Trajectories of clinical characteristics, complications and treatment choices in data-driven subgroups of type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to explore the added value of subgroups that categorise individuals with type 2 diabetes by k-means clustering for two primary care registries (the Netherlands and Scotland), inspired by Ahlqvist's novel diabetes subgroups and previously analysed by Slieker et al. METHODS: We used two Dutch and Scottish diabetes cohorts (N=3054 and 6145; median follow-up=11.2 and 12.3 years, respectively) and defined five subgroups by k-means clustering with age at baseline, BMI, HbA1c, HDL-cholesterol and C-peptide. We investigated differences between subgroups by trajectories of risk factor values (random intercept models), time to diabetes-related complications (logrank tests and Cox models) and medication patterns (multinomial logistic models). We also compared directly using the clustering indicators as predictors of progression vs the k-means discrete subgroups. Cluster consistency over follow-up was assessed. RESULTS: Subgroups' risk factors were significantly different, and these differences remained generally consistent over follow-up. Among all subgroups, individuals with severe insulin resistance faced a significantly higher risk of myocardial infarction both before (HR 1.65; 95% CI 1.40, 1.94) and after adjusting for age effect (HR 1.72; 95% CI 1.46, 2.02) compared with mild diabetes with high HDL-cholesterol. Individuals with severe insulin-deficient diabetes were most intensively treated, with more than 25% prescribed insulin at 10 years of diagnosis. For severe insulin-deficient diabetes relative to mild diabetes, the relative risks for using insulin relative to no common treatment would be expected to increase by a factor of 3.07 (95% CI 2.73, 3.44), holding other factors constant. Clustering indicators were better predictors of progression variation relative to subgroups, but prediction accuracy may improve after combining both. Clusters were consistent over 8 years with an accuracy ranging from 59% to 72%. CONCLUSIONS/INTERPRETATION: Data-driven subgroup allocations were generally consistent over follow-up and captured significant differences in risk factor trajectories, medication patterns and complication risks. Subgroups serve better as a complement rather than as a basis for compressing clustering indicators.

Bioelectronic Direct Current Stimulation at the Transition Between Reversible and Irreversible Charge Transfer.

Many biological processes rely on endogenous electric fields (EFs), including tissue regeneration, cell development, wound healing, and cancer metastasis. Mimicking these biological EFs by applying external direct current stimulation (DCS) is therefore the key to many new therapeutic strategies. During DCS, the charge transfer from electrode to tissue relies on a combination of reversible and irreversible electrochemical processes, which may generate toxic or bio-altering substances, including metal ions and reactive oxygen species (ROS). Poly(3,4-ethylenedioxythiophene) (PEDOT) based electrodes are emerging as suitable candidates for DCS to improve biocompatibility compared to metals. This work addresses whether PEDOT electrodes can be tailored to favor reversible biocompatible charge transfer. To this end, different PEDOT formulations and their respective back electrodes are studied using cyclic voltammetry, chronopotentiometry, and direct measurements of H2 O2 and O2 . This combination of electrochemical methods sheds light on the time dynamics of reversible and irreversible charge transfer and the relationship between capacitance and ROS generation. The results presented here show that although all electrode materials investigated generate ROS, the onset of ROS can be delayed by increasing the electrode's capacitance via PEDOT coating, which has implications for future bioelectronic devices that allow longer reversibly driven pulse durations during DCS.

Analytical validation and algorithm improvement of HepatoPredict kit to assess hepatocellular carcinoma prognosis before a liver transplantation.

