VECMAtk: a scalable verification, validation and uncertainty quantification toolkit for scientific simulations.

We present the VECMA toolkit (VECMAtk), a flexible software environment for single and multiscale simulations that introduces directly applicable and reusable procedures for verification, validation (V&V), sensitivity analysis (SA) and uncertainty quantication (UQ). It enables users to verify key aspects of their applications, systematically compare and validate the simulation outputs against observational or benchmark data, and run simulations conveniently on any platform from the desktop to current multi-petascale computers. In this sequel to our paper on VECMAtk which we presented last year [1] we focus on a range of functional and performance improvements that we have introduced, cover newly introduced components, and applications examples from seven different domains such as conflict modelling and environmental sciences. We also present several implemented patterns for UQ/SA and V&V, and guide the reader through one example concerning COVID-19 modelling in detail. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.

Towards blood flow in the virtual human: efficient self-coupling of HemeLB.

Many scientific and medical researchers are working towards the creation of a virtual human-a personalized digital copy of an individual-that will assist in a patient's diagnosis, treatment and recovery. The complex nature of living systems means that the development of this remains a major challenge. We describe progress in enabling the HemeLB lattice Boltzmann code to simulate 3D macroscopic blood flow on a full human scale. Significant developments in memory management and load balancing allow near linear scaling performance of the code on hundreds of thousands of computer cores. Integral to the construction of a virtual human, we also outline the implementation of a self-coupling strategy for HemeLB. This allows simultaneous simulation of arterial and venous vascular trees based on human-specific geometries.

The heterogeneous multiscale method applied to inelastic polymer mechanics.

Mechanisms emerging across multiple scales are ubiquitous in physics and methods designed to investigate them are becoming essential. The heterogeneous multiscale method (HMM) is one of these, concurrently simulating the different scales while keeping them separate. Owing to the significant computational expense, developments of HMM remain mostly theoretical and applications to physical problems are scarce. However, HMM is highly scalable and is well suited for high performance computing. With the wide availability of multi-petaflop infrastructures, HMM applications are becoming practical. Rare applications to mechanics of materials at low loading amplitudes exist, but are generally confined to the elastic regime. Beyond that, where history-dependent, irreversible or nonlinear mechanisms occur, not only computational cost but also data management issues arise. The micro-scale description loses generality, developing a specific microstructure based on the deformation history, which implies inter alia that as many microscopic models as discrete locations in the macroscopic description must be simulated and stored. Here, we present a detailed description of the application of HMM to inelastic mechanics of materials, with emphasis on the efficiency and accuracy of the scale-bridging methodology. The method is well suited to the estimation of macroscopic properties of polymers (and derived nanocomposites) starting from knowledge of their atomistic chemical structure. Through application of the resulting workflow to polymer fracture mechanics, we demonstrate deviation in the predicted fracture toughness relative to a single-scale molecular dynamics approach, thus illustrating the need for such concurrent multiscale methods in the predictive estimation of macroscopic properties. This article is part of the theme issue 'Multiscale modelling, simulation and computing: from the desktop to the exascale'.

Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse.

Sleep is associated with marked alterations in ventilatory control that lead to perturbations in respiratory timing, breathing pattern, ventilation, pharyngeal collapsibility, and sleep-related breathing disorders (SRBD). Mouse models offer powerful insight into the pathogenesis of SRBD; however, methods for obtaining the full complement of continuous, high-fidelity respiratory, electroencephalographic (EEG), and electromyographic (EMG) signals in unrestrained mice during sleep and wake have not been developed. We adapted whole body plethysmography to record EEG, EMG, and respiratory signals continuously in unrestrained, unanesthetized mice. Whole body plethysmography tidal volume and airflow signals and a novel noninvasive surrogate for respiratory effort (respiratory movement signal) were validated against simultaneously measured gold standard signals. Compared with the gold standard, we validated 1) tidal volume (correlation, R(2) = 0.87, P < 0.001; and agreement within 1%, P < 0.001); 2) inspiratory airflow (correlation, R(2) = 0.92, P < 0.001; agreement within 4%, P < 0.001); 3) expiratory airflow (correlation, R(2) = 0.83, P < 0.001); and 4) respiratory movement signal (correlation, R(2) = 0.79-0.84, P < 0.001). The expiratory airflow signal, however, demonstrated a decrease in amplitude compared with the gold standard. Integrating respiratory and EEG/EMG signals, we fully characterized sleep and breathing patterns in conscious, unrestrained mice and demonstrated inspiratory flow limitation in a New Zealand Obese mouse. Our approach will facilitate studies of SRBD mechanisms in inbred mouse strains and offer a powerful platform to investigate the effects of environmental and pharmacological exposures on breathing disturbances during sleep and wakefulness.

