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The Journal of Hospital Infection Jun 2024Continuous fluid infusions delivered between therapies by piggy-back systems avoid disconnection and reconnection of central venous catheters (CVC), thereby reducing...
BACKGROUND
Continuous fluid infusions delivered between therapies by piggy-back systems avoid disconnection and reconnection of central venous catheters (CVC), thereby reducing opportunities for line contamination. However, the impact of continuous versus intermittent infusions on central line-associated bloodstream infections (CLABSI) is unknown.
AIM
To investigate the effect of temporary infusion interruption and line disconnection, with or without use of a 70% isopropyl alcohol cap (IPA-C) use on CLABSI rates in haematology patients.
METHODS
Quasi-experimental study in two haemato-oncology units. At baseline (P1, September 2020 - August 2021), continuous intravenous piggy-back infusions were mandatory. In a first intervention phase (P2, September 2021 - August 2022), infusion disconnections were implemented with use of a 70% isopropyl alcohol cap (IPA-C) for passive decontamination. In a second intervention phase (P3, September 2022 - August 2023), infusion disconnections continued without the use of IPA-C. Rates of CLABSI were compared across the three intervention periods using segmented Poisson regression.
FINDINGS
A total of 11,039 catheter-days across 764 CVC and 16,226 patient-days were included. 21 CLABSI were recorded across all intervention periods. Compared with P1, incidence rate ratios (IRRs) for CLABSI did not significantly change in P2 (IRR 0.76 [95% CI 0.27-2.15]) and P3 (IRR 0.79 [CI 95% 0.28-2.22]). No CVCs were removed due to occlusion during the study period. Five of 21 CLABSI were polymicrobial, and coagulase-negative staphylococci were isolated in 19/21 cases (90%).
CONCLUSION
Interruption of continuous infusions in haemato-oncology patients with a CVC was not associated with a substantial change in CLABSI rates, whether or not an IPA-C was used.
PubMed: 38945400
DOI: 10.1016/j.jhin.2024.05.021 -
Pharmacological Research Jun 2024Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer...
Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.
PubMed: 38945380
DOI: 10.1016/j.phrs.2024.107252 -
Journal of Dairy Science Jun 2024High-yielding dairy cows encounter metabolic challenges in early lactation. Typically, β-hydroxybutyrate (BHB), measured at a specific time point is employed to...
High-yielding dairy cows encounter metabolic challenges in early lactation. Typically, β-hydroxybutyrate (BHB), measured at a specific time point is employed to diagnose the metabolic status of cows based on a predetermined threshold. However, in early lactation, BHB is highly dynamic, and there is high interindividual variability in its time profile. This could limit the effectiveness of the single measurement and threshold-based diagnosis probably contributing to the disparities in reports linking metabolic status with productive and reproductive outcomes. This research delves into the examination of the trajectories of BHB to unveil inter-cow variations and identify latent metabolic groups. We compiled a data set from 2 observational studies involving a total of 195 lactations from multiparous Holstein Friesian cows. The data set encompasses measurements of BHB, NEFA, and insulin from blood samples collected at 3, 6, 9, and 21 d in milk (DIM), along with weekly determinations of milk composition and fatty acids (FA) proportions in milk fat. In both experiments, milk yield (MY) and feed intake were recorded daily during the first month of lactation. We explored interindividual and intraindividual variations in metabolic responses using the trajectories of blood BHB and evaluated the presence of distinct metabolic groups based on such variations. For this purpose, we employed the growth mixture model (GMM), a trajectory clustering technique. Our findings unveil novel insights into the diverse metabolic responses among cows, encompassing both trajectory patterns and the magnitude of blood BHB concentrations. Specifically, we identified 3 latent metabolic groups: the "QuiBHB" cluster (≈10%) exhibited a higher initial BHB concentration than other clusters, peaking on d 9 (average maximum BHB of 2.4 mM) and then declining by d 21; the "SloBHB" cluster (≈23%) started with a lower BHB concentration, gradually increasing until d 9, and at the highest BHB concentration at d 21 (1.6 mM serum BHB at the end of the experimental period); and the "LoBHB" cluster (≈67%) began with the lowest serum BHB concentration (serum BHB <0.75 mM), remaining relatively stable throughout the sampling period. Notably, the 3 metabolic groups exhibited significant physiological disparities, evident in blood NEFA and insulin concentrations. The QuiBHB and SloBHB cows exhibited higher NEFA and lower insulin concentrations as compared with the LoBHB cows. Interestingly, these metabolic differences extended to MY and DMI during the first month of lactation. The elevated BHB concentrations observed in QuiBHB cows were linked with lower