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Journal of Diabetes Investigation Jun 2024Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β-cells. Here, we investigated...
AIMS/INTRODUCTION
Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β-cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α-cells.
MATERIALS AND METHODS
Experiments were carried out in high-fat, high-sucrose diet-fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme-linked immunosorbent assay; the latter eliminates cross-reactivities with other proglucagon-derived peptides.
RESULTS
Plasma glucagon, insulin and glucagon-like peptide-1 levels were increased by imeglimin administration in high-fat, high-sucrose diet-fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long-term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long-term administration of imeglimin did not alter α-cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein-1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I.
CONCLUSIONS
Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation.
PubMed: 38874179
DOI: 10.1111/jdi.14249 -
Mathematical Biosciences and... Mar 2024The leader-following consensus (LFC) issue is investigated in this paper for multi-agent systems (MASs) subject to actuator saturation with semi-Markov switching...
The leader-following consensus (LFC) issue is investigated in this paper for multi-agent systems (MASs) subject to actuator saturation with semi-Markov switching topologies (SMST). A new consensus protocol is proposed by using a semi-Markov process to model the switching of network topologies. Compared to the traditional Markov switching topologies, the SMST is more general and practical because the transition rates are time-varying. By using the local sector conditions and a suitable Lyapunov-Krasovskii functional, some sufficient conditions are proposed such that the leaderfollowing mean-square consensus is locally achieved. Based on the derived sufficient conditions, an optimization problem is analyzed to determine the consensus feedback gains and to find a maximal estimate of the domain of consensus attraction (DOCA) of a closed-loop model. At the end, a numerical case is presented to verify the performance of the design method.
PubMed: 38872520
DOI: 10.3934/mbe.2024217 -
Systematic Reviews Jun 2024Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar,...
The optimal second-line therapy for older adults with type 2 diabetes mellitus: protocol for a systematic review and network meta-analysis using individual participant data (IPD).
BACKGROUND
Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar, the choice of which second-line therapy to prescribe next is not clear from currently available evidence. The existence of frailty and comorbidities in older adults further increases the complexity of medical decision-making. As only a relatively small proportion of trials report results separately for older adults, the relative efficacy and safety of second-line therapies in older adults with type 2 diabetes mellitus are unknown and require further investigation. This individual participant data (IPD) network meta-analysis evaluates the relative efficacy and safety of second-line therapies on their own or in combination in older adults with type 2 diabetes mellitus.
METHODS
All relevant published and unpublished trials will be identified. Studies published prior to 2015 will be identified from two previous comprehensive aggregate data network meta-analyses. Searches will be conducted in CENTRAL, MEDLINE, and EMBASE from 1st January 2015 onwards, and in clinicaltrials.gov from inception. Randomised controlled trials with at least 100 estimated older adults (≥ 65 years) receiving at least 24 weeks of intervention that assess the effects of glucose-lowering drugs on mortality, glycemia, vascular and other comorbidities outcomes, and quality of life will be eligible. The screening and data extraction process will be conducted independently by two researchers. The quality of studies will be assessed using the Cochrane risk of bias tool 2. Anonymised IPD of all eligible trials will be requested via clinical trial portals or by contacting the principal investigators or sponsors. Received data will be reanalysed where necessary to standardise outcome metrics. Network meta-analyses will be performed to determine the relative effectiveness of therapies.
DISCUSSION
With the increasing number of older adults with type 2 diabetes worldwide, an IPD network meta-analysis using data from all eligible trials will provide new insights into the optimal choices of second-line antidiabetic drugs to improve patient management and reduce unnecessary adverse events and the subsequent risk of comorbidities in older adults.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42021272686.
Topics: Humans; Diabetes Mellitus, Type 2; Systematic Reviews as Topic; Aged; Hypoglycemic Agents; Network Meta-Analysis; Metformin; Research Design
PubMed: 38872216
DOI: 10.1186/s13643-024-02558-5 -
BMJ Open Jun 2024Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk.
METHODS AND ANALYSIS
We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation.
ETHICS AND DISSEMINATION
We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309).
TRIAL REGISTRATION NUMBER
NCT05148715.
Topics: Humans; Calcineurin Inhibitors; Pilot Projects; Delayed Graft Function; Kidney Transplantation; Tissue Donors; Tacrolimus; Brain Death; Graft Survival; Quebec; Randomized Controlled Trials as Topic; Immunosuppressive Agents; Multicenter Studies as Topic; Male; Ontario; Adult; Female
PubMed: 38871657
DOI: 10.1136/bmjopen-2024-086777 -
PloS One 2024Oral antineoplastic agents have caused a paradigm shift in cancer treatment, however, they produce many unique challenges. Although oral antineoplastics can have complex...