The administration of an oral carbohydrate-containing fluid prior to major elective upper-gastrointestinal surgery preserves skeletal muscle mass postoperatively--a randomised clinical trial.

AIM: Recent evidence suggests that the provision of energy-containing fluids is safe and may impact positively on markers of recovery. The aims of this study were to assess the tolerance of preoperative carbohydrate fluid administration and to determine its effect on postoperative metabolic and clinical responses. METHODS: Patients admitted to the Royal Infirmary of Edinburgh for major, elective abdominal surgery were recruited to this double-blind, randomised study and received either a placebo drink or carbohydrate (12.6g/100ml) drink (CHOD). Patients consumed 800 ml of their drink on the evening before surgery and 400 ml on the day of surgery 2-3 h before the induction of anaesthesia. Nutritional status was determined using body mass index (BMI) and upper arm anthropometry; all measurements were taken preoperatively, postoperatively and at discharge. Blood glucose and insulin concentrations were also measured preoperatively and on the first post operative day. Length of hospital stay (LOS) and postoperative complications were recorded. RESULTS: Seventy-two patients were recruited and 65 (34 male:31 female) completed this study. Thirty-four patients were randomised to receive the placebo drink (control group) and 31 patients to receive the carbohydrate drink (CHOD group). Groups were well-matched in terms of gender and age. There were no differences between the two groups at baseline for BMI (control: -25.1+/-1.7 kg/m2; CHOD -25.2+/-1.2 kg/m2), upper arm anthropometry or surgical procedure. At discharge loss of muscle mass (arm muscle circumference) was significantly greater in the control group when compared with the CHOD group (control: -1.1+/-0.15 cm; CHOD: -0.5+/-0.16 cm; P<0.05). Baseline insulin (control: 20.7+/-4.9 mU/l; CHOD: 24.6+/-6.2 mU/l) and glucose (control: 6.0+/-1.4 mmol/l; CHOD 5.7+/-1.4 mmol/l) were comparable in the two groups and did not differ postoperatively. No complications were recorded as a result of preoperative fluid consumption. Postoperative morbidity occurred in six patients from each group. Median LOS in the control group was 10 days (IQR=6), and 8 days (IQR=4) in the CHOD group. CONCLUSION: Preoperative consumption of carbohydrate-containing fluids is safe. Provision of a carbohydrate energy source prior to surgery may attenuate depletion of muscle mass after surgery. Further studies are required to determine if this preservation of muscle mass is reflected in improved function and reduced rehabilitation time.

Reduction in energy expenditure after liver transplantation.

After successful liver transplantation (LTx), excessive weight gain is common among recipients. This rapid change in body morphology has been attributed to immunosuppressive regimens. The liver's role as a metabolic sensor and its autonomic innervation are pivotal in relaying humoral and neural information to the hypothalamus, where ingestive behavior is determined and has largely been ignored. We examined and assessed the contribution of drugs, energy intake, and energy expenditure on weight gain after LTx. Twenty-three patients were followed up at 3-mo intervals after LTx. Energy expenditure was measured by indirect calorimetry and dietary intake by diet diaries, and body composition was assessed with anthropometry and multifrequency bioelectrical impedance analysis. Cumulative drug doses were calculated, and associations between body composition and immunosuppressive regimens and energy expenditure were examined. Nine months after LTx, 20 of 23 (87%) recipients were overweight or obese, despite three-fourths of this cohort being on weight-reduction regimens. After LTx, a decrease in measured energy expenditure was observed (60.3 +/- 1.6 kJ/kg of body cell mass pre-LTx versus 53.7 +/- 2.2 kJ/kg of body cell mass after 9 mo; P < 0.05). Multiple stepwise regression analysis showed that, when adjusted for body weight, the strongest predictor of fat mass at 9 mo after LTx was resting energy expenditure. Weight gain after LTx is not predicted by immunosuppressive drug dosage. The strong association between weight gain and energy economy might be a consequence of the loss of hepatic metabolic integration and accelerated further by increased energy intake. Effective management of weight gain will not be achieved until the mechanisms involved in altered energy homeostasis are elucidated.

Influence of the metabolic sequelae of liver cirrhosis on nutritional intake.