Objectives: To verify the analytical performance of the HepatoPredict kit, a novel tool developed to stratify Hepatocellular Carcinoma (HCC) patients according to their risk of relapse after a Liver Transplantation (LT). Methods: The HepatoPredict tool combines clinical variables and a gene expression signature in an ensemble of machine-learning algorithms to forecast the benefit of a LT in HCC patients. To ensure the accuracy and reliability of this method, extensive analytical validation was conducted to verify its specificity and robustness. The experiments were designed following the guidelines for multi-target genomic assays such as ISO201395-2019, MIQE, CLSI-MM16, CLSI-MM17, and CLSI-EP17-A. The validation process included reproducibility between operators and between RNA extractions and RT-qPCR runs, and interference of input RNA levels or varying reagent levels. A recently retrained version of the HepatoPredict algorithms was also tested. Results: The validation process demonstrated that the HepatoPredict kit met the required standards for robustness (p > 0.05), analytical specificity (inclusivity of 95 %), and sensitivity (LoB, LoD, linear range, and amplification efficiency between 90 and 110 %). The operator, equipment, input RNA, and reagents used had no significant effect on the HepatoPredict results. Additionally, the testing of a recently retrained version of the HepatoPredict algorithm, showed that this new version further improved the accuracy of the kit and performed better than existing clinical criteria in accurately identifying HCC patients who are more likely to benefit LT. Conclusions: Even with the introduced variations in molecular and clinical variables, the HepatoPredict kit's prognostic information remains consistent. It can accurately identify HCC patients who are more likely to benefit from a LT. Its robust performance also confirms that it can be easily integrated into standard diagnostic laboratories.

Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study.

Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.

Cardiovascular disease burden due to productivity losses in European Society of Cardiology countries.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death across Europe. We estimated lost earnings (productivity losses) associated with premature mortality due to CVD, and separately for its main sub-categories of coronary heart disease and cerebrovascular disease, across 54 country members of the European Society of Cardiology (ESC). METHODS AND RESULTS: We used a standardized approach to estimate working years and earnings lost due to premature death resulting from CVD across the 54 ESC member countries in 2018. Our population-based approach was based on national data on the number of deaths, employment rates, and earnings by age group and sex. We discounted future working years and earnings lost to present values using a 3.5% annual rate. In 2018, there were 4.4 million deaths due to CVD across the 54 countries, with 7.1 million working years lost. This represented productivity losses due to premature death of €62 billion in 2018. Deaths due to coronary heart disease accounted for 47% (€29 billion) of all CVD costs, and cerebrovascular disease accounted for 18% (€11 billion). Approximately 60% (€37 billion) of all productivity losses occurred in the 28 European Union member states, despite accounting for only 42% (1.8 million) of deaths and 21% (1.5 million) of working years lost across the 54 countries. CONCLUSION: Our study provides a snapshot of the economic consequences posed by premature mortality due to CVD across 54 countries in 2018. The considerable variation across countries highlights the potential gains from policies targeting prevention and care of cardiovascular diseases.

Comparison of medical resources and costs among patients with coronary heart disease and impaired glucose tolerance in the Acarbose Cardiovascular Evaluation trial.

BACKGROUND: The Acarbose Cardiovascular Evaluation (ACE) trial (ISRCTN91899513) evaluated the alpha-glucosidase inhibitor acarbose, compared with placebo, in 6522 patients with coronary heart disease and impaired glucose tolerance in China and showed a reduced incidence of diabetes. We assessed the within-trial medical resource use and costs, and quality-adjusted life years (QALYs). METHODS: Resource use data were collected prospectively within the ACE trial. Hospitalizations, medications, and outpatient visits were valued using Chinese unit costs. Medication use was measured in drug days, with cardiovascular and diabetes drugs summed across the trial by participant. Health-related quality of life was captured using the EuroQol-5 Dimension-3 Level questionnaire. Regression analyses were used to compare resource use, costs, and QALYs, accounting for regional variation. Costs and QALYs were discounted at 3% yearly. RESULTS: Hospitalizations were 6% higher in the acarbose arm during the trial (rate ratio 1.06, p = .009), but there were no significant differences in total inpatient days (rate ratio 1.04, p = .30). Total costs per participant, including study drug, were significantly higher for acarbose (¥ [Yuan] 56 480, £6213), compared with placebo (¥48 079, £5289; mean ratio 1.18, p < 0.001). QALYs reported by participants in the acarbose arm (3.96 QALYs) were marginally higher than in the placebo arm (3.95 QALYs), but the difference was not statistically significant (0.01 QALYs; p = .58). CONCLUSIONS: Acarbose, compared with placebo, participants cost more due to study drug costs and reported no statistically significant difference in QALYs. These higher within-trial costs could potentially be offset in future by savings from the acarbose-related lower incidence of diabetes.

