Optimization of antimicrobial treatment in sepsis.

Sepsis represents a serious risk to the life of any patient, which is why it is crucial to start an effective treatment in all its extremes as soon as possible, that is, the chosen antibiotics must have activity against the pathogen that produces the condition and, in addition, they must be dosed considering the patient's situation in all its extremes. It should be considered that it will be necessary to adjust the dose when there is edema (drugs with reduced volume of distribution), hypoproteinemia (drugs bound to proteins in a high proportion), obesity, and also when they require the use of external techniques such as ECMO or any of the different types of hemodialysis and hemofiltration.

Pharmacokinetics/Pharmacodynamics and tolerability of cefiderocol in the clinical setting.

Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.

Identification of genes associated with environmental persistence in Campylobacter jejuni and Campylobacter coli isolates from processing in a broiler abattoir.

The aim of this study was to determine the prevalence of the htrA, htrB and ppk1 genes -all of which are related to environmental persistence- in C. jejuni and C. coli isolates obtained from abattoir samples at the arrival of broilers (initial stage) and in meat products after processing (final stage). A total of 119 DNA extracts (55 C. jejuni and 64 C. coli) were included in the study. Identification of genes was performed by conventional PCR (one for each gene). The overall prevalence was 40.3%, 93.3% and 68.9% for the htrA, htrB and ppk1 genes, respectively. Statistically significant differences were found (p < 0.05) between prevalence of C. jejuni and C. coli for all three genes. In C. coli the prevalence was significantly higher for the htrA (p = 0.007) and htrB (p = 0.015) genes, while ppk1 gene prevalence was significantly higher in C. jejuni (p < 0.001). In addition, statistically significant increase in the frequency of htrA (p = 0.007) and htrB (p = 0.013) genes in the final product compared to broilers on arrival at the abattoir was observed in C. jejuni, but not in C. coli. These results suggest that htrA and htrB genes are involved in environmental persistence of Campylobacter jejuni.

Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study.

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

Relación del machismo con la aceptación de la diabetes mellitus tipo 2 en hombres adultos / Machismo relationship with type 2 diabetes mellitus acceptance among adult men / Relação do machismo com a aceitação do diabetes mellitus tipo 2 em homens adultos

RESUMEN Introducción La aceptación de la diabetes mellitus tipo 2 contribuye al apego del tratamiento y al control de la enfermedad. Pero se ha reportado que los hombres tienen menor aceptación al diagnóstico de este padecimiento. En los hombres mexicanos la no aceptación puede estar relacionada con el machismo. Objetivo Identificar la relación del machismo con la aceptación de la diabetes mellitus tipo 2. Metodología Se realizó un estudio transversal y correlacional. La población de interés fue de hombres con diabetes mellitus tipo 2 entre 20 y 59 años de edad registrados en centros de atención primaria del área metropolitana de Monterrey, Nuevo León, México. Se obtuvo una muestra de 121 participantes a través de un muestreo por conveniencia. Los instrumentos utilizados fueron el Inventario de Conformidad de las Normas Masculinas y la Escala Aceptación en DMT2. Para el análisis estadístico se empleó el programa SPSS versión 25; se realizó un modelo de regresión lineal múltiple. Resultados Los resultados señalan que los hombres con percepción de mayor machismo, jornadas laborales extensas y consumo elevado de cigarrillos aceptan menos el diagnóstico y la enfermedad de la diabetes mellitus tipo 2. Para las subdimensiones del machismo, la homofobia fue el mejor predictor de la aceptación o no de la diabetes mellitus tipo 2. Conclusiones El profesional de salud debe desarrollar programas para la aceptación de la diabetes mellitus tipo 2 en hombres de reciente diagnóstico que contribuyan a aceptar su enfermedad, y así, permitan mejorar el autocuidado, control glucémico y prevención de complicaciones.