BACKGROUND: The liver plays a central role in ingestive behavior; alterations in metabolic signaling to the brain stem as a result of chronic liver disease could influence intake. OBJECTIVE: We examined the influence of metabolic sequelae of liver disease on nutrient intake and nutritional status. DESIGN: Nutritional status and spontaneous dietary intake were examined in 65 cirrhotic patients and 14 control subjects. The response to feeding was investigated in 14 control subjects and a subgroup of 31 cirrhotic patients. Comparisons were made between patients with primary biliary cirrhosis (PBC) and hepatocellular cirrhosis (HC). RESULTS: Patients were nutritionally depleted. The fasting rate of lipid oxidation in the HC group was greater than in the control group (P < 0.01). In the fasting state, only HC patients were hyperinsulinemic [121.2+/-78.5 compared with 41.3+/-18.6 pmol/L in control subjects (P < 0.001) and 64.7+/-15.8 pmol/L in PBC patients (P < 0.05)] and this persisted during the response to feeding. In the fed state, the magnitude of change in carbohydrate oxidation was greatest in the HC group (HC: 34.6%; control: 23.1%; PBC: 25.2%). Carbohydrate and energy intakes of the HC group were lower than in control subjects (carbohydrate: 193+/-38.3 compared with 262+/-48.1 g/d, P < 0.05; energy: 6.29+/-1.40 compared with 9.0+/-2.12 MJ/d, P < 0.05). CONCLUSIONS: Reductions in carbohydrate intake could be mediated by hyperinsulinemia and compounded by preferential uptake of carbohydrate. This may enhance gastrointestinal satiety signaling and contribute to hypophagia.

Changes in nutritional status associated with unresectable pancreatic cancer.

Weight loss is common in patients with pancreatic cancer; however, the nature and progress of their nutritional depletion are not well documented. In this study, pre-illness weight and duration of weight loss were recorded in 20 patients with histologically confirmed unresectable cancer of the pancreas. Patients then underwent nutritional analysis at monthly intervals until death. The median period of assessment was 27 weeks (interquartile range 22.5-38.0 weeks). At the time of diagnosis, all patients had lost weight [median 14.2% (10.0-20.0%) of pre-illness stable weight], and this weight loss was progressive, increasing to a median of 24.5% by the time of the last assessment (P =0.0004). Body mass index was significantly reduced from a pre-illness median value of 24.9 kg m-2 (22.4-27.4 kg m-2) to 20.7 kg m-2 (19.5-23.6 kg m-2) at the time of diagnosis and further to 17.7 kg m-2 (16.6-23.1 kg m-2) just before death (P =0.0003). Further evidence of tissue depletion was evident from the significant reductions in lean body mass [43.4 kg (36.9-53.0 kg) to 40.1 kg (33.5-50.7 kg) P =0.008] and fat mass [12.5 kg (8.9-17.8 kg) to 9.6 kg (6.3-15.1 kg) P =0.03). This study confirms that the majority of patients with unresectable pancreatic cancer have already undergone significant weight loss by the time of diagnosis and that the natural history of this process is one of inexorable progression. These results highlight the need for selective non-toxic therapeutic intervention to attenuate cachexia and indicate that such interventions should be instituted early in the course of the disease.

Peer relationships as a source of support for adolescent mothers.

PIP: There is speculation that the pregnancy and parenthood of adolescent mothers cause changes in their peer relationships such that their peers become less able to provide support. Little empirical evidence exists to support such speculation. The authors assessed the relative amounts and types of support provided by friends and relatives to adolescent mothers, and examined peer support in relation to parenting stress. Invitations were sent to all 480 women recruited through public access birth records in two northeastern Ohio counties who were 19 years old and younger and who had given birth to their first child during the previous nine months. The counties incorporate urban, suburban, and rural communities. 66 women volunteered, of whom 46 eventually participated in the study. They were aged 13-19 years (mean age, 17.43 years) at the birth of their child. Approximately 66% were White and 12 were married. Of the 36 women who reported their family income, 88% reported yearly income of less than $20,000; of those, 15 reported income of less than $5000. 28 of the adolescent mothers were unemployed. 22 were enrolled in school at the time of data collection. Of the 24 who were not enrolled in school, 15 had already completed 12th grade. The Inventory of Social Contacts measured levels of perceived child-rearing, emotional, and material support and interference from family and friends, while the Parenting Stress Index assessed self-reported parenting stress arising from child and parent characteristics. Results of repeated-measures ANOVAs and Pearson correlations indicate that, compared to family, friends provide more emotional support and less interference. Parenting stress is buffered more effectively by the support provided by friends.^ieng

Munchausen syndrome by proxy: an exploratory study of pediatric nurses' knowledge and involvement.

