Patológica , Angiografia Coronária/métodos , Doença da Artéria Coronariana/complicações , Estenose Coronária/complicações , Estenose Coronária/cirurgia , Seguimentos , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Resultado do TratamentoRESUMO
The great diversity of the invertebrate community thriving in the deepest sections of the gypsum karst system of the Monte Conca sinkhole (Sicily, Italy) suggests the existence of a complex food web associated with a sulfidic pool and chemoautotrophic microbial activity. To shed light on the peculiarity of this biological assemblage, we investigated the species composition of the invertebrate community and surveyed trophic interactions by stable isotope analysis. The faunal investigation conducted by visual censuses and hand sampling methods led to the discovery of a structured biological assemblage composed of both subterranean specialized and non-specialized species, encompassing all trophic levels. The community was remarkably diverse in the sulfidic habitat and differed from other non-sulfidic habitats within the cave in terms of stable isotope ratios. This pattern suggests the presence of a significant chemoautotrophic support by the microbial communities to the local food web, especially during the dry season when the organic input from the surface is minimal. However, when large volumes of water enter the cave due to local agricultural activities (i.e., irrigation) or extreme precipitation events, the sulfidic habitat of the cave is flooded, inhibiting the local autotrophic production and threatening the conservation of the entire ecosystem.
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Ecossistema , Microbiota , Animais , Sulfato de Cálcio , Invertebrados , Sicília , SulfetosRESUMO
Takotsubo syndrome is a rare cause of systolic dysfunction and can be found as a clinical manifestation of pheochromocytoma. We present a case of rapid onset of systolic dysfunction with cardiogenic shock, which developed after the surgical excision of an adrenal gland tumor in a 60-year-old male. Coronary angiography excluded coronary artery disease. The echocardiography and ventriculography images suggested Takotsubo cardiomyopathy pattern. Following 2 weeks of inotropic and vasopressor therapy, the left ventricular function gradually improved, until complete resolution.
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INTRODUCTION: In 2020, the ESTRO course on image-guided radiotherapy and chemotherapy in gynaecological cancer was converted into an online version due to the COVID-19 pandemic. This paper describes the change process and evaluates the impact on participants compared with previous live courses. METHODS AND MATERIALS: The 2019 live course contained 41 h of educational content, comprising 33 h of synchronous activities (lectures, interactive activities, videos) and 8 h of homework (contouring, dose planning). For the online course, the lectures were provided as pre-course material (11 mandatory, 22 optional). Contouring/dose planning homework was unchanged. The synchronous sessions were reconfigured as six 2-hour webinars (total educational content ~38 h).Participant numbers/characteristics, engagement and satisfaction for six live courses and the online course were compared. RESULTS: Participant numbers for the online and live courses were similar (90 vs. mean 96). There were more participants from outside Europe (28% vs. mean 18%) and more non-doctors (47% vs. mean 33%). Proportion of participants responding to the pre-course questionnaire was similar (77% vs. mean 78%) but post-course questionnaire response was lower (62% vs. mean 92%).43% participants viewed ≥75% of mandatory lectures before the webinars. 86% viewed the optional lectures. Submissions of contouring and dose planning homework was higher (contouring 77%-90% vs. 56%-69%, dose planning 74%-89% vs. 29%-57%).96% (47/49) participants rated the online course as Excellent (43%) or Good (53%). Overall satisfaction was similar (4.4 vs. mean 4.6). CONCLUSION: Participant satisfaction and engagement with the online course remained high despite less contact time with faculty.
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BACKGROUND: Peritoneal dialysis (PD) is underutilized in many parts of the world despite pro-PD health policies. The physical and cognitive demands of PD means that over half of eligible patients require some form of assistance. As such, many countries now offer assisted PD (aPD) programs to help patients start or stay on PD as opposed to in-center hemodialysis (HD). In order to evaluate the potential scope of aPD, it is important to review the outcomes and cost considerations of aPD. SUMMARY: We reviewed available data from different countries and regions for health outcomes between aPD and in-center HD, with a focus on quality of life (QoL), mortality, hospitalization, and technique survival. We also evaluated studies discussing the overall costs of delivering aPD, including training, operating costs, and indirect costs and compared these to in-center HD costs for the same regions. Key Messages: aPD patients are older and more frail than either self-care PD patients and many in-center HD patients. We found no evidence for any difference in QoL, mortality, or hospitalization between aPD and in-center HD after adjustment for these differences. There is some evidence for an association between nurse assistance and improved technique survival as compared to family assistance or self-care PD. Despite increased cost of providing assistance in PD, it is still significantly less expensive than in-center HD in Western Europe and Canada.
