A neural network potential based on pairwise resolved atomic forces and energies.

Molecular simulations have become a key tool in molecular and materials design. Machine learning (ML)-based potential energy functions offer the prospect of simulating complex molecular systems efficiently at quantum chemical accuracy. In previous work, we have introduced the ML-based PairF-Net approach to neural network potentials, that adopts a pairwise interatomic scheme to predicting forces within a molecular system. Here, we further develop the PairF-Net model to intrinsically incorporate energy conservation and couple the model to a molecular mechanical (MM) environment within the OpenMM package. The updated PairF-Net model yields energy and force predictions and dynamical distributions in good agreement with the rMD17 dataset of ten small organic molecules in the gas-phase. We further show that these in vacuo ML models of small molecules can be applied to force predictions in aqueous solution via hybrid ML/MM simulations. We present a new benchmark dataset for these ten molecules in solution, obtained from QM/MM simulations, which we denote as rMD17-aq (https://zenodo.org/records/10048644); and assess the ability of PairF-Net to reproduce the molecular energy, atomic forces and dynamical distributions of these solution conformations via ML/MM simulations.

Decoding the Interplay between Topology and Surface Charge in Graphene Oxide Membranes During Humidity Induced Swelling.

Graphene oxide (GO) membranes are known to have a complex morphology that depends on the degree of oxidation of the graphene flake and the membrane preparation technique. In this study, using Grand Canonical Monte Carlo simulations, we investigate the mechanism of swelling of GO membranes exposed to different relative humidity (RH) values and show how this is intimately related to the graphene surface chemistry. We show that the structure of the GO membrane changes while the membrane adsorbs water from the environment and that graphene oxide flakes become charged as the membrane is loaded with water and swells. A detailed comparison between simulation and experimental adsorption data reveals that the flake surface charge drives the water adsorption mechanism at low RH when the membrane topology is still disordered and the internal pores are small and asymmetric. As the membrane is exposed to higher RH (80%), the flake acquires more surface charge as more oxide groups deprotonate, and the pores grow in size, yet maintain their disordered geometry. Only for very high relative humidity (98%) does the membrane undergo structural changes. At this level of humidity, the pores in the membrane become slit-like but the flake surface charge remains constant. Our results unveil a very complex mechanism of swelling and show that a single molecular model cannot fully capture the ever-changing chemistry and morphology of the membrane as it swells. Our computational procedure provides the first atomically resolved insight into the GO membrane structure of experimental samples.

Hierarchical Aggregation in a Complex Fluid─The Role of Isomeric Interconversion.

There is an ever-increasing body of evidence that metallic complexes involving amphiliphic ligands do not form normal solutions in organic solvents. Instead, they form complex fluids with intricate structures. For example, the metallic complexes may aggregate into clusters, and these clusters themselves may aggregate into superclusters. To gain a deeper insight into the mechanisms at play, we have used an improved force field to conduct extensive molecular dynamics simulations of a system composed of zirconium nitrate, water, nitric acid, tri-n-butyl phosphate, and n-octane. The important new finding is that a dynamic equilibrium between the cis and trans isomers of the metal complex is likely to play a key role in the aggregation behavior. The isolated cis and trans isomers have similar energies, but simulation indicates that the clusters consist predominantly of cis isomers. With increasing metal concentration, we hypothesize that more clustering occurs and the chemical equilibrium shifts toward the cis isomer. It is possible that such isomeric effects play a role in the liquid-liquid extraction of other species and the inclusion of such effects in flow sheet modeling may lead to a better description of the process.

General practitioners' role in improving health care in care homes: a realist review.

BACKGROUND: Despite recent focus on improving health care in care homes, it is unclear what role general practitioners (GPs) should play. To provide evidence for future practice we set out to explore how GPs have been involved in such improvements. METHODS: Realist review incorporated theory-driven literature searches and stakeholder interviews, supplemented by focussed searches on GP-led medication reviews and end-of-life care. Medline, Embase, CINAHL, PsycInfo, Web of Science, and the Cochrane library were searched. Grey literature was identified through internet searches and professional networks. Studies were included based upon relevance. Data were coded to develop and test contexts, mechanisms, and outcomes for improvements involving GPs. RESULTS: Evidence was synthesized from 30 articles. Programme theories described: (i) "negotiated working with GPs," where other professionals led improvement and GPs provided expertise; and (ii) "GP involvement in national/regional improvement programmes." The expertise of GPs was vital to many improvement programmes, with their medical expertise or role as coordinators of primary care proving pivotal. GPs had limited training in quality improvement (QI) and care home improvement work had to be negotiated in the context of wider primary care commitments. CONCLUSIONS: GPs are central to QI in health care in care homes. Their contributions relate to their specialist expertise and recognition as leaders of primary care but are challenged by available time and resources to develop this role.