DMI and MY as compared with SloBHB and LoBHB cows. Accordingly, these animals were considered metabolically impaired. Conversely, SloBHB cows displayed higher MY along with increased DMI, and thus the elevated BHB might be indicative of an adaptive response for these cows. The QuiBHB cows also displayed higher proportions of unsaturated FA (UFA), monounsaturated FA (MUFA), and total C18:1 FA in milk during the first week of lactation. Prediction of the QuiBHB cows using these FA and test day variables resulted in moderate predictive accuracy (ROC > 0.7). Given the limited sample size for the development of prediction models, and the variation in DIM among samples in the same week, the result is indicative of the predictive potential of the model and room for model optimization. In summary, distinct metabolic groups of cows could be identified based on the trajectories of blood BHB in early lactation.
PubMed: 38945267
DOI: 10.3168/jds.2024-24762 -
Journal of Dairy Science Jun 2024Yogurt is popular as a natural and healthy food, but its flavor greatly affects acceptability by consumers. Flavor compounds of yogurt is generally produced by the... (Review)
Review
Yogurt is popular as a natural and healthy food, but its flavor greatly affects acceptability by consumers. Flavor compounds of yogurt is generally produced by the metabolism of lactose, protein and fat, and the resulting flavors include carbonyls, acids, esters and alcohols, etc. Each flavor compounds could individually provide the corresponding flavor, or it can be combined with other compounds to form a new flavor. The flavor network was formed among the metabolites of milk components, and acetaldehyde, as the central compounds, played a role in connecting the whole network. The flavor compounds can be affected by many factors, such as the use of different raw milks, ways of homogenization, sterilization, fermentation, post ripening, storage condition and packaging materials, etc., which can affect the overall flavor of yogurt. This paper provides an overview of the volatile flavor compounds in yogurt, the pathways of production of the main flavor compounds during yogurt fermentation, and the factors that influence the flavor of yogurt including type of raw milk, processing, and storage. It also tries to provide theoretical guidance for the product of yogurt in ideal flavor, but further research is needed to provide a more comprehensive description of the flavor system of yogurt.
PubMed: 38945263
DOI: 10.3168/jds.2024-24875 -
Journal of Dairy Science Jun 2024The primary objective of this study was to evaluate the association between preweaning diarrhea and measures of survival, health and production. The measures of interest...
The primary objective of this study was to evaluate the association between preweaning diarrhea and measures of survival, health and production. The measures of interest included survival (mortality before first calving and time to removal from the herd), health (retained fetal membranes, metritis, mastitis and somatic cell count), and production (305d mature equivalent milk yield and time to first calving). A secondary objective was to investigate if these associations varied according to the age of the calf when the case of diarrhea occurred. Herd records from a farm located in Southern Australia were used to conduct a retrospective cohort study where subjects (calves) with diarrhea were enrolled at the time of their first case along with 2 subjects without diarrhea, matched for age (±3 d) and date of birth (±15 d), amounting to 9833 calves in the data set. Survival analysis was conducted to determine if preweaning diarrhea was associated with death in the short term (first 20 d after enrollment), medium term (21 to 100 d after enrollment) and long-term (101 d after enrollment to first calving). Crude incidence rate ratios, Kaplan-Meier curves and hazard ratios (HR, Cox regression) were derived for each event-based outcome (e.g., death, calving, mastitis). Multivariable linear models were used for continuous outcomes. Calves with preweaning diarrhea had greater mortality rates in the short term (hazard ratio, HR = 2.48, 95% CI: 1.87-3.29) and medium term (HR = 1.89, 95% CI: 1.41-2.55) but not in the long term (HR = 0.98, 95% CI: 0.79-1.22). A small negative association between preweaning diarrhea and time to first calving was found, with calves with diarrhea calving 4 d later than calves without diarrhea (HR = 0.95, 95% CI: 0.91-1.00). Rates of post-calving removal from the herd (death or culling) were higher in calves with a history of preweaning diarrhea (HR = 1.13, 95% CI: 1.01 to 1.26), as were peak lactation log somatic cell count (+0.08, 95% CI: 0.02 to 0.14). Further research is needed to replicate these novel findings as they are based on exploratory analyses and could be spurious findings. No substantial associations were observed for the other measures of interest. Our study findings support existing research demonstrating the significance of preweaning diarrhea as a significant cause of calf mortality, and raises new hypotheses about other potential impacts during lactation.
