Marine mollusc extracts-Potential source of SARS-CoV-2 antivirals.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus and the causative agent of coronavirus disease 2019 (Covid-19). There is an urgent need for effective antivirals to treat current Covid-19 cases and protect those unable to be vaccinated against SARS-CoV-2. Marine molluscs live in an environment containing high virus densities (>107 virus particles per ml), and there are an estimated 100,000 species in the phylum Mollusca, demonstrating the success of their innate immune system. Mollusc-derived antivirals are yet to be used clinically despite the activity of many extracts, including against human viruses, being demonstrated in vitro. Hemolymph of the Pacific oyster (Crassostrea gigas) has in vitro antiviral activity against herpes simplex virus and human adenovirus, while antiviral action against SARS-CoV-2 has been proposed by in silico studies. Such evidence suggests that molluscs, and in particular C. gigas hemolymph, may represent a source of antivirals for human coronaviruses.

Incidence and causes of early unplanned readmission after hospitalisation with peripheral arterial disease in Australia and New Zealand.

OBJECTIVE: To evaluate the characteristics and predictors of unplanned readmission within 30 days of hospitalisation for the treatment of peripheral arterial disease (PAD) in Australia and New Zealand. DESIGN: Analysis of hospitalisations data in the Admitted Patient Collection for each Australian state and territory and the New Zealand National Minimum Dataset (Hospital Events). SETTING: All public and 80% of private hospitals in Australia and New Zealand. PARTICIPANTS: Adults (18 years or older) hospitalised with a primary or conditional secondary diagnosis of PAD during 1 January 2010 - 31 December 2015. MAIN OUTCOME MEASURE: Rate of unplanned readmission (any cause) within 30 days of hospitalisation with PAD. RESULTS: Of 104 979 admissions included in our analysis (mean patient age, 73.7 years; SD, 12.4 years), 9765 were followed by at least one unplanned readmission within 30 days of discharge (9.3%): 3395 within one week (34.8%) and 7828 within three weeks (80.2%). The most frequent readmission primary diagnoses were atherosclerosis (1477, 15.3%), type 2 diabetes (1057, 10.8%), and "complications of procedures not elsewhere classified" (963, 9.9%). Readmission was more frequent after acute (4830 of 26 304, 18.4%) than elective PAD hospitalisations (4935 of 78 675, 6.3%), but the readmission characteristics were similar. Factors associated with greater likelihood of readmission included acute PAD hospitalisations (odds ratio [OR], 2.04; 95% CI, 1.96-2.17), surgical intervention during the PAD hospitalisation (OR, 1.74; 95% CI, 1.64-1.84), and chronic limb-threatening ischaemia (OR, 1.55; 95% CI, 1.47-1.63). CONCLUSION: Unplanned readmissions within 30 days of hospitalisation for PAD are often for potentially preventable reasons. Their number should be reduced to improve clinical outcomes for people with PAD.

Thirty-Day Unplanned Readmissions Following Hospitalisation for Atrial Fibrillation in Australia and New Zealand.

AIMS: Atrial fibrillation (AF) is a leading cause of hospitalisations, yet little is known about 30-day readmissions following discharge despite increasing policy focus on reducing readmissions. We assessed the rate, timing, causes and predictors of 30-day unplanned readmission following an acute and elective AF hospitalisation using population-wide data. METHODS: We studied all patients hospitalised for AF from 2010 to 2015 at all public and most private hospitals in Australia and New Zealand. The main outcome measures were unplanned readmissions within 30 days of discharge, primary diagnosis associated with these readmissions, and their predictors as modelled by logistic regression. RESULTS: Among 301,654 patients hospitalised for AF (mean age 69.2±13.6 yrs, 55.6% female, 65.2% acute presentations), 29,750 (9.9%) experienced an unplanned readmission within 30 days with 62.6% occurring by 14 days. Unplanned readmissions occurred more frequently following an acute versus elective AF hospitalisations (12.5% vs 4.9%, p<0.001). The most common diagnoses associated with readmissions were recurrence of AF (n=9,890, 33.2%), and preventable conditions including heart failure (n=2,683, 9.0%), pneumonia (n=724, 2.4%) and acute myocardial infarction (n=510, 1.7%). A higher risk of 30-day readmission was associated with congenital cardiac/circulatory defect (OR 2.18, CI 1.44-3.30), congestive heart failure (OR 1.34, CI 1.30-1.39), and arrhythmia/conduction disorders (OR 1.25, CI 1.21-1.28). CONCLUSION: Almost 1 in 10 AF hospitalisations resulted in unplanned readmission within 30-days, mostly for AF recurrence. Improved clinical management of AF and transitional care planning are required to reduce unplanned readmissions following AF hospitalisations.