Review of the allocation criteria for heart transplant in Spain in 2023. SEC-Heart Failure Association/ONT/SECCE consensus document.

Heart transplant (HT) remains the best therapeutic option for patients with advanced heart failure (HF). The allocation criteria aim to guarantee equitable access to HT and prioritize patients with a worse clinical status. To review the HT allocation criteria, the Heart Failure Association of the Spanish Society of Cardiology (HFA-SEC), the Spanish Society of Cardiovascular and Endovascular Surgery (SECCE) and the National Transplant Organization (ONT), organized a consensus conference involving adult and pediatric cardiologists, adult and pediatric cardiac surgeons, transplant coordinators from all over Spain, and physicians and nurses from the ONT. The aims of the consensus conference were as follows: a) to analyze the organization and management of patients with advanced HF and cardiogenic shock in Spain; b) to critically review heart allocation and priority criteria in other transplant organizations; c) to analyze the outcomes of patients listed and transplanted before and after the modification of the heart allocation criteria in 2017; and d) to propose new heart allocation criteria in Spain after an analysis of the available evidence and multidisciplinary discussion. In this article, by the HFA-SEC, SECCE and the ONT we present the results of the analysis performed in the consensus conference and the rationale for the new heart allocation criteria in Spain.

Cost-effectiveness analysis of a pragmatic randomized trial evaluating surgical reconstruction versus rehabilitation in patients with long-standing anterior cruciate ligament injury.

Aims: The aim of this study was to estimate the incremental use of resources, costs, and quality of life outcomes associated with surgical reconstruction compared to rehabilitation for long-standing anterior cruciate ligament (ACL) injury in the NHS, and to estimate its cost-effectiveness. Methods: A total of 316 patients were recruited and randomly assigned to either surgical reconstruction or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment). Healthcare resource use and health-related quality of life data (EuroQol five-dimension five-level health questionnaire) were collected in the trial at six, 12, and 18 months using self-reported questionnaires and medical records. Using intention-to-treat analysis, differences in costs, and quality-adjusted life years (QALYs) between treatment arms were estimated adjusting for baseline differences and following multiple imputation of missing data. The incremental cost-effectiveness ratio (ICER) was estimated as the difference in costs divided by the difference in QALYs between reconstruction and rehabilitation. Results: At 18 months, patients in the surgical reconstruction arm reported higher QALYs (0.052 (95% confidence interval (CI) -0.012 to 0.117); p = 0.177) and higher NHS costs (£1,017 (95% CI 557 to 1,476); p < 0.001) compared to rehabilitation. This resulted in an ICER of £19,346 per QALY with the probability of surgical reconstruction being cost-effective of 51% and 72% at a willingness-to-pay threshold of £20,000 and £30,000 per QALY, respectively. Conclusion: Surgical reconstruction as a management strategy for patients with long-standing ACL injury is more effective, but more expensive, at 18 months compared to rehabilitation management. In the UK setting, surgical reconstruction is cost-effective.

Randomised controlled trial of automated VR therapy to improve positive self-beliefs and psychological well-being in young people diagnosed with psychosis: a study protocol for the Phoenix VR self-confidence therapy trial.

