Green-Kubo expressions for transport coefficients from dissipative particle dynamics simulations revisited.

This article addresses the debate about the correct application of Green-Kubo expressions for transport coefficients from dissipative particle dynamics simulations. We demonstrate that the Green-Kubo expressions are valid provided that (i) the dynamic model conserves the physical property, whose transport is studied, and (ii) the fluctuations satisfy detailed balance. As a result, the traditional expressions used in molecular dynamics can also be applied to dissipative particle dynamics simulations. However, taking the calculation of the shear viscosity as a paradigmatic example, a random contribution, whose strength scales as 1/δt1/2, with δt the time-step, can cause difficulties if the stress tensor is not separated into the different contributions. We compare our expression to that of Ernst and Brito (M. H. Ernst and R. Brito, Europhys. Lett., 2006, 73, 183-189), which arises from a diametrically different perspective. We demonstrate that the two expressions are completely equivalent and find exactly the same result both analytically and numerically. We show that the differences are not due to the lack of time-reversibility but instead from a pre-averaging of the random contributions. Despite the overall validity of Green-Kubo expressions, we find that the Einstein-Helfand relations (D. C. Malaspina et al. Phys. Chem. Chem. Phys., 2023, 25, 12025-12040) do not suffer from the need to decompose the stress tensor and can readily be used with a high degree of accuracy. Consequently, Einstein-Helfand relations should be seen as the preferred method to calculate transport coefficients from dissipative particle dynamics simulations.

Transport coefficients from Einstein-Helfand relations using standard and energy-conserving dissipative particle dynamics methods.

In this article we demonstrate that contrary to general belief, the standard Einstein-Helfand (EH) formulas are valid for the evaluation of transport coefficients of systems containing dissipative and random forces provided that for these mesoscopic systems: (i) the corresponding conservation laws are satisfied, and (ii) the transition probabilities satisfy detailed balance. Dissipative particle dynamics (DPD) and energy-conserving DPD methods (DPDE), for instance, are archetypical of such mesoscopic approaches satisfying these properties. To verify this statement, we have derived a mesoscopic heat flux form for the DPDE method, suitable for the calculation of the thermal conductivity from an EH expression. We have compared EH measurements against non-equilibrium simulation values for different scenarios, including many-body potentials, and have found excellent agreement in all cases. The expressions are valid notably for systems with density- and temperature-dependent potentials, such as the recently developed generalised DPDE method (GenDPDE) [Avalos et al., Phys. Chem. Chem. Phys., 2019, 21, 24891]. We thus demonstrate that traditional EH formulas in equilibrium simulations can be widely used to obtain transport coefficients, provided that the appropriate expression for the associated flux is used.

Static in vitro digestion model adapted to the general older adult population: an INFOGEST international consensus.

Understanding the mechanisms of food digestion is of paramount importance to determine the effect foods have on human health. Significant knowledge on the fate of food during digestion has been generated in healthy adults due to the development of physiologically-relevant in vitro digestion models. However, it appears that the performance of the oro-gastrointestinal tract is affected by ageing and that a model simulating the digestive conditions found in a younger adult (<65 years) is not relevant for an older adult (>65 years). The objectives of the present paper were: (1) to conduct an exhaustive literature search to find data on the physiological parameters of the older adult oro-gastrointestinal tract, (2) to define the parameters of an in vitro digestion model adapted to the older adult. International experts have discussed all the parameters during a dedicated workshop organized within the INFOGEST network. Data on food bolus properties collected in the older adult were gathered, including food particle size found in older adult boluses. In the stomach and small intestine, data suggest that significant physiological changes are observed between younger and older adults. In the latter, the rate of gastric emptying is slowed down, the pH of the stomach content is higher, the amount of secretions and thus the hydrolytic activities of gastric and intestinal digestive enzymes are reduced and the concentration of bile salts lower. The consensus in vitro digestion model of the older adult proposed here will allow significant progress to be made in understanding the fate of food in this specific population, facilitating the development of foods adapted to their nutritional needs. Nevertheless, better foundational data when available and further refinement of the parameters will be needed to implement the proposed model in the future.

An assessment of the potential impact of the introduction of male mammographers into the National Health Service breast screening programme.