Efficacy of phage cocktail AB-SA01 therapy in diabetic mouse wound infections caused by multidrug-resistant Staphylococcus aureus.

BACKGROUND: Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus. Antibiotic-resistant Staphylococcus aureus is frequently isolated from DFU infections. Bacteriophages (phages) represent an alternative or adjunct treatment to antibiotic therapy. Here we describe the efficacy of AB-SA01, a cocktail of three S. aureus Myoviridae phages, made to current good manufacturing practice (cGMP) standards, and which has undergone two phase I clinical trials, in treatment of multidrug-resistant (MDR) S. aureus infections. RESULTS: Wounds of saline-treated mice showed no healing, but expanded and became inflamed, ulcerated, and suppurating. In contrast, AB-SA01 treatment decreased the bacterial load with efficacy similar or superior to vancomycin treatment. At the end of the treatment period, there was a significant decrease (p < 0.001) in bacterial load and wound size in infected phage- and vancomycin-treated groups compared with infected saline-treated mice. In phage-treated mice, wound healing was seen similar to vancomycin treatment. No mortality was recorded associated with infections, and post-mortem examinations did not show any evident pathological lesions other than the skin wounds. No adverse effects related to the application of phages were observed. CONCLUSION: Topical application of phage cocktail AB-SA01 is effective, as shown by bacterial load reduction and wound closure, in the treatment of diabetic wound infections caused by MDR S. aureus. Our results suggest that topical phage cocktail treatment may be effective in treating antibiotic-resistant S. aureus DFU infections.

Mini-review: efficacy of lytic bacteriophages on multispecies biofilms.

There is potential for phages to prevent and control bacterial biofilms, but few studies have examined the effect of phages on the multispecies biofilms that characterize most bacterial infections. This paper reviews the mechanism of action of phages, the evidence supporting the view that phage therapy will be effective against bacterial targets and the opposite viewpoint, phage application approaches, and the comparative advantage of phage therapy in multispecies biofilms. The few reports measuring the actions of lytic phages against multispecies biofilms are also reviewed. The authors are cautiously optimistic about the application of phages against their targets when in multispecies biofilms because some lysis mechanisms do not require species specificity.

Patients' and caregivers' needs, experiences, preferences and research priorities in spiritual care: A focus group study across nine countries.

BACKGROUND: Spiritual distress is prevalent in advanced disease, but often neglected, resulting in unnecessary suffering. Evidence to inform spiritual care practices in palliative care is limited. AIM: To explore spiritual care needs, experiences, preferences and research priorities in an international sample of patients with life-limiting disease and family caregivers. DESIGN: Focus group study. SETTING/PARTICIPANTS: Separate patient and caregiver focus groups were conducted at 11 sites in South Africa, Kenya, South Korea, the United States, Canada, the United Kingdom, Belgium, Finland and Poland. Discussions were transcribed, translated into English and analysed thematically. RESULTS: A total of 74 patients participated: median age 62 years; 53 had cancer; 48 were women. In total, 71 caregivers participated: median age 61 years; 56 were women. Two-thirds of participants were Christian. Five themes are described: patients' and caregivers' spiritual concerns, understanding of spirituality and its role in illness, views and experiences of spiritual care, preferences regarding spiritual care, and research priorities. Participants reported wide-ranging spiritual concerns spanning existential, psychological, religious and social domains. Spirituality supported coping, but could also result in framing illness as punishment. Participants emphasised the need for staff competence in spiritual care. Spiritual care was reportedly lacking, primarily due to staff members' de-prioritisation and lack of time. Patients' research priorities included understanding the qualities of human connectedness and fostering these skills in staff. Caregivers' priorities included staff training, assessment, studying impact, and caregiver's spiritual care needs. CONCLUSION: To meet patient and caregiver preferences, healthcare providers should be able to address their spiritual concerns. Findings should inform patient- and caregiver-centred spiritual care provision, education and research.

Marine Snails and Slugs: a Great Place To Look for Antiviral Drugs.

