Relative Effectiveness of High-Dose vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults with Cardiovascular Disease: A Prespecified Analysis of the DANFLU-1 Randomized Clinical Trial.

Background: Influenza vaccination reduces the risk of adverse outcomes in patients with cardiovascular disease (CVD). We sought to evaluate whether the presence of CVD modified the relative effectiveness of high-dose (QIV-HD) vs. standard-dose (QIV-SD) quadrivalent influenza vaccine in this prespecified analysis of the DANFLU-1 trial. Methods: DANFLU-1 was a pragmatic, open-label, randomized feasibility trial of QIV-HD vs. QIV-SD in adults aged 65-79 years during the 2021/2022 influenza season in Denmark. Vaccines were allocated in a 1:1 ratio. Baseline and follow-up data regarding diagnoses and mortality were obtained from Danish national registers. The trial is registered at Clinicaltrials.gov: NCT05048589. The CVDs assessed included heart failure (HF), ischemic heart disease (IHD), atrial fibrillation, and a combined group denoted "chronic CVD" consisting of the aforementioned diseases, among others. Prespecified outcomes included hospitalizations for pneumonia or influenza, respiratory disease, CVD, cardiorespiratory disease, all-cause hospitalizations, and mortality. Effect modification was tested using interaction terms. Results: The final study population included 12,477 participants (mean age 71.7±3.9 years, 5,877 (47.1%) female), of whom 2,540 (20.4%) had chronic CVD. QIV-HD vs. QIV-SD was associated with a lower incidence of hospitalizations for pneumonia or influenza (IRR 0.30 (95%-CI 0.14-0.64)) and all-cause mortality (IRR 0.51 (0.30-0.86)) regardless of chronic CVD (p for interaction=0.57 and 0.49, respectively). The relative effectiveness of QIV-HD vs. QIV-SD against all-cause hospitalizations was modified in participants with chronic CVD (Overall: IRR 0.87 (0.76-0.99); no chronic CVD: 0.79 (0.67-0.92); chronic CVD: 1.11 (0.88-1.39); p for interaction=0.026). No other effect modification was observed by the presence of chronic CVD, HF, IHD, or atrial fibrillation. Conclusions: The relative effectiveness of QIV-HD vs. QIV-SD was consistent against hospitalizations for pneumonia or influenza and all-cause mortality regardless of chronic CVD. However, the relative effectiveness against all-cause hospitalizations was modified by the presence of chronic CVD. These results should be considered hypothesis-generating.

Plasma activin A rises with declining kidney function and is independently associated with mortality in patients with chronic kidney disease.

Background: Plasma (p-)activin A is elevated in chronic kidney disease-mineral and bone disorder (CKD-MBD). Activin A inhibition ameliorates CKD-MBD complications (vascular calcification and bone disease) in rodent CKD models. We examined whether p-activin A was associated with major adverse cardiovascular events (MACE), all-cause mortality and CKD-MBD complications in CKD patients. Methods: The study included 916 participants (741 patients and 175 controls) from the prospective Copenhagen CKD cohort. Comparisons of p-activin A with estimated glomerular filtration rate (eGFR), coronary and thoracic aorta Agatston scores, and bone mineral density (BMD) were evaluated by univariable linear regression using Spearman's rank correlation, analysis of covariance and ordinal logistic regression with adjustments. Association of p-activin A with rates of MACE and all-cause mortality was evaluated by the Aalen-Johansen or Kaplan-Meier estimator, with subsequent multiple Cox regression analyses. Results: P-activin A was increased by CKD stage 3 (124-225 pg/mL, P < .001) and correlated inversely with eGFR (r = -0.53, P < 0.01). P-activin A was associated with all-cause mortality [97 events, hazard ratio 1.55 (95% confidence interval 1.04; 2.32), P < 0.05] after adjusting for age, sex, diabetes mellitus (DM) and eGFR. Median follow-up was 4.36 (interquartile range 3.64-4.75) years. The association with MACE was not significant after eGFR adjustment. Agatston scores and BMD were not associated with p-activin A. Conclusion: P-activin A increased with declining kidney function and was associated with all-cause mortality independently of age, sex, DM and eGFR. No association with MACE, vascular calcification or BMD was demonstrated.

The metabolic signature of cardiovascular disease and arterial calcification in patients with chronic kidney disease.