INTRODUCTION: The NHS breast screening programme only employs female mammographers to carry out breast screening. The screening service is experiencing a shortage of staff and introducing male mammographers into the service is a potential solution. This research aimed to determine if the introduction of male mammographers would impact acceptance rates of the offer of screening, how women feel about the potential change and what the impact would be at a programme level. METHODS: The research was conducted in 3 stages. Initially 24 face-to-face interviews were conducted with women aged 45-70 and 19 interviews over the telephone with stakeholders; these interviews explored what women's reaction would be to the introduction of male mammographers. These interviews informed the content of a questionnaire that was completed online by 1000 women aged 50-71. It explored what women would do if offered a test with a male mammographer and how they felt about the potential change. RESULTS: Over half, 53.4% stated they would attend a routine mammogram if the mammographer was male, 15.3% said they would attend if a female chaperone was present, and 31.3% stated they would refuse to attend. The face-to-face interviews suggested women view routine breast screening differently to other healthcare interactions because it is an optional service and not a treatment. As a result, participants had higher expectations both in terms of expecting a choice over the gender of the mammographer and a need to feel comfortable. CONCLUSION AND IMPLICATIONS FOR PRACTICE: The findings indicate that the percentage of eligible women attending breast screening may decrease if male mammographers were introduced. This impact of introducing male mammographers would need to be carefully weighed up against the potential gains in workforce numbers in opening up mammography to male practitioners.

Microbial transglutaminase alters the immunogenic potential and cross-reactivity of horse and cow milk proteins.

Horse milk is a valuable raw material and a very attractive alternative for scientific research to address the issue of cow milk (CM) allergy due to its protein profile. A decrease in immunoreactive properties can be achieved by thermal, enzymatic, and hydrolytic processing. Therefore, the aim of this study was to explore the possibility of reducing the immunoreactivity of horse milk proteins by microbial transglutaminase (TG) polymerization. To determine how TG linking alters immunoreactivity under simulated digestion of the examined milk, analyses were performed before, during, and after digestion. The dose-dependent (1, 10, and 100 U) effects of microbial TG on horse and cow milk were analyzed. A consecutive 3-stage digestion was simulated with salivary, gastric, and intestinal fluids. The effects of digestion were analyzed by SDS-PAGE, particle size analysis, and size-exclusion chromatography. Immunoreactivity was assessed using competitive ELISA (ß-lactoglobulin and α-casein) and immunodot (sera from 7 patients aged 3 to 13 years who are allergic to CM proteins). Horse milk contained almost half of the amount of total proteins in CM. The dose 1 U/g of total milk protein changed the immunoreactivity of both cow and horse milk. With increasing TG doses, α-casein immunoreactivity increased, and ß-lactoglobulin decreased. After total digestion, horse milk was characterized by 2.4-fold lower average IgE and 4.8-fold lower IgG reactivity than CM. We found that TG alters the IgE and IgG reactivity of CM after in vitro digestion. Horse milk was less reactive to IgE and IgG than was CM, with animal and patient sera. The effect of TG on immunoreactivity depends on enzyme quantity and milk protein type. The diet based on modified horse milk proteins could be an alternative for some patients with CM protein allergy; however, confirmation through clinical trials is needed.

Can dynamic in vitro digestion systems mimic the physiological reality?

During the last decade, there has been a growing interest in understanding the fate of food during digestion in the gastrointestinal tract in order to strengthen the possible effects of food on human health. Ideally, food digestion should be studied in vivo on humans but this is not always ethically and financially possible. Therefore simple static in vitro digestion models mimicking the gastrointestinal tract have been proposed as alternatives to in vivo experiments but these models are quite basic and hardly recreate the complexity of the digestive tract. In contrast, dynamic models that allow pH regulation, flow of the food and injection in real time of digestive enzymes in the different compartments of the gastrointestinal tract are more promising to accurately mimic the digestive process. Most of the systems developed so far have been compared for their performances to in vivo data obtained on animals and/or humans. The objective of this article is to review the validation towards in vivo data of some of the dynamic digestion systems currently available in order to determine what aspects of food digestion they are able to mimic. Eight dynamic digestion systems are presented as well as their validation towards in vivo data. Advantages and limits of each simulator is discussed. This is the result of a cooperative international effort made by some of the scientists involved in Infogest, an international network on food digestion.