Molluscs, comprising one of the most successful phyla, lack clear evidence of adaptive immunity and yet thrive in the oceans, which are rich in viruses. There are thought to be nearly 120,000 species of Mollusca, most living in marine habitats. Despite the extraordinary abundance of viruses in oceans, molluscs often have very long life spans (10 to 100 years). Thus, their innate immunity must be highly effective at countering viral infections. Antiviral compounds are a crucial component of molluscan defenses against viruses and have diverse mechanisms of action against a wide variety of viruses, including many that are human pathogens. Antiviral compounds found in abalone, oyster, mussels, and other cultured molluscs are available in large supply, providing good opportunities for future research and development. However, most members of the phylum Mollusca have not been examined for the presence of antiviral compounds. The enormous diversity and adaptations of molluscs imply a potential source of novel antiviral compounds for future drug discovery.

'I think you just learnt as you went along' - community clergy's experiences of and attitudes towards caring for dying people: A pilot study.

BACKGROUND: Spiritual distress is a factor associated with poor outcomes at the end of life. Timely interventions, assessing and meeting spiritual distress, among patients are contained within nationally agreed guidance. Community clergy are well placed to work alongside healthcare professionals and chaplains to meet spiritual needs. METHODS: Qualitative interviews among Christian clergy in two South East London boroughs and a self-completed Death Anxiety Questionnaire. RESULTS: Fourteen clergy were interviewed from six Christian denominations. Participants described their experiences of ordination training and how helpful this had been for their work among Christian communities. Respondents were invited to discuss their knowledge of and involvement with palliative care services. Each interviewee also accounted for their understanding of pastoral care and spiritual care and considered whether any differences existed between these terms and, if so, what they were. Overall, clergy lacked any detailed formal training and had little experience of working with or relating to palliative care providers. Recommendations are made to improve educational opportunities and working relationships. CONCLUSIONS: Creating opportunities for clergy and palliative care staff to meet and undertake shared training will enhance the quality and level of care for people dying at home who wish to receive spiritual support. Enabling clergy to develop links with local palliative care centres will enhance confidence for both clergy and staff.

Culture and spirituality: essential components of palliative care.

Palliative care advocates a holistic, multiprofessional approach to the care of people with life-threatening disease. In addition to the control of physical symptoms attention should also be paid to psychosocial, cultural and spiritual aspects of the patient's experience of illness. Guidance documents and research evidence reflect the complexity of the patient's journey and the need to regularly assess these areas of need over time. Cultural background can shape how patients respond to life-threatening illness, as can the beliefs held by the patients, whether religious or more broadly spiritual. Research evidence shows the importance of identifying and addressing cultural and spiritual aspects of care held by patients, families and staff. These are often neglected in clinical practice due to the focus on biomedical concerns and staff discomfort in engaging with beliefs and culture. Recent studies have highlighted gaps in the research, and some methodological difficulties and indicate many patients welcome healthcare staff enquiring about the importance of their beliefs and culture. Identifying research priorities is necessary to guide future research and strengthen the evidence base.

Antiviral immunity in marine molluscs.

Marine molluscs, like all living organisms, are constantly exposed to viruses and have evolved efficient antiviral defences. We review here recent developments in molluscan antiviral immunity against viruses belonging to the order Herpesvirales. Emerging results suggest an interferon-like response and autophagy are involved in the antiviral defence of bivalves to viral infection. Multi-functional plasma proteins from gastropods and bivalves have been identified to have broad-spectrum antiviral activity against mammalian viruses. The antiviral defences present in molluscs can be enhanced by genetic selection, as shown by the presence of oyster strains specifically resistant to ostreid herpesvirus type 1. Whether varying amounts or different isoforms of these antiviral plasma proteins contributes to genetic resistance is worthy of further research. Other evolutionarily conserved antiviral mechanisms, such as RNA interference and apoptosis, still need further characterization.

Oyster viperin retains direct antiviral activity and its transcription occurs via a signalling pathway involving a heat-stable haemolymph protein.