INTRODUCTION: The confidence of young people diagnosed with psychosis is often low. Positive self-beliefs may be few and negative self-beliefs many. A sense of defeat and failure is common. Young people often withdraw from many aspects of everyday life. Psychological well-being is lowered. Psychological techniques can improve self-confidence, but a shortage of therapists means that very few patients ever receive such help. Virtual reality (VR) offers a potential route out of this impasse. By including a virtual coach, treatment can be automated. As such, delivery of effective therapy is no longer reliant on the availability of therapists. With young people with lived experience, we have developed a staff-assisted automated VR therapy to improve positive self-beliefs (Phoenix). The treatment is based on established cognitive behavioural therapy and positive psychology techniques. A case series indicates that this approach may lead to large improvements in positive self-beliefs and psychological well-being. We now aim to conduct the first randomised controlled evaluation of Phoenix VR. METHODS AND ANALYSIS: 80 patients with psychosis, aged between 16 and 30 years old and with low levels of positive self-beliefs, will be recruited from National Health Service (NHS) secondary care services. They will be randomised (1:1) to the Phoenix VR self-confidence therapy added to treatment as usual or treatment as usual. Assessments will be conducted at 0, 6 (post-treatment) and 12 weeks by a researcher blind to allocation. The primary outcome is positive self-beliefs at 6 weeks rated with the Oxford Positive Self Scale. The secondary outcomes are psychiatric symptoms, activity levels and quality of life. All main analyses will be intention to treat. ETHICS AND DISSEMINATION: The trial has received ethical approval from the NHS Health Research Authority (22/LO/0273). A key output will be a high-quality VR treatment for patients to improve self-confidence and psychological well-being. TRIAL REGISTRATION NUMBER: ISRCTN10250113.

Outcomes of rapid deployment aortic valve replacement with concomitant cardiac procedures.

Background: Rapid deployment aortic valve replacement (RD-AVR) has been recently introduced with encouraging results. Outcomes of isolated RD-AVR include good hemodynamic profile, facilitation of minimally invasive techniques, and reduction of surgical times. However, role of this prosthesis in concomitant surgery is not well known. Methods: In 2016, we formed a registry to monitor the introduction of this prosthesis, RApid Deployment Aortic Replacement (RADAR). We aim to report mid-term outcomes focusing on patients who had RD-AVR combined with other surgical procedures. Results: Between July 2012 and February 2021, 370 patients were included in this registry (mean age, 75.8±8.0 years; 64.32% male; mean EuroSCORE II, 3.5±2.8). Of these, 128 (34.59%) had concomitant procedures including myocardial revascularization surgery in 69 patients (53.91%), surgery on the ascending aorta in 34 (26.56%), and procedures on other valves in 10 patients (7.81%). There were no significant differences between the isolated AVR and concomitant AVR groups in postoperative complications, in-hospital mortality (4.72% vs. 3.32%, P=0.524), or hemodynamic behavior of these prostheses. Three-year survival was 83.73% and 89.89% in the isolated and concomitant AVR group respectively. There was no difference in survival between the two groups (log-rank test, P=0.4124). Conclusions: Our results support the safety and efficacy of the Edwards INTUITY valve system even in complex aortic valve disease with additional cardiac procedures. RD-AVR could become a useful tool for concomitant surgeries where surgical times are expected to be prolonged.

Patient journey and costs through a brain health clinic compared with a memory clinic: a costing study.

BACKGROUND: Dementia and Alzheimer's disease are the leading cause of death in England, with prevalence estimated to rise with an ageing population. 2021 cost estimates were £25 billion, rising to an estimated £47 billion in 2050. Brain health clinics (BHC) offer patients with memory concerns access to higher quality memory assessment and imaging than memory clinics, which are the usual care. BHCs aim to offer patients a more accurate and timely diagnosis, resulting in more specific treatment options. BHCs also offer patients the opportunity to take part in research. We aimed to compare the cost of a patient journey through a BHC and a memory clinic as part of an evaluation of the BHC model. METHODS: For this costing study, we consulted staff from one BHC and one memory clinic in the south of England in March 2023, to identify the patient journey and estimate clinical and research resources, time, and costs. We estimated personnel costs using time-per-task estimations multiplied by staff salary and verified with full-time-equivalent estimations for clinical and research tasks overall. BHC costs included both the BHC appointment and a follow-up appointment of reduced duration at the memory clinic. Memory clinic costs included a memory clinic appointment of normal duration. We estimated costs for both clinical (memory clinics and BHC) and research (BHC) tasks (not shown here). FINDINGS: BHC costs were 3·5 times more expensive (£1428) than memory clinic costs (£414). Approximately 150 patients are seen in BHCs yearly (total cost £214 200) compared with 600 patients seen in memory clinics yearly (total cost £248 400). BHC patients re-entering the memory clinic pathway required shorter appointments, thus offering cost savings of £230 per appointment in the memory clinic. INTERPRETATION: BHC costs were higher due to a lower throughput of patients and higher cost of high-quality imaging and assessment compared with memory clinics. However, these costs might prove to provide value for money when considering the gains in quality of life for patients and carers. Future work is planned to gather further outcome data to understand the added value of BHCs. Limitations include only assessing costs for one BHC and one memory clinic; further cost estimates are preferrable. FUNDING: None.