PubMed: 38945259
DOI: 10.3168/jds.2023-24544 -
Virologica Sinica Jun 2024Bats are the natural reservoir hosts for SARS-related coronavirus (SARSr-CoV) and other highly pathogenic microorganisms. Therefore, it is conceivable that an individual...
Bats are the natural reservoir hosts for SARS-related coronavirus (SARSr-CoV) and other highly pathogenic microorganisms. Therefore, it is conceivable that an individual bat may harbor multiple microbes. However, there is limited knowledge on the overall co-circulation of microorganisms in bats. Here, we conducted a 16-year monitoring of bat viruses in south and central China and identified 238 SARSr-CoV positive samples across nine bat species from ten provinces or administrative districts. Among these, 76 individual samples were selected for further metagenomics analysis. We found a complex microenvironment characterized by the general co-circulation of microbes from two different sources: mammal-associated viruses or environment-associated microbes. The later includes commensal bacteria, enterobacteria-related phages, and insect or fungal viruses of food origin. Results showed that 25% (19/76) of the samples contained at least one another mammal-associated virus, notably alphacoronaviruses (13/76) such as AlphaCoV/YN2012, HKU2-related CoV and AlphaCoV/Rf-HuB2013, along with viruses from other families. Notably, we observed three viruses co-circulating within a single bat, comprising two coronavirus species and one picornavirus. Our analysis also revealed the potential presence of pathogenic bacteria or fungi in bats. Furthermore, we obtained 25 viral genomes from the 76 bat SARSr-CoV positive samples, some of which formed new evolutionary lineages. Collectively, our study reveals the complex microenvironment of bat microbiome, facilitating deeper investigations into their pathogenic potential and the likelihood of cross-species transmission.
PubMed: 38945213
DOI: 10.1016/j.virs.2024.06.008 -
Toxicology Jun 2024Ochratoxin A (OTA) is a rat renal carcinogen that induces karyomegaly and micronuclei in proximal tubular epithelial cells (PTECs). We previously performed comprehensive...
Involvement of multiple epigenetic mechanisms by altered DNA methylation from the early stage of renal carcinogenesis before proliferative lesion formation upon repeated administration of ochratoxin A.
Ochratoxin A (OTA) is a rat renal carcinogen that induces karyomegaly and micronuclei in proximal tubular epithelial cells (PTECs). We previously performed comprehensive gene profiling of alterations in promoter-region methylation and gene expression in PTECs of rats treated with OTA for 13 weeks. The OTA-specific gene profile was obtained by excluding genes showing expression changes similar to those upon treatment with 3-chloro-1,2-propanediol, a renal carcinogen not inducing karyomegaly. In this study, we validated the candidate genes using methylated DNA enrichment PCR and real-time RT-PCR, and identified Gen1, Anxa3, Cdkn1a, and Osm as genes showing OTA-specific epigenetic changes. These genes and related molecules were subjected to gene expression and immunohistochemical analyses in the PTECs of rats treated with OTA, other renal carcinogens, or non-carcinogenic renal toxicants for 4 or 13 weeks. Cdkn1a upregulation and increase of p21 karyomegalic PTECs were observed with OTA, matching the findings associated with micronucleus-inducing carcinogens. This suggested that the increase of p21 karyomegalic PTECs is linked to micronucleus formation, which in turn accelerates chromosomal instability. The upregulation of Cdkn1a-related genes with OTA suggests the acquisition of a senescence-associated secretory phenotype, which promotes the establishment of a carcinogenic environment. Meanwhile, OTA specifically caused a decrease of GEN1 PTECs reflecting Gen1 downregulation and an increase of ANXA3 PTECs reflecting Anxa3 upregulation, as well as Osm upregulation. OTA may efficiently disrupt pathways for repairing the DNA double-strand breaks that it itself causes, via Gen1 downregulation, and enhance cell proliferation through the upregulation of Anxa3 and Osm. This may exacerbate the chromosomal instability from the early stage of OTA-induced renal carcinogenesis before proliferative lesions form. OTA may cause renal carcinogenesis involving multiple epigenetic mechanisms.