The genome sequence of the common buff snailkiller, Tetanocera ferruginea (Fallén, 1820).

We present a genome assembly from an individual male Tetanocera ferruginea (the common buff snailkiller; Arthropoda; Insecta; Diptera; Sciomyzidae). The genome sequence is 790.4 megabases in span. Most of the assembly is scaffolded into 7 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 17.07 kilobases in length.

'Weighing up risks': a model of care home staff decision-making about potential resident hospital transfers.

BACKGROUND: care home staff play a crucial role in managing residents' health and responding to deteriorations. When deciding whether to transfer a resident to hospital, a careful consideration of the potential benefits and risks is required. Previous studies have identified factors that influence staff decision-making, yet few have moved beyond description to produce a conceptual model of the decision-making process. OBJECTIVES: to develop a conceptual model to describe care home staff's decision-making when faced with a resident who potentially requires a transfer to the hospital. METHODS: data collection occurred in England between May 2018 and November 2019, consisting of 28 semi-structured interviews with 30 members of care home staff across six care home sites and 113 hours of ethnographic observations, documentary analysis and informal conversations (with staff, residents, visiting families, friends and healthcare professionals) at three of these sites. RESULTS: a conceptual model of care home staff's decision-making is presented. Except in situations that staff perceived to be urgent enough to require an immediate transfer, resident transfers tended to occur following a series of escalations. Care home staff made complex decisions in which they sought to balance a number of potential benefits and risks to: residents; staff (as decision-makers); social relationships; care home organisations and wider health and social care services. CONCLUSIONS: during transfer decisions, care home staff make complex decisions in which they weigh up several forms of risk. The model presented offers a theoretical basis for interventions to support deteriorating care home residents and the staff responsible for their care.

A molecular simulation study into the stability of hydrated graphene nanochannels used in nanofluidics devices.

Graphene-based nanochannels are a popular choice in emerging nanofluidics applications because of their tunable and nanometer-scale channels. In this work, molecular dynamics (MD) simulations were employed both to (i) assess the stability of dry and hydrated graphene nanochannels and (ii) elucidate the properties of water confined in these channels, using replica-scale models with 0.66-2.38 nm channel heights. The use of flexible nanochannel walls allows the nanochannel height to relax in response to the solvation forces arising from the confined fluid and the forces between the confining surfaces, without the need for application of arbitrarily high external pressures. Dry nanochannels were found to completely collapse if the initial nanochannel height was less than 2 nm, due to attractive van der Waals interactions between the confining graphene surfaces. However, the presence of water was found to prevent total nanochannel collapse, due to repulsive hydration forces opposing the attractive van der Waals force. For nanochannel heights less than ∼1.7 nm, the confining surfaces must be relaxed to obtain accurate hydration pressures and water diffusion coefficients, by ensuring commensurability between the number of confined water layers and the channel height. For very small (∼0.7 nm), hydrated channels a pressure of 231 MPa due to the van der Waals forces was obtained. In the same system, the confined water forms a mobile, liquid monolayer with a diffusion coefficient of 4.0 × 10-5 cm2 s-1, much higher than bulk liquid water. Although this finding conflicts with most classical MD simulations, which predict in-plane order and arrested dynamics, it is supported by experiments and recently published first-principles MD simulations. Classical simulations can therefore be used to predict the properties of water confined in sub-nanometre graphene channels, providing sufficiently realistic molecular models and accurate intermolecular potentials are employed.

High-throughput molecular simulations reveal the origin of ion free energy barriers in graphene oxide membranes.

Graphene oxide (GO) membranes are highly touted as materials for contemporary separation challenges including desalination, yet understanding of the interplay between their structure and salt rejection is limited. K+ ion permeation through hydrated GO membranes was investigated by combining structurally realistic molecular models and high-throughput molecular dynamics simulations. We show that it is essential to consider the complex GO microstructure to quantitatively reproduce experimentally-derived free energy barriers to K+ permeation for membranes with various interlayer distances less than 1.3 nm. This finding confirms the non-uniformity of GO nanopores and the necessity of the high-throughput approach for this class of material. The large barriers arise due to significant dehydration of K+ inside the membrane, which can have as few as 3 coordinated water molecules, compared to 7 in bulk solution. Thus, even if the membranes have an average pore size larger than the ion's hydrated diameter, the significant presence of pores whose size is smaller than the hydrated diameter creates bottlenecks for the permeation process.

A Literature Review of Biological and Bio-Rational Control Strategies for Slugs: Current Research and Future Prospects.