BACKGROUND
Oral antineoplastic agents have caused a paradigm shift in cancer treatment, however, they produce many unique challenges. Although oral antineoplastics can have complex administration regimes, low adherence rates and high possibilities of drug-drug interactions, they are administered unsupervised at home. Cancer services pharmacists have the required skillsets to improve patient outcomes associated with oral antineoplastic treatment by increasing patient health literacy, improving concordance and optimising administration protocols.
AIM
To evaluate patients' perceptions, experiences and overall satisfaction with dedicated clinical pharmacist consultations in patients treated with oral antineoplastic agents at a major public hospital.
METHOD
In this retrospective cross-sectional study at a quaternary hospital in Western Australia, data were collected by a paper questionnaire (mailed in March 2022) to a random sample of 191 patients initiated on oral antineoplastic drugs between January 2021 and February 2022. Demographics, prescribed antineoplastic drug/s, cancer type data were collected including using 5-point Likert scale questions assess patients' overall satisfaction with the clinical pharmacist consultations.
RESULTS
The questionnaire response rate was 27.7% (52/188) (mean age 63.2 years; 57.5% female). Most patients (42/52; 80.8%) were satisfied with pharmacist consultations, trusted the pharmacist's advice (45/52; 86.5%), considered that the pharmacist improved their understanding of how to manage side effects (43/52; 82.7%) and they provided an important service in outpatient care (45/52; 86.5%).
CONCLUSION
Overall, patients reported positive perceptions, experiences, and satisfaction with the cancer services pharmacist counselling services during their oral antineoplastic treatment.
Topics: Humans; Female; Male; Middle Aged; Antineoplastic Agents; Pharmacists; Administration, Oral; Cross-Sectional Studies; Aged; Retrospective Studies; Neoplasms; Counseling; Surveys and Questionnaires; Patient Satisfaction; Adult; Ambulatory Care Facilities; Perception; Outpatients
PubMed: 38870231
DOI: 10.1371/journal.pone.0304011 -
PloS One 2024Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI, renal cortical perfusion is deficient despite normal macrovascular organ blood flow. This intra-renal perfusion abnormality may be amenable to pharmacological manipulation, which may offer mechanistic insight into the pathophysiology of septic AKI. The aim of the current study is to investigate the effects of vasopressin and angiotensin II on renal microcirculatory perfusion in a cohort of patients with septic shock.
METHODS AND ANALYSIS
In this single centre, mechanistically focussed, randomised controlled study, 45 patients with septic shock will be randomly allocated to either of the study vasopressors (vasopressin or angiotensin II) or standard therapy (norepinephrine). Infusions will be titrated to maintain a mean arterial pressure (MAP) target set by the attending clinician. Renal microcirculatory assessment will be performed for the cortex and medulla using contrast-enhanced ultrasound (CEUS) and urinary oxygen tension (pO2), respectively. Renal macrovascular flow will be assessed via renal artery ultrasound. Measurement of systemic macrovascular flow will be performed through transthoracic echocardiography (TTE) and microvascular flow via sublingual incident dark field (IDF) video microscopy. Measures will be taken at baseline, +1 and +24hrs following infusion of the study drug commencing. Blood and urine samples will also be collected at the measurement time points. Longitudinal data will be compared between groups and over time.
DISCUSSION
Vasopressors are integral to the management of patients with septic shock. This study aims to further understanding of the relationship between this therapy, renal perfusion and the development of AKI. In addition, using CEUS and urinary pO2, we hope to build a more complete picture of renal perfusion in septic shock by interrogation of the constituent parts of the kidney. Results will be published in peer-reviewed journals and presented at academic meetings.
TRIAL REGISTRATION
The REPERFUSE study was registered on Clinical Trials.gov (NCT06234592) on the 30th Jan 24.
Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Microcirculation; Acute Kidney Injury; Kidney; Vasopressins; Angiotensin II; Male; Female; Norepinephrine; Renal Circulation; Middle Aged; Adult
PubMed: 38870103
DOI: 10.1371/journal.pone.0304227 -
Integrative Cancer Therapies 2024Natural products are increasingly gaining interest as potential new drug candidates for cancer treatment. Herbal formula, which are combinations of several herbs, are... (Review)
Review
BACKGROUND
Natural products are increasingly gaining interest as potential new drug candidates for cancer treatment. Herbal formula, which are combinations of several herbs, are primarily used in East Asia and have a long history of use that continues today. Recently, research exploring the combination of herbal formulas and chemotherapy for cancer treatment has been on the rise.
METHODS
This study reviewed research on the co-administration of herbal formulas and chemotherapy for cancer treatment. The databases PubMed, Embase, and Cochrane Library were used for article searches. The following keywords were employed: "Antineoplastic agents," "Chemotherapy," "Phytotherapy," "Herbal medicine," "Drug synergism," and "Synergistic effect." The selection process focused on studies that investigated the synergistic interaction between herbal formulas and chemotherapeutic agents.