BACKGROUND AND AIMS: The relationship between chronic kidney disease (CKD) and cardiovascular events is well-established. Clinically recognised risk factors of cardiovascular disease cannot fully explain this association. The objective of the present cross-sectional study was to investigate associations between serum metabolites and prevalent cardiovascular disease, as well as subclinical cardiovascular disease measured as coronary artery calcium score (CACS) in patients with CKD. METHODS: More than 200 preselected metabolites were quantified using nuclear magnetic resonance spectroscopy in 725 patients and 174 controls from the Copenhagen CKD Cohort. CACS was determined by computed tomography. RESULTS: Mean age of patients was 57.8 years, and 444 (61.3%) were men. Most of patients had hypercholesterolemia, and 133 (18.3%) had type 2 diabetes. Overall, 85 metabolites were significantly associated with prevalent cardiovascular disease in a model adjusted for eGFR, age, and sex, as well as Bonferroni correction for multiple testing (p < 0.001). After further adjusting for diabetes, BMI, smoking, and cholesterol-lowering medication, the significance was lost for all but six metabolites (concentration of ApoA-1, cholesterol in total HDL and HDL2, total lipids and phospholipids in large HDL particles, and the ratio of phospholipids to total lipids in smaller VLDL particles). Of the 85 metabolites associated with prevalent cardiovascular disease, 71 were also associated with CACS in a similar pattern. Yet, in the model adjusted for all seven cardiovascular risk factors, only serum glucose levels and the ratio of triglycerides to total lipids in larger LDL particles remained significant. CONCLUSIONS: In patients with CKD, associations with prevalent cardiovascular disease were mainly found for HDL-related metabolites, while CACS was associated with glucose levels and increased triglycerides to total lipids ratio in LDL particles.

Differential characteristics of healthcare-associated compared to community-acquired febrile urinary tract infections in males.

The objective of this study was to analyse the characteristics of healthcare-associated febrile urinary tract infection (HCA-FUTI) compared to community-acquired FUTI (CA-FUTI) in men. An ambispective cross-sectional study in which we recorded clinical and microbiology data and outcomes from males with FUTI attended in the Emergency Department was carried out. A total of 479 males with FUTI, 162 (33.8%) HCA-FUTI and 317 (66.2%) CA-FUTI, were included. HCA-FUTI patients were older (p < 0.001), had higher Charlson scores (p < 0.001) and received previous antimicrobial treatment more frequently (p < 0.001) compared to CA-FUTI patients. HCA-FUTI was less likely caused by Escherichia coli (p < 0.001) and more frequently by Klebsiella spp. (p = 0.02), Enterobacter spp. (p < 0.001) and Pseudomonas aeruginosa (p < 0.001). Resistance to ceftriaxone (p = 0.006), gentamicin (p < 0.001), quinolones (p < 0.001), co-trimoxazole (p = 0.001) and fosfomycin (p = 0.009) was higher among E. coli strains isolated from males with HCA-FUTI and so was the prevalence of extended-spectrum beta-lactamase and AmpC E. coli and Klebsiella spp.-producing strains (p = 0.012). Inadequate antimicrobial treatment and all-cause in-hospital mortality was associated with HCA-FUTI (p < 0.001 and p = 0.004, respectively). Independent factors for mortality were severe sepsis or septic shock [odds ratio (OR) 29; 95% confidence interval (CI): 3.9-214] and cirrhosis (OR 23.7; 95% CI: 1.6-350.6). Male patients with HCA-FUTI have different clinical characteristics, outcomes and microbiological features compared to CA-FUTI patients. Previous contact with the healthcare system has to be taken into consideration when deciding the optimal antimicrobial treatment in males with FUTI.

Differential effects of insemination volume and substance on reproductive changes in honey bee queens (Apis mellifera†L.).

Mating causes dramatic changes in female insects at the behavioural, physiological and molecular level. The factors driving these changes (e.g. seminal proteins, seminal volume) and the molecular pathways by which these factors are operating have been characterized only in a handful of insect species. In the present study, we use instrumental insemination of honey bee queens to examine the role of the insemination substance and volume in triggering post-mating changes. We also examine differences in gene expression patterns in the fat bodies of queens with highly activated ovaries to determine if events during copulation can cause long-term changes in gene expression. We found that the instrumental insemination procedure alone caused cessation of mating flights and triggered ovary activation, with high-volume inseminated queens having the greatest ovary activation. Hierarchical clustering grouped queens primarily by insemination substance and then insemination volume, suggesting that while volume may trigger short-term physiological changes (i.e. ovary activation) substance plays a greater role in regulating long-term transcriptional changes. The results of gene ontology analysis and comparison with previous studies suggest that both insemination substance and volume trigger molecular post-mating changes by altering overlapping gene pathways involved in honey bee reproduction. We also discuss the effects on two genes (vitellogenin and transferrin) involved in reproduction and defence responses.

