Taking the Monte-Carlo gamble: How not to buckle under the pressure!

Consistent buckling distortions of a large membrane patch (200 × 200 Å) are observed during molecular dynamics (MD) simulations using the Monte-Carlo (MC) barostat in combination with a hard Lennard-Jones (LJ) cutoff. The buckling behavior is independent of both the simulation engine and the force field but requires the MC barostat-hard LJ cutoff combination. Similar simulations of a smaller patch (90 × 90 Å) do not show buckling, but do show a small, systematic reduction in the surface area accompanied by ~1 Å thickening suggestive of compression. We show that a mismatch in the way potentials and forces are handled in the dynamical equations versus the MC barostat results in a compressive load on the membrane. Moreover, a straightforward application of elasticity theory reveals that a minimal compression of the linear dimensions of the membrane, inversely proportional to the edge length, is required for buckling, explaining this differential behavior. We recommend always using LJ force or potential-switching when the MC barostat is employed to avoid undesirable membrane deformations.

Relationship between prescribed opioids, pain management satisfaction, and pain intensity in oncology outpatients.

BACKGROUND: Pain is the most severe and commonest symptom for patients with cancer. Patients' pain management satisfaction is an essential indicator of quality care and further affects their willingness to seek care. PURPOSE: This study aimed to examine the correlations between patients' prescribed opioids, pain management satisfaction, and pain intensity. METHODS: This study adopted a cross-sectional correlation design, recruited a total of 123 patients with cancer pain through convenience sampling, and used two research scales, namely the Chinese version of the Pain Treatment Satisfaction Scale and the Brief Pain Inventory-Short Form. RESULTS: The findings indicated that the correlations of prescribed opioid dosage with pain management satisfaction (r = - .10, p > .05) and pain intensity (worst pain, least pain, average pain, and pain right now; r = - .05 to .01, p > .05) were nonsignificant. The correlations of pain management satisfaction with pain intensity (r = .24 to .32, p < .01), pain interference (r = .32, p < .01), and pain relief (r = - .25, p < .01) were all significant, but that with the worst pain (r = .06, p > .05) was nonsignificant. CONCLUSIONS: Medical professionals providing cancer pain management should focus on medicines strategies and individuals' pain relief requirements. In particular, patients with the worst pain require extra investigations into their needs, and their satisfaction with their level of pain should be further evaluated.

Developing a death literacy index.

Performing end-of-life care can be a catalyst for developing a capacity called death literacy. This study aimed to develop a comprehensive and useable measure of death literacy that has the potential to assess interventions with individuals, communities, and societies. Using a mixed methods approach, a Death Literacy Index was developed from personal narratives and input from practitioners and experts. Refined on a sample of 1330 Australians using exploratory and confirmatory factor analysis and structural equation modeling, a 29-item Death Literacy Index was found to be reliable and demonstrated construct validity. Further studies are needed to test predictive validity.

Factors influencing the coping strategies of liver cancer patients undergoing transarterial chemoembolization.

AIM: This study explored the association between social support, resilience and coping strategies among patients with liver cancer and evaluated the extent to which patients' use of various coping strategies can be explained by social support and resilience. METHODS: This cross-sectional study comprised 119 patients who experienced transarterial chemoembolization related to liver cancer and who completed the Social Support Scale, the Resilience Scale and the Ways of Coping Checklist-Revised. RESULTS: Results indicated a significant positive correlation between social support and use of problem-focused coping strategies and overall coping strategies. In addition, results showed a significant positive correlation between resilience and use of problem-focused strategies, emotion-focused strategies and overall coping strategies. Social support accounted for 14% of variance in use of problem-focused strategies and 7.6% of the variance in overall coping strategies. Resilience accounted for 30.5% of the variance in use of problem-focused strategies, 8.5% in use of emotion-focused strategies and 21.6% of overall coping strategies. CONCLUSION: Results of this study highlight the importance of social support and resilience in patients' coping strategies related to liver cancer treatment.