Terrestrial gastropod molluscs (slugs and snails) (Mollusca: Gastropoda) cause significant crop damage around the world. There is no formal approach for differentiating between slugs and snails; however, an organism is usually considered a slug when there is no external shell, or when the shell is small in comparison to the body, and a snail when there is a large external shell. Although snails are an important pest of many crops, this review focuses on slug pests and their nonchemical control measures. A recent study by the UK Agriculture and Horticulture Development Board concluded that the failure to control slugs could cost the UK agriculture industry over GBP 100 million annually, with similar figures reported around the world. Whilst slugs are mostly controlled using chemical molluscicide products, some actives have come under scrutiny due to their detrimental environmental effects and impact on nontarget organisms. This has resulted in the ban of actives such as methiocarb in the UK and EU, and, more recently, the ban of metaldehyde in the UK. Therefore, there is an urgent need to find alternative and effective nontoxic solutions in the interest of global food security. In this paper, we have integrated extant literature on the three main biological control agents of slugs, namely nematodes, carabid beetles and sciomyzid flies, and various promising bio-rational slug control strategies. The review also highlights current research gaps and indicates some relevant potential future directions towards developing environmentally benign slug control solutions.

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

Initial Studies Directed toward the Rational Design of Aqueous Graphene Dispersants.

This study presents preliminary experimental data suggesting that sodium 4-(pyrene-1-yl)butane-1-sulfonate (PBSA), 5, an analogue of sodium pyrene-1-sulfonate (PSA), 1, enhances the stability of aqueous reduced graphene oxide (RGO) graphene dispersions. We find that RGO and exfoliated graphene dispersions prepared in the presence of 5 are approximately double the concentration of those made with commercially available PSA, 1. Quantum mechanical and molecular dynamics simulations provide key insights into the behavior of these molecules on the graphene surface. The seemingly obvious introduction of a polar sulfonate head group linked via an appropriate alkyl spacer to the aromatic core results in both more efficient binding of 5 to the graphene surface and more efficient solvation of the polar head group by bulk solvent (water). Overall, this improves the stabilization of the graphene flakes by disfavoring dissociation of the stabilizer from the graphene surface and inhibiting reaggregation by electrostatic and steric repulsion. These insights are currently the subject of further investigations in an attempt to develop a rational approach to the design of more effective dispersing agents for rGO and graphene in aqueous solution.

Outcomes of hospital admissions among frail older people: a 2-year cohort study.

BACKGROUND: 'Frailty crises' are a common cause of hospital admission among older people and there is significant focus on admission avoidance. However, identifying frailty before a crisis occurs is challenging, making it difficult to effectively target community services. Better longer-term outcome data are needed if services are to reflect the needs of the growing population of older people with frailty. AIM: To determine long-term outcomes of older people discharged from hospital following short (<72 hours) and longer hospital admissions compared by frailty status. DESIGN AND SETTING: Two populations aged ≥70 years discharged from hospital units: those following short 'ambulatory' admissions (<72 hours) and those following longer inpatient stays. METHOD: Data for 2-year mortality and hospital use were compared using frailty measures derived from clinical and hospital data. RESULTS: Mortality after 2 years was increased for frail compared with non-frail individuals in both cohorts. Patients in the ambulatory cohort classified as frail had increased mortality (Rockwood hazard ratio 2.3 [95% confidence interval {CI} = 1.5 to 3.4]) and hospital use (Rockwood rate ratio 2.1 [95% CI = 1.7 to 2.6]) compared with those patients classified as non-frail. CONCLUSION: Individuals with frailty who are discharged from hospital experience increased mortality and resource use, even after short 'ambulatory' admissions. This is an easily identifiable group that is at increased risk of poor outcomes. Health and social care systems might wish to examine their current care response for frail older people discharged from hospital. There may be value in a 'secondary prevention' approach to frailty crises targeting individuals who are discharged from hospital.

In Silico Design and Characterization of Graphene Oxide Membranes with Variable Water Content and Flake Oxygen Content.

Graphene oxide (GO) membranes offer exceptional promise for certain aqueous separation challenges, such as desalination. Central to unlocking this promise and optimizing performance for a given separation is the establishment of a detailed molecular-level understanding of how the membrane's composition affects its structural and transport properties. This understanding is currently lacking, in part due to the fact that, until recently, molecular models with a realistic distribution of oxygen functionalities and interlayer flake structure were unavailable. To understand the effect of composition on the properties of GO membranes, models with water contents and oxygen contents, varying between 0% and 40% by weight, were prepared in this work using classical molecular dynamics simulations. The change in membrane interlayer distance distribution, water connectivity, and water diffusivity with water and oxygen content was quantified. Interlayer distance distribution analysis showed that the swelling of GO membranes could be controlled by separately tuning both the flake oxygen content and the membrane water content. Water-molecule cluster analysis showed that a continuous and fully connected network of water nanopores is not formed until the water content reaches ∼20%. The diffusivity of water in the membrane was also found to strongly depend on both the water and the oxygen content. These insights help understand the structure and transport properties of GO membranes with sub-nanometer interlayer distances and could be exploited to enhance the performance of GO membranes for aqueous separation applications. More broadly, the high-throughput in silico approach adopted could be applied to other nanomaterials with intrinsic non-stoichiometry and structural heterogeneity.

