Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron.

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics.

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide.

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, ß = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, ß = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications.

Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications.

The ultrastructure of spermatozoa of two species of Aegla (A. parana and A. quilombola) (Crustacea, Decapoda) endemic to Brazil.

The previously published ultrastructure of Aegla spermatozoa contributed to the phylogenetics of this unique taxon. The present study describes the spermatozoa of two additional aeglids, Aegla parana and A. quilombola. The spermatozoa consist of two hemispheres of the approximate same size and a bilayered acrosomal vesicle; both characteristics of the genus Aegla. The similarity of spermatozoa ultrastructure observed between A. parana and A. quilombola and the endemic Australian anomuran, Lomis hirta (Lomidae) reflects a sister group relationship, even though both are from different regions of the world and different environments today. Aeglid spermatozoa share the same organization with Lomis including the two equal size hemispheres separated by a membrane also two layers in the acrosomal vesicle with the external layer being surrounded by another membrane. The number of spermatozoa microtubular arms is unclear in Aegla, however, they are present in both the nucleus and cytoplasm. This observation does not agree with the presence of spermatozoa arms only in the nucleus, as an exclusive character for Aegla, as proposed previously. The presence of lipid-droplets and peroxisomes was observed only in the spermatozoa of A. quilombola. The greatly reduced number of spermatozoa observed in all specimens analyzed raises concerns about the conservation of several threatened species. In addition, the absence of any spermatophores seems to be a characteristic of the Aeglidae to date.

Identification of Transporter Polymorphisms Influencing Metformin Pharmacokinetics in Healthy Volunteers.

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.

Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson's disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.

Bioavailability of Oniria®, a Melatonin Prolonged-Release Formulation, Versus Immediate-Release Melatonin in Healthy Volunteers.

BACKGROUND: Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro. OBJECTIVES: The main objective of the present study was to evaluate the relative oral bioavailability of Oniria®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin. METHODS: We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria® and the reference melatonin (periods 2 and 3). RESULTS: Two phases were clearly differentiated in the PK profile of Oniria®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a Cmax value close to 4000 pg/mL. However, in the delayed phase, Oniria® showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria®, not only in the induction of sleep, but also in the maintenance. CONCLUSION: Oniria® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.

First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers.

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients.

Benefits of the application of heat and pressure on peripheral venous cannulation in adults: A randomized controlled trial.

AIM: To evaluate the effectiveness of the application of topical heat, high pressure or a combination of both on antebrachial venous cannulation. DESIGN: A cross-over clinical trial blinded for haemolysis analysis. METHODS: This cross-over clinical trial with two periods was performed in the Clinical Trial Unit of Hospital Universitario de La Princesa (Madrid) during June-July of 2017 in 59 healthy adults who were randomly allocated to one of three interventions: (1) Using dry topical heat for 7 min produced by two hot seed bags (N = 21), (2) Applying controlled pressure from a sphygmomanometer inflated to 100 mmHg (N = 18) and (3) combining heat and pressure (N = 20) in one period out of two. All interventions were contrasted to standard clinical practice in the other period. The comparator involved a standard tourniquet around the upper arm to restrict venous blood flow. The primary outcome was effectiveness measured as vein cannulation at first attempt. Secondary outcomes were vein perception, pain, haemolysis in blood samples and adverse events. RESULTS: All the interventions were more effective than comparator. Vein perception was optimized in about all individuals. Moreover, pain relief was significantly higher when high pressure was applied. Haemolysis was not affected in any of the three interventions. In addition, no serious adverse events appeared. CONCLUSION: High pressure is determined to be the most effective in vein catheterization, pain relief, vein perception and quality of blood sample inalterability. Moreover, it is safe considering that only one adverse event appeared. IMPACT: Vein cannulation is a very common invasive technique, where repeated failures have been registered. Thus, we consider it relevant to develop interventions to achieve venous catheterization at first attempt to alleviate the pain and anxiety associated with this technique. We advocate using high pressure intervention for emergency, due to swiftest method and feasible in case of lacking resources, such as sphygmomanometers in the ambulance. Interventions can be extrapolated to healthy young adults, adults and patients who have healthy vein status perception. Pressure intervention could be an alternative to heat intervention when performing vein cannulation due to its lower risk of transient paresthesia for older people who often suffer from arterial hypertension.