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Diálise Peritoneal , Hospitalização/economia , Humanos , Falência Renal Crônica/economia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Avaliação de Resultados em Cuidados de Saúde , Diálise Peritoneal/economia , Diálise Peritoneal/métodos , Diálise Peritoneal/mortalidade , Qualidade de VidaRESUMO
BACKGROUND: An open-label phase II, multicenter clinical trial was conducted at 11 Haemophilia Centres in Italy, Romania, and Turkey, to evaluate the pharmacokinetics (PK), efficacy, and safety of high purity, plasma-derived, double virus inactivated and double nano-filtered factor IX (pd-FIX) concentrate (Kedrion FIX), EudraCT Number: 2005-006186-14. MATERIAL AND METHODS: 16 previously treated patients (PTPs) with severe or moderately severe haemophilia B were enrolled in the study. At enrolment, 14 underwent the first PK assessment (PK I), and the second PK (PK II) assessment was performed after six months of treatment (5 on-demand and nine prophylaxis) at the end of the study. PK parameters were evaluated by Non-Compartmental Analysis (NCA), One-Compartment model (OCM), and Two-Compartment Model (TCM). Efficacy of Kedrion FIX in all 16 patients was evaluated by the number of bleeding events, and clinical response following the infusions. Periodic FIX inhibitor assays and thrombogenicity tests were scheduled throughout the study to assess the safety of the drug. RESULTS: As compared to the published data on PK of pdFIX, Kedrion FIX displayed a longer half-life (22.37-55.73 hrs), reduced clearance, and regular volume of distribution at PK I by both NCA and OCM. The comparison of outcomes of PK II with those of PK I by OCM, also showed significant changes, particularly in patients on prophylaxis, who showed some improved parameters of PK. Due to two outlier values at the end of the trial, the NCA parameters of PK I were not compared to those of PK II. Breakthrough bleeds were successfully treated with 1 or 2 infusions. No significant adverse events were observed during the study. DISCUSSION: During the six-month clinical study period, the use of Kedrion FIX resulted in a safe and effective pd-FIX concentrate with excellent PK characteristics.
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Fator IX , Hemofilia B , Meia-Vida , Hemofilia B/tratamento farmacológico , Hemorragia/induzido quimicamente , Humanos , TurquiaRESUMO
Due to authors' internal mistake they have misspelled the name of one of the co-authors in this article.
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Jeffrey Modell Foundation centers' network activities in Central and Eastern Europe (JMF CEE) have contributed to the development of care for patients with primary immunodeficiencies. On the data continuously collected from individual centers in participating countries since 2011, we demonstrate a steady improvement in a number of aspects concerning complex care for patients with primary immunodeficiencies. The presented data show an improvement of awareness about these rare diseases across the whole Central and Eastern European region, an increase in newly diagnosed patients as well as genetically confirmed cases, earlier establishment of diagnosis, and improved access to clinical treatment. We also present an active patient involvement that is reflected in the expansion of patient organization centers and their activities. The cooperation within the JMF CEE network has also contributed to greater international exposure of participating centers and further to the gradual development of research activities in the rapidly evolving field of primary immunodeficiencies. The improvement of all important aspects of the complex field of primary immunodeficiencies within the JMF CEE network documents the strength and advantages of the joint and coordinated networking.
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Doenças da Imunodeficiência Primária/epidemiologia , Europa Oriental/epidemiologia , Feminino , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnósticoRESUMO
Concern for early degeneration limits the use of bioprosthetic heart valves. A 77-year-old man who underwent surgical aortic valve replacement at age 70 for severe aortic stenosis (AoS) presented with premature bioprosthesis degeneration and AoS recurrence. Transthoracic echocardiography demonstrated severe AoS and aortic regurgitation, a 30% ejection fraction, and pulmonary hypertension. Transesophageal echocardiography revealed that the aortic regurgitation was due to a 5-mm paravalvular leak (PVL). A high EuroScoreII excluded surgical treatment. Simultaneous transcatheter aortic valve replacement and PVL closure with an Occlutech PLD Square 5 Twist PVL closure device were performed with good results and improved clinical status.
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Estenose da Valva Aórtica/cirurgia , Falha de Prótese , Idoso , Insuficiência da Valva Aórtica/etiologia , Estenose da Valva Aórtica/diagnóstico , Bioprótese , Ecocardiografia , Humanos , Masculino , Recidiva , Substituição da Valva Aórtica TranscateterRESUMO
Moraxella catarrhalis frequently colonises the oropharynges of healthy individuals. Disease is usually limited to the oropharynx, upper airways and lower airways in patients with predisposing conditions. The pathogen rarely causes more invasive disease. We present the case of a 65-year-old woman with Crohn's disease on azathioprine, who was diagnosed with native valve M. catarrhalis endocarditis and vertebral osteomyelitis several weeks after an upper respiratory tract infection. She presented to hospital with 5 weeks of worsening malaise, nausea, relapsing fevers, weight loss, acute-on-chronic exacerbation of lower back pain and diffuse myalgia. Transoesophageal echocardiogram showed a 12 mm vegetation on her mitral valve, contrast-enhanced MRI was consistent with L4 osteomyelitis and blood cultures were persistently positive for M. catarrhalis She was initially treated with ceftriaxone 2 g intravenously daily, and although her symptoms initially resolved, she experienced a relapse of osteomyelitis with L3 extension a few weeks after treatment discontinuation.