A Telescoping View of Solute Architectures in a Complex Fluid System.

Short- and long-range correlations between solutes in solvents can influence the macroscopic chemistry and physical properties of solutions in ways that are not fully understood. The class of liquids known as complex (structured) fluids-containing multiscale aggregates resulting from weak self-assembly-are especially important in energy-relevant systems employed for a variety of chemical- and biological-based purification, separation, and catalytic processes. In these, solute (mass) transfer across liquid-liquid (water, oil) phase boundaries is the core function. Oftentimes the operational success of phase transfer chemistry is dependent upon the bulk fluid structures for which a common functional motif and an archetype aggregate is the micelle. In particular, there is an emerging consensus that mass transfer and bulk organic phase behaviors-notably the critical phenomenon of phase splitting-are impacted by the effects of micellar-like aggregates in water-in-oil microemulsions. In this study, we elucidate the microscopic structures and mesoscopic architectures of metal-, water-, and acid-loaded organic phases using a combination of X-ray and neutron experimentation as well as density functional theory and molecular dynamics simulations. The key conclusion is that the transfer of metal ions between an aqueous phase and an organic one involves the formation of small mononuclear clusters typical of metal-ligand coordination chemistry, at one extreme, in the organic phase, and their aggregation to multinuclear primary clusters that self-assemble to form even larger superclusters typical of supramolecular chemistry, at the other. Our metrical results add an orthogonal perspective to the energetics-based view of phase splitting in chemical separations known as the micellar model-founded upon the interpretation of small-angle neutron scattering data-with respect to a more general phase-space (gas-liquid) model of soft matter self-assembly and particle growth. The structure hierarchy observed in the aggregation of our quinary (zirconium nitrate-nitric acid-water-tri-n-butyl phosphate-n-octane) system is relevant to understanding solution phase transitions, in general, and the function of engineered fluids with metalloamphiphiles, in particular, for mass transfer applications, such as demixing in separation and synthesis in catalysis science.

Design Rules for Graphene and Carbon Nanotube Solvents and Dispersants.

The constantly widening industrial applications of carbon-based nanomaterials puts into sharp perspective the lack of true solvents in which the materials spontaneously exfoliate to individual molecules. This work shows that the different geometry of graphene compared to that of carbon nanotubes can change the potency of a molecule to act as a solvent or dispersant. Through analysis of the structure/function relationships, we derive a number of design rules that will aid the identification of the best solvent or dispersant candidates.

Tunable sieving of ions using graphene oxide membranes.

Graphene oxide membranes show exceptional molecular permeation properties, with promise for many applications. However, their use in ion sieving and desalination technologies is limited by a permeation cutoff of ∼9 Š(ref. 4), which is larger than the diameters of hydrated ions of common salts. The cutoff is determined by the interlayer spacing (d) of ∼13.5 Å, typical for graphene oxide laminates that swell in water. Achieving smaller d for the laminates immersed in water has proved to be a challenge. Here, we describe how to control d by physical confinement and achieve accurate and tunable ion sieving. Membranes with d from ∼9.8 Što 6.4 Šare demonstrated, providing a sieve size smaller than the diameters of hydrated ions. In this regime, ion permeation is found to be thermally activated with energy barriers of ∼10-100 kJ mol-1 depending on d. Importantly, permeation rates decrease exponentially with decreasing sieve size but water transport is weakly affected (by a factor of <2). The latter is attributed to a low barrier for the entry of water molecules and large slip lengths inside graphene capillaries. Building on these findings, we demonstrate a simple scalable method to obtain graphene-based membranes with limited swelling, which exhibit 97% rejection for NaCl.

Effective Polarization in Pairwise Potentials at the Graphene-Electrolyte Interface.

At the graphene-electrolyte interface, the polarizability of both the surface and the solution plays a major role in defining the interfacial structure and dynamics of the ions. Current molecular models predict different ion adsorption behavior at the interface depending on whether surface or solution polarization is included in the model. Here, we propose a simple method to parametrize the ion-carbon interaction from density functional theory, implicitly modeling the solution using the conductor-like polarizable continuum model. The new model simultaneously takes into account the polarizability of both the graphene sheet and the solution without the need to use time-consuming polarizable potentials and can predict the ion adsorption trend so far only achievable using first-principles simulations. Simulations performed with 1 M electrolyte solutions of different ions show that cations are strongly adsorbed onto the graphene surface with a trend (Li+ < Na+ < K+) opposite to that predicted by the gas-phase calculations and different from that obtained from the single-ion simulations.