A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms.

Motivated by growing evidence for pathway heterogeneity and alternative functions of molecular machines, we demonstrate a computational approach for investigating two questions: (1) Are there multiple mechanisms (state-space pathways) by which a machine can perform a given function, such as cotransport across a membrane? (2) How can additional functionality, such as proofreading/error-correction, be built into machine function using standard biochemical processes? Answers to these questions will aid both the understanding of molecular-scale cell biology and the design of synthetic machines. Focusing on transport in this initial study, we sample a variety of mechanisms by employing Metropolis Markov chain Monte Carlo. Trial moves adjust transition rates among an automatically generated set of conformational and binding states while maintaining fidelity to thermodynamic principles and a user-supplied fitness/functionality goal. Each accepted move generates a new model. The simulations yield both single and mixed reaction pathways for cotransport in a simple environment with a single substrate along with a driving ion. In a "competitive" environment including an additional decoy substrate, several qualitatively distinct reaction pathways are found which are capable of extremely high discrimination coupled to a leak of the driving ion, akin to proofreading. The array of functional models would be difficult to find by intuition alone in the complex state-spaces of interest.

A kinetic mechanism for enhanced selectivity of membrane transport.

Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intracellular matrix of the organelles (only in eukaryotes). In recent years, a number of high resolution structures have supported this general framework for a wide class of transport molecules, although additional states along the transport pathway are emerging as critically important. Given that substrate binding is often weak in order to enhance overall transport rates, there exists the distinct possibility that transporters may transport the incorrect substrate. This is certainly the case for many pharmaceutical compounds that are absorbed in the gut or cross the blood brain barrier through endogenous transporters. Docking studies on the bacterial sugar transporter vSGLT reveal that many highly toxic compounds are compatible with binding to the orthosteric site, further motivating the selective pressure for additional modes of selectivity. Motivated by recent work in which we observed failed substrate delivery in a molecular dynamics simulation where the energized ion still goes down its concentration gradient, we hypothesize that some transporters evolved to harness this 'slip' mechanism to increase substrate selectivity and reduce the uptake of toxic molecules. Here, we test this idea by constructing and exploring a kinetic transport model that includes a slip pathway. While slip reduces the overall productive flux, when coupled with a second toxic molecule that is more prone to slippage, the overall substrate selectivity dramatically increases, suppressing the accumulation of the incorrect compound. We show that the mathematical framework for increased substrate selectivity in our model is analogous to the classic proofreading mechanism originally proposed for tRNA synthase; however, because the transport cycle is reversible we identified conditions in which the selectivity is essentially infinite and incorrect substrates are exported from the cell in a 'detoxification' mode. The cellular consequences of proofreading and membrane slippage are discussed as well as the impact on future drug development.

Palliative care in the context of immune and targeted therapies: A qualitative study of bereaved carers' experiences in metastatic melanoma.

BACKGROUND: Immune and targeted therapies continue to transform treatment outcomes for those with metastatic melanoma. However, the role of palliative care within this treatment paradigm is not well understood. AIM: To explore bereaved carers' experiences of immune and targeted therapy treatment options towards end of life for patients with metastatic melanoma. DESIGN: An interpretive, qualitative study using a social constructivist framework was utilised. Interviews were recorded, transcribed and analysed using grounded theory methods. SETTING/PARTICIPANTS: Participants (n = 20) were bereaved carers of patients who had received some form of immune and/or targeted therapy at one of three Australian metropolitan melanoma treatment centres. RESULTS: Carers struggled to reconcile the positive discourse around the success of immune and targeted therapies in achieving long-term disease control, and the underlying uncertainty in predicting individual responses to therapy. Expectations that immune and targeted therapies necessarily provide longer-term survival were evident. Difficulty in prognostication due to clinical uncertainty and a desire to maintain hope resulted in lack of preparedness for treatment failure and end of life. CONCLUSION: Immune and targeted therapies have resulted in increased prognostic challenges. There is a need to engage, educate and support patients and carers to prepare and plan amid these challenges. Educational initiatives must focus on improving communication between patients, carers and clinicians; the differences between palliative and end-of-life care; and increased competency of clinicians in having goals-of-care discussions. Clinicians must recognise and communicate the benefit of collaborative palliative care to meet patient and family needs holistically and comprehensively.

