Pre- and postconditioning describe mechanisms whereby short ischemic periods protect an organ against a longer period of ischemia. Interestingly, short ischemic periods of a limb, in itself harmless, ...may increase the ischemia tolerance of remote organs, e.g. the heart (remote conditioning, RC). Although several studies have shown reduced biomarker release by RC, a reduction of complications and improvement of patient outcome still has to be demonstrated. Atrial fibrillation (AF) is one of the most common complications after coronary artery bypass graft surgery (CABG), affecting 27-46% of patients. It is associated with increased mortality, adverse cardiovascular events, and prolonged in-hospital stay. We hypothesize that remote ischemic pre- and/or post-conditioning reduce the incidence of AF following CABG, and improve patient outcome.
This study is a randomized, controlled, patient and investigator blinded multicenter trial. Elective CABG patients are randomized to one of the following four groups: 1) control, 2) remote ischemic preconditioning, 3) remote ischemic postconditioning, or 4) remote ischemic pre- and postconditioning. Remote conditioning is applied at the arm by 3 cycles of 5 minutes of ischemia and reperfusion. Primary endpoint is the incidence AF in the first 72 hours after surgery, detected using a Holter-monitor. Secondary endpoints include length-of-stay on the intensive care unit and in-hospital, and the occurrence of major adverse cardiovascular events at 30 days, 3 months and 1 year.Based on an expected incidence in the control group of 27%, 195 patients per group are needed to detect with 80% power a reduction by 45% following either pre- or postconditioning, while allowing for a 10% dropout and at an alpha of 0.05. With the combined intervention expected to be stronger, we need 75 patients in this group to detect a reduction in incidence of AF of 60%.
The RICO-trial (the effect of Remote Ischemic Conditioning on atrial fibrillation and Outcome) is a randomized controlled multicenter trial, designed to investigate whether remote ischemic pre- and/or post-conditioning of the arm reduce the incidence of AF following CABG surgery.
ClinicalTrials.gov under NCT01107184.
Cells need to adapt to dynamic environments. Yeast that fail to cope with dynamic changes in the abundance of glucose can undergo growth arrest. We show that this failure is caused by imbalanced ...reactions in glycolysis, the essential pathway in energy metabolism in most organisms. The imbalance arises largely from the fundamental design of glycolysis, making this state of glycolysis a generic risk. Cells with unbalanced glycolysis coexisted with vital cells. Spontaneous, nongenetic metabolic variability among individual cells determines which state is reached and, consequently, which cells survive. Transient ATP (adenosine 5'-triphosphate) hydrolysis through futile cycling reduces the probability of reaching the imbalanced state. Our results reveal dynamic behavior of glycolysis and indicate that cell fate can be determined by heterogeneity purely at the metabolic level.
The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC‐4 trial. Real‐world data on the effectiveness of ...gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015‐2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8‐40.7) for GEMCAP and 22.1 months (95% CI 20.6‐25.0) for GEM (HR: 0.71, 95% CI 0.56‐0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57‐0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.
What's new?
The benefit of treating pancreatic ductal adenocarcinoma (PDAC) with a combination of gemcitabine plus capecitabine (vs gemcitabine alone) was previously shown in a carefully controlled clinical trial. But does this approach work as well in the real world? In this study, the authors found that the answer is yes—patients had significantly better overall survival (OS) with the combined therapy than with gemcitabine alone. These results may aid in the selection of adjuvant chemotherapy for patients who are not eligible for modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin).
The appropriate duration of postoperative antibiotics for complex appendicitis is unclear. The increasing global threat of antimicrobial resistance warrants restrictive antibiotic use, which could ...also reduce side-effects, length of hospital stay, and costs.
In this pragmatic, open-label, non-inferiority trial in 15 hospitals in the Netherlands, patients with complex appendicitis (aged ≥8 years) were randomly assigned (1:1) to receive 2 days or 5 days of intravenous antibiotics after appendicectomy. Randomisation was stratified by centre, and treating physicians and patients were not masked to treatment allocation. The primary endpoint was a composite endpoint of infectious complications and mortality within 90 days. The main outcome was the absolute risk difference (95% CI) in the primary endpoint, adjusted for age and severity of appendicitis, with a non-inferiority margin of 7·5%. Outcome assessment was based on electronic patient records and a telephone consultation 90 days after appendicectomy. Efficacy was analysed in the intention-to-treat and per-protocol populations. Safety outcomes were analysed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register, NL5946.
Between April 12, 2017, and June 3, 2021, 13 267 patients were screened and 1066 were randomly assigned, 533 to each group. 31 were excluded from intention-to-treat analysis of the 2-day group and 30 from the 5-day group owing to errors in recruitment or consent. Appendicectomy was done laparoscopically in 955 (95%) of 1005 patients. The telephone follow-up was completed in 664 (66%) of 1005 patients. The primary endpoint occurred in 51 (10%) of 502 patients analysed in the 2-day group and 41 (8%) of 503 patients analysed in the 5-day group (adjusted absolute risk difference 2·0%, 95% CI −1·6 to 5·6). Rates of complications and re-interventions were similar between trial groups. Fewer patients had adverse effects of antibiotics in the 2-day group (45 9% of 502 patients) than in the 5-day group (112 22% of 503 patients; odds ratio OR 0·344, 95% CI 0·237 to 0·498). Re-admission to hospital was more frequent in the 2-day group (58 12% of 502 patients) than in the 5-day group (29 6% of 503 patients; OR 2·135, 1·342 to 3·396). There were no treatment-related deaths.
