Three Dimensional Visualization and Fractal Analysis of Mosaic Patches in Rat Chimeras: Cell Assortment in Liver, Adrenal Cortex and Cornea

The production of organ parenchyma in a rapid and reproducible manner is critical to normal development. In chimeras produced by the combination of genetically distinguishable tissues, mosaic patterns of cells derived from the combined genotypes can be visualized. These patterns comprise patches of contiguously similar genotypes and are different in different organs but similar in a given organ from individual to individual. Thus, the processes that produce the patterns are regulated and conserved. We have previously established that mosaic patches in multiple tissues are fractal, consistent with an iterative, recursive growth model with simple stereotypical division rules. Fractal dimensions of various tissues are consistent with algorithmic models in which changing a single variable (e.g. daughter cell placement after division) switches the mosaic pattern from islands to stripes of cells. Here we show that the spiral pattern previously observed in mouse cornea can also be visualized in rat chimeras. While it is generally held that the pattern is induced by stem cell division dynamics, there is an unexplained discrepancy in the speed of cellular migration and the emergence of the pattern. We demonstrate in chimeric rat corneas both island and striped patterns exist depending on the age of the animal. The patches that comprise the pattern are fractal, and the fractal dimension changes with the age of the animal and indicates the constraint in patch complexity as the spiral pattern emerges. The spiral patterns are consistent with a loxodrome. Such data are likely to be relevant to growth and cell division in organ systems and will help in understanding how organ parenchyma are generated and maintained from multipotent stem cell populations located in specific topographical locations within the organ. Ultimately, understanding algorithmic growth is likely to be essential in achieving organ regeneration in vivo or in vitro from stem cell populations

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p<0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p<0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - An observational study in 29 countries

BACKGROUND Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN This was a prospective international 1-week observational study using the ‘Assess Respiratory Risk in Surgical Patients in Catalonia risk score’ (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (V T) size was 500 ml, or 7 to 9 ml kg−1 predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P ˂ 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P ˂ 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high V T and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome.</p

Intraoperative transfusion practices in Europe

BACKGROUND: Transfusion of allogeneic blood influences outcome after surgery. Despite widespread availability of transfusion guidelines, transfusion practices might vary among physicians, departments, hospitals and countries. Our aim was to determine the amount of packed red blood cells (pRBC) and blood products transfused intraoperatively, and to describe factors determining transfusion throughout Europe. METHODS: We did a prospective observational cohort study enrolling 5803 patients in 126 European centres that received at least one pRBC unit intraoperatively, during a continuous three month period in 2013. RESULTS: The overall intraoperative transfusion rate was 1.8%; 59% of transfusions were at least partially initiated as a result of a physiological transfusion trigger- mostly because of hypotension (55.4%) and/or tachycardia (30.7%). Haemoglobin (Hb)- based transfusion trigger alone initiated only 8.5% of transfusions. The Hb concentration [mean (sd)] just before transfusion was 8.1 (1.7) g dl(-1) and increased to 9.8 (1.8) g dl(-1) after transfusion. The mean number of intraoperatively transfused pRBC units was 2.5 (2.7) units (median 2). CONCLUSION: Although European Society of Anaesthesiology transfusion guidelines are moderately implemented in Europe with respect to Hb threshold for transfusion (7-9 g dl(-1)), there is still an urgent need for further educational efforts that focus on the number of pRBC units to be transfused at this threshold. CLINICAL TRIAL REGISTRATION: NCT 01604083

The Association of Intraoperative driving pressure with postoperative pulmonary complications in open versus closed abdominal surgery patients - a posthoc propensity score-weighted cohort analysis of the LAS VEGAS study

BackgroundIt is uncertain whether the association of the intraoperative driving pressure (Delta P) with postoperative pulmonary complications (PPCs) depends on the surgical approach during abdominal surgery. Our primary objective was to determine and compare the association of time-weighted average Delta P (Delta P-TW) with PPCs. We also tested the association of Delta P-TW with intraoperative adverse events.MethodsPosthoc retrospective propensity score-weighted cohort analysis of patients undergoing open or closed abdominal surgery in the 'Local ASsessment of Ventilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study, that included patients in 146 hospitals across 29 countries. The primary endpoint was a composite of PPCs. The secondary endpoint was a composite of intraoperative adverse events.ResultsThe analysis included 1128 and 906 patients undergoing open or closed abdominal surgery, respectively. The PPC rate was 5%. Delta P was lower in open abdominal surgery patients, but Delta P-TW was not different between groups. The association of Delta P-TW with PPCs was significant in both groups and had a higher risk ratio in closed compared to open abdominal surgery patients (1.11 [95%CI 1.10 to 1.20], P &lt; 0.001 versus 1.05 [95%CI 1.05 to 1.05], P &lt; 0.001; risk difference 0.05 [95%CI 0.04 to 0.06], P &lt; 0.001). The association of &lt;Delta&gt;P-TW with intraoperative adverse events was also significant in both groups but had higher odds ratio in closed compared to open abdominal surgery patients (1.13 [95%CI 1.12- to 1.14], P &lt; 0.001 versus 1.07 [95%CI 1.05 to 1.10], P &lt; 0.001; risk difference 0.05 [95%CI 0.030.07], P &lt; 0.001).Conclusions&lt;Delta&gt;P is associated with PPC and intraoperative adverse events in abdominal surgery, both in open and closed abdominal surgery.Trial registrationLAS VEGAS was registered at clinicaltrials.gov (trial identifier NCT01601223)

Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients: Post-hoc analysis of LAS VEGAS study

Background: Limited information is available regarding intraoperative ventilator settings and the incidence of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgical procedures. The aim of this post-hoc analysis of the 'Multicentre Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study was to examine the ventilator settings of patients undergoing neurosurgical procedures, and to explore the association between perioperative variables and the development of PPCs in neurosurgical patients. Methods: Post-hoc analysis of LAS VEGAS study, restricted to patients undergoing neurosurgery. Patients were stratified into groups based on the type of surgery (brain and spine), the occurrence of PPCs and the assess respiratory risk in surgical patients in Catalonia (ARISCAT) score risk for PPCs. Results: Seven hundred eighty-four patients were included in the analysis; 408 patients (52%) underwent spine surgery and 376 patients (48%) brain surgery. Median tidal volume (VT) was 8 ml [Interquartile Range, IQR = 7.3-9] per predicted body weight; median positive end-expiratory pressure (PEEP) was 5 [3 to 5] cmH20. Planned recruitment manoeuvres were used in the 6.9% of patients. No differences in ventilator settings were found among the sub-groups. PPCs occurred in 81 patients (10.3%). Duration of anaesthesia (odds ratio, 1.295 [95% confidence interval 1.067 to 1.572]; p = 0.009) and higher age for the brain group (odds ratio, 0.000 [0.000 to 0.189]; p = 0.031), but not intraoperative ventilator settings were independently associated with development of PPCs. Conclusions: Neurosurgical patients are ventilated with low VT and low PEEP, while recruitment manoeuvres are seldom applied. Intraoperative ventilator settings are not associated with PPCs