Effusion under the microscope.

Pseudochylothorax is a very rare form of pleural effusion. It is also called chyliform or cholesterol pleural effusion. It is usually a unilateral process and approximately one-third of patients are asymptomatic at presentation. We report a case of a 60 year old man with a background of rheumatoid arthritis who presented with progressive dyspnea. Chest X-ray revealed a new left pleural effusion and a small persistent right pleural effusion. He presented 5 years prior due to recurrent pleural effusion and no diagnosis was made. Repeat thoracentesis yielded 350 milliliters of thick, milky, tan-colored fluid.

Glucuronidation of trans-3'-hydroxycotinine by UGT2B17 and UGT2B10.

OBJECTIVES: Trans-3'-Hydroxycotinine (3HC) and its glucuronide are major nicotine metabolites excreted in the urine of smokers and other tobacco users. Although several members of the UDP-glucuronosyltransferase (UGT) family of enzymes were previously shown to be active in catalyzing the formation of 3HC and its glucuronide, a comprehensive screening of all known human UGT1A and 2B enzymes for glucuronidation activity against 3HC was not previously performed. METHODS: In the present study, human liver microsomes (HLM), eight UGT1A and six UGT2B enzymes were screened for activity against 3HC. RESULTS: UGT2B17 exhibited the highest O-glucuronidation activity, exhibiting a four-fold lower (P<0.005) KM (8.3 mmol/l) compared with that observed for UGTs 1A9 (35 mmol/l) or 2B7 (31 mmol/l) and a KM smaller compared with that observed for human liver microsomes (HLM; 26 mmol/l). The KM for 3HC-O-Gluc formation was 3.1-fold lower (P<0.0005) in HLM from male participants exhibiting the wild-type genotype UGT2B17 (*1/*1) compared with that in HLM from participants homozygous for the UGT2B17 deletion genotype [UGT2B17 (*2/*2)]. Both UGTs 2B10 and 1A4 exhibited 3HC-N-Gluc formation activity, with UGT2B10 exhibiting a four-fold lower (P<0.05) KM (13 mmol/l) compared with that observed for UGT1A4 (57 mmol/l) and, which was similar to the KM observed in HLM (14 mmol/l). There was 91 (P<0.0001) and 39% (P<0.001) decreases in the 3HC-N-Gluc formation activities in HLM from participants with the UGT2B10 (*2/*2) and UGT2B10 (*1/*2) genotypes, respectively, compared with that of HLM from participants with the wild-type UGT2B10 (*1/*1) genotype. CONCLUSION: These results suggest that UGT2B17 and UGT2B10 play key roles in the glucuronidation of 3HC in the human liver and that functional polymorphisms in UGT2B17 and UGT2B10 are associated with significantly reduced glucuronidation activities against 3HC.

Genome-wide analysis of brain transcriptional changes in honey bee (Apis mellifera L.) queens exposed to carbon dioxide and physical manipulation.

Mating is a complex process causing many behavioural and physiological changes, but the factors triggering them and the underlying molecular processes are not well characterized. In the present study we examine the effects of CO(2) (a commonly used anaesthetic in instrumental insemination that causes changes similar to those occurring after mating) and physical manipulation (which may mimic certain aspects of copulation) on the behavioural, physiological and brain transcriptional changes in honey bee queens. We show that while CO(2) causes cessation of mating flights and ovary activation, physical manipulation has additional effects on ovary activation and brain transcriptional changes. Comparisons with previous studies of honey bees and female Drosophila indicate that common molecular mechanisms may be responsible for regulating reproductive changes across different mating regimes and insect orders.

Glucuronidation genotypes and nicotine metabolic phenotypes: importance of functional UGT2B10 and UGT2B17 polymorphisms.