A qualitative meta-synthesis investigating the experiences of the patient's family when treatment is withdrawn in the intensive care unit.

AIM: To synthesize qualitative studies of patients' families' experiences and perceptions of end-of-life care in the intensive care unit when life-sustaining treatments are withdrawn. DESIGN: Qualitative meta-synthesis. DATA SOURCES: Comprehensive search of 18 electronic databases for qualitative studies published between January 2005 - February 2019. REVIEW METHOD: Meta-aggregation. RESULTS: Thirteen studies met the inclusion criteria. A conceptual 'Model of Preparedness' was developed reflecting the elements of end-of-life care most valued by families: 'End-of-life communication'; 'Valued attributes of patient care'; 'Preparing the family'; 'Supporting the family'; and 'Bereavement care'. CONCLUSION: A family-centred approach to end-of-life care that acknowledges the values and preferences of families in the intensive care unit is important. Families have unmet needs related to communication, support, and bereavement care. Effective communication and support are central to preparedness and if these care components are in place, families can be better equipped to manage the death, their sadness, loss, and grief. The findings suggest that health professionals may benefit from specialist end-of-life care education to support families and guide the establishment of preparedness. IMPACT: Understanding the role and characteristics of preparedness during end-of-life care will inform future practice in the intensive care unit and may improve family member satisfaction with care and recovery from loss. Nurses are optimally positioned to address the perceived shortfalls in end-of-life care. These findings have implications for health education, policies, and standards for end-of-life care in the intensive care unit.

Stochastic steps in secondary active sugar transport.

Secondary active transporters, such as those that adopt the leucine-transporter fold, are found in all domains of life, and they have the unique capability of harnessing the energy stored in ion gradients to accumulate small molecules essential for life as well as expel toxic and harmful compounds. How these proteins couple ion binding and transport to the concomitant flow of substrates is a fundamental structural and biophysical question that is beginning to be answered at the atomistic level with the advent of high-resolution structures of transporters in different structural states. Nonetheless, the dynamic character of the transporters, such as ion/substrate binding order and how binding triggers conformational change, is not revealed from static structures, yet it is critical to understanding their function. Here, we report a series of molecular simulations carried out on the sugar transporter vSGLT that lend insight into how substrate and ions are released from the inward-facing state of the transporter. Our simulations reveal that the order of release is stochastic. Functional experiments were designed to test this prediction on the human homolog, hSGLT1, and we also found that cytoplasmic release is not ordered, but we confirmed that substrate and ion binding from the extracellular space is ordered. Our findings unify conflicting published results concerning cytoplasmic release of ions and substrate and hint at the possibility that other transporters in the superfamily may lack coordination between ions and substrate in the inward-facing state.

Informal care networks' views of palliative care services: Help or hindrance?

Most people indicate their preference to die at home; however, in the developed world, most die in hospital. Dying at home requires complex factors to be in place in health services and informal networks of care to successfully provide support. This study examines the ways health systems, services, and individual health care professionals influence care at home at the end of life. Three principles guide the reorientation of health services and enable their transition from hindrance to help: re-evaluation of organizational values, recognition of the primacy of caring networks, and realignment of the inherent paternalism in health care provision.

Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets.