PubMed: 38945198
DOI: 10.1016/j.tox.2024.153875 -
Acta Biomaterialia Jun 2024This paper presents an inverse finite element (FE) approach aimed at estimating multi-layered human penile tissues. The inverse FE approach integrates experimental...
This paper presents an inverse finite element (FE) approach aimed at estimating multi-layered human penile tissues. The inverse FE approach integrates experimental force-displacement and boundary deformation data of penile tissues with a developed FE model and uses new experimental data on human penile tissue. The experimental study encompasses whole organ plate-compression tests and individual layer tensile and compression tests, providing comprehensive insights into the tissue's mechanical behaviour. The biomechanical characterisation of penile tissue is of crucial significance for understanding its mechanical behaviour under various physiological and pathological conditions. The FE model is constructed using the realistic geometry of the penile segment and appropriate constitutive models for each tissue layer to leverage the accuracy and consistency of the model. Through systematic variation of tissue parameters in the inverse FE algorithm, simulations achieve the best match with both force-displacement and deformed boundary results obtained from the whole organ plate-compression tests. Test results from individual tissue layers are also utilised to assess the estimated parameters. The proposed inverse FE approach allows for the estimation of penile tissue parameters with high precision and reliability, shedding light on the mechanical properties of this complex biological organ. This work has applications not only in urology but also for researchers in various disciplines of biomechanics. As a result, our study contributes to advancing the understanding of human penile tissue mechanics whilst the methodology could also be applied to a range of other soft biological tissues. STATEMENT OF SIGNIFICANCE: This research uses a multi-target inverse finite element (FE) approach for estimating the material parameters of human penile tissues. By integrating experimental data and a realistic FE model, this study achieves high-precision constitutive model parameter estimation, offering key insights into penile tissue mechanics under various loading conditions. The significance of this work lies in the use of this inverse FE approach for fresh-frozen human penile tissues, to identify the mechanical properties and constitutive models for both segregated tunica albuginea and corpus cavernosum as well as intact penile tissue segments. The study's scientific impact lies in its advancement of the understanding of human urological tissue mechanics, impacting researchers and clinicians alike.
PubMed: 38945188
DOI: 10.1016/j.actbio.2024.06.035 -
Journal of the American Medical... Jun 2024Although the cardiac benefits of maintaining a lifelong exercise routine are undisputed, to what extent late-in-life exercise training can ameliorate cardiac aging...
OBJECTIVE
Although the cardiac benefits of maintaining a lifelong exercise routine are undisputed, to what extent late-in-life exercise training can ameliorate cardiac aging remains unclear. We examined the impact of a 12-month exercise training program on cardiac reserve, static cardiac structure, and cardiac function in older adults.
DESIGN
This study was a single-center, randomized trial using Zelen design. Participants in the center-based exercise (CBE) group underwent an individualized multicomponent exercise training program.
SETTING AND PARTICIPANTS
In total, 120 community-dwelling older adults aged 65-85 years were evenly divided into a CBE group and a control group.
METHODS
The primary outcome indicator was absolute change in peak oxygen uptake (peakVO) per kilogram from baseline to 12 months. The secondary outcome indicators were the absolute changes in other cardiopulmonary exercise test indices and cardiac magnetic resonance parameters. This study has been registered at the Chinese Clinical Trial Registry Network (ChiCTR XXXX).