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Endocardite Bacteriana/etiologia , Infecções por Moraxellaceae/complicações , Osteomielite/etiologia , Idoso , Antibacterianos/uso terapêutico , Ecocardiografia Transesofagiana , Endocardite Bacteriana/sangue , Endocardite Bacteriana/diagnóstico por imagem , Endocardite Bacteriana/tratamento farmacológico , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Moraxella catarrhalis/isolamento & purificação , Infecções por Moraxellaceae/sangue , Infecções por Moraxellaceae/diagnóstico , Infecções por Moraxellaceae/tratamento farmacológico , Osteomielite/sangue , Osteomielite/diagnóstico , Osteomielite/tratamento farmacológicoRESUMO
INTRODUCTION: Statins have several pleiotropic effects that have the potential to be beneficial during pregnancy. This study evaluates the available evidence for the teratogenicity of statins, and their utility in treating preeclampsia and dyslipidemia in pregnancy, as good alternatives in these domains are currently lacking. AREAS COVERED: The possible teratogenicity of statins is a primary focus of this paper. We also evaluated for some possible non-teratogenic effects, such as changes in birth weight and rates of spontaneous abortion, among mothers exposed to statins during pregnancy. Regarding potential uses, this study mainly discusses statin utility in preventing and treating preeclampsia and treating dyslipidemia in pregnancy. Within the latter, we explore the relationship between dyslipidemia and preeclampsia, the potential consequences of delaying statin therapy where indicated, and the impact of supra-physiological levels of cholesterol in utero on offspring. The literature search was conducted using Embase, Web of Science, PubMed, and Scopus. EXPERT OPINION: Based on current evidence, statins are likely not teratogenic. Limited, but promising evidence exists for their efficacy in treating and preventing preeclampsia. In utero exposure to high cholesterol may negatively impact offspring, and should be thoroughly investigated.
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Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pré-Eclâmpsia/tratamento farmacológico , Animais , Colesterol/sangue , Dislipidemias/complicações , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Pré-Eclâmpsia/prevenção & controle , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/prevenção & controleRESUMO
BACKGROUND: Cinnamon is a rich botanical source of polyphenols, whose positive effects on blood lipid concentrations have been hypothesized, but have not been conclusively studied. OBJECTIVE: The objective of the study was to systematically review and evaluate the effect of administration of cinnamon on blood lipid concentrations. METHODS: We assessed 13 randomized controlled trials with 750 participants investigating the effect of cinnamon supplementation on blood lipid concentrations. A meta-analysis was performed using random effect models, with weighted mean differences (WMDs; with 95% confidence interval [CI]) for endpoints calculated using a random effects model. RESULTS: No statistically significant effect of cinnamon was observed on blood low-density lipoprotein cholesterol (LDL-C; WMD: -0.16 mmol/L [-6.19 mg/dL], 95% CI: -0.35, 0.03 [-13.53, 1.16], P = .10) and high-density lipoprotein cholesterol (HDL-C; WMD: 0.05 mmol/L [1.92 mg/dL], 95% CI: -0.03, 0.12 [-0.03, 4.64], P = .21) concentrations. However, a statistically significant reduction in blood triglycerides (WMD: -0.27 mmol/L [-23.91 mg/dL], 95% CI: -0.39, -0.14 [-34.54, -12.40], P < .01) and total cholesterol concentrations (WMD: -0.36 mmol/L [-13.92 mg/dL], 95% CI: -0.63, -0.09 [-24.36, -3.48], P < .01) was observed. HDL-C was significantly elevated after the omission of 1 study (WMD: 0.04 mmol/L [1.54 mg/dL], 95% CI: 0.03, 0.06 [1.16, 2.32], P < .01) during our sensitivity analysis. A meta-regression analysis was conducted, and no significant association was found between changes in lipid parameters and cinnamon dose. In contrast, changes in blood levels of total cholesterol (slope: 0.09; 95% CI: 0.02, 0.16; P < .01), LDL-C (slope: 0.05; 95% CI: 0.001, 0.10; P = .05) and triglycerides (slope: 0.06; 95% CI: 0.04, 0.09; P < .01) were significantly and positively associated with the duration of supplementation. No statistically significant association was found between blood HDL-C changes and duration of supplementation. CONCLUSION: Cinnamon supplementation significantly reduced blood triglycerides and total cholesterol concentrations without any significant effect on LDL-C and HDL-C.
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Cinnamomum zeylanicum/química , Lipídeos/sangue , Fitosteróis/uso terapêutico , Polifenóis/uso terapêutico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Humanos , Polifenóis/química , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos/sangueRESUMO
BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development. METHODS: We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch). RESULTS: We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5-135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases. CONCLUSIONS: By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.
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História Natural/métodos , Adulto , Hemofilia A/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
INTRODUCTION: Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. AIM: To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. METHODS: This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg-1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg-1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. RESULTS: Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. CONCLUSIONS: These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products.