RESULTS
Among the 30 studies included, 25 herbal formulas and 7 chemotherapies were used. The chemotherapy agents co-administered included cisplatin, 5-fluorouracil, docetaxel, doxorubicin, oxaliplatin, irinotecan, and gemcitabine. The types of cancer most frequently studied were lung, breast, and colon cancers. Most studies evaluating the anticancer efficacy of combined herbal formula and chemotherapy treatment were conducted in vitro or in vivo.
DISCUSSION
Most studies reported synergistic effects on cytotoxicity, apoptosis, and tumor growth inhibition. These effects were found to be associated with cell cycle arrest, anti-angiogenesis, and gene expression regulation. Further studies leading to clinical trials are required. Clinical experiences in East Asian countries could provide insights for future research.
Topics: Humans; Drug Synergism; Neoplasms; Apoptosis; Phytotherapy; Antineoplastic Agents; Animals; Plants, Medicinal; Antineoplastic Combined Chemotherapy Protocols; Herbal Medicine
PubMed: 38867515
DOI: 10.1177/15347354241259416 -
Antimicrobial Resistance and Infection... Jun 2024This study aimed to develop and apply a nomogram with good accuracy to predict the risk of CRAB infections in neuro-critically ill patients. In addition, the...
Development and application of a risk nomogram for the prediction of risk of carbapenem-resistant Acinetobacter baumannii infections in neuro-intensive care unit: a mixed method study.
OBJECTIVE
This study aimed to develop and apply a nomogram with good accuracy to predict the risk of CRAB infections in neuro-critically ill patients. In addition, the difficulties and expectations of application such a tool in clinical practice was investigated.
METHODS
A mixed methods sequential explanatory study design was utilized. We first conducted a retrospective study to identify the risk factors for the development of CRAB infections in neuro-critically ill patients; and further develop and validate a nomogram predictive model. Then, based on the developed predictive tool, medical staff in the neuro-ICU were received an in-depth interview to investigate their opinions and barriers in using the prediction tool during clinical practice. The model development and validation is carried out by R. The transcripts of the interviews were analyzed by Maxqda.
RESULTS
In our cohort, the occurrence of CRAB infections was 8.63% (47/544). Multivariate regression analysis showed that the length of neuro-ICU stay, male, diabetes, low red blood cell (RBC) count, high levels of procalcitonin (PCT), and number of antibiotics ≥ 2 were independent risk factors for CRAB infections in neuro-ICU patients. Our nomogram model demonstrated a good calibration and discrimination in both training and validation sets, with AUC values of 0.816 and 0.875. Additionally, the model demonstrated good clinical utility. The significant barriers identified in the interview include "skepticism about the accuracy of the model", "delay in early prediction by the indicator of length of neuro-ICU stay", and "lack of a proper protocol for clinical application".
CONCLUSIONS
We established and validated a nomogram incorporating six easily accessed indicators during clinical practice (the length of neuro-ICU stay, male, diabetes, RBC, PCT level, and the number of antibiotics used) to predict the risk of CRAB infections in neuro-ICU patients. Medical staff are generally interested in using the tool to predict the risk of CRAB, however delivering clinical prediction tools in routine clinical practice remains challenging.
Topics: Humans; Nomograms; Acinetobacter baumannii; Male; Female; Retrospective Studies; Middle Aged; Intensive Care Units; Carbapenems; Acinetobacter Infections; Risk Factors; Aged; Anti-Bacterial Agents; Adult; Critical Illness
PubMed: 38867312
DOI: 10.1186/s13756-024-01420-6 -
BMC Genomics Jun 2024The Portuguese oyster Crassostrea angulata, a bivalve of significant economic and ecological importance, has faced a decline in both production and natural populations... (Comparative Study)
Comparative Study
BACKGROUND
The Portuguese oyster Crassostrea angulata, a bivalve of significant economic and ecological importance, has faced a decline in both production and natural populations due to pathologies, climate change, and anthropogenic factors. To safeguard its genetic diversity and improve reproductive management, cryopreservation emerges as a valuable strategy. However, the cryopreservation methodologies lead to some damage in structures and functions of the cells and tissues that can affect post-thaw quality. Transcriptomics may help to understand the molecular consequences related to cryopreservation steps and therefore to identify different freezability biomarkers. This study investigates the molecular damage induced by cryopreservation in C. angulata D-larvae, focusing on two critical steps: exposure to cryoprotectant solution and the freezing/thawing process.