Economic burden of cardiovascular diseases in the European Union: a population-based cost study.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) impacts significantly health and social care systems as well as society through premature mortality and disability, with patients requiring care from relatives. Previous pan-European estimates of the economic burden of CVD are now outdated. This study aims to provide novel, up-to-date evidence on the economic burden across the 27 European Union (EU) countries in 2021. METHODS: Aggregate country-specific resource use data on morbidity, mortality, and health, social and informal care were obtained from international sources, such as the Statistical Office of the European Communities, enhanced by data from the European Society of Cardiology Atlas programme and patient-level data from the Survey of Health, Ageing and Retirement in Europe. Country-specific unit costs were used, with cost estimates reported on a per capita basis, after adjustment for price differentials. RESULTS: CVD is estimated to cost the EU €282 billion annually, with health and long-term care accounting for €155 billion (55%), equalling 11% of EU-health expenditure. Productivity losses accounted for 17% (€48 billion), whereas informal care costs were €79 billion (28%). CVD represented a cost of €630 per person, ranging from €381 in Cyprus to €903 in Germany. Coronary heart disease accounted for 27% (€77 billion) and cerebrovascular diseases for 27% (€76 billion) of CVD costs. CONCLUSIONS: This study provides contemporary estimates of the wide-ranging impact of CVD on all aspects of the economy. The data help inform evidence-based policies to reduce the impact of CVD, promoting care access and better health outcomes and economic sustainability.

Exergames in Older Adult Community Centers and Nursing Homes to Improve Balance and Minimize the Risk of Falls in Older Adults: A Systematic Review and Meta-Analysis.

There is a substantial gap in our knowledge regarding the efficacy of exergames on the reduction of fall risk in older adults. This systematic review analyzes the findings of clinical trials describing the efficacy of exergames to improve balance or reduce the risk of falls in individuals above 60 years of age who are residents in community centers or nursing homes. We searched Google Scholar, PubMed, and Embase up to January 2023. Initially, 52,294 records were screened. After applying the inclusion and exclusion criteria, 20 studies were included in this systematic review. Meta-analyses revealed statistically significant reductions in the risk of falls and improvements in balance. Exergaming tended to produce positive benefits according to the results obtained using different instruments (TUG, PPA, BBS, and others), control groups, and times of intervention. Nevertheless, a substantial proportion of studies exhibited a high risk of bias and only one had a long follow-up period. Although a large body of evidence supports the view that exergaming is suitable for reducing fall risk and improving balance in older adults, some gaps remain in our knowledge about such benefits.

Electrotaxis evokes directional separation of co-cultured keratinocytes and fibroblasts.

Bioelectric communication plays a significant role in several cellular processes and biological mechanisms, such as division, differentiation, migration, cancer metastasis, and wound healing. Ion flow across cellular walls leads to potential gradients and subsequent formation of constant or time-varying electric fields(EFs), which regulate cellular processes. An EF is natively generated towards the wound center during epithelial wound healing, aiming to align and guide cell migration, particularly of macrophages, fibroblasts, and keratinocytes. While this phenomenon, known as electrotaxis or galvanotaxis, has been extensively investigated across many cell types, it is typically explored one cell type at a time, which does not accurately represent cellular interactions during complex biological processes. Here we show the co-cultured electrotaxis of epidermal keratinocytes and dermal fibroblasts with a salt-bridgeless microfluidic approach for the first time. The electrotactic response of these cells was first assessed in mono-culture to establish a baseline, resulting in the characteristic cathodic migration for keratinocytes and anodic for fibroblasts. Both cell types retained their electrotactic properties in co-culture leading to clear cellular partition even in the presence of cellular collisions. The methods leveraged here pave the way for future co-culture electrotaxis experiments where the concurrent influence of cell types can be thoroughly investigated.