RESULTS
In total, 47 older adults in the control group and 49 in the CBE group ultimately completed the 12-month follow-up and were analyzed. Of all participants, 52 (46.4%) were men, and the mean age was 71.22 ± 4.55 years. The absolute change in peakVO/kg was significantly different between the CBE and control groups by +3.32 mL/kg/min (95% CI 2.10-4.53; P < .001), and a sex-related difference was observed. Additionally, the right ventricular peak filling and ejection rate improved to a greater degree in the CBE than control group (+65.57 mL/s, P = .006; +56.39 mL/s, P = .026, respectively).
CONCLUSIONS AND IMPLICATIONS
A 12-month exercise training program started later in life was effective in improving cardiopulmonary reserve, and men showed a better response to training than women. The right ventricular function increased after late-in-life exercise training.
PubMed: 38945172
DOI: 10.1016/j.jamda.2024.105117 -
The Lancet. Neurology Jun 2024The accuracy of prognostication in patients with cervical spinal cord injury (SCI) needs to be improved. We aimed to explore the prognostic value of preserved spinal...
BACKGROUND
The accuracy of prognostication in patients with cervical spinal cord injury (SCI) needs to be improved. We aimed to explore the prognostic value of preserved spinal tissue bridges-injury-spared neural tissue adjacent to the lesion-for prediction of sensorimotor recovery in a large, multicentre cohort of people with SCI.
METHODS
For this longitudinal study, we included patients with acute cervical SCI (vertebrae C1-C7) admitted to one of three trauma or rehabilitation centres: Murnau, Germany (March 18, 2010-March 1, 2021); Zurich, Switzerland (May 12, 2002-March 2, 2019); and Denver, CO, USA (Jan 12, 2010-Feb 16, 2017). Patients were clinically assessed at admission (baseline), at discharge (3 months), and at 12 months post SCI. Midsagittal tissue bridges were quantified from T2-weighted images assessed at 3-4 weeks post SCI. Fractional regression and unbiased recursive partitioning models, adjusted for age, sex, centre, and neurological level of injury, were used to assess associations between tissue bridge width and baseline-adjusted total motor score, pinprick score, and light touch scores at 3 months and 12 months. Patients were stratified into subgroups according to whether they showed better or worse predicted recovery.
FINDINGS
The cohort included 227 patients: 93 patients from Murnau (22 [24%] female); 43 patients from Zurich (four [9%] female); and 91 patients from Denver (14 [15%] female). 136 of these participants (from Murnau and Zurich) were followed up for up to 12 months. At 3 months, per preserved 1 mm of tissue bridge at baseline, patients recovered a mean of 9·3% (SD 0·9) of maximal total motor score (95% CI 7·5-11.2), 8·6% (0·8) of maximal pinprick score (7·0-10·1), and 10·9% (0·8) of maximal light touch score (9·4-12·5). At 12 months post SCI, per preserved 1 mm of tissue bridge at baseline, patients recovered a mean of 10·9% (1·3) of maximal total motor score (8·4-13·4), 5·7% (1·3) of maximal pinprick score (3·3-8·2), and 6·9% (1·4) of maximal light touch score (4·1-9·7). Partitioning models identified a tissue bridge cutoff width of 2·0 mm to be indicative of higher or lower 3-month total motor, pinprick, and light touch scores, and a cutoff of 4·0 mm to be indicative of higher and lower 12-month scores. Compared with models that contained clinical predictors only, models additionally including tissue bridges had significantly improved prediction accuracy across all three centres.
INTERPRETATION
Tissue bridges, measured in the first few weeks after SCI, are associated with short-term and long-term clinical improvement. Thus, tissue bridges could potentially be used to guide rehabilitation decision making and to stratify patients into more homogeneous subgroups of recovery in regenerative and neuroprotective clinical trials.
FUNDING
Wings for Life, International Foundation for Research in Paraplegia, EU project Horizon 2020 (NISCI grant), and ERA-NET NEURON.
PubMed: 38945142
DOI: 10.1016/S1474-4422(24)00173-X