Little is known about the response of non-model invertebrates, such as oysters, to virus infection. The vertebrate innate immune system detects virus-derived nucleic acids to trigger the type I IFN pathway, leading to the transcription of hundreds of IFN-stimulated genes (ISGs) that exert antiviral functions. Invertebrates were thought to lack the IFN pathway based on the absence of IFN or ISGs encoded in model invertebrate genomes. However, the oyster genome encodes many ISGs, including the well-described antiviral protein viperin. In this study, we characterized oyster viperin and showed that it localizes to caveolin-1 and inhibits dengue virus replication in a heterologous model. In a second set of experiments, we have provided evidence that the haemolymph from poly(I : C)-injected oysters contains a heat-stable, protease-susceptible factor that induces haemocyte transcription of viperin mRNA in conjunction with upregulation of IFN regulatory factor. Collectively, these results support the concept that oysters have antiviral systems that are homologous to the vertebrate IFN pathway.

Ontogeny and water temperature influences the antiviral response of the Pacific oyster, Crassostrea gigas.

Disease is caused by a complex interaction between the pathogen, environment, and the physiological status of the host. Determining how host ontogeny interacts with water temperature to influence the antiviral response of the Pacific oysters, Crassostrea gigas, is a major goal in understanding why juvenile Pacific oysters are dying during summer as a result of the global emergence of a new genotype of the Ostreid herpesvirus, termed OsHV-1 µvar. We measured the effect of temperature (12 vs 22 °C) on the antiviral response of adult and juvenile C. gigas injected with poly I:C. Poly I:C up-regulated the expression of numerous immune genes, including TLR, MyD88, IκB-1, Rel, IRF, MDA5, STING, SOC, PKR, Viperin and Mpeg1. At 22 °C, these immune genes showed significant up-regulation in juvenile and adult oysters, but the majority of these genes were up-regulated 12 h post-injection for juveniles compared to 26 h for adults. At 12 °C, the response of these genes was completely inhibited in juveniles and delayed in adults. Temperature and age had no effect on hemolymph antiviral activity against herpes simplex virus (HSV-1). These results suggest that oysters rely on a cellular response to minimise viral replication, involving recognition of virus-associated molecular patterns to induce host cells into an antiviral state, as opposed to producing broad-spectrum antiviral compounds. This cellular response, measured by antiviral gene expression of circulating hemocytes, was influenced by temperature and oyster age. We speculate whether the vigorous antiviral response of juveniles at 22 °C results in an immune-mediated disorder causing mortality.

Anti-viral gene induction is absent upon secondary challenge with double-stranded RNA in the Pacific oyster, Crassostrea gigas.

Oyster farming is one of the most important aquaculture industries in the world. However, its productivity is increasingly limited by viral disease and we do not yet have management practices, such as protective vaccination, that can control these disease outbreaks. Hence, in the current study we investigated the expression of known anti-viral genes in oysters (Crassostrea gigas) in response to primary and secondary encounter with a virus associated molecular pattern (dsRNA), and tested whether a common form of epigenetic gene regulation (DNA methylation) was associated with the expression of these anti-viral genes. Injection of dsRNA into the adductor muscle resulted in the rapid and transient expression of virus recognition receptors (TLR & MDA5), whereas several anti-viral signalling (IRF & SOC-1) and effector (PKR & viperin) genes were still up-regulated at one week post primary challenge (p < 0.05). This primary encounter with dsRNA appeared to deplete the immune system because anti-viral gene induction was absent in the gills when oysters were given a second injection of dsRNA at 1-week post-primary injection. The expression of DNA methylation genes (DNMT1, DNMT3b, TDG, TET2) and DNA methylation profiles up-stream of specific anti-viral genes (STING, SOC-1 & Viperin) did not change in response to dsRNA injection (p > 0.05). These results collectively suggest that C. gigas does not have an enhanced anti-viral gene response (immune-priming) to secondary dsRNA challenge and that the sustained up-regulation of anti-viral signalling and effector genes following primary challenge is unlikely to be associated with upstream DNA methylation levels.

Conceptualizations of dignity at the end of life: exploring theoretical and cultural congruence with dignity therapy.

