Management of pain in advanced disease.

BACKGROUND: Pain is common in advanced malignancy but also prevalent in other non-malignant life-limiting diseases such as advanced heart disease; end stage renal failure and multiple sclerosis. Patients with renal or liver impairment need specific consideration, as most analgesics rely on either or both for their metabolism and excretion. SOURCES OF DATA: Recent evidence-based guidelines and the systematic reviews that have informed their recommendations. AREAS OF AGREEMENT: The principles of the WHO (World Health Organisation) analgesic ladder are commonly endorsed as a structured approach to the management of pain. For neuropathic pain, the efficacy of different agents is similar and choice of drug more guided by side effects, drug interactions and cost. AREAS OF CONTROVERSY: Evidence supporting the WHO analgesic ladder is disputed and alternatives suggested, but no overwhelming evidence for an alternative approach exists to date. GROWING POINTS: Alternative approaches to the WHO analgesic ladder, new analgesic agents, e.g. rapid onset oral/intranasal fentanyl.

High-fat diet disrupts REG3γ and gut microbial rhythms promoting metabolic dysfunction.

Gut microbial diurnal oscillations are important diet-dependent drivers of host circadian rhythms and metabolism ensuring optimal energy balance. However, the interplay between diet, microbes, and host factors sustaining intestinal oscillations is complex and poorly understood. Here, using a mouse model, we report the host C-type lectin antimicrobial peptide Reg3γ works with key ileal microbes to orchestrate these interactions in a bidirectional manner and does not correlate with the intestinal core circadian clock. High-fat diet is the primary driver of microbial oscillators that impair host metabolic homeostasis, resulting in arrhythmic host Reg3γ expression that secondarily drives abundance and oscillation of key gut microbes. This illustrates transkingdom coordination of biological rhythms primarily influenced by diet and reciprocal sensor-effector signals between host and microbial components, ultimately driving metabolism. Restoring the gut microbiota's capacity to sense dietary signals mediated by specific host factors such as Reg3γ could be harnessed to improve metabolic dysfunction.

Nurses' views of the coping and support mechanisms experienced in managing terminal haemorrhage.

INTRODUCTION: Although palliative care is a rewarding specialty, it presents emotive personal challenges for the health professionals working within it. Terminal haemorrhage is arguably the most feared and distressing event in the palliative care setting, both for the patient and for the health professionals looking after them. The aim of this study was to explore and reflect on the coping and support mechanisms that have helped nurses to manage these events. METHOD: Purposive sampling was used to recruit nurses from palliative care and oncology who had personal experience of managing terminal haemorrhage. Semi-structured interviews were used to collect qualitative data that were then analysed using interpretative phenomenological analysis. Saturation of data was reached after 11 participants had been interviewed. RESULTS: The participants had a combined experience of managing 37 patients with a terminal haemorrhage. The key themes that emerged were the role of the 'autopilot', having a plan, education and training, the value of debriefing and peer support, and the importance of supporting the whole team. Education and training specifically about terminal haemorrhage and structured debriefing after such events were both identified by the participants as currently unmet needs. CONCLUSION: Professionals working in areas in which patients are at particular risk of terminal haemorrhage require adequate training and education prior to these events and a structure for formal debriefing and peer support afterwards.

Palliative medicine education-Bed Race, The End of Life Board Game in undergraduates.

BACKGROUND: Educational board games facilitate active learning to conceptualise knowledge, and, promote collaborative learning and team work. Despite increasing interest in them, use in palliative and end of life care has been very limited to date. METHOD: In 'Bed race, The End of Life Game', participants are divided into four teams who move a model hospital bed around a board to collect items (syringe driver; Do Not Attempt Resuscitation form; oral hydration gel; a 'heart'; Just In Case medicines). To obtain items at themed 'checkpoints', each team needs to answer quiz questions, which require application of clinical knowledge and/or communication skills. Pregame and postgame quiz scores and feedback were collected from 12 game sessions involving 251 year 5 medical students. RESULTS: 169 (67%) of students completed pregame and postgame anonymous quiz questions and free-text feedback. Postgame quiz scores were higher for each topic, and the difference in the paired pregame and postgame questionnaires was statistically significant (p<0.05). Themes from the free-text feedback included 'engaging and fun'; 'relevant learning'; 'peer learning and team work'. CONCLUSIONS: Educational board games are not a new panacea for education, but the concept can be successfully applied in palliative care.