Glucuronidation is an important pathway in the metabolism of nicotine, with previous studies suggesting that ∼22% of urinary nicotine metabolites are in the form of glucuronidated compounds. Recent in vitro studies have suggested that the UDP-glucuronosyltransferases (UGT) 2B10 and 2B17 play major roles in nicotine glucuronidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotine-glucuronide, cotinine-glucuronide, and trans-3'-hydroxycotinine (3HC)-glucuronide in human liver microsomes in vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and functional polymorphisms in UGTs 2B10 and 2B17 was analyzed in urine specimens from 104 Caucasian smokers. Based on their percentage of total urinary nicotine metabolites, the levels of nicotine-glucuronide and cotinine-glucuronide were 42% (P < 0.0005) and 48% (P < 0.0001), respectively, lower in the urine from smokers exhibiting the UGT2B10 (*1/*2) genotype and 95% (P < 0.05) and 98% (P < 0.05), respectively, lower in the urine from smokers with the UGT2B10 (*2/*2) genotype compared with the urinary levels in smokers having the wild-type UGT2B10 (*1/*1) genotype. The level of 3HC-glucuronide was 42% (P < 0.001) lower in the urine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype compared with the levels in urine from wild-type UGT2B17 subjects. These data suggest that UGTs 2B10 and 2B17 play important roles in the glucuronidation of nicotine, cotinine, and 3HC and suggest that the UGT2B10 codon 67 SNP and the UGT2B17 gene deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers.

Influence of the boundary thermal conditions on the air change efficiency indexes.

The influence of a thermal heterogeneity boundary conditions on the air change efficiency (ACE) of a mechanical ventilation system in a test room was experimentally evaluated by means of the "step-down" tracer gas technique in 24 different experimental conditions. The experiments were performed under isothermal condition, varying the air supply temperature with respect to the walls and varying the surface temperature of a wall with respect to the other walls and the supply air, simulating both heating and cooling situations. Changing the position of the outlet grid two different configurations of the ventilation system were tested. The nominal supply air velocity varied between 0.04 and 0.11 m/s, corresponding to a range from 1 to 3 ach, and the temperature differences varied from 0 to 5 degrees C. Results are reported in terms of air change efficiency indexes, both local and global. The global air change efficiency (ACE), values are presented as a function of the Archimedes number (Ar), whose values were in the range 0 to 181. The reported results suggest that the Ar number may be used to organize the ACE values when in the presence of thermal heterogeneity, both in the external envelope and in the supplied air. The obtained results show that there is a logarithmic relation between Ar and ACE. In particular, for both ventilation strategies tested, the increase of the absolute value of Ar leads to an increase of ACE when the supply air is warmer than the walls, and to a decrease of ACE when the supply air is colder than the walls. Under isothermal conditions the Reynolds number (Re) fairly correlates the experimental results.

Identification of an anaerobically induced phosphoenolpyruvate-dependent fructose-specific phosphotransferase system and evidence for the Embden-Meyerhof glycolytic pathway in the heterofermentative bacterium Lactobacillus brevis.

Heterofermentative gram-positive bacteria are believed to metabolize sugars exclusively via the pentose phosphoketolase pathway following uptake via sugar:cation symport. Here we show that anaerobic growth of one such bacterium, Lactobacillus brevis, in the presence of fructose induces the synthesis of a phosphotransferase system and glycolytic enzymes that allow fructose to be metabolized via the Embden-Meyerhof pathway.

[The pH of feces in children with acute diarrhea during the first hours of oral rehydration]. / El pH de las heces en los niños con diarrea aguda durante las primeras horas de rehidratación oral.

We studied 108 children between 3 and 36 months of age with acute diarrhea and dehydration when their diarrhea continued more than 24 hours following initiation of ORT and in whom we measured pH and glucose of stools with strips in all evacuations. According to the average stool pH and glucose in the first six hours, the patients were grouped in pH < or = 5.5 and > 5.5 and a glucose < or = 1+ and > 1+. The pH of stools < or = 5.5 increased significantly (P < or = .0005) in children between > 6-12 hours and by 48 hours, it was similar to those with an initial average pH 6.6 Stool glucose declined considerably between > 12 and 24 hours. Contrary to what we expected to find, children with pH > 5.5 excreted more stools and had a higher ORT intake in the first 24 hours. The systematic studies of pH and glucose of stools did not appear to be useful for children with acute diarrhea who had a satisfactory evolution.