The Effect of Arginine on the Phase Stability of Aqueous Hen Egg-White Lysozyme Solutions.

The effect of arginine on the phase stability of the hen egg-white lysozyme (HEWL) has been studied via molecular dynamics computer simulations, as well as experimentally via cloud-point temperature determination. The experiments show that the addition of arginine increases the stability of the HEWL solutions. The computer simulation results indicate that arginine molecules tend to self-associate. If arginine residues are located on the protein surface, the free arginine molecules stay in their vicinity and prevent the way protein molecules "connect" through them to form clusters. The results are not sensitive to a particular force field and suggest a possible microscopic mechanism of the stabilizing role of arginine as an excipient.

The mechanism of self-association of human γ-D crystallin from molecular dynamics simulations.

The aggregation of human γ-D crystallin is associated with the age-onset cataract formation. Here, we extensively investigated the self-association mechanism of human γ-D crystallin through molecular dynamics computer simulations. By mutating the protein surface we found that electrostatic interactions between charged amino acids play a crucial role in its self-association. We have confirmed the two-fold role of arginine molecules. If they are located as residues on the protein surface they can initiate protein contacts and contribute to their stickiness with noteworthy hydrophobic interactions through stacking of their methylene groups. But if they are added as free arginine in the protein solution they can also stabilize it, by associating with the protein surface and also with themselves to form effective inter-protein spacers that obstruct protein aggregation.

Altered basal ganglia infraslow oscillation and resting functional connectivity in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a painful condition commonly accompanied by movement disturbances and often affects the upper limbs. The basal ganglia motor loop is central to movement, however, non-motor basal ganglia loops are involved in pain, sensory integration, visual processing, cognition, and emotion. Systematic evaluation of each basal ganglia functional loop and its relation to motor and non-motor disturbances in CRPS has not been investigated. We recruited 15 upper limb CRPS and 45 matched healthy control subjects. Using functional magnetic resonance imaging, infraslow oscillations (ISO) and resting-state functional connectivity in motor and non-motor basal ganglia loops were investigated using putamen and caudate seeds. Compared to controls, CRPS subjects displayed increased ISO power in the putamen contralateral to the CRPS affected limb, specifically, in contralateral putamen areas representing the supplementary motor area hand, motor hand, and motor tongue. Furthermore, compared to controls, CRPS subjects displayed increased resting connectivity between these putaminal areas as well as from the caudate body to cortical areas such as the primary motor cortex, supplementary and cingulate motor areas, parietal association areas, and the orbitofrontal cortex. These findings demonstrate changes in basal ganglia loop function in CRPS subjects and may underpin motor disturbances of CRPS.

BioMThermDB 1.0: Thermophysical Database of Proteins in Solutions.

We present here a freely available web-based database, called BioMThermDB 1.0, of thermophysical and dynamic properties of various proteins and their aqueous solutions. It contains the hydrodynamic radius, electrophoretic mobility, zeta potential, self-diffusion coefficient, solution viscosity, and cloud-point temperature, as well as the conditions for those determinations and details of the experimental method. It can facilitate the meta-analysis and visualization of data, can enable comparisons, and may be useful for comparing theoretical model predictions with experiments.

Influence of Low Molecular Weight Salts on the Viscosity of Aqueous-Buffer Bovine Serum Albumin Solutions.

Pharmaceutical design of protein formulations aims at maximum efficiency (protein concentration) and minimum viscosity. Therefore, it is important to know the nature of protein-protein interactions and their influence on viscosity. In this work, we investigated the dependence of the viscosity of BSA in an aqueous 20 mM acetate buffer at pH = 4.3 on protein concentration and on temperature (5-45 °C). The viscosity of the solution increased with protein concentration and was 230% higher than the viscosity of the protein-free formulation at 160 mg/mL. The viscosity decreased by almost 60% in the temperature range from 5 to 45 °C. The agreement of the modified Arrhenius theory with experiment was quantitative, whereas a hard-sphere model provided only a qualitative description of the experimental results. We also investigated the viscosity of a 100 mg/mL BSA solution as a function of the concentration of added low molecular weight salts (LiCl, NaCl, KCl, RbCl, CsCl, NaBr, NaI) in the range of salt concentrations up to 1.75 mol/L. In addition, the particle size and zeta potential of BSA-salt mixtures were determined for solutions containing 0.5 mol/L salt. The trends with respect to the different anions followed a direct Hofmeister series (Cl- > Br- > I-), whereas for cations in the case of viscosity the indirect Hofmeister series was observed (Li+ > Na+ > K+ > Rb+ > Cs+), but the values of particle sizes and zeta potential did not show cation-specific effects. Since the protein is positively charged at pH = 4.3, anions are more attracted to the protein surface and shield its charge, while the interaction with cations is less pronounced. We hypothesize that salt surface charge shielding reduces protein colloidal stability and promotes protein aggregate formation.