Osteoarthritis (OA) is a chronic disease that degrades the joints and is often associated with increasing age and obesity. The two most common sites of OA in adults are the knee and hip joints. Increased mechanical stress on the joint from obesity can cause the articular cartilage to degrade and release damage-associated molecular patterns (DAMPs). These DAMPs are involved in various molecular pathways that interact with nuclear factor-kappa B and result in the transcription of inflammatory cytokines and activation of matrix metalloproteinases that progressively destroy cartilage. This review focuses on the interactions and contribution to the pathogenesis and progression of OA through the DAMPs: high-mobility group box 1 (HMGB-1), the receptor for advanced glycation end-products (RAGE), the alarmin proteins S100A8 and S100A9, and heparan sulfate. HMGB-1 is released from damaged or necrotic cells and interacts with toll-like receptors (TLRs) and RAGE to induce inflammatory signals, as well as behave as an inflammatory cytokine to activate innate immune cells. RAGE interacts with HMGB-1, advanced glycation end-products, and innate immune cells to increase local inflammation. The alarmin proteins are released following cell damage and interact through TLRs to increase local inflammation and cartilage degradation. Heparan sulfate has been shown to facilitate the binding of HMGB-1 to RAGE and could play a role in the progression of OA. Targeting these DAMPs may be the potential therapeutic strategies for the treatment of OA.

Increased expression of damage-associated molecular patterns (DAMPs) in osteoarthritis of human knee joint compared to hip joint.

Osteoarthritis (OA) is a degenerative disease characterized by the destruction of cartilage. The greatest risk factors for the development of OA include age and obesity. Recent studies suggest the role of inflammation in the pathogenesis of OA. The two most common locations for OA to occur are in the knee and hip joints. The knee joint experiences more mechanical stress, cartilage degeneration, and inflammation than the hip joint. This could contribute to the increased incidence of OA in the knee joint. Damage-associated molecular patterns (DAMPs), including high-mobility group box-1, receptor for advanced glycation end products, and alarmins (S100A8 and S100A9), are released in the joint in response to stress-mediated chondrocyte and cartilage damage. This facilitates increased cartilage degradation and inflammation in the joint. Studies have documented the role of DAMPs in the pathogenesis of OA; however, the comparison of DAMPs and its influence on OA has not been discussed. In this study, we compared the DAMPs between OA knee and hip joints and found a significant difference in the levels of DAMPs expressed in the knee joint compared to the hip joint. The increased levels of DAMPs suggest a difference in the underlying pathogenesis of OA in the knee and the hip and highlights DAMPs as potential therapeutic targets for OA in the future.

Solid and liquid modernity: A comparison of the social geography of places to die in the UK and Australia.

Preferred place of care and death is a widely used quality measure for palliative and end of life care services. In this article we explore the use of Zygmunt Bauman's ideas on solid and liquid modernity to understand the complexity of the social geographical contexts of delivering and receiving care. Although solid ways of dying offer certainty and standardized care, more liquid ways allow for individualized care connected to family and communities. Understanding the complex tensions between solid and liquid aspects of palliative care may allow practitioners to help dying people to die in the ways and places they prefer.

The mechanism of sodium and substrate release from the binding pocket of vSGLT.

Membrane co-transport proteins that use a five-helix inverted repeat motif have recently emerged as one of the largest structural classes of secondary active transporters. However, despite many structural advances there is no clear evidence of how ion and substrate transport are coupled. Here we report a comprehensive study of the sodium/galactose transporter from Vibrio parahaemolyticus (vSGLT), consisting of molecular dynamics simulations, biochemical characterization and a new crystal structure of the inward-open conformation at a resolution of 2.7 Å. Our data show that sodium exit causes a reorientation of transmembrane helix 1 that opens an inner gate required for substrate exit, and also triggers minor rigid-body movements in two sets of transmembrane helical bundles. This cascade of events, initiated by sodium release, ensures proper timing of ion and substrate release. Once set in motion, these molecular changes weaken substrate binding to the transporter and allow galactose readily to enter the intracellular space. Additionally, we identify an allosteric pathway between the sodium-binding sites, the unwound portion of transmembrane helix 1 and the substrate-binding site that is essential in the coupling of co-transport.

Evaluation of a pilot of nurse practitioner led, GP supported rural palliative care provision.