Nausea and vomiting in advanced cancer.

Nausea and vomiting are distinct symptoms, commonly occurring together but which should be assessed separately. Both are prevalent in patients with advanced cancer. Data are taken from The Cochrane Library (2010) and Ovid MEDLINE (1966-2010). Most current guidelines advocate an aetiology-based approach to the management of nausea and vomiting. Choice of anti-emetic is based on a clinical assessment of the likely pathophysiological component of the emetogenic pathway that is being triggered and selecting an anti-emetic drug that blocks the key receptors involved. Some authors propose a more empirical approach. The limited available evidence would suggest that both an empirical or aetiology-based approach may have similar overall efficacy. There are no published studies directly comparing the two. Standardized assessment and outcome tools are needed to enable well-designed studies to establish efficacy for conventional agents and also compare efficacy with the newer, more expensive ones.

Do 'virtual postcards' enhance blended learning?

BACKGROUND: In the traditional 'postcard' educational technique, learners write learning points on a postcard at the end of a face-to-face teaching session. The teacher subsequently posts them back to the learners in order to remind and reinforce learning. Cardiff University's Palliative Care Masters programme adapted the traditional postcard technique to suit a modern blended learning course, introducing the concept of 'virtual postcards'. METHODS: Students were asked to complete a postcard for face-to-face teaching sessions on 'symptom control' and were free to use their postcard as they wished, e.g. to draw pictures, to list key bullet points, etc. A selection of postcards were subsequently scanned and uploaded into the corresponding online module. These were visible to all students so that they could learn from each other's virtual postcards. RESULTS: Most students felt that the virtual postcards were a useful learning material (12% did not). Around half of the students felt that having a selection of the virtual postcards was preferable to all of them being uploaded (52%; 28% expressed no preference). Students were divided as to whether this would have become too monotonous to repeat for all topics in face-to-face teaching (40% felt that these should just be used for some topics, 18% had no preference, and 42% felt that these would be useful for all topics). DISCUSSION: In general, the students found virtual postcards useful as part of blended learning, and liked learning from other people's virtual postcards as well as from their own. There needs to be a balance between how often the technique is employed, and how many postcards are uploaded, to avoid information overload and losing value.

Mediators of Host-Microbe Circadian Rhythms in Immunity and Metabolism.

Circadian rhythms are essential for nearly all life forms, mediated by a core molecular gene network that drives downstream molecular processes involved in immune function and metabolic regulation. These biological rhythms serve as the body's metronome in response to the 24-hour light:dark cycle and other timed stimuli. Disrupted circadian rhythms due to drastic lifestyle and environmental shifts appear to contribute to the pathogenesis of metabolic diseases, although the mechanisms remain elusive. Gut microbiota membership and function are also key mediators of metabolism and are highly sensitive to environmental perturbations. Recent evidence suggests rhythmicity of gut microbes is essential for host metabolic health. The key molecular mediators that transmit rhythmic signals between microbes and host metabolic networks remain unclear, but studies suggest the host immune system may serve as a conduit between these two systems, providing homeostatic signals to maintain overall metabolic health. Despite this knowledge, the precise mechanism and communication modalities that drive these rhythms remain unclear, especially in humans. Here, we review the current literature examining circadian dynamics of gut microbes, the immune system, and metabolism in the context of metabolic dysregulation and provide insights into gaps and challenges that remain.

The FUSE binding protein is a cellular factor required for efficient replication of hepatitis C virus.

Hepatitis C virus (HCV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma and one of the primary indications for liver transplantation. The molecular mechanisms underlying the actions of host factors in HCV replication remain poorly defined. FUSE (far upstream element of the c-myc proto-oncogene) binding protein (FBP) is a cellular factor that we have identified as a binder of HCV 3' nontranslated region (3'NTR). Mapping of the binding site showed that FBP specifically interacts with the poly(U) tract within the poly(U/UC) region of the 3'NTR. Silencing of FBP expression by small interfering RNA in cells carrying HCV subgenomic replicons severely reduced viral replication, while overexpression of FBP significantly enhanced viral replication. We confirmed these observations by an in vitro HCV replication assay in the cell-free replicative lysate, which suggested that there is a direct correlation between the cellular FBP level and HCV replication. FBP immunoprecipitation coprecipitated HCV nonstructural protein 5A (NS5A), indicating that FBP interacts with HCV NS5A, which is known to function as a link between HCV translation and replication. Although FBP is mainly localized in the nucleus, we found that in MH14 cells a significant level of this protein is colocalized with NS5A in the cytosol, a site of HCV replication. While the mechanism of FBP involvement in HCV replication is yet to be delineated, our findings suggest that it may be an important regulatory component that is essential for efficient replication of HCV.