The influence of excipients on the viscosity of monoclonal antibody solutions.

The aggregation propensity of monoclonal antibodies can be modified by adding different cosolutes into the solution. A simple coarse-grained model in the combination with the thermodynamic perturbation theory was used to predict cluster distribution and viscosity of the solutions of IgG4 monoclonal anibody in the presence of L-Arginine Hydrochloride. The data were analysed using binding polynomial to describe the binding of cosolute (Arginine) to the antibody molecule. The results show that by binding to the antibody molecule the cosolute occupies some of the binding sites of the antibody, and in this way reduces the amount of binding sites available to other antibody molecules. The aggregation propensity of the antibody molecules is therefore reduced.

Studying the mechanism of phase separation in aqueous solutions of globular proteins via molecular dynamics computer simulations.

Proteins are the most abundant biomacromolecules in living cells, where they perform vital roles in virtually every biological process. To maintain their function, proteins need to remain in a stable (native) state. Inter- and intramolecular interactions in aqueous protein solutions govern the fate of proteins, as they can provoke their unfolding or association into aggregates. The initial steps of protein aggregation are difficult to capture experimentally, therefore we used molecular dynamics simulations in this study. We investigated the initial phase of aggregation of two different lysozymes, hen egg-white (HEWL) and T4 WT* lysozyme and also human lens γ-D crystallin by using atomistic simulations. We monitored the phase stability of their aqueous solutions by calculating time-dependent density fluctuations. We found that all proteins remained in their compact form despite aggregation. With an extensive analysis of intermolecular residue-residue interactions we discovered that arginine is of paramount importance in the initial stage of aggregation of HEWL and γ-D crystallin, meanwhile lysine was found to be the most involved amino acid in forming initial contacts between T4 WT* molecules.

Altered resting activity patterns and connectivity in individuals with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder that typically occurs in the limbs, usually the upper limb. CRPS usually develops from a peripheral event but its maintenance relies on changes within the central nervous system. While functional abnormalities in the thalamus and primary somatosensory cortex (S1) of the brain are some of the most consistently reported brain findings in CRPS, the mechanisms are yet to be explored in full, not least of all how these two regions interact and how they might relate to clinical deficits, such as the commonly reported poor tactile acuity in this condition. This study recruited 15 upper-limb CRPS subjects and 30 healthy controls and used functional magnetic resonance imaging (fMRI) to investigate infra-slow oscillations (ISOs) in critical pain regions of the brain in CRPS. As hypothesised, we found CRPS was associated with increases in resting signal intensity ISOs (0.03-0.06 Hz) in the thalamus contralateral to the painful limb in CRPS subjects. Interestingly, there was no such difference between groups in S1, however CRPS subjects displayed stronger thalamo-S1 functional connectivity than controls, and this was related to pain. As predicted, CRPS subjects displayed poor tactile acuity on the painful limb which, interestingly, was also related to thalamo-S1 functional connectivity strength. Our findings provide novel evidence of altered patterns of resting activity and connectivity in CRPS which may underlie altered thalamocortical loop dynamics and the constant perception of pain.

How Water's Properties Are Encoded in Its Molecular Structure and Energies.