ABSTRACT Introduction Accepting a diagnosis of type 2 diabetes mellitus contributes to the adher- ence to the treatment and control of the illness; however, it has been reported that men tend to have a lower acceptance of this diagnosis. Among Mexican men, in particular, this low acceptance could be related to their machismo. Objective To identify the relationship of machismo with the acceptance of a type 2 diabetes mellitus diagnosis. Methodology This is a transversal and correlational study. The population of interest were Mexican men diagnosed with type 2 diabetes mellitus between 20 and 59 years registered in centers of primary attention in the city of Monterrey, Mexico. The sample was constituted of 121 participants chosen by convenience. The instruments used were the Conformity to Masculine Norms Inventory and the Acceptance Scale for DM2. The statistical analysis and the multiple linear regression model were carried out using SPSS v25. Results Findings suggest that men who show machismo, who have long labor shifts, and who consume large quantities of cigarettes tend not to accept a diagnosis of type 2 diabetes mellitus. Regarding the subdimensions of the machismo construct, homophobia was the best predictor of accepting or not a diagnosis of type 2 diabetes mellitus. Conclusions Healthcare professionals should develop programs aimed at improving the acceptance attitude of a type 2 diabetes mellitus diagnosis among men, including those with machismo, in order to better manage self-care, glucose control, and also prevent complications.

RESUMO Introdução A aceitação do diabetes mellitus tipo 2 contribui para a adesão ao tratamento e controle da doença. Mas, tem sido relatado que os homens têm menos aceitação do diagnóstico desta doença. Nos homens mexicanos, a não aceitação pode estar relacionada ao machismo. Objetivo Identificar a relação do machismo com a aceitação do diabetes mellitus tipo 2. Metodologia Foi realizado um estudo transversal e correlacional. A população de interesse foram homens com diabetes mellitus tipo 2 entre 20 e 59 anos registrados em centros de atenção primária na área metropolitana de Monterrey, Nuevo León, México. Foi obtida uma amostra de 121 participantes por amostragem de conveniência. Os instrumentos utilizados foram o Inventário de Conformidade com Normas Masculinas e a Escala de Aceitação DMT2. Para a análise estatística utilizou-se o programa SPSS versão 25; um modelo de regressão linear múltipla foi realizado. Resultados Os resultados indicam que homens com percepção de maior machismo, longas jornadas de trabalho e alto consumo de cigarro aceitam menos o diagnóstico e a doença de diabetes mellitus tipo 2. Para as subdimensões do machismo, a homofobia foi o melhor preditor de aceitação ou não de diabetes melito tipo 2. Conclusões O profissional de saúde deve desenvolver programas de aceitação da diabetes mellitus tipo 2 em homens recém-diagnosticados que contribuam para a aceitação da sua doença e, assim, permitam melhorar o autocuidado, o controlo glicémico e a prevenção de complicações.

Derivation of multivariate indices of milk composition, coagulation properties, and curd yield in Manchega dairy sheep.

This study approaches the interrelation patterns between composition of milk and whey, curd yield, chromaticity, syneresis, and technological quality of Manchega sheep milk using multivariate factor analysis. In addition, the effect of the main husbandry components (flock, prolificacy, season of the year, stage of lactation, and parity) on the common latent factors that define the pattern of variation of Manchega milk was assessed. For this purpose, 1,200 individual Manchega ewe milk samples from 4 different flocks registered under the Protected Designation of Origin Queso Manchego were analyzed (50 ewes/flock). Samples were collected in 2 different seasons of the year (spring and autumn) and at 3 time points per season: early, mid-, and late lactation. The obtained results suggested that curd yield mainly depends on milk composition, and the retention of water in the curd is related to coagulation traits. Thus, composition and moisture content could be useful indicators to assess the efficiency and quality of milk intended for cheesemaking, regardless of the analysis of coagulation properties. Finally, in terms of husbandry, a direct effect of flock and stage of lactation was observed on all analyzed factors, with a lower influence of season and parity.