Safe and effective prescribing for symptom management in palliative care.

Palliative and end of life care forms an important part of the role of any doctor in training, and an awareness of a structured approach to managing common symptoms and end of life care is essential. Common symptoms include pain, nausea and vomiting, constipation, and breathlessness. Anticipatory prescribing of the 4 A's (analgesic, anti-emetic, anxiolytic, and anti-secretory) is a proactive approach to ensure medication is available, if required, for common symptoms in the last hours to days of life, such as pain, upper airway secretions, anxiety, and agitation. Prescribing or medication errors in relation to symptom control in palliative care can relate to individual errors, poor communication, poor care coordination, equipment and care planning. There are some important key points relating to prescribing to consider, for example, using recognized conversions when changing between opioids and from the oral to syringe drivers route; that diamorphine and morphine are not equipotent; prescribing liquid opioids in milligrams not millilitres where there are multiple concentrations available; making the indication for steroids clear when used, as they are multiple possible indications (and also their intended duration, to avoid unintended longer term sequelae of steroid use); and avoiding the use of oxygen for symptomatic relief of breathlessness in the absence of hypoxia.

Peptide inhibition of HIV-1: current status and future potential.

More than 2 decades of intensive research has focused on defining replication mechanisms of HIV type 1 (HIV-1), the etiologic agent of AIDS. The delineation of strategies for combating this viral infection has yielded many innovative approaches toward this end. HIV-1 is a lentivirus in the family retroviridae that is relatively small with regard to both structure and genome size, having a diploid RNA genome of approximately 9 kb, with only three major genes and several gene products resulting from alternate splicing and translational frameshifting. Most marketed drugs for treating AIDS are inhibitors of HIV-1 reverse transcriptase or protease enzymes, but new targets include the integrase enzyme, cell surface interactions that facilitate viral entry, and also virus particle maturation and assembly. The emergence of drug-resistant variants of HIV-1 has been the main impediment to successful treatment of AIDS. Thus, there is a pressing need to develop novel treatment strategies targeting multiple stages of the virus life-cycle. Research efforts aimed at developing successful means for combating HIV-1 infection have included development of peptide inhibitors of HIV-1. This article summarizes past and current endeavors in the development of peptides that inhibit replication of HIV-1 and the role of peptide inhibitors in the search for new anti-HIV drugs.

The challenge pathway: A mixed methods evaluation of an innovative care model for the palliative and end-of-life care of people with dementia (Innovative practice).

An innovative service for the palliative and end-of-life care of people with dementia was introduced at a UK hospice. This evaluation involved analysis of audit data, semi-structured interviews with project staff (n=3) and surveys of family carers (n=15) and professionals (n=20). The service has increased access to palliative, end-of-life care and other services. Improvements were reported in the knowledge, confidence and care skills of family carers and professionals. Carers felt better supported and it was perceived that the service enabled more patients to be cared for at home or in their usual place of care.

Anti-HIV-1 activity of anti-TAR polyamide nucleic acid conjugated with various membrane transducing peptides.