Usefulness of circulating microRNAs miR-146a and miR-16-5p as prognostic biomarkers in community-acquired pneumonia.

INTRODUCTION: Patients with community-acquired pneumonia (CAP) undergo a dysregulated host response that is related to mortality. MicroRNAs (miRNAs) participate in this response, but their expression pattern and their role as biomarkers in CAP have not been fully characterized. METHODS: A prospective observational study was performed in a cohort of 153 consecutive patients admitted to hospital with CAP. Clinical and analytical variables were collected, and the main outcome variable was 30-day mortality. Small RNA was purified from plasma of these patients obtained on the first day of admission, and miRNA expression was analyzed by RT-PCR. Univariate and multivariate analyses were carried out through the construction of a logistic regression model. The proposed model was compared with established prognostic clinical scales using ROC curve analysis. RESULTS: The mean age of the patients included was 74.7 years [SD 15.9]. Their mean PSI was 100.9 [SD 34.6] and the mean modified Charlson index was 2.9 [SD 3.0]. Both miR-146a and miR-16-5p showed statistically significant association with 30-day mortality after admission due to CAP (1.10 vs. 0.23 and 51.74 vs. 35.23, respectively), and this association remained for miR-16-5p in the multivariate analysis adjusted for age, gender and history of bronchoaspiration (OR 0.95, p = 0.021). The area-under-the-curve (AUC) of our adjusted multivariate model (AUC = 0.954 95%CI [0.91-0.99]), was better than those of prognostic scales such as PSI (AUC = 0.799 [0.69-0.91]) and CURB-65 (AUC = 0.722 [0.58-0.86]). CONCLUSIONS: High levels of miR-146a-5p and miR-16-5p upon admission due to CAP are associated with lower mortality at 30 days of follow-up. Both miRNAs could be used as biomarkers of good prognosis in subjects hospitalized with CAP.

Estudio del porcentaje de neutrófilos y el cociente de neutrófilos-linfocitos como marcadores pronósticos en pacientes hospitalizados por neumonía adquirida en la comunidad / Neutrophil Count Percentage and Neutrophil-Lymphocyte Ratio as Prognostic Markers in Patients Hospitalized for Community-Acquired Pneumonia

Introducción: La neumonía adquirida en la comunidad (NAC) es una infección frecuente y grave. El objetivo de este trabajo es estudiar la utilidad pronóstica del porcentaje de neutrófilos (NCP) y del cociente neutrófilos/linfocitos (NLR) en pacientes con NAC. Métodos: Estudio retrospectivo de pacientes hospitalizados por NAC con analítica al ingreso y una segunda extracción de control a los 3-5 días. Se consideraron variables desenlace la mortalidad a 30 y 90 días. Resultados: Se incluyó a 209 pacientes. Los pacientes que sobrevivieron redujeron significativamente el NCP y el NLR entre la analítica al diagnóstico y la de control (desde el 85,8 hasta el 65,4% para NCP y de 10,1 a 3,2 para NLR). Fallecieron 25 pacientes en los primeros 90 días. En ellos hubo un menor descenso no significativo para el NCP (del 84,8 al 74,0%) y para NLR (de 9,9 a 6,9). Los valores de NCP y NLR en la analítica de control fueron significativamente mayores en los pacientes fallecidos que en los supervivientes. Aquellos pacientes que presentaron en la analítica de control un NCP superior al 85% o un NLR superior a 10, presentaron un riesgo de mortalidad superior tras ajuste multivariable (HR para NCP 12 y para NLR 6,5). Conclusión: NCP y NLR son parámetros sencillos y de bajo coste, con utilidad pronóstica especialmente al medirse a los 3-5 días del diagnóstico de NAC. Niveles altos de NLR o NCP se asocian con mayor riesgo de mortalidad a los 90 días