Using multivariate analysis to explore the relationships between color, composition, hygienic quality, and coagulation of milk from Manchega sheep.

This study explores the relationships between composition, hygienic quality, and color values of milk to evaluate whether colorimetry could be used as a valid predictor of the quality of raw milk and its coagulation. For this purpose, we performed analyses in 1,200 individual samples of Manchega sheep milk from 4 flocks from the region of Castilla-La Mancha, Spain. Based on the measured variables, we determined the differences and similarities between coagulating and noncoagulating samples using discriminant analysis techniques. The variables with a higher discriminant ability were lactose content, somatic cell score, pH, and the color values lightness (L*) and red/green value (a*). The model based on color values showed a predictive ability similar to that found in the model based on milk composition and hygienic quality. Canonical correlation analysis allowed us to explore the relationships between both sets of variables. Canonical correlations for the first and second pair of canonical values were 0.794 and 0.438, respectively. Both values were significant and represented 92.82% of the observed variability. The correlation structure showed that color values had a strong correlation with fat and protein content and with total solids, and they had a weak correlation with lactose content and somatic cell score. The 2 first combinations of standardized canonical variability could be considered a predictable measure of the composition and, to a lesser extent, the hygiene of milk. Measurement of color values could be a rapid and effective means of supplementing standard analyses when determining the coagulation ability of Manchega sheep milk.

The pharmacodynamic bases of the prescription of antimicrobials.

In the past, the dose of an antibiotic was chosen, always from among those that were well tolerated, by considering those with the ability to exceed the MIC of bacteria in plasma. This approach, which has still not widely changed, is contrast-ed with the pharmacokinetic and pharmacodynamic (PK/PD) relationships, which indicate that the efficacy of antibiotics is directly related to parameters that relate the sequence of con-centrations over time with a parameter of the MIC effect in vitro. Until now, three types of PK/PD relationships have been established for antibiotics: the inhibitory coefficient (Cmax/MIC), the efficacy time (T>CMI) and the relationship between the exposure of the drug and the MIC (AUC/MIC).

Ceftobiprole: pharmacokinetics and PK/PD profile.

Ceftobiprole shows many similar pharmacokinetic properties to other cephalosporins, except for not being orally bioactive, and that it is administered by IV infusion as the prodrug ceftobiprole medocaril, which is subsequently hydrolyzed in the blood into the active molecule. Distribution focus in extracellular fluid and active antibiotic concentration has been proven in different corporal tissues using dosing regimen of 500 mg intravenous infusion over 2 h every 8 h. Ceftobiprole is eliminated exclusively into the urine, thus the reason why dose adjustment is required for patients with moderate or severe renal impairment, or increased creatinine clearance. However, there is no need for dose adjustments related with other comorbidities and patients' conditions such as age, body weight. Although considering distribution features, molecular weight and dose fraction, increase dosing regimen might be necessary in patients using renal replacement therapy. The half-life of ceftobiprole is more than 3 h, allowing to easily reach optimal PK/PD parameters with the infusion time of 2 h, using the usual dosing regimen.

Pharmacokinetics of anidulafungin in critically ill patients with Candida peritonitis.

OBJECTIVE: To describe the pharmacokinetic (PK) profile of anidulafungin and to evaluate its concentration in the peritoneal fluid (PF) of patients suspected of suffering from peritoneal infection undergoing abdominal surgery, in order to ensure that therapeutic levels are achieved within the peritoneal cavity. METHODS: A descriptive, open, prospective, observational, multicentre and non-interventional study was performed. Anidulafungin was used at conventional doses. Blood and PF samples were obtained on day 2 of treatment or on any of the following days. RESULTS: A total of 31 patients in a serious clinical condition, as demonstrated by high mean clinical severity scale scores (APACHE II and SOFA scores), were included in the study. The mean area under the curve (AUC) in PF was 30% (31±19%) of that determined in the plasma and the maximum concentration (Cmax) reached in PF (mg/l) was close to 1 (0.9±0.5). No adverse effects were observed in any of the 31 patients. CONCLUSIONS: Anidulafungin at conventional doses reaches PF concentrations that exceed the minimum inhibitory concentration of the usual Candida spp, which explains the proven efficacy of this echinocandin in the treatment of Candida peritonitis in critically ill patients.