2 days of postoperative intravenous antibiotics for complex appendicitis is non-inferior to 5 days in terms of infectious complications and mortality within 90 days, based on a non-inferiority margin of 7·5%. These findings apply to laparoscopic appendicectomy conducted in a well resourced health-care setting. Adopting this strategy will reduce adverse effects of antibiotics and length of hospital stay.
The Netherlands Organization for Health Research and Development.
Abstract
Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different ...pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1–3 after intubation, 66 from day 4–6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO
2
/FiO
2
-ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (
p
= 0.017) and PEEP was 11.8 (SD 2.8) cmH
2
O vs. 11.3 (SD 3.4) cmH
2
O, (
p
= 0.475), for ICU survivors and non-survivors. At day 1–3, compliance was ~ 55 mL/cmH
2
O vs. ~ 45 mL/cmH
2
O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12–13 cmH
2
O. At day 4–6 compliance changed to ~ 50 mL/cmH
2
O vs. ~ 38 mL/cmH
2
O. At day 7 and beyond, compliance was ~ 38 mL/cmH
2
O with the intersection at a PEEP of ~ 9 cmH
2
O vs. ~ 25 mL/cmH
2
O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH
2
O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups.
Many prediction models for coronavirus disease 2019 (COVID-19) have been developed. External validation is mandatory before implementation in the intensive care unit (ICU). We selected and validated ...prognostic models in the Euregio Intensive Care COVID (EICC) cohort.
In this multinational cohort study, routine data from COVID-19 patients admitted to ICUs within the Euregio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, outcomes, and reporting. Furthermore, general ICU scores were assessed. Discrimination was assessed by area under the receiver operating characteristic curves (AUCs) and calibration by calibration-in-the-large and calibration plots. A random-effects meta-analysis was used to pool results.
551 patients were admitted. Mean age was 65.4 ± 11.2 years, 29% were female, and ICU mortality was 36%. Nine out of 238 published models were externally validated. Pooled AUCs were between 0.53 and 0.70 and calibration-in-the-large between −9% and 6%. Calibration plots showed generally poor but, for the 4C Mortality score and Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) score, moderate calibration.
Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimination and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision-making.
To compare costs for 2 days versus 5 days of postoperative antibiotics within the antibiotics after an aPPendectomy In Complex appendicitis trial.Background:Recent studies suggest that restrictive ...antibiotic use leads to a significant reduction in hospital stays without compromising patient safety. Its potential effect on societal costs remains underexplored.
This was a pragmatic, open-label, multicenter clinical trial powered for noninferiority. Patients with complex appendicitis (age ≥ 8 years) were randomly allocated to 2 days or 5 days of intravenous antibiotics after appendectomy. Patient inclusion lasted from June 2017 to June 2021 in 15 Dutch hospitals. The final follow-up was on September 1, 2021. The primary trial endpoint was a composite endpoint of infectious complications and mortality within 90 days. In the present study, the main outcome measures were overall societal costs (comprising direct health care costs and costs related to productivity loss) and cost-effectiveness. Direct health care costs were recorded based on data in the electronic patient files, complemented by a telephone follow-up at 90 days. In addition, data on loss of productivity were acquired through the validated Productivity Cost Questionnaire at 4 weeks after surgery. Cost estimates were based on prices for the year 2019.
In total, 1005 patients were evaluated in the "intention-to-treat" analysis: 502 patients were allocated to the 2-day group and 503 to the 5-day group. The mean difference in overall societal costs was - €625 (95% CI: -€ 958 to -€ 278) to the advantage of the 2-day group. This difference was largely explained by reduced hospital stay. Productivity losses were similar between the study groups. Restricting postoperative antibiotics to 2 days was cost-effective, with estimated cost savings of €31,117 per additional infectious complication.
Two days of postoperative antibiotics for complex appendicitis results in a statistically significant and relevant cost reduction, as compared with 5 days. Findings apply to laparoscopic appendectomy in a well-resourced health care setting.
Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess ...treatment modalities and overall survival by tumor origin.
Patients diagnosed with non-metastatic periampullary cancer in 2012–2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan–Meier analysis and multivariable Cox regression analyses, stratified by origin.
Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55–0.69) and DC (HR = 0.69; 95% CI 0.48–0.98), but not AC (HR = 0.87; 95% CI 0.62–1.22) and DA (HR = 0.85; 95% CI 0.48–1.50).
This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA.
Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of ...female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.
To determine the effects of behavioural interventions in people with oropharyngeal dysphagia.
Systematic literature searches were conducted to retrieve randomized controlled trials in four different ...databases (CINAHL, Embase, PsycINFO, and PubMed). The methodological quality of eligible articles was assessed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2), after which meta-analyses were performed using a random-effects model.
A total of 37 studies were included. Overall, a significant, large pre-post interventions effect size was found. To compare different types of interventions, all behavioural interventions and conventional dysphagia treatment comparison groups were categorised into compensatory, rehabilitative, and combined compensatory and rehabilitative interventions. Overall, significant treatment effects were identified favouring behavioural interventions. In particular, large effect sizes were found when comparing rehabilitative interventions with no dysphagia treatment, and combined interventions with compensatory conventional dysphagia treatment. When comparing selected interventions versus conventional dysphagia treatment, significant, large effect sizes were found in favour of Shaker exercise, chin tuck against resistance exercise, and expiratory muscle strength training.
Behavioural interventions show promising effects in people with oropharyngeal dysphagia. However, due to high heterogeneity between studies, generalisations of meta-analyses need to be interpreted with care.
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