Potential Value of Identifying Type 2 Diabetes Subgroups for Guiding Intensive Treatment: A Comparison of Novel Data-Driven Clustering With Risk-Driven Subgroups.

OBJECTIVE: To estimate the impact on lifetime health and economic outcomes of different methods of stratifying individuals with type 2 diabetes, followed by guideline-based treatment intensification targeting BMI and LDL in addition to HbA1c. RESEARCH DESIGN AND METHODS: We divided 2,935 newly diagnosed individuals from the Hoorn Diabetes Care System (DCS) cohort into five Risk Assessment and Progression of Diabetes (RHAPSODY) data-driven clustering subgroups (based on age, BMI, HbA1c, C-peptide, and HDL) and four risk-driven subgroups by using fixed cutoffs for HbA1c and risk of cardiovascular disease based on guidelines. The UK Prospective Diabetes Study Outcomes Model 2 estimated discounted expected lifetime complication costs and quality-adjusted life-years (QALYs) for each subgroup and across all individuals. Gains from treatment intensification were compared with care as usual as observed in DCS. A sensitivity analysis was conducted based on Ahlqvist subgroups. RESULTS: Under care as usual, prognosis in the RHAPSODY data-driven subgroups ranged from 7.9 to 12.6 QALYs. Prognosis in the risk-driven subgroups ranged from 6.8 to 12.0 QALYs. Compared with homogenous type 2 diabetes, treatment for individuals in the high-risk subgroups could cost 22.0% and 25.3% more and still be cost effective for data-driven and risk-driven subgroups, respectively. Targeting BMI and LDL in addition to HbA1c might deliver up to 10-fold increases in QALYs gained. CONCLUSIONS: Risk-driven subgroups better discriminated prognosis. Both stratification methods supported stratified treatment intensification, with the risk-driven subgroups being somewhat better in identifying individuals with the most potential to benefit from intensive treatment. Irrespective of stratification approach, better cholesterol and weight control showed substantial potential for health gains.

BRCA1 VUS: A functional analysis to differentiate pathogenic from benign variants identified in clinical diagnostic panels for breast cancer.

Genetic testing for susceptibility genes through next­generation sequencing (NGS) has become a widely used technique. Using this, a number of genetic variants have been identified, several of which are variants of unknown significance (VUS). These VUS can either be pathogenic or benign. However, since their biological effect remains unclear, functional assays are required to classify their functional nature. As the use of NGS becomes more mainstream as a diagnostic tool in clinical practice, the number of VUS is expected to increase. This necessitates their biological and functional classification. In the present study, a VUS was identified in the BRCA1 gene (NM_007294.3:c.1067A>G) in two women at risk for breast cancer, for which no functional data has been reported. Therefore, peripheral lymphocytes were isolated from the two women and also from two women without the VUS. DNA from all samples were sequenced by NGS of a breast cancer clinical panel. Since the BRCA1 gene is involved in DNA repair and apoptosis, the functional assays chromosomal aberrations, cytokinesis­blocked micronucleus, comet, γH2AX, caspase and TUNEL assays were then conducted on these lymphocytes after a genotoxic challenge by ionizing radiation or doxorubicin to assess the functional role of this VUS. The micronucleus and TUNEL assays revealed a lower degree of DNA induced­damage in the VUS group compared with those without the VUS. The other assays showed no significant differences between the groups. These results suggested that this BRCA1 VUS is likely benign, since the VUS carriers were apparently protected from deleterious chromosomal rearrangements, subsequent genomic instability and activation of apoptosis.

Evidence for a lack of inotropic and chronotropic effects of glucagon and glucagon receptors in the human heart.

