Exploring hypotheses of the actions of TGF-beta 1 in epidermal wound healing using a 3D computational multiscale model of the human epidermis

In vivo and in vitro studies give a paradoxical picture of the actions of the key regulatory factor TGF-beta 1 in epidermal wound healing with it stimulating migration of keratinocytes but also inhibiting their proliferation. To try to reconcile these into an easily visualized 3D model of wound healing amenable for experimentation by cell biologists, a multiscale model of the formation of a 3D skin epithelium was established with TGF-beta 1 literature-derived rule sets and equations embedded within it. At the cellular level, an agent-based bottom-up model that focuses on individual interacting units ( keratinocytes) was used. This was based on literature-derived rules governing keratinocyte behavior and keratinocyte/ECM interactions. The selection of these rule sets is described in detail in this paper. The agent-based model was then linked with a subcellular model of TGF-beta 1 production and its action on keratinocytes simulated with a complex pathway simulator. This multiscale model can be run at a cellular level only or at a combined cellular/subcellular level. It was then initially challenged ( by wounding) to investigate the behavior of keratinocytes in wound healing at the cellular level. To investigate the possible actions of TGF-beta 1, several hypotheses were then explored by deliberately manipulating some of these rule sets at subcellular levels. This exercise readily eliminated some hypotheses and identified a sequence of spatial-temporal actions of TGF-beta 1 for normal successful wound healing in an easy-to-follow 3D model. We suggest this multiscale model offers a valuable, easy-to-visualize aid to our understanding of the actions of this key regulator in wound healing, and provides a model that can now be used to explore pathologies of wound healing

Gross hematuria caused by a congenital intrarenal arteriovenous malformation: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report the case of a woman who presented with gross hematuria and was treated with a percutaneous embolization.</p> <p>Case presentation</p> <p>A 48-year-old Caucasian woman presented with gross hematuria, left flank pain, and clot retention. The patient had no history of renal trauma, hypertension, urolithiasis, or recent medical intervention with percutaneous instrumentation. The patient did not report any bleeding disorder and was not taking any medication. Her systolic and diastolic blood pressure values were normal at presentation. The patient had anemia (8 mg/dL) and tachycardia (110 bpm). She underwent color and spectral Doppler sonography, multi-slice computed tomography, and angiography of the kidneys, which showed a renal arteriovenous malformation pole on top of the left kidney.</p> <p>Conclusions</p> <p>The feeding artery of the arteriovenous malformation was selectively embolized with a microcatheter introduced using a right transfemoral approach. By using this technique, we stopped the bleeding, preserved renal parenchymal function, and relieved the patient's symptoms. The hemodynamic effects associated with the abnormality were also corrected.</p

Post-exercise recovery for the endurance athlete with type 1 diabetes: a consensus statement.

There has been substantial progress in the knowledge of exercise and type 1 diabetes, with the development of guidelines for optimal glucose management. In addition, an increasing number of people living with type 1 diabetes are pushing their physical limits to compete at the highest level of sport. However, the post-exercise recovery routine, particularly with a focus on sporting performance, has received little attention within the scientific literature, with most of the focus being placed on insulin or nutritional adaptations to manage glycaemia before and during the exercise bout. The post-exercise recovery period presents an opportunity for maximising training adaption and recovery, and the clinical management of glycaemia through the rest of the day and overnight. The absence of clear guidance for the post-exercise period means that people with type 1 diabetes should either develop their own recovery strategies on the basis of individual trial and error, or adhere to guidelines that have been developed for people without diabetes. This Review provides an up-to-date consensus on post-exercise recovery and glucose management for individuals living with type 1 diabetes. We aim to: (1) outline the principles and time course of post-exercise recovery, highlighting the implications and challenges for endurance athletes living with type 1 diabetes; (2) provide an overview of potential strategies for post-exercise recovery that could be used by athletes with type 1 diabetes to optimise recovery and adaptation, alongside improved glycaemic monitoring and management; and (3) highlight the potential for technology to ease the burden of managing glycaemia in the post-exercise recovery period

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

A critical evaluation of current methods for exercise prescription in women and men

Common methods to prescribe exercise intensity are based on fixed percentages of maximum rate of oxygen uptake (V ̇O2max), peak work rate (WRpeak), maximal HR (HRmax). However, it is unknown how these methods compare to the current models to partition the exercise intensity spectrum. Purpose: Thus, the aim of this study was to compare contemporary gold-standard approaches for exercise prescription based on fixed percentages of maximum values to the well-established, but underutilized, "domain" schema of exercise intensity. Methods: One hundred individuals participated in the study (women, 46; men, 54). A cardiopulmonary ramp-incremental test was performed to assess V ̇O2max, WRpeak, HRmax, and the lactate threshold (LT), and submaximal constant-work rate trials of 30-min duration to determine the maximal lactate steady-state (MLSS). The LT and MLSS were used to partition the intensity spectrum for each individual in three domains of intensity: moderate, heavy, and severe. Results: V ̇O2max in women and men was 3.06 ± 0.41 L·min and 4.10 ± 0.56 L·min, respectively. Lactate threshold and MLSS occurred at a greater %V ̇O2max and %HRmax in women compared with men (P < 0.05). The large ranges in both sexes at which LT and MLSS occurred on the basis of %V ̇O2max (LT, 45%-74%; MLSS, 69%-96%), %WRpeak (LT, 23%-57%; MLSS, 44%-71%), and %HRmax (LT, 60%-90%; MLSS, 75%-97%) elicited large variability in the number of individuals distributed in each domain at the fixed-percentages examined. Conclusions: Contemporary gold-standard methods for exercise prescription based on fixed-percentages of maximum values conform poorly to exercise intensity domains and thus do not adequately control the metabolic stimulus