How are water's material properties encoded within the structure of the water molecule? This is pertinent to understanding Earth's living systems, its materials, its geochemistry and geophysics, and a broad spectrum of its industrial chemistry. Water has distinctive liquid and solid properties: It is highly cohesive. It has volumetric anomalies-water's solid (ice) floats on its liquid; pressure can melt the solid rather than freezing the liquid; heating can shrink the liquid. It has more solid phases than other materials. Its supercooled liquid has divergent thermodynamic response functions. Its glassy state is neither fragile nor strong. Its component ions-hydroxide and protons-diffuse much faster than other ions. Aqueous solvation of ions or oils entails large entropies and heat capacities. We review how these properties are encoded within water's molecular structure and energies, as understood from theories, simulations, and experiments. Like simpler liquids, water molecules are nearly spherical and interact with each other through van der Waals forces. Unlike simpler liquids, water's orientation-dependent hydrogen bonding leads to open tetrahedral cage-like structuring that contributes to its remarkable volumetric and thermal properties.

Development of a framework to describe patient and family harm from disrespect and promote improvements in quality and safety: a scoping review.

PURPOSE: Patients and families may experience 'non-physical' harm from interactions with the healthcare system, including emotional, psychological, socio-behavioral or financial harm, some of which may be related to experiences of disrespect. We sought to use the current literature to develop a practical, improvement-oriented framework to recognize, describe and help prevent such events. DATA SOURCES: Searches were performed in PubMed, Embase, PsychINFO, CINAHL, Health Business Elite and ProQuest Dissertations & Theses: Global: Health & Medicine, from their inception through July 2017. STUDY SELECTION: Two authors reviewed titles, abstracts, full texts, references and cited-by lists to identify articles describing approaches to understanding patient/family experiences of disrespect. DATA EXTRACTION: Findings were evaluated using integrative review methodology. RESULTS OF DATA SYNTHESIS: Three-thousand eight hundred and eighty two abstracts were reviewed. Twenty three articles were identified. Components of experiences of disrespect included: (1) numerous care processes; (2) a wide range of healthcare professional and organizational behaviors; (3) contributing factors, including patient- and professional-related factors, the environment of work and care, leadership, policies, processes and culture; (4) important consequences of disrespect, including behavioral changes and health impacts on patients and families, negative effects on professionals' subsequent interactions, and patient attrition from organizations and (5) factors both intrinsic and extrinsic to patients that can modify the consequences of disrespect. CONCLUSION: A generalizable framework for understanding disrespect experienced by patients/families in healthcare may help organizations better prevent non-physical harms. Future work should prospectively test and refine the framework we described so as to facilitate its integration into organizations' existing operational systems.

Establishing a publicly available national database of US news articles reporting agriculture-related injuries and fatalities.

BACKGROUND: The AgInjuryNews system and dataset are a news report repository and information source for agricultural safety professionals, policymakers, journalists, and law enforcement officials. METHODS: AgInjuryNews was designed as a primary storage and retrieval system that allows users to: identify agricultural injury/fatality events; identify injury agents and emerging issues; provide safety messages for media in anticipation of trends; and raise awareness and knowledge of agricultural injuries and prevention strategies. Data are primarily collected through Google Alerts and a digital media subscription service. Articles are screened, reviewed, coded, and entered into the system. RESULTS: As of January 1, 2018, the system contained 3028 unique incidents. Of those, 650 involved youth, and 1807 were fatalities. The system also had registered 329 users from 39 countries. CONCLUSIONS: AgInjuryNews combines injury reports into one dataset and may be the most current and comprehensive publicly available collection of news reports on agricultural injuries and deaths.

A Multi-Stakeholder Consensus-Driven Research Agenda for Better Understanding and Supporting the Emotional Impact of Harmful Events on Patients and Families.

BACKGROUND: The nature and consequences of patient and family emotional harm stemming from preventable medical error, such as losing a loved one or surviving serious medical injury, is poorly understood. Patients and families, clinicians, social scientists, lawyers, and foundation/policy leaders were brought together to establish research priorities for this issue. METHODS: A one-day conference of diverse stakeholder groups to establish a consensus-driven research agenda focused on (1) priorities for research on the short-term and long-term emotional impact of harmful events on patients and families, (2) barriers and enablers to conducting such research, and (3) actionable steps toward better supporting harmed patients and families now. RESULTS: Stakeholders discussed patient and family experiences after serious harmful events, including profound isolation, psychological distress, damaging aspects of medical culture, health care aversion, and negative effects on communities. Stakeholder groups reached consensus, defining four research priorities: (1) Establish conceptual framework and patient-centered taxonomy of harm and healing; (2) Describe epidemiology of emotional harm; (3) Determine how to make emotional harm and long-term impacts visible to health care organizations and society at large; and (4) Develop and implement best practices for emotional support of patients and families. The group also created a strategy for overcoming research barriers and actionable "Do Now" approaches to improve the patient and family experience while research is ongoing. CONCLUSION: Emotional and other long-term impacts of harmful events can have profound consequences for patients and families. Stakeholders designed a path forward to inform approaches that better support harmed patients and families, with both immediately actionable and longer-term research strategies.