BACKGROUND: Providing end of life care in rural areas is challenging. We evaluated in a pilot whether nurse practitioner (NP)-led care, including clinical care plans negotiated with involved health professionals including the general practitioner(GP), ± patient and/or carer, through a single multidisciplinary case conference (SMCC), could influence patient and health system outcomes. METHODS: Setting - Australian rural district 50 kilometers from the nearest specialist palliative care service. PARTICIPANTS: Adults nearing the end of life from any cause, life expectancy several months. Intervention- NP led assessment, then SMCC as soon as possible after referral. A clinical care plan recorded management plans for current and anticipated problems and who was responsible for each action. Eligible patients had baseline, 1 and 3 month patient-reported assessment of function, quality of life, depression and carer stress, and a clinical record audit. Interviews with key service providers assessed the utility and feasibility of the service. RESULTS: Sixty-two patients were referred to the service, forty from the specialist service. Many patients required immediate treatment, prior to both the planned baseline assessment and the planned SMCC (therefore ineligible for enrollment). Only six patients were assessed per protocol, so we amended the protocol. There were 23 case conferences. Reasons for not conducting the case conference included the patient approaching death, or assessed as not having immediate problems. Pain (25 %) and depression (23 %) were the most common symptoms discussed in the case conferences. Ten new advance care plans were initiated, with most patients already having one. The NP or RN made 101 follow-up visits, 169 phone calls, and made 17 referrals to other health professionals. The NP prescribed 24 new medications and altered the dose in nine. There were 14 hospitalisations in the time frame of the project. Participants were satisfied with the service, but the service cost exceeded income from national health insurance alone. CONCLUSIONS: NP-coordinated, GP supported care resulted in prompt initiation of treatment, good follow up, and a care plan where all professionals had named responsibilities. NP coordinated palliative care appears to enable more integrated care and may be effective in reducing hospitalisations.

Identification and characteristics of patients with palliative care needs in Brazilian primary care.

BACKGROUND: The Brazilian healthcare system offers universal coverage but lacks information about how patients with PC needs are serviced by its primary care program, Estratégia Saúde da Família (ESF). METHODS: Cross-sectional study in community settings. Patients in ESF program were screened using a Palliative Care Screening Tool (PCST). Included patients were assessed with Karnofsky Performance Scale (KPS), Edmonton Symptom Assessment System (ESAS) and Palliative Care Outcome Scale (POS). RESULTS: Patients with PC needs are accessing the ESF program regardless of there being no specific PC support provided. From 238 patients identified, 73 (43 women, 30 men) were identified as having a need for PC, and the mean age was 77.18 (95 % Confidence Interval = ±2,78) years, with non-malignant neurologic conditions, such as dementia and cerebrovascular diseases, being the most common (53 % of all patients). Chronic conditions (2 or more years) were found in 70 % of these patients, with 71 % scoring 50 or less points in the KPS. Overall symptom intensity was low, with the exception of some cases with moderate and high score, and POS average score was 14.16 points (minimum = 4; maximum = 28). Most patients received medication and professional support through the primary care units, but limitations of services were identified, including lack of home visits and limited multi-professional approaches. CONCLUSION: Patients with PC needs were identified in ESF program. Basic health care support is provided but there is a lack of attention to some specific needs. PC policies and professional training should be implemented to improve this area.

Structural determinants of water permeation through the sodium-galactose transporter vSGLT.

Sodium-glucose transporters (SGLTs) facilitate the movement of water across the cell membrane, playing a central role in cellular homeostasis. Here, we present a detailed analysis of the mechanism of water permeation through the inward-facing state of vSGLT based on nearly 10 µs of molecular dynamics simulations. These simulations reveal the transient formation of a continuous water channel through the transporter that permits water to permeate the protein. Trajectories in which spontaneous release of galactose is observed, as well as those in which galactose remains in the binding site, show that the permeation rate, although modulated by substrate occupancy, is not tightly coupled to substrate release. Using a, to our knowledge, novel channel-detection algorithm, we identify the key residues that control water flow through the transporter and show that solvent gating is regulated by side-chain motions in a small number of residues on the extracellular face. A sequence alignment reveals the presence of two insertion sites in mammalian SGLTs that flank these outer-gate residues. We hypothesize that the absence of these sites in vSGLT may account for the high water permeability values for vSGLT determined via simulation compared to the lower experimental estimates for mammalian SGLT1.