Introduction: Community-acquired pneumonia (CAP) is a common serious infection. This study aimed to evaluate the prognostic utility of neutrophil count percentage (NCP) and neutrophil-lymphocyte ratio (NLR) in patients with CAP. Methods: Retrospective study of hospitalized patients with CAP. Patients had a blood test at admission and 3-5 days after hospitalization (early-stage test). The main outcome variables were 30-day and 90-day mortality. Results: Two hundred and 9 patients were included. Patients who survived had significant reductions in both NCP and NLR between admission and the day 3-5 blood tests (from 85.8% to 65.4% for NCP and from 10.1 to 3.2 for NLR). Twenty-five patients died in the first 90 days. Patients who died had lower, non-significant reductions in NCP (from 84.8% to 74%) and NLR (from 9.9 to 6.9) and significantly higher early-stage NCP and NLR than those who survived. NCP values higher than 85% and NLR values higher than 10 in the early-stage blood test were associated with a higher risk of mortality, even after multivariate adjustment (HR for NCP: 12; HR for NLR: 6.5). Conclusion: NCP and NLR are simple, low-cost parameters with prognostic utility, especially when measured 3-5 days after CAP diagnosis. High NLR and/or NCP levels are associated with a greater risk of mortality at 90 days

Neutrophil Count Percentage and Neutrophil-Lymphocyte Ratio as Prognostic Markers in Patients Hospitalized for Community-Acquired Pneumonia. / Estudio del porcentaje de neutrófilos y el cociente de neutrófilos-linfocitos como marcadores pronósticos en pacientes hospitalizados por neumonía adquirida en la comunidad.

INTRODUCTION: Community-acquired pneumonia (CAP) is a common serious infection. This study aimed to evaluate the prognostic utility of neutrophil count percentage (NCP) and neutrophil-lymphocyte ratio (NLR) in patients with CAP. METHODS: Retrospective study of hospitalized patients with CAP. Patients had a blood test at admission and 3-5 days after hospitalization (early-stage test). The main outcome variables were 30-day and 90-day mortality. RESULTS: Two hundred and 9patients were included. Patients who survived had significant reductions in both NCP and NLR between admission and the day 3-5 blood tests (from 85.8% to 65.4% for NCP and from 10.1 to 3.2 for NLR). Twenty-five patients died in the first 90 days. Patients who died had lower, non-significant reductions in NCP (from 84.8% to 74%) and NLR (from 9.9 to 6.9) and significantly higher early-stage NCP and NLR than those who survived. NCP values higher than 85% and NLR values higher than 10 in the early-stage blood test were associated with a higher risk of mortality, even after multivariate adjustment (HR for NCP: 12; HR for NLR: 6.5). CONCLUSION: NCP and NLR are simple, low-cost parameters with prognostic utility, especially when measured 3-5 days after CAP diagnosis. High NLR and/or NCP levels are associated with a greater risk of mortality at 90 days.

Correction: Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: Importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio.

[This corrects the article DOI: 10.1371/journal.pone.0173947.].

Management of invasive populations of the freshwater crayfish Procambarus clarkii (Decapoda, Cambaridae): test of a population-control method and proposal of a standard monitoring approach.

Invasive species are one of the main threats to biodiversity. When an alien species is introduced into a new environment, fast identification and definition of management strategies may avoid or minimize impacts. When an invasive species is already established, the most adopted approaches are population control and monitoring. In order to perform such strategies, assessment of characteristics of the invasive population is imperative. This study tested a new method of population size estimation and monitoring in an invasive population of crayfish Procambarus clarkii in a conservation area in the Atlantic Rain Forest (Southeastern Brazil). The population dynamics was studied for 1 year to examine the efficacy of the selected method and to evaluate if the population is stable. Later, the effect of periodical removal of animals on the population size was tested. The method of population estimation used in this study proved to be very effective. We recommend using it to monitor invasive populations of P. clarkii. The population size varied discretely over the year with variable but low growth rate, indicating that the population is already established which introduce a notable threat to native species. The continuous removal of specimens proved to be inefficient since the growth rate was higher after the removal. One intensive removal event might be more effective than a continuous moderate removal as the one applied in this study.