A Road Map for Advancing the Practice of Respect in Health Care: The Results of an Interdisciplinary Modified Delphi Consensus Study.

BACKGROUND: Most health care organizations' efforts to reduce harm focus on physical harm, but other forms of harm are both prevalent and important. These "nonphysical" harms can be framed using the concepts of respect and dignity: Disrespect is an affront to dignity and can cause harm. Organizations should strive to eliminate disrespect to patients, to families, and among health care professionals. METHODS: A diverse, interdisciplinary panel of experts was convened to discuss strategies to guide health care systems to embrace an expanded definition of patient harm that includes nonphysical harm. Subsequently, using a modified Delphi process, a guide was developed for health care professionals and organizations to improve the practice of respect across the continuum of care. RESULTS: Five rounds of surveys were required to reach predefined metrics of consensus. Delphi participants identified a total of 25 strategies associated with six high-level recommendations: "Leaders must champion a culture of respect and dignity"; with other professionals sharing the responsibility to "Promote accountability"; "Engage and support the health care workforce"; "Partner with patients and families"; "Establish systems to learn about and improve the practice of respect"; and "Expand the research agenda and measurement tools, and disseminate what is learned." CONCLUSION: Harm from disrespect is the next frontier in preventable harm. This consensus statement provides a road map for health care organizations and professionals interested in engaging in a reliable practice of respect. Further work is needed to develop the specific tactics that will lead health care organizations to prevent harm from disrespect.

Protein aggregation in salt solutions.

Protein aggregation is broadly important in diseases and in formulations of biological drugs. Here, we develop a theoretical model for reversible protein-protein aggregation in salt solutions. We treat proteins as hard spheres having square-well-energy binding sites, using Wertheim's thermodynamic perturbation theory. The necessary condition required for such modeling to be realistic is that proteins in solution during the experiment remain in their compact form. Within this limitation our model gives accurate liquid-liquid coexistence curves for lysozyme and γ IIIa-crystallin solutions in respective buffers. It provides good fits to the cloud-point curves of lysozyme in buffer-salt mixtures as a function of the type and concentration of salt. It than predicts full coexistence curves, osmotic compressibilities, and second virial coefficients under such conditions. This treatment may also be relevant to protein crystallization.

Palliative Care and Cardiovascular Disease and Stroke: A Policy Statement From the American Heart Association/American Stroke Association.

The mission of the American Heart Association/American Stroke Association includes increasing access to high-quality, evidence-based care that improves patient outcomes such as health-related quality of life and is consistent with the patients' values, preferences, and goals. Awareness of and access to palliative care interventions align with the American Heart Association/American Stroke Association mission. The purposes of this policy statement are to provide background on the importance of palliative care as it pertains to patients with advanced cardiovascular disease and stroke and their families and to make recommendations for policy decisions. Palliative care, defined as patient- and family-centered care that optimizes health-related quality of life by anticipating, preventing, and treating suffering, should be integrated into the care of all patients with advanced cardiovascular disease and stroke early in the disease trajectory. Palliative care focuses on communication, shared decision making about treatment options, advance care planning, and attention to physical, emotional, spiritual, and psychological distress with inclusion of the patient's family and care system. Our policy recommendations address the following: reimbursement for comprehensive delivery of palliative care services for patients with advanced cardiovascular disease and stroke; strong payer-provider relationships that involve data sharing to identify patients in need of palliative care, identification of better care and payment models, and establishment of quality standards and outcome measurements; healthcare system policies for the provision of comprehensive palliative care services during hospitalization, including goals of care, treatment decisions, needs of family caregivers, and transition to other care settings; and health professional education in palliative care as part of licensure requirements.

A Clinician's Guide to Privacy and Communication in the ICU.