Establishing research in a palliative care clinical setting: perceived barriers and implemented strategies.

There are many challenges in developing research projects in research-naïve clinical settings, especially palliative care where resistance to participate in research has been identified. These challenges to the implementation of research are common in nursing practice and are associated with attitudes towards research participation, and some lack of understanding of research as a process to improve clinical practice. This is despite the professional nursing requirement to conduct research into issues that influence palliative care practice. The purpose of this paper is to describe the process of implementing a clinical research project in collaboration with the clinicians of a palliative care community team and to reflect on the strategies implemented to overcome the challenges involved. The challenges presented here demonstrate the importance of proactively implementing engagement strategies from the inception of a research project in a clinical setting.

Exploring the 'citizen organization': an evaluation of a regional Australian community-based palliative care service model.

Background: Little Haven is a rural, community-based specialist palliative care service in Gympie, Australia. Its goals are to provide highest quality of care, support and education for those experiencing or anticipating serious illness and loss. Families and communities work alongside clinical services, with community engagement influencing compassionate care and support of dying people, their families and communities. Public Health Palliative Care promotes community engagement by community-based palliative care services and is grounded in equal partnerships between civic life, community members, patients and carers, and service providers. This takes many forms, including what we have termed the 'citizen organization'. Objectives: This paper reports on an evaluation of Little Haven's model of care and explores the organization's place as a 'citizen' of the community it services. Design: A co-designed evaluation approach utilizing mixed-method design is used. Methods: Multiple data sources obtained a broad perspective of the model of care including primary qualitative data from current patients, current carers, staff, volunteers and organizational stakeholders (interviews and focus groups); and secondary quantitative survey data from bereaved carers. Thematic analysis and descriptive statistics were generated. Results: This model of care demonstrates common service elements including early access to holistic, patient/family-centred, specialized palliative care at little or no cost to users, with strong community engagement. These elements enable high-quality care for patients and carers who describe the support as 'over and above', enabling good quality of life and care at home. Staff and volunteers perceive the built-in flexibility of the model as critical to its outcomes; the interface between the service and the community is similarly stressed as a key service element. Organizational stakeholders observed the model as a product of local activism and accountability to the community. Conclusion: All participant groups agree the service model enables the delivery of excellent care. The construction of a community palliative care service as a citizen organization emerged as a new concept.

'Citizen organization': an Australian community-based palliative care service model Little Haven is a rural, community-based specialist palliative care service in Gympie, Australia. It aims to provide highest quality of care, support and education for those experiencing or anticipating serious illness and loss. Families and communities work alongside clinical services, with community engagement influencing compassionate care and support of dying people, their families and communities. Public Health Palliative Care promotes community engagement by community-based palliative care services in equal partnerships between civic organizations, community members, patients and carers, and service providers. We undertook an evaluation of Little Haven's model of care by speaking with current patients, current and past carers, staff, volunteers and stakeholders about their experiences of Little Haven. We found that Little Haven's model contains the essential elements of a palliative care service and provides early access to holistic, patient/family-centred, specialized palliative care at little or no cost to users. They have strong community engagement with a strong background in community activism. We identified that Little Haven's 'being in the community' goes beyond service provision or even sentiment. We observed a symbiotic relationship between the organization and the community it supports in what we have termed the 'citizen organization'. The distinctive characteristic of the citizen organization is its inseparability from the community in which it dwells.

Public Health Palliative Care and Public Palliative Care Education.

This Special Issue, "Public Health Palliative Care (PHPC) and Public Palliative Care Education (PPCE)", highlights recent advances and challenges in PHPC and PPCE [...].