Caudal regression syndrome in a fetus of a glucokinase-maturity-onset diabetes of the young pregnancy.

BACKGROUND: Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is a form of diabetes caused by heterozygous inactivating mutations in the GCK gene. Affected individuals maintain their fasting glucose levels at a higher set point (5.4-8.3 mmol/l) than the general population. Hyperglycaemia in women with Type 1 or Type 2 diabetes is known to confer increased risk of fetal congenital abnormalities. The association between GCK-MODY and congenital abnormalities, however, remains uncertain. CASE REPORT: A 35-year-old woman in her third pregnancy was diagnosed with gestational diabetes at 13 weeks' gestation (fasting blood glucose 6.0 mmol/L, 1-h blood glucose 9.2 mmol/l, 2-h blood glucose 7.3 mmol/l). The morphology scan at 19+2 weeks' gestation showed a Type III sacral agenesis. The woman elected to terminate the pregnancy. Her postpartum oral glucose tolerance test was suggestive of GCK-MODY (fasting blood glucose 7.4 mmol/l, 1-h blood glucose 9.3 mmol/l, 2-h blood glucose 7.3 mmol/l). Mutation analysis of the GCK gene identified a novel heterozygous GCK missense mutation, p.V199M, classified as likely pathogenic, providing molecular confirmation of the suspected GCK-MODY diagnosis. DISCUSSION: Sacral agenesis is a rare form of sacral abnormality affecting 0.005% to 0.1% of pregnancies. It is a subtype of the caudal regression sequence, a cardinal feature of diabetic embryopathy. This case raises the question as to whether hyperglycaemia in GCK-MODY may increase the risk of fetal caudal regression syndrome as reported in women with pre-existing diabetes mellitus. Improved diagnostic rates of GCK-MODY, and MODY registers that include pregnancy outcomes, are important to further elucidate risk of congenital abnormalities in GCK-MODY.

"Not such a kid thing anymore": Young adults' perspectives on transfer from paediatric to adult cardiology care.

BACKGROUND: Transfer of adolescents with congenital heart disease from paediatric cardiology providers to specialized adult congenital heart disease (ACHD) care providers is becoming a standard practice. However, some paediatric cardiologists continue to provide care for their patients into adult life. Little is known about the perspectives of young adult patients who have been transferred to ACHD clinics versus those who continue to receive their cardiology care in paediatric settings. METHODS: Content and thematic analysis of structured telephone interviews with 21 young adults age 18-25 (13 transferred to ACHD clinic and 8 who had not transferred) was conducted to identify similarities and differences in patient characteristics of those in ACHD versus paediatric settings. RESULTS: There were no appreciable differences in gender, age, heart disease type, and independence between those transferred to ACHD care versus those not transferred. Participants in both groups were aware of differences between the paediatric and ACHD care settings and providers, with some favouring the familiarity offered by the paediatric setting and providers. Participants had varying views on parental involvement in their care; most of them had attended clinic appointments on their own. Those who had transferred to ACHD care acknowledged that it would take time to adjust to new relationships. Positive perspectives on actual or anticipated transfer to ACHD care included a growing sense of autonomy and responsibility, as well as access to reproductive information relevant to ACHD patients. CONCLUSIONS: The absence of patient characteristics distinguishing those in ACHD care versus those still followed in paediatric care suggests that system, provider, and parent factors, rather than patient factors, may account for patients' perspectives on transfer to ACHD care.

Microcalorimetry of the intestinal mucus: Hydrogen bonding and self-assembly of mucin.

The effect of mucin hydrogen bonding on the structure of intestinal mucus has been studied with micro-differential scanning mirocalorimetry (µ-DSC), supported by spectroscopy. The experiments were performed in water-dimethyl sulfoxide (DMSO) solutions, using either water-DMSO mixtures of an appropriate DMSO content or water as blanks, as to isolate the effects of the solvent to hydrogen bonding. When using matched water-DMSO blanks, thermal events at low temperatures are linked to the negation of mucin-DMSO interactions, while events at higher temperatures are linked to the break-up of hydrogen bonds connecting the sugars of the individual macromolecules. When using a matched solvent as blank, alterations in Cp, such as increases at 10% and 15% DMSO, have been linked to the break-up and creation of quaternary structures. In the case of water as blank, a monotonic but not linear decrease in enthalpy, hence extent of hydrogen bonding, is observed. The above are complemented by UV spectroscopy: A blue shift of the conjugated aminoacids in the presence of DMSO suggests that the inherent stability of mucin is not only due to steric volume exclusions, but also due to extensive hydrogen bonding on behalf of the sugar moieties.