The transactivator responsive region (TAR) present in the 5'-NTR of the HIV-1 genome represents a potential target for antiretroviral intervention and a model system for the development of specific inhibitors of RNA-protein interaction. Earlier, we have shown that an anti-TAR polyamide nucleotide analog (PNA(TAR)) conjugated to a membrane transducing (MTD) peptide, transportan, is efficiently taken up by the cells and displays potent antiviral and virucidal activity [B. Chaubey, S. Tripathi, S. Ganguly, D. Harris, R. A. Casale and V. N. Pandey (2005) Virology, 331, 418-428]. In the present communication, we have conjugated five different MTD peptides, penetratin, tat peptide, transportan-27, and two of its truncated derivatives, transportan-21 and transportan-22, to a 16mer PNA targeted to the TAR region of the HIV-1 genome. The individual conjugates were examined for their uptake efficiency as judged by FACScan analysis, uptake kinetics using radiolabeled conjugate, virucidal activity and antiviral efficacy assessed by inhibition of HIV-1 infection/replication. While FACScan analysis revealed concentration-dependent cellular uptake of all the PNA(TAR)-peptide conjugates where uptake of the PNA(TAR)-penetratin conjugate was most efficient as >90% MTD was observed within 1 min at a concentration of 200 nM. The conjugates with penetratin, transportan-21 and tat-peptides were most effective as an anti-HIV virucidal agents with IC50 values in the range of 28-37 nM while IC50 for inhibition of HIV-1 replication was lowest with PNA(TAR)-transportan-27 (0.4 microM) followed by PNA(TAR)-tat (0.72 microM) and PNA(TAR)-penetratin (0.8 microM). These results indicate that anti-HIV-1 PNA conjugated with MTD peptides are not only inhibitory to HIV-1 replication in vitro but are also potent virucidal agents which render HIV-1 virions non-infectious upon brief exposure.

Delirium in advanced disease.

Delirium in advanced disease, while common, is often not recognised or poorly treated. The aim of management of delirium is to assess and treat reversible causes in combination with environmental, psychological and pharmacological intervention to control symptoms. Delirium presents significant distress and impedes communication between patients and their families at the end of life. A structured approach to recognise, assess and manage delirium is essential for all clinicians caring for patients with terminal illness.

Forget me not: palliative care for people with dementia.

Dementia is a progressive life limiting condition with increasing prevalence and complex needs. Palliative care needs of patients with dementia are often poorly addressed; symptoms such as pain are under treated while these patients are over subjected to burdensome interventions. Research into palliative care in dementia remains limited but recent developments together with national guidelines and policies set foundations for improving the delivery of palliative care to this group of the population.

An audit of "do not attempt resuscitation" decisions in two district general hospitals: do current guidelines need changing?

INTRODUCTION: Doctors in all specialties are involved in making "do not attempt resuscitation" (DNAR) decisions; this can be a difficult and challenging process. Guidelines exist to provide an ethical and legal framework for the process and documentation of these decisions. OBJECTIVE: To audit the documentation of resuscitation decisions in a sample of medical inpatients from two district general hospitals. METHOD: A retrospective case note audit of 50 medical inpatients, in which a DNAR decision had been made (28 from hospital 1, 22 from hospital 2). RESULTS: Average age was 78.9 years (48% male:52% female). In both hospitals DNAR decisions were usually discussed with relatives (84%), documented in nursing notes (100%) and made by senior team members (90%). Although the decision was usually dated and clearly documented (98%), abbreviations were commonly used in hospital 2 (45.5% vs 0% in hospital 1, p<0.05). Decisions regarding other treatment were not consistently documented (78.6% and 72.7%, respectively) and there was little evidence that decisions were reviewed (14.3% and 31.8%). The decision was rarely discussed with the patient (6% of all patients), although 66% of patients were not in a position to have a discussion. CONCLUSIONS: Specific forms for recording DNAR decisions improve the clarity of documentation. Current recommendations to discuss resuscitation with patients are controversial and not followed. However, many patients are not in a position to hold a discussion when the need arises and the guidelines should advocate early discussion during a hospital admission in patients where this is appropriate, prior discussion with family and/or wider use of advanced directives.

Should we involve terminally ill patients in teaching medical students? A systematic review of patient's views.

OBJECTIVE: To review available published research that has explored how terminally ill patients feel about being involved in undergraduate medical teaching. METHODS: A systematic review using narrative synthesis. Qualitative or quantitative publications were included if they directly explored the views of adult patients, with a terminal diagnosis, about their involvement in undergraduate clinical teaching. RESULTS: Seven publications met the inclusion criteria: one case report, one qualitative study and five questionnaire-based studies. A total of 269 patients were included across all studies. Patients were predominantly studied in a hospice or hospice day care setting. Both patients who had, and who had not, previously been involved in student teaching were captured by the included publications. In general, the views of patients were highly positive: overall 85%-100% were in favour of involvement in teaching. There were also some negative aspects, such as: concerns about being physically examined by a student; finding involvement in teaching tiring; feeling unable to decline consent to participate. CONCLUSIONS: An assumption that clinical undergraduate medical teaching involving terminally ill patients may be too burdensome is not reflected overall in studies that have sought the views of the patients themselves. Understanding the patient's perspective provides a number of practical points in relation to how clinical teaching should be adapted in this patient group; for example, using smaller student group sizes; direct supervision if physical examination performed; short encounters with multiple patients rather than a longer encounter with one patient; adequate informed consent beforehand and without the students automatically being present.

