Explore the vast range of titles available.

Background Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. Methods Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% f T>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results The median (IQR) of meropenem AUC 0–24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. Conclusions An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. Trial registration The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10 ). Registered on 27 December 2016.

Respiratory infections are frequent and life-threatening complications of surgery. This study aimed to evaluate the clinical, microbiological and treatment characteristics of severe postoperative pneumonia (POP) and tracheobronchitis (POT) in a large series of patients. This single-center, prospective observational cohort study included patients with POP or POT requiring intensive care unit admission in the past 10 years. We recorded demographic, clinical, microbiological and therapeutic data. A total of 207 patients were included, and 152 (73%) were men. The mean (SD) age was 70 (13) years and the mean (SD) ARISCAT score was 46 (19). Ventilator-associated pneumonia was reported in 21 patients (10%), hospital-acquired pneumonia was reported in 132 (64%) and tracheobronchitis was reported in 54 (26%). The mean (SD) number of days from surgery to POP/POT diagnosis was 6 (4). The mean (SD) SOFA score was 5 (3). Respiratory microbiological sampling was performed in 201 patients (97%). A total of 177 organisms were cultured in 130 (63%) patients, with a high proportion of Gram-negative and multi-drug resistant (MDR) bacteria (20%). The most common empirical antibiotic therapy was a triple-drug regimen covering MDR Gram-negative bacteria and MRSA. In conclusion, surgical patients are a high-risk population with a high proportion of early onset severe POP/POT and nosocomial bacteria isolation.

Background The high energy content of alcohol makes its consumption a potential contributor to the obesity epidemic. Aim of the study To determine whether alcohol consumption is a risk factor for abdominal obesity, taking into account energy underreporting. Methods The subjects were Spanish men (n = 1491) and women (n = 1563) aged 25-74 years who were examined in 1999-2000, in a population-based cross-sectional survey in northeastern Spain (Girona). Dietary intake, including alcohol consumption, was assessed using a food frequency questionnaire. Anthropometric variables were measured. Results The mean consumption of alcohol was 18.1 ± 20.7 g/d in men and 5.3 ± 10.4 g/d in women. 19.3% of men and 2.3% of women reported alcohol consumption of more than 3 drinks per day. The consumption of alcohol was directly associated with total energy intake in men (P < 0.001) and women (P = 0.001). The proportion of energy underreporting significantly (P < 0.001) decreased with higher amounts of alcohol drinking in both genders. Multiple logistic regression analysis, controlled for energy underreporting, smoking, educational level, leisure-time physical activity, energy, and diet quality, revealed that consuming more than 3 drinks of alcohol (>30 g ethanol) was significantly associated with the risk of abdominal obesity (Odds ratio 1.80; 1.05, 3.09) and exceeding recommended energy consumption (Odds ratio 1.97; 1.32, 2.93) in men. A very small number (2.13%) of women in this population reported high levels of alcohol consumption. Conclusions Alcohol consumption in elevated amounts was associated with risk of abdominal obesity in men, independent of energy underreporting.

The mechanisms of chemotherapy resistance in triple negative breast cancer remain unclear, and so, new molecules which might mediate this resistance could optimize treatment response. Here we analyzed the involvement of the miRNA-449 family in the response to doxorubicin. The cell viability, cell-cycle phases, and the expression of in silico target genes and proteins of sensitive/resistant triple negative breast cancer cell lines were evaluated in response to doxorubicin treatment and after gain/loss of miRNAs-449 function achieved by transient transfection. Triple negative breast cancer patients were selected for ex vivo experiments and to evaluate gene and miRNAs expression changes after treatment, as well as survival analysis by Kaplan-Meier. Doxorubicin treatment upregulated miRNAs-449 and DNA-damage responder factors E2F1 and E2F3 in triple negative breast cancer sensitive breast cancer cells, while expression remained unaltered in resistant ones. In vitro overexpression of miRNAs-449 sensitized cells to the treatment and significantly reduced the resistance to doxorubicin. These changes showed also a strong effect on cell cycle regulation. Finally, elevated levels of miRNA-449a associated significantly with better survival in chemotherapy-treated triple negative breast cancer patients. These results reveal for the first time the involvement of the miRNA-449 family in doxorubicin resistance and their predictive and prognostic value in triple negative breast cancer patients.

Background Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. Objective To compare the influence of distinctive trajectories of alcohol consumption throughout a woman’s life on development of breast cancer (BC). Methods 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women’s lifetime. Results Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. Conclusions The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk.