OBJECTIVE: To review the legal issues concerning family members' access to information when patients are in the ICU. DATA SOURCES: U.S. Code, U.S. Code of Federal Regulations, and state legislative codes. DATA EXTRACTION: Relevant legal statutes and regulations were identified and reviewed by the two attorney authors (L. F., M. A. V.). STUDY SELECTION: Not applicable. DATA SYNTHESIS: Review by all coauthors. CONCLUSIONS: The Health Insurance Portability and Accountability Act and related laws should not be viewed as barriers to clinicians sharing information with ICU patients and their loved ones. Generally, under Health Insurance Portability and Accountability Act, personal representatives have the same authority to receive information that patients would otherwise have. Persons involved in the patient's care also may be given information relevant to the episode of care unless the patient objects. ICUs should develop policies for handling the issues we identify about such information sharing, including policies for responding to telephone inquiries and methods for giving patients the opportunity to object to sharing information with individuals involved in their care. ICU clinicians also should be knowledgeable of their state's laws about how to identify patients' personal representatives and the authority of those representatives. Finally, ICU clinicians should be aware of any special restrictions their state places on medical information. In aggregate, these strategies should help ICU managers and clinicians facilitate robust communication with patients and their loved ones.

Volumetric and calorimetric properties of aqueous ionene solutions.

The volumetric (partial and apparent molar volumes) and calorimetric properties (apparent heat capacities) of aqueous cationic polyelectrolyte solutions - ionenes - were studied using the oscillating tube densitometer and differential scanning calorimeter. The polyion's charge density and the counterion properties were considered as variables. The special attention was put to evaluate the contribution of electrostatic and hydrophobic effects to the properties studied. The contribution of the CH2 group of the polyion's backbone to molar volumes and heat capacities was estimated. Synergistic effect between polyion and counterions was found.

Phase behaviour of a continuous shouldered well model fluid. A grand canonical Monte Carlo study.

The phase behavior of the continuous shouldered well model fluid proposed by Franzese [J. Mol. Liq. 136 (2007) 267] was examined using the Monte Carlo computer simulations in the grand canonical ensemble. The essential parts of the vapour-liquid and liquid-liquid coexistence envelopes were obtained. The Widom lines departing from coexistence envelopes were calculated using maxima of the fluctuations of the number of particles as a function of chemical potential along various isotherms. The region embracing anomalies in the properties of the model was located using the approximate criterion that involves the excess pair entropy.. The temperature of maximum density line was built by performing canonical Monte Carlo simulations. Our results are consistent with previous results from molecular dynamics constant pressure-constant temperature simulations and provide wider insight into the phase behavior of the model by using the chemical potential as the external parameter.

Modelling the Correlation Between Molecular Electrostatic Potential and pKa on Sets of Carboxylic Acids, Phenols and Anilines.

Calculations of molecular electrostatic potential were correlated with experimental pKa values for different sets of acidic molecules (carboxylic acids, phenols, and anilines) to obtain linear relationships of variable quality. A single tri-parameter model function was constructed to describe the pKa dependence on MEP maxima together with two automatically generated molecular descriptors, namely the counts of carboxylic acid and amine functional groups.

Effects of the translational and rotational degrees of freedom on the hydration of simple solutes.

Molecular dynamics simulations with separate thermostats for rotational and translational motion were used to study the effect of these degrees of freedom on the structure of water around model solutes. To describe water molecules we used the SPC/E model. The simplest solute studied here, the hydrophobe, was represented as a Lennard-Jones particle. Since direct interaction between the hydrophobe and water molecules has no angular dependence the influence of the increase of the rotational temperature on the solvation of a hydrophobe is only indirect. In the next step the central solute was assumed to be charged with either a positive or a negative charge to mimic an ion in water. Hence, depending on the charge of the ion, the neighboring water molecules assumed different angular distributions. The principal conclusions of this work are: (i) an increase of the translational temperature always decreases the height of the first peak in the solute-water radial distribution function; (ii) an increase of the rotational temperature yields an increase in the first peak in the solute-water radial distribution function for hydrophobes and cations; (iii) in contrast to this, the solvation peak decreases around ions with sufficiently large negative charge; and (iv) an increase of the rotational temperature affects cations in an opposite way to anions. For this reason complex molecules with a small net charge may not be very sensitive to variation of the rotational temperature.