Phylogenetic and environmental components of inter-specific variability in the antioxidant defense system in freshwater anomurans Aegla (Crustacea, Decapoda).

The antioxidant defense system (ADS) protects organisms against the potential oxidative stress induced by environmental features, underlying processes of habitat diversification. The anomurans Aegla constitute the most threatened freshwater decapods of South America, occupying pristine habitats with narrow distribution. Using phylogenetic comparative methods, we addressed: Is the variability of habitat physicochemical parameters and tissue ADS phylogenetically structured? How do environmental features correlate with ADS? How do they vary among species? Several physicochemical parameters of water, as well as metals in sediments, were measured in ten aeglid species' habitats. Additionally, metal accumulation and ADS parameters [metallothionein-like proteins (MTLP), antioxidant capacity against peroxyl radicals (ACAP), and glutathione system (GSH-GSSG)] were evaluated in hepatopancreas. Water conductivity and pH showed phylogenetic signal, while all other physicochemical traits demonstrated plastic variability. Metals were present at natural concentrations, which are corroborated by the relative stable GSH/GSSG ratio, and by their absence of correlation with bioaccumulation levels and MTLP, both phylogenetically structured. However, metal variability across species' niches is associated with ACAP, a potential biomarker tool. Thus, the physiological sensitivity of aeglids is environmentally driven but also  phylogenetically constrained, unraveling the importance of systematic framework for cross-species investigations and future monitoring strategies of these conspicuous freshwater animals.

Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: Importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio.

INTRODUCTION: The increase and persistence of inflammation in community-acquired pneumonia (CAP) patients can lead to higher mortality. Biomarkers capable of measuring this inadequate inflammatory response are likely candidates to be related with a bad outcome. We investigated the association between concentrations of several inflammatory markers and mortality of CAP patients. MATERIAL AND METHODS: This was a prospective study of hospitalised CAP patients in a Spanish university hospital. Blood tests upon admittance and in the early-stage evolution (72-120 hours) were carried out, where C-reactive protein, procalcitonin, proadrenomedullin, copeptin, white blood cell, Lymphocyte Count Percentage (LCP), Neutrophil Count Percentage (NCP) and Neutrophil/Lymphocyte Ratio (NLR) were measured. The outcome variable was mortality at 30 and 90 days. Statistical analysis included logistic regression, ROC analysis and area-under-curve test. RESULTS: 154 hospitalised CAP patients were included. Patients who died during follow-up had higher levels of procalcitonin, copeptin, proadrenomedullin, lower levels of LCP, and higher of NCP and NLR. Remarkably, multivariate analysis showed a relationship between NCP and mortality, regardless of age, severity of CAP and comorbidities. AUC analysis showed that NLR and NCP at admittance and during early-stage evolution achieved a good diagnostic power. ROC test for NCP and NLR were similar to those of the novel serum biomarkers analysed. CONCLUSIONS: NLR and NCP, are promising candidate predictors of mortality for hospitalised CAP patients, and both are cheaper, easier to perform, and at least as reliable as the new serum biomarkers. Future implementation of new biomarkers would require comparison not only with classic inflammatory parameters like White Blood Cell count but also with NLR and NCP.

Morphological and molecular data reveal the cryptic diversity among populations of Aegla paulensis (Decapoda, Anomura, Aeglidae), with descriptions of four new species and comments on dispersal routes and conservation status.

The taxonomy of the Brazilian aeglid species Aegla paulensis Schmitt, 1942 from two disjunct hydrographic basins is revised using morphological and molecular data. Results show that six disjunctive populations of Aegla paulensis form a species complex. Aegla paulensis sensu stricto is redescribed and Aegla rosanae Campos Jr., 1998 is revalidated. The four remaining populations previously assigned to Aegla paulensis are now recognized as different species, namely Aegla  vanini n. sp., Aegla japi n. sp., Aegla jaragua n. sp. and Aegla jundiai n. sp. All new species are described and illustrated and are well supported by both morphological and molecular data. Aegla lancinhas Bond-Buckup & Buckup in Santos et al., 2015, which until recently was confounded with Aegla paulensis s. str., is supported as a valid species. A key to all members of the A. paulensis species complex is provided, and their phylogenetic and biogeographic relationships to other closely related species is discussed.