When oxygen becomes limiting, cells reduce mitochondrial respiration and increase ATP production through anaerobic fermentation of glucose. The Hypoxia Inducible Factors (HIFs) play a key role in this metabolic shift by regulating the transcription of key enzymes of glucose metabolism. Here we show that oxygen regulates the expression of the muscle glycogen synthase (GYS1). Hypoxic GYS1 induction requires HIF activity and a Hypoxia Response Element within its promoter. GYS1 gene induction correlated with a significant increase in glycogen synthase activity and glycogen accumulation in cells exposed to hypoxia. Significantly, knockdown of either HIF1alpha or GYS1 attenuated hypoxia-induced glycogen accumulation, while GYS1 overexpression was sufficient to mimic this effect. Altogether, these results indicate that GYS1 regulation by HIF plays a central role in the hypoxic accumulation of glycogen. Importantly, we found that hypoxia also upregulates the expression of UTP:glucose-1-phosphate urydylyltransferase (UGP2) and 1,4-alpha glucan branching enzyme (GBE1), two enzymes involved in the biosynthesis of glycogen. Therefore, hypoxia regulates almost all the enzymes involved in glycogen metabolism in a coordinated fashion, leading to its accumulation. Finally, we demonstrated that abrogation of glycogen synthesis, by knock-down of GYS1 expression, impairs hypoxic preconditioning, suggesting a physiological role for the glycogen accumulated during chronic hypoxia. In summary, our results uncover a novel effect of hypoxia on glucose metabolism, further supporting the central importance of metabolic reprogramming in the cellular adaptation to hypoxia.

Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity. A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months. The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected. In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.

BackgroundAccelerated catch-up growth following intrauterine restriction increases the risk of developing visceral adiposity and metabolic abnormalities. However, the underlying molecular mechanisms of such metabolic programming are still poorly understood.MethodsA Wistar rat model of catch-up growth following intrauterine restriction was used. A gene expression array was performed in the retroperitoneal adipose tissue sampled at postnatal day (PD) 42.ResultsFive hundred and forty-six differentially expressed genes (DEGs) were identified (adjusted p value < 0.05). Gene ontology enrichment analysis identified pathways related to immune and lipid metabolic processes, brown fat cell differentiation, and regulation of PI3K. Ccl21, Npr3, Serpina3n, Pnpla3, Slc2a4, and Serpina12 were validated to be upregulated in catch-up pups (all p < 0.01) and related to several fat expansion and metabolic parameters, including body weight at PD42, postnatal body weight gain, white and brown adipose tissue mass, plasma triglycerides, and insulin resistance index (all p < 0.05).ConclusionsGenes related to immune and metabolic processes were upregulated in retroperitoneal adipose tissue following catch-up growth in juvenile rats and were found to be associated with fat expansion and metabolic parameters. Our results provide evidence for several dysregulated genes in white adipose tissue that could help develop novel strategies to prevent the metabolic abnormalities associated with catch-up growth.ImpactCatch-up growth presents several dysregulated genes in white adipose tissue related to metabolic abnormalities.Ccl21, Npr3, Serpina3n, Pnpla3, Slc2a4, and Serpina12 were validated to be upregulated in catch-up pups and related to visceral fat expansion and metabolic parameters.Profiling and validation of these dysregulated genes in visceral adipose tissue could help develop novel strategies to prevent the metabolic abnormalities associated with catch-up growth.

The SARS-CoV-2 Spike protein mediates docking of the virus onto cells prior to viral invasion. Several cellular receptors facilitate SARS-CoV-2 Spike docking at the cell surface, of which ACE2 plays a key role in many cell types. The intermediate filament protein vimentin has been reported to be present at the surface of certain cells and act as a co-receptor for several viruses; furthermore, its potential involvement in interactions with Spike proteins has been proposed. Nevertheless, the potential colocalization of vimentin with Spike and its receptors on the cell surface has not been explored. Here we have assessed the binding of Spike protein constructs to several cell types. Incubation of cells with tagged Spike S or Spike S1 subunit led to discrete dotted patterns at the cell surface, which consistently colocalized with endogenous ACE2, but sparsely with a lipid raft marker. Vimentin immunoreactivity mostly appeared as spots or patches unevenly distributed at the surface of diverse cell types. Of note, vimentin could also be detected in extracellular particles and in the cytoplasm underlying areas of compromised plasma membrane. Interestingly, although overall colocalization of vimentin-positive spots with ACE2 or Spike was moderate, a selective enrichment of the three proteins was detected at elongated structures, positive for acetylated tubulin and ARL13B. These structures, consistent with primary cilia, concentrated Spike binding at the top of the cells. Our results suggest that a vimentin-Spike interaction could occur at selective locations of the cell surface, including ciliated structures, which can act as platforms for SARS-CoV-2 docking.

Background The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC. Methods The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing. Results A total of 54 patients were assigned to arms A ( N  = 22), B ( N  = 25), and C ( N  = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2–35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5–4.1) and 3.8 (95%CI, 1.5–9.6) months; median OS was 15.5 (95%CI, 11.8–19.3) and 11.5 (95%CI, 8.8–25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status. Conclusions Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial. Trial registration www.clinicaltrials.gov , NCT04464174. Registered 09 July 2020.