BACKGROUND: Glucagon is thought to increase heart rate and contractility by stimulating glucagon receptors and increasing 3',5'-cyclic adenosine monophosphate (cAMP) production in the myocardium. This has been confirmed in animal studies but not in the human heart. The cardiostimulatory effects of glucagon have been correlated with the degree of cardiac dysfunction, as well as with the enzymatic activity of phosphodiesterase (PDE), which hydrolyses cAMP. In this study, the presence of glucagon receptors in the human heart and the inotropic and chronotropic effects of glucagon in samples of failing and nonfailing (NF) human hearts were investigated. METHODS: Concentration‒response curves for glucagon in the absence and presence of the PDE inhibitor IBMX were performed on samples obtained from the right (RA) and left atria (LA), the right (RV) and left ventricles (LV), and the sinoatrial nodes (SNs) of failing and NF human hearts. The expression of glucagon receptors was also investigated. Furthermore, the inotropic and chronotropic effects of glucagon were examined in rat hearts. RESULTS: In tissues obtained from failing and NF human hearts, glucagon did not exert inotropic or chronotropic effects in the absence or presence of IBMX. IBMX (30 µM) induced a marked increase in contractility in NF hearts (RA: 83 ± 28% (n = 5), LA: 80 ± 20% (n = 5), RV: 75 ± 12% (n = 5), and LV: 40 ± 8% (n = 5), weaker inotropic responses in the ventricular myocardium of failing hearts (RV: 25 ± 10% (n = 5) and LV: 10 ± 5% (n = 5) and no inotropic responses in the atrial myocardium of failing hearts. IBMX (30 µM) increased the SN rate in failing and NF human hearts (27.4 ± 3.0 beats min-1, n = 10). In rat hearts, glucagon induced contractile and chronotropic responses, but only contractility was enhanced by 30 µM IBMX (maximal inotropic effect of glucagon 40 ± 8% vs. 75 ± 10%, in the absence or presence of IBMX, n = 5, P < 0.05; maximal chronotropic response 77.7 ± 6.4 beats min-1 vs. 73 ± 11 beats min-1, in the absence or presence of IBMX, n = 5, P > 0.05). Glucagon receptors were not detected in the human heart samples. CONCLUSIONS: Our results conflict with the view that glucagon induces inotropic and chronotropic effects and that glucagon receptors are expressed in the human heart.

Haematic antegrade repriming to enhance recovery after cardiac surgery from the perfusionist side.

Background: New era of cardiac surgery aims to provide an enhanced postoperative recovery through the implementation of every step of the process. Thus, perfusion strategy should adopt evidence-based measures to reduce the impact of cardiopulmonary bypass (CPB). Hematic Antegrade Repriming (HAR) provides a standardized procedure combining several measures to reduce haemodilutional priming to 300 mL. Once the safety of the procedure in terms of embolic release has been proven, the evaluation of its beneficial effects in terms of transfusion and ICU stay should be assessed to determine if could be considered for inclusion in Enhanced Recovery After Cardiac Surgery (ERACS) programs. Methods: Two retrospective and non-randomized cohorts of high-risk patients, with similar characteristics, were assessed with a propensity score matching model. The treatment group (HG) (n = 225) received the HAR. A historical cohort, exposed to conventional priming with 1350 mL of crystalloid confirmed the control group (CG) (n = 210). Results: Exposure to any transfusion was lower in treated (66.75% vs. 6.88%, p < 0.01). Prolonged mechanical ventilation (>10 h) (26.51% vs. 12.62%; p < 0.01) and extended ICU stay (>2 d) (47.47% vs. 31.19%; p < 0.01) were fewer for treated. HAR did not increase early morbidity and mortality. Related savings varied from 581 to 2741.94 $/patient, depending on if direct or global expenses were considered. Discussion: By reducing the gaseous and crystalloid emboli during CPB initiation, HAR seems to have a beneficial impact on recovery and reduces the overall transfusion until discharge, leading to significant cost savings per process. Due to the preliminary and retrospective nature of the research and its limitations, our findings should be validated by future prospective and randomized studies.