An equation to predict the maximal lactate steady state from ramp-incremental test data

Objectives: The maximal lactate steady state (MLSS) represents the highest exercise intensity at which an elevated blood lactate concentration ([Lac]b) is stabilized above resting values. MLSS quantifies the boundary between the heavy-to-very-heavy intensity domains but its determination is not widely performed due to the number of trials required. Design: This study aimed to: (i) develop a mathematical equation capable of predicting MLSS using variables measured during a single ramp-incremental cycling test and (ii) test the accuracy of the optimized mathematical equation. Methods: The predictive MLSS equation was determined by stepwise backward regression analysis of twelve independent variables measured in sixty individuals who had previously performed ramp-incremental exercise and in whom MLSS was known (MLSSobs). Next, twenty-nine different individuals were prospectively recruited to test the accuracy of the equation. These participants performed ramp-incremental exercise to exhaustion and two-to-three 30-min constant-power output cycling bouts with [Lac]b sampled at regular intervals for determination of MLSSobs. Predicted MLSS (MLSSpred) and MLSSobs in both phases of the study were compared by paired t-test, major-axis regression and Bland-Altman analysis. Results: The predictor variables of MLSS were: respiratory compensation point (Wkg-1), peak oxygen uptake (V ̇O2peak) (mlkg-1min-1) and body mass (kg). MLSSpred was highly correlated with MLSSobs (r=0.93; p<0.01). When this equation was tested on the independent group, MLSSpred was not different from MLSSobs (234±43 vs. 234±44W; SEE 4.8W; r=0.99; p<0.01). Conclusions: These data support the validity of the predictive MLSS equation. We advocate its use as a time-efficient alternative to traditional MLSS testing in cycling

Evaluating the accuracy of using fixed ranges of METs to categorize exertional intensity in a heterogeneous group of healthy individuals: Implications for cardiorespiratory fitness and health outcomes

Background Appropriate quantification of exertional intensity remains elusive. Objective To compare, in a large and heterogeneous cohort of healthy females and males, the commonly used intensity classification system (i.e., light, moderate, vigorous, near-maximal) based on fixed ranges of metabolic equivalents (METs) to an individualized schema based on the exercise intensity domains (i.e., moderate, heavy, severe). Methods A heterogenous sample of 565 individuals (females 165; males 400; age range 18–83 years old) were included in the study. Individuals performed a ramp-incremental exercise test from which gas exchange threshold (GET), respiratory compensation point (RCP) and maximum oxygen uptake (VO2max) were determined to build the exercise intensity domain schema (moderate = METs ≤ GET; heavy = METs > GET but ≤ RCP; severe = METs > RCP) for each individual. Pearson’s chi-square tests over contingency tables were used to evaluate frequency distribution within intensity domains at each MET value. A multi-level regression model was performed to identify predictors of the amplitude of the exercise intensity domains. Results A critical discrepancy existed between the confines of the exercise intensity domains and the commonly used fixed MET classification system. Overall, the upper limit of the moderate-intensity domain ranged between 2 and 13 METs and of the heavy-intensity domain between 3 and 18 METs, whereas the severe-intensity domain included METs from 4 onward. Conclusions Findings show that the common practice of assigning fixed values of METs to relative categories of intensity risks misclassifications of the physiological stress imposed by exercise and physical activity. These misclassifications can lead to erroneous interpretations of the dose–response relationship of exercise and physical activity

Oxynet: A collective intelligence that detects ventilatory thresholds in cardiopulmonary exercise tests

The problem of the automatic determination of the first and second ventilatory thresholds (VT1 and VT2) from cardiopulmonary exercise test (CPET) still leads to controversy. The reliability of the gold standard methodology (i.e. expert visual inspection) feeds into the debate and several authors call for more objective automatic methods to be used in the clinical practice. In this study, we present a framework based on a collaborative approach, where a web-application was used to crowd-source a large number (1245) of CPET data of individuals with different aerobic fitness. The resulting database was used to train and test an artificial intelligence (i.e. a convolutional neural network) algorithm. This automatic classifier is currently implemented in another web-application and was used to detect the ventilatory thresholds in the available CPET. A total of 206 CPET were used to evaluate the accuracy of the estimations against the expert opinions. The neural network was able to detect the ventilatory thresholds with an average mean absolute error of 178 (198) mlO2/min (11.1%, r = 0.97) and 144 (149) mlO2/min (6.1%, r = 0.99), for VT1 and VT2 respectively. The performance of the neural network in detecting VT1 deteriorated in case of individuals with poor aerobic fitness. Our results suggest the potential for a collective intelligence system to outperform isolated experts in ventilatory thresholds detection. However, the inclusion of a larger number of VT1 examples certified by a community of experts will be likely needed before the abilities of this collective intelligence can be translated into the clinical use of CPET