RESULTS
Expression analysis revealed 3 differentially expressed genes between larvae exposed to cryoprotectant solution and fresh larvae and 611 differentially expressed genes in cryopreserved larvae against fresh larvae. The most significantly enriched gene ontology terms were "carbohydrate metabolic process", "integral component of membrane" and "chitin binding" for biological processes, cellular components and molecular functions, respectively. Kyoto Encyclopedia of Genes and Genomes enrichment analysis identified the "neuroactive ligand receptor interaction", "endocytosis" and "spliceosome" as the most enriched pathways. RNA sequencing results were validate by quantitative RT-PCR, once both techniques presented the same gene expression tendency and a group of 11 genes were considered important molecular biomarkers to be used in further studies for the evaluation of cryodamage.
CONCLUSIONS
The current work provided valuable insights into the molecular repercussions of cryopreservation on D-larvae of Crassostrea angulata, revealing that the freezing process had a more pronounced impact on larval quality compared to any potential cryoprotectant-induced toxicity. Additionally, was identify 11 genes serving as biomarkers of freezability for D-larvae quality assessment. This research contributes to the development of more effective cryopreservation protocols and detection methods for cryodamage in this species.
Topics: Animals; Cryopreservation; Crassostrea; Cryoprotective Agents; Larva; Gene Expression Profiling; Transcriptome; Gene Ontology
PubMed: 38867206
DOI: 10.1186/s12864-024-10473-1 -
BMC Infectious Diseases Jun 2024Bacterial infections (BIs) are widespread in ICUs. The aims of this study were to assess compliance with antibiotic recommendations and factors associated with... (Observational Study)
Observational Study
BACKGROUND
Bacterial infections (BIs) are widespread in ICUs. The aims of this study were to assess compliance with antibiotic recommendations and factors associated with non-compliance.
METHODS
We conducted an observational study in eight French Paediatric and Neonatal ICUs with an antimicrobial stewardship programme (ASP) organised once a week for the most part. All children receiving antibiotics for a suspected or proven BI were evaluated. Newborns < 72 h old, neonates < 37 weeks, age ≥ 18 years and children under surgical antimicrobial prophylaxis were excluded.
RESULTS
139 suspected (or proven) BI episodes in 134 children were prospectively included during six separate time-periods over one year. The final diagnosis was 26.6% with no BI, 40.3% presumed (i.e., not documented) BI and 35.3% documented BI. Non-compliance with antibiotic recommendations occurred in 51.1%. The main reasons for non-compliance were inappropriate choice of antimicrobials (27.3%), duration of one or more antimicrobials (26.3%) and length of antibiotic therapy (18.0%). In multivariate analyses, the main independent risk factors for non-compliance were prescribing ≥ 2 antibiotics (OR 4.06, 95%CI 1.69-9.74, p = 0.0017), duration of broad-spectrum antibiotic therapy ≥ 4 days (OR 2.59, 95%CI 1.16-5.78, p = 0.0199), neurologic compromise at ICU admission (OR 3.41, 95%CI 1.04-11.20, p = 0.0431), suspected catheter-related bacteraemia (ORs 3.70 and 5.42, 95%CIs 1.32 to 15.07, p < 0.02), a BI site classified as "other" (ORs 3.29 and 15.88, 95%CIs 1.16 to 104.76, p < 0.03), sepsis with ≥ 2 organ dysfunctions (OR 4.21, 95%CI 1.42-12.55, p = 0.0098), late-onset ventilator-associated pneumonia (OR 6.30, 95%CI 1.15-34.44, p = 0.0338) and ≥ 1 risk factor for extended-spectrum β-lactamase-producing Enterobacteriaceae (OR 2.56, 95%CI 1.07-6.14, p = 0.0353). Main independent factors for compliance were using antibiotic therapy protocols (OR 0.42, 95%CI 0.19-0.92, p = 0.0313), respiratory failure at ICU admission (OR 0.36, 95%CI 0.14-0.90, p = 0.0281) and aspiration pneumonia (OR 0.37, 95%CI 0.14-0.99, p = 0.0486).
CONCLUSIONS
Half of antibiotic prescriptions remain non-compliant with guidelines. Intensivists should reassess on a day-to-day basis the benefit of using several antimicrobials or any broad-spectrum antibiotics and stop antibiotics that are no longer indicated. Developing consensus about treating specific illnesses and using department protocols seem necessary to reduce non-compliance. A daily ASP could also improve compliance in these situations.
TRIAL REGISTRATION
ClinicalTrials.gov: number NCT04642560. The date of first trial registration was 24/11/2020.
Topics: Humans; Anti-Bacterial Agents; Guideline Adherence; Intensive Care Units, Pediatric; France; Female; Male; Infant; Infant, Newborn; Child, Preschool; Prospective Studies; Bacterial Infections; Child; Antimicrobial Stewardship; Adolescent; Risk Factors
PubMed: 38867164
DOI: 10.1186/s12879-024-09472-0