Description of the newly-hatched juvenile of Aegla perobae (Crustacea: Decapoda: Aeglidae).

The present paper contains the complete description of the external morphology of the first juvenile stage of Aegla perobae analysed through light microscopy (LM) and scanning electron microscopy (SEM). Newly-hatched juveniles were obtained from ovigerous females kept under laboratory conditions. Hatching is asynchronous, taking 2-4 days for all juveniles of a single brood to hatch. Average carapace dimensions are 1.54 mm wide and 1.69 mm long (rostrum excluded). Morphology of the carapace, of the cephalothoracic appendages (antennule, antenna, mandible, maxillule, maxilla, maxillipeds, and pereopods), of the pleon, and of the tail fan (telson plus uropods) are described in detail. Aegla perobae juveniles can be readily differentiate from the first juveniles of other aeglids species described so far by the upwardly curved condition of the distal region of the rostrum and the distinct groove along the orbital sinus produced the elevated free in this area. Pleopods 2-5 are present as rudimentary digitiform buds. Rudimentary pleopods are still present in adult males of the species, a trait not yet described in freshwater aeglids. This curious condition is compared and discussed in the light of the current knowledge of early postembryonic developmental patterns found in other anomurans.

The incidence of cardiovascular events after hospitalization due to CAP and their association with different inflammatory markers.

BACKGROUND: Late prognosis of Community-Acquired Pneumonia (CAP) patients is related to cardiovascular events. Persistence of inflammation-related markers, defined by high circulatory levels of interleukin 6 and 10 (IL-6/IL-10), is associated with a higher post-event mortality rate for CAP patients. However, association between these markers and other components of the immune response, and the risk of cardiovascular events, has not been adequately explored. The main objectives of this study are: 1) to quantify the incidence of cardiovascular disease, in the year post-dating their hospital admittance due to CAP and, 2) to describe the distribution patterns of a wide spectrum of inflammatory markers upon admittance to and release from hospital, and to determine their relationship with the incidence of cardiovascular disease. METHODS/DESIGN: A cohort prospective study. All patients diagnosed and hospitalized with CAP will be candidates for inclusion. The study will take place in the Universitary Hospital La Princesa, Spain, during two years. Two samples of blood will be taken from each patient: the first upon admittance and the second one prior to release, in order to analyse various immune agents. The main determinants are: pro-adrenomedullin, copeptin, IL-1, IL-6, TNF-α, IL-17, IFN-γ, IL-10 and TGF-ß, E-Selectin, ICAM-1, VCAM-1 and subpopulations of peripheral T lymphocytes (T regulator, Th1 and Th17), together with other clinical and analytical variables. Follow up will start at admittance and finish a year after discharge, registering incidence of death and cardiovascular events. The main objective is to establish the predictive power of different inflammatory markers in the prognosis of CAP, in the short and long term, and their relationship with cardiovascular disease. DISCUSSION: The level of some inflammatory markers (IL-6/IL-10) has been proposed as a means to differentiate the degree of severity of CAP, but their association with cardiovascular risk is not well established. In this study we aim to define new inflammatory markers associated with cardiovascular disease that could be helpful for the prognosis of CAP patients, by describing the distribution of a wide spectrum of inflammatory mediators and analyzing their association with the incidence of cardiovascular disease and mortality one year after release from hospital.

Description of the newly-hatched juvenile of Aegla paulensis (Decapoda, Anomura, Aeglidae).

The postembryonic development of Aegla paulensis is epimorphic (= direct), in which the hatching form is a juvenile that morphologically resembles the adult. Hatching is asynchronous, taking 3-5 days for all juveniles from a single brood to hatch. This paper provides a complete description of the external morphology of the newly-hatched juvenile of A. paulensis as analyzed through light microscopy (LM) and scanning electron microscopy (SEM). One of the striking features ob- served in the newly-hatched juvenile of A. paulensis was the presence of four pairs of rudimentary pleopods, a trait never described before in early juveniles of Aegla. Additional novelties include three unique types of setae and two types of pore sensilla.