A retrospective epidemiological analysis of shared risk factors for bovine trichomoniasis and bovine genital campylobacteriosis in La Pampa province (Argentina).

The venereal diseases bovine trichomoniasis (BT) and bovine genital campylobacteriosis (BGC) cause economic losses in endemic areas like La Pampa province in Argentina, where beef cattle are usually managed extensively. The eradication of both diseases is a priority in Argentine. The aim of this case-control study was to identify shared and specific risk factors of both diseases from the data obtained from the Provincial Program for the Control and Eradication of BT and BGC in La Pampa (PCE). The study population included 5777 breeding beef herds tested for BT and BGC in 2013. The study comprised 3481 herds that were surveyed in situ by official PCE veterinarians, distributed as follows: 3159 negative herds (with no BT or BGC positive bulls), 121 BT case herds (with at least a BT positive bull), 170 BGC case herds (with at least a BGC positive bull) and 31 BT and BGC co-infected case herds (with at least a positive bull for each disease). Three multivariable analyses were performed in order to identify the risk factors using a logistic regression model. Results showed that the risk factors shared by both diseases were the number of bulls (OR for BT = 1.03, 95% CI: 1.02-1.04, p < 0.001; OR for BGC = 1.02, 95% CI: 1.01-1.03, p < 0.001; OR for BT and BGC co-infection = 1.02, 95% CI: 1.01-1.04, p = 0.003) and the presence in the previous year of each disease (OR for BT = 18.69, 95% CI: 11.82-29.57, p < 0.001; OR for BGC = 4.65, 95% CI: 3.18-6.81, p < 0.001; OR for BT and BGC co-infection = 39.18, 95% CI: 16.72-91.80, p < 0.001). Disease-specific risk factors were continuous breeding season for BT (OR = 1.59, 95% CI: 1.04-2.47, p = 0.034), and inadequate condition of the fences for BGC (OR = 1.51, 95% CI: 1.06-2.15, p = 0.022). An integrated approach to venereal disease management needs to consider the risk characteristics identified in this study. This could lead to reduce both diseases and improve the efficiency of BT and BGC control activities in La Pampa.

Multivariate analysis of the milk coagulation process in ovine breeds from Spain.

In Spain, ewe milk is mainly used for cheesemaking, and farming systems have traditionally been based on the use of autochthonous breeds. However, in recent years, the progressive introduction of highly productive foreign breeds in Spanish farms has led to an increasing interest in the characterization of dairy sheep breeds to evaluate whether genetic selection schemes should focus on productivity or milk technological aptitude. The purpose of this work was to explore milk composition and coagulation to classify 4 of the main dairy sheep breeds used in Spain. This study included 832 individual ewe milk samples from the breeds Manchega, Assaf, Merino de Grazalema, and Merino de Los Pedroches. Samples were analyzed for native pH, composition (fat, protein, lactose, and total solids), coagulation properties, and individual laboratory curd yield. An indicator of coagulation efficiency was also determined. Canonical discriminant analysis was performed to establish differences and similarities among breeds based on the measured variables. In addition, cluster analysis was performed to study and quantify the concrete relationships among the discriminated groups. Discriminant analysis proved to be a powerful tool to accurately draw distinctions between breeds. In all cases, discrimination among breeds was evident and the 4 breeds could be easily differentiated. Cluster analysis showed greater similarity between Merino de Grazalema and Assaf compared with the other breeds, and F-statistics indicated a higher discriminating ability for the variables related to milk composition. However, Merino de Grazalema and Manchega were difficult to separate according to milk composition, but the coagulation process differenced them clearly. Coagulation also evidenced similarities between Manchega and Merino de Los Pedroches, although the latter was revealed to be the most different breed of all 4, which could lay the ground for its differentiation as an independent breed in the Official Catalogue of Spanish Livestock Breeds.