Insertion of a small peptide of six amino acids into the beta7-beta8 loop of the p51 subunit of HIV-1 reverse transcriptase perturbs the heterodimer and affects its activities.

BACKGROUND: HIV-1 RT is a heterodimeric enzyme, comprising of the p66 and p51 subunits. Earlier, we have shown that the beta7-beta8 loop of p51 is a key structural element for RT dimerization (Pandey et al., Biochemistry 40: 9505, 2001). Deletion or alanine substitution of four amino acid residues of this loop in the p51 subunit severely impaired DNA binding and catalytic activities of the enzyme. To further examine the role of this loop in HIV-1 RT, we have increased its size such that the six amino acids loop sequences are repeated in tandem and examined its impact on the dimerization process and catalytic function of the enzyme. RESULTS: The polymerase and the RNase H activities of HIV-1 RT carrying insertion in the beta7-beta8 loop of both the subunits (p66INS/p51INS) were severely impaired with substantial loss of DNA binding ability. These enzymatic activities were restored when the mutant p66INS subunit was dimerized with the wild type p51. Glycerol gradient sedimentation analysis revealed that the mutant p51INS subunit was unable to form stable dimer either with the wild type p66 or mutant p66INS. Furthermore, the p66INS/p66INS mutant sedimented as a monomeric species, suggesting its inability to form stable homodimer. CONCLUSION: The data presented herein indicates that any perturbation in the beta7-beta8 loop of the p51 subunit of HIV-1 RT affects the dimerization process resulting in substantial loss of DNA binding ability and catalytic function of the enzyme.

Guideline for the management of terminal haemorrhage in palliative care patients with advanced cancer discharged home for end-of-life care.

OBJECTIVE: Terminal haemorrhage is a rare and distressing emergency in palliative oncology. We present an algorithm for the management of terminal haemorrhage in patients likely to receive end-of-life care at home, based on a literature review of the management of terminal haemorrhage for patients with advanced cancer, where a DNAR (do not attempt resuscitation) order is in place and the patient wishes to die at home. METHOD: A literature review was conducted to identify literature on the management of terminal haemorrhage in patients with advanced cancer who are no longer amenable to active interventional/invasive procedures. Electronic databases, the grey literature, local guidelines from hospitals and hospices, and online web portals were all searched systematically. The literature review was used to formulate a management algorithm. RESULTS: The evidence base is very limited. A three-step practical algorithm is suggested: preparing for the event, managing the event ('ABC') and 'aftercare'. Step 1 involves the identification and optimisation of risk factors. Step 2 (the event) consists of A (assure and re-assure the patient), B (be there - above all stay with the patient) and C (comfort, calm, consider dark towels and anxiolytics if possible). Step 3 (the aftercare) involves the provision of practical and psychological support to those involved including relatives and professionals. CONCLUSION: Terminal haemorrhage is a rare yet highly feared complication of advanced cancer, for which there is a limited evidence base to guide management. The suggested three-step approach to managing this situation gives professionals a logical framework within which to work.

Overcoming the challenges of bedside teaching in the palliative care setting.

Bedside teaching is the process of active learning in the presence of a patient and is one of the most traditional teaching techniques used in undergraduate medicine. Students and patients both appear to benefit from the experience of bedside teaching. However, bedside teaching with medical students and palliative care patients presents a number of challenges for the patient, the learner and the educator. Key considerations for bedside teaching in the palliative care context include: sensitivity to 'protection', of palliative care patients by colleagues in relation to their involvement in bedside teaching; consideration of the patient's carer/relative as they will often be present for prolonged periods at the bedside; a maximum of one or two students (not the 'up to six' traditionally used in this type of teaching); multiple short encounters with several patients as opposed to a longer encounter with one patient; and sensitivity to the potential impact of the session on the learner as undergraduate medical students and junior doctors may find that while worthwhile and rewarding, the teaching session is also personally emotionally challenging.