The awareness and involvement of pediatric nurses in the type of child abuse known as Munchausen syndrome by proxy (MSBP) was explored in this study. A questionnaire assessing knowledge about and extent of involvement in the identification of MSBP cases and demographic information was completed by 320 registered nurses (RNS) employed at a children's hospital. Fewer than half of the subjects (47%) responded that they had heard of MSBP. Those who had heard of MSBP demonstrated only a moderate level of knowledge of the signs and signals of the syndrome. Thirty-four percent of those nurses who had heard of MSBP had been involved in the detection of cases. Findings suggest that it might be important for pediatric hospitals to include information about MSBP in their own required classes or in-house seminars.

Evaluation of multi-frequency bio-impedance analysis for the assessment of extracellular and total body water in surgical patients.

1. Multi-frequency bio-impedance analysis has been used to estimate extracellular and total body water in a heterogeneous group of 43 surgical patients (23 males, 20 females). 2. Radioisotope-dilution methods were used for the measurement of extracellular and total body water. 3. Resistance and reactance were measured between wrist and ankle at frequencies from 5 kHz to 1 MHz. 4. Extracellular and total body water were estimated by multiple stepwise regression using the radioisotope values as the dependent variables. The parameters included in the regression were: resistance and reactance at each frequency, body habitus parameters, plasma albumin and plasma sodium. 5. The standard errors of the estimates between the measured and estimated values were 1.73 litres (coefficient of variation 9.6%) and 2.17 litres (coefficient of variation 6.0%) for extracellular and total body water, respectively. 6. These errors represent a useful improvement relative to those obtained from anthropometric estimates. However, the improvements relative to the use of a single frequency (50 kHz) are not clinically significant.

Recurrent anterior glenohumeral joint dislocation and torsion of the humerus.

Two computerized axial tomographic sections, one taken just below the coracoid process and the other about 2.5 cm proximal to the interepicondylar line, were used to determine glenoid version and humeral torsion in 19 patients with recurrent anterior glenohumeral joint dislocation and in 23 controls. Analysis of interobserver variation revealed the method to be reliable. There was no difference in glenoid version between the two groups. However, humeral torsion was greater in patients (153 degrees) than in controls (144 degrees). It appears that increased humeral torsion may predispose to glenohumeral joint dislocation.

Assay of timolol in human plasma using gas chromatography with electron-capture detection.

A simple and sensitive gas chromatographic method has been developed for the determination of timolol in plasma using electron-capture detection and propranolol as internal standard. Timolol was extracted using butyl chloride and derivatized using trifluoroacetic anhydride in butyl acetate. The lower detection limit for the assay was found to be 1 ng/ml from 1 ml of plasma. Extracted standards gave within-day precision of 12.55, 9.68 and 3.78% for 1, 20 and 100 ng/ml plasma samples, respectively. A recovery of at least 80% of timolol was found using the extraction method described. The assay was used in a randomized cross-over bioequivalence trial using an oral administration of 20 mg of timolol. Pharmacokinetic parameters compare favourably with other literature values.

Bioelectrical impedance analysis in the measurement of the body composition of surgical patients.

The evaluation of nutritional status in surgical patients remains a difficult problem. Bioelectrical impedance analysis (BIA) is a new method of body composition analysis which is easily performed at the bedside. This study determined the accuracy of BIA in the measurement of total body water (TBW) and potassium (TBK) in a heterogeneous group of surgical patients. The resistance and reactance components of impedance were measured with a whole body impedance analyser. Tritiated water dilution and whole body monitoring were the reference methods for TBW and TBK analysis. With the BIA technique the coefficient of variation for the estimation of TBW was 8.1 per cent and for TBK was 6.4 per cent. Allowing for the errors of the reference methods these results show that BIA is of limited value in the estimation of TBW but may provide a useful index of TBK.

Benign giant cell tumour with metastases to bone and lung. One case studied over 20 years.

We report a case of benign giant cell tumour which over a 20-year period has given rise to pulmonary and bony metastases. The indolent nature of these metastases is remarkable, with considerable implications for the long-term management of such cases.

The conservative treatment of acromioclavicular dislocation. Review after five years.

The treatment of acromioclavicular injuries is controversial; few studies document the late results. We have reviewed 53 patients about five years after conservative management, in nine for subluxation and 44 for dislocation. Subjective and objective results were satisfactory in all cases except for one with painful subluxation, who was the only patient to change her occupation because of the injury. At review, joint stability was demonstrated by improvement in position and by the very small increase in the coracoclavicular gap on stress radiographs.