Correlation between in vitro and in vivo data on food digestion. What can we predict with static in vitro digestion models?

During the last decade, there has been a growing interest in understanding food's digestive fate in order to strengthen the possible effects of food on human health. Ideally, food digestion should be studied in vivo on humans but this is not always ethically and financially possible. Therefore, simple in vitro digestion models mimicking the gastrointestinal tract have been proposed as alternatives to in vivo experiments. Thus, it is no surprise that these models are increasingly used by the scientific community, although their various limitations to fully mirror the complexity of the digestive tract. Therefore, the objective of this article was to call upon the collective experiences of scientists involved in Infogest (an international network on food digestion) to review and reflect on the applications of in vitro digestion models, the parameters assessed in such studies and the physiological relevance of the data generated when compared to in vivo data. The authors provide a comprehensive review in vitro and in vivo digestion studies investigating the digestion of macronutrients (i.e., proteins, lipids, and carbohydrates) as well as studies of the bioaccessibility and bioavailability of micronutrients and phytochemicals. The main conclusion is that evidences show that despite the simplicity of in vitro models they are often very useful in predicting outcomes of the digestion in vivo. However, this has relies on the complexity of in vitro models and their tuning toward answering specific questions related to human digestion physiology, which leaves a vast room for future studies and improvements.

Incidence and natural history of hen's egg allergy in the first 2 years of life-the EuroPrevall birth cohort study.

BACKGROUND: Parents and health staff perceive hen's egg allergy (HEA) as a common food allergy in early childhood, but the true incidence is unclear because population-based studies with gold-standard diagnostic criteria are lacking. OBJECTIVE: To establish the incidence and course of challenge-confirmed HEA in children, from birth until the age of 24 months, in different European regions. METHODS: In the EuroPrevall birth cohort study, children with a suspected HEA and their age-matched controls were evaluated in 9 countries, using a standardized protocol including measurement of HE-specific immunoglobulin E-antibodies in serum, skin prick tests, and double-blind, placebo-controlled food challenges (DBPCFC). RESULTS: Across Europe, 12 049 newborns were enrolled, and 9336 (77.5%) were followed up to 2 years of age. In 298 children, HEA was suspected and DBPCFC was offered. HEA by age two was confirmed in 86 of 172 challenged children (mean raw incidence 0.84%, 95% confidence interval (95% CI) 0.67-1.03). Adjusted mean incidence of HEA was 1.23% (95% CI 0.98-1.51) considering possible cases among eligible children who were not challenged. Centre-specific incidence ranged from United Kingdom (2.18%, 95% CI 1.27-3.47) to Greece (0.07%). Half of the HE-allergic children became tolerant to HE within 1 year after the initial diagnosis. CONCLUSIONS: The largest multinational European birth cohort study on food allergy with gold-standard diagnostic methods showed that the mean adjusted incidence of HEA was considerably lower than previously documented, although differences in incidence rates among countries were noted. Half of the children with documented HEA gained tolerance within 1 year postdiagnosis.

The EuroPrevall outpatient clinic study on food allergy: background and methodology.

BACKGROUND: The EuroPrevall project aimed to develop effective management strategies in food allergy through a suite of interconnected studies and a multidisciplinary integrated approach. To address some of the gaps in food allergy diagnosis, allergen risk management and socio-economic impact and to complement the EuroPrevall population-based surveys, a cross-sectional study in 12 outpatient clinics across Europe was conducted. We describe the study protocol. METHODS: Patients referred for immediate food adverse reactions underwent a consistent and standardized allergy work-up that comprised collection of medical history; assessment of sensitization to 24 foods, 14 inhalant allergens and 55 allergenic molecules; and confirmation of clinical reactivity and food thresholds by standardized double-blind placebo-controlled food challenges (DBPCFCs) to milk, egg, fish, shrimp, peanut, hazelnut, celeriac, apple and peach. RESULTS: A standardized methodology for a comprehensive evaluation of food allergy was developed and implemented in 12 outpatient clinics across Europe. A total of 2121 patients (22.6% <14 years) reporting 8257 reactions to foods were studied, and 516 DBPCFCs were performed. CONCLUSIONS: This is the largest multicentre European case series in food allergy, in which subjects underwent a comprehensive, uniform and standardized evaluation including DBPCFC, by a methodology which is made available for further studies in food allergy. The analysis of this population will provide information on the different phenotypes of food allergy across Europe, will allow to validate novel in vitro diagnostic tests, to establish threshold values for major allergenic foods and to analyse the socio-economic impact of food allergy.