Coagulation efficiency and its determinant factors: A case study for Manchega ewe milk in the region of Castilla-La Mancha, Spain.

Milk coagulation, especially in small ruminant species, is often hard to evaluate, as coagulation traits are normally considered individually and several factors related to udder health might distort yield calculation. Due to the lack of studies about these factors, our objective was to determine milk coagulation efficiency (CE) and its determinants using a deterministic technical efficiency approach, an ordinary least square regression model, and ANOVA. Milk from 300 Manchega ewes was collected and analyzed for composition, milk coagulation properties, and hygienic quality. The study results indicate that the estimated CE in Manchega ewes was 0.69, implying an important proportion of the animals produce poorly coagulating milk. The results of the ordinary least square regression model and ANOVA revealed that the main factor causing inefficiency was the initial pH of milk. Crude protein, casein and plasmin activity had moderate effects on CE, and, finally, other factors such as freezing point depression, somatic cell count, colony-forming units, and fat concentration had minor effects.

Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives.

Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons.

Microglia are immune cells that play a crucial role in maintaining brain homeostasis. Among the mechanisms of communication between microglia and neurons, the CX3CL1/CX3CR1 axis exerts a central modulatory role. Animals lacking CX3CR1 microglial receptor (CX3CR1-/- mice) exhibit marked alterations not only in microglia but also in neurons located in various regions of the brain. Here we show that microglial depletion of CX3CR1 leads to the deficient synaptic integration of adult-born granule neurons in the dentate gyrus (DG), both at the afferent and efferent level. Regarding the alterations in the former level, these cells show a reduced number of dendritic spines, which also exhibit morphological changes, namely enlargement and shortening. With respect to changes at the efferent level, these cells show a reduced area of axonal terminals. Both at the afferent and efferent level, synapses show ultrastructural enlargement, but they are depleted of synaptic vesicles, which suggests impaired functionality. We also show that selective increased microglial activation and extracellular matrix deposition in the zones in which the afferent synaptic contacts of these cells occur, namely in the molecular and the granule layer of the DG. In order to evaluate the impact of these structural alterations from a functional point of view, we performed a battery of behavioral tests related to hippocampal-dependent emotional behavior. We observed that female CX3CR1-/- mice exhibit a hyperactive, anxiolytic-like and depressive-like phenotype. These data shed light on novel aspects of the regulation of adult hippocampal neurogenesis by microglia that could be highly relevant for research into mood disorders.

Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons.

Tau is a neuronal microtubule-associated protein with countless physiological functions. Although the detrimental effects of insoluble aggregated Tau have been widely studied, recent evidence supports the notion that soluble Tau (composed mostly of monomers and dimers) is also toxic for neurons. Here we evaluated the long-term impact of a single stereotaxic injection of human soluble Tau on hippocampal granule neurons in mice. At the ultrastructural level, soluble Tau reduced the number of afferent synapses and caused a dramatic depletion of synaptic vesicles both in afferent and efferent synapses. Furthermore, the use of an RFP-expressing retrovirus revealed that soluble Tau altered the morphology of newborn granule neurons and reduced their afferent (dendritic spines) and efferent (mossy fiber terminals) connectivity. Finally, soluble Tau caused specific impairment of behavioral pattern separation capacity. Our results thus demonstrate for the first time that soluble Tau causes long-term detrimental effects on the morphology and connectivity of newborn granule neurons and that these effects correlate with impaired behavioral pattern separation skills. These data might be relevant for the field of neurodegenerative disorders, since they contribute to reinforcing the pathological roles played by distinct Tau species in vivo.