Potato spindle tuber viroid: Stability on Common Surfaces and Inactivation With Disinfectants.

The length of time Potato spindle tuber viroid (PSTVd) remained infective in extracted tomato leaf sap on common surfaces and the effectiveness of disinfectants against it were investigated. When sap from PSTVd-infected tomato leaves was applied to eight common surfaces (cotton, wood, rubber tire, leather, metal, plastic, human skin, and string) and left for various periods of time (5 min to 24 h) before rehydrating the surface and rubbing onto healthy tomato plants, PSTVd remained infective for 24 h on all surfaces except human skin. It survived best on leather, plastic, and string. It survived less well after 6 h on wood, cotton, and rubber and after 60 min on metal. On human skin, PSTVd remained infective for only 30 min. In general, rubbing surfaces contaminated with dried infective sap directly onto leaves caused less infection than when the sap was rehydrated with distilled water but overall results were similar. The effectiveness of five disinfectant agents at inactivating PSTVd in sap extracts was investigated by adding them to sap from PSTVd-infected leaves before rubbing the treated sap onto leaves of healthy tomato plants. Of the disinfectants tested, 20% nonfat dried skim milk and a 1:4 dilution of household bleach (active ingredient sodium hypochlorite) were the most effective at inactivating PSTVd infectivity in infective sap. When reverse-transcription polymerase chain reaction was used to test the activity of the five disinfectants against PSTVd in infective sap, it detected PSTVd in all instances except in sap treated with 20% nonfat dried skim milk. This study highlights the stability of PSTVd in infective sap and the critical importance of utilizing hygiene practices such as decontamination of clothing, tools, and machinery, along with other control measures, to ensure effective management of PSTVd and, wherever possible, its elimination in solanaceous crops.

A standardised static in vitro digestion method suitable for food - an international consensus.

Simulated gastro-intestinal digestion is widely employed in many fields of food and nutritional sciences, as conducting human trials are often costly, resource intensive, and ethically disputable. As a consequence, in vitro alternatives that determine endpoints such as the bioaccessibility of nutrients and non-nutrients or the digestibility of macronutrients (e.g. lipids, proteins and carbohydrates) are used for screening and building new hypotheses. Various digestion models have been proposed, often impeding the possibility to compare results across research teams. For example, a large variety of enzymes from different sources such as of porcine, rabbit or human origin have been used, differing in their activity and characterization. Differences in pH, mineral type, ionic strength and digestion time, which alter enzyme activity and other phenomena, may also considerably alter results. Other parameters such as the presence of phospholipids, individual enzymes such as gastric lipase and digestive emulsifiers vs. their mixtures (e.g. pancreatin and bile salts), and the ratio of food bolus to digestive fluids, have also been discussed at length. In the present consensus paper, within the COST Infogest network, we propose a general standardised and practical static digestion method based on physiologically relevant conditions that can be applied for various endpoints, which may be amended to accommodate further specific requirements. A frameset of parameters including the oral, gastric and small intestinal digestion are outlined and their relevance discussed in relation to available in vivo data and enzymes. This consensus paper will give a detailed protocol and a line-by-line, guidance, recommendations and justifications but also limitation of the proposed model. This harmonised static, in vitro digestion method for food should aid the production of more comparable data in the future.

The Tayside insulin management course: an effective education programme in type 1 diabetes.

AIMS: The Tayside insulin management (TIM) course is an intensive insulin management programme for adults with type 1 diabetes. The aim was to assess its effectiveness. METHODS: Haemoglobin A1c (HbA1c) and body mass index (BMI) from individuals with type 1 diabetes were collected 3 months before, and 6 and 24 months after the programme. The programme involved a full day of education per week for 4 weeks in a row. Quality of life was assessed using the standardised Audit of Diabetes-Dependent Quality of Life (ADDQoL) questionnaire completed both before and 3 months after the course. Subjects were also asked to complete a pre- and postcourse questionnaire gathering information about aspects of their diabetes management. In addition, individual satisfaction with course content and delivery was recorded. RESULTS: Participants had a median reduction in haemoglobin A1c (HbA1c) of 4 mmol/mol (0.4%) after 6 months and 5 mmol/mol (0.5%) 2 years after the course (p < 0.001). Mean daily dose of short-acting insulin decreased from 31.5 (1.9) units to 27.3 (1.9, p < 0.001). There was no significant change in BMI. There was an improvement in all 18 domains of the ADDQoL questionnaire. There was a decrease in hypoglycaemia unawareness from 34.3 ± 47.8% of patients to 8.6 ± 28% (p < 0.001), and a decrease in self-reported lipohypertrophy from 27.8% to 11.1% (p = 0.001). There was a significant reduction in the mean number of diabetic ketoacidosis and severe hypoglycaemic episodes. The number of blood glucose checks changed from 2.8 ± 2.1 to 3.2 ± 1.1 (p = 0.058) per day. Participant satisfaction with all aspects of course content and delivery was high. CONCLUSIONS: TIM is an effective intensive education programme for patients with type 1 diabetes.

Effect of calcium ions on in vitro pellicle formation from parotid and whole saliva.

The salivary pellicle is a protein-rich, bacteria-free, self-assembling film that adsorbs to all surfaces within the oral cavity. The pellicle has numerous functions that are vital for maintaining oral health. Currently however, there are no commercially available artificial salivas that accurately mimic the complex film forming properties (i.e. film thickness and viscoelasticity) of human saliva. To understand these properties further we have examined the in vitro formation of the salivary pellicle, by adsorbing stimulated parotid saliva (PS) and whole mouth saliva (WMS) from 14 healthy volunteers, onto oxidised silicon surfaces, using a quartz crystal microbalance with dissipation monitoring (QCMD) and a dual polarisation interferometer (DPI). A dramatic impact on the hydrated mass, polymer mass, thickness and polymer concentration of the pellicle for both WMS and PS was observed when the natural calcium concentration of the respective salivas was increased from 0 mM to 10mM. In addition, QCMD data showed that on addition of 10mM calcium the salivary pellicle formed by both PS and WMS became more predominantly elastic. The results presented here also suggest that calcium can easily diffuse in and out of the pellicle, permitting free calcium exchange between the saliva and the adsorbed pellicle under physiological conditions, which may potentially facilitate the mineralisation of enamel.

Development of a standardized low-dose double-blind placebo-controlled challenge vehicle for the EuroPrevall project.

BACKGROUND: Double-blind placebo-controlled food challenge (DBPCFC) is the gold standard for diagnosing food allergy. Standardized materials and protocols are essential for comparing DBPCFC results for multicentre studies such as EuroPrevall. This required the development and piloting of a standardized vehicle and low-dose protocol for confirming food allergy and determination of minimum eliciting doses (MEDs). METHODS: A low-dose DBPCFC protocol was developed, with eight titrated protein doses from 3 µg to 1 g. This was delivered using a simple, microbiologically stable food base incorporating allergenic food ingredients manufactured at three sites and centrally distributed to clinical centres. Allergen blinding was assessed by a professional sensory testing panel using a triangle test. Homogeneity and allergen content were confirmed by ELISA and clinical efficacy was assessed in a pilot study, using celeriac and hazelnut as exemplars. RESULTS: Celeriac and hazelnut ingredients were sufficiently blinded in the dessert. The dessert meals were successfully piloted with hazelnut in allergy clinics in Spain, the Netherlands and Italy and with celeriac and hazelnut in Zurich. The challenges elicited a range of subjective and objective reactions ranging in severity from mild itching of the oral mucosa to bronchospasm. CONCLUSIONS: A standardized challenge vehicle proven to sufficiently blind processed, powdered hazelnut and celeriac ingredients and that can be reproducibly manufactured has been developed. This pilot study shows that the vehicle is promising for the confirmation of food allergy and determination of MEDs in adults and children with body weight >28.8 kg (approximately 7-11 years old).