AIM: To explore the conceptualization of patients' dignity in the context of end-of-life care in Taiwan. BACKGROUND: Dignity therapy - a novel nurse-delivered psychotherapeutic intervention - has been demonstrated to have potential to alleviate terminal patients' psycho-existential distress in western countries. In Taiwan, over half of end-of-life patients experience psychological-spiritual suffering and dignity therapy might be helpful in improving this situation. Hence, a preliminary study to clarify Taiwanese conceptualizations of 'dignity' was conducted prior to planning a feasibility study to gauge the potential cultural fit of an intervention of this type. DESIGN: Qualitative exploration. METHODS: Nine people with terminal cancer and ten health professionals were recruited from palliative care services in 2008. In-depth interviews were audiotaped and transcribed verbatim. A hermeneutic approach was employed to analyse and interpret data. FINDINGS: Being a valuable person is the core meaning of patients' dignity and this comprised intrinsic characteristics and extrinsic factors. Intrinsic characteristics of dignity encompassed living a moral life, having peace of mind and a sense of existence involving the perception of resignation to God's will. Extrinsic factors that influenced patients' dignity included illness-related distress, care delivery and the perception of being loved. A dynamic relationship between these elements determined the state of patients' dignity. CONCLUSION: The concept of dignity is culturally bound and understood differently in the Chinese and Western context; such differences should be considered when planning and delivering care. Modifications should be made to dignity therapy to ensure it is culturally congruent with Taiwanese patients' beliefs.

Lytic activity of phages against bacterial pathogens infecting diabetic foot ulcers.

Complications of diabetes, such as diabetic foot ulcers (DFUs), are common, multifactorial in origin, and costly to treat. DFUs are the cause of nearly 90% of limb amputations among persons with diabetes. In most chronic infections such as DFU, biofilms are involved. Bacteria in biofilms are 100-1000 times more resistant to antibiotics than their planktonic counterparts. Multidrug-resistant (MDR) Staphylococcus aureus and Pseudomonas aeruginosa infections in DFUs may require alternative therapeutic agents such as bacteriophages ("phages"). This study describes the lytic activity of phage cocktails AB-SA01 (3-phage cocktail) and AB-PA01 (4-phage cocktail), which target S. aureus and P. aeruginosa, respectively. The host range and lytic effect of AB-SA01 and AB-PA01 on a planktonic culture, single-species biofilm, and mixed-species biofilm were evaluated. In vitro testing showed that 88.7% of S. aureus and 92.7% of P. aeruginosa isolates were susceptible to AB-SA01 and AB-PA01, respectively, in the planktonic state. The component phages of AB-SA01 and AB-PA01 infected 66% to 94.3% of the bacterial isolates tested. Furthermore, AB-SA01 and AB-PA01 treatment significantly (p < 0.05) reduced the biofilm biomass of their hosts, regardless of the antibiotic-resistant characteristics of the isolates and the presence of a non-susceptible host. In conclusion, the strong lytic activity, broad host range, and significant biofilm biomass reduction of AB-SA01 and AB-PA01 suggest the considerable potential of phages in treating antibiotic-resistant S. aureus and P. aeruginosa infections alone or as coinfections in DFUs.

Exploring the impact of dignity therapy on distressed patients with advanced cancer: three case studies.

BACKGROUND: Dignity therapy (DT) has been developed to help reduce distress experienced by people nearing the end of life; however, evaluations of this novel intervention have largely involved non-distressed samples. OBJECTIVE: The objective of this study was to explore in detail the impact of DT on distressed patients with advanced cancer. METHODS: We used a case study approach. Three patients with the highest levels of dignity-related distress who received DT were explored in depth. We collected quantitative and qualitative outcomes from patients in face-to-face interviews at baseline and at 1 and 4 weeks after completion of the intervention. We assessed dignity-related distress using the Patient Dignity Inventory. Patients rated the benefits of DT at completion of the intervention and at both follow-ups. We conducted qualitative interviews exploring experiences of DT with patients and with two recipients of generativity documents produced by patients. RESULTS: These patients were experiencing a wide range of major or overwhelming physical and psychosocial problems when they received the intervention, most of which would not be expected to be helped by DT. All felt that DT had helped them and had helped or would help their families; however, patients' concerns about their current situation made delivering the intervention challenging, and DT-relevant problems returned when a patients' condition deteriorated. CONCLUSIONS: The extent to which DT can help these patients and their families, either as a stand-alone therapy or as an adjunct to other therapies, needs to be determined in studies focussing on distressed patients, particularly those with problems likely to be helped by the therapy.

Meanings of happiness among two ethnic groups living with advanced cancer in south London: a qualitative study.

OBJECTIVE: Happiness is a central component in quality of life but little is known about its meanings among people living with an advanced disease and those from diverse communities. This study explores and compares, for the first time, the centrality and interpretations of happiness across two cultural groups living with advanced cancer. METHODS: Semi-structured interviews among 26 Black Caribbean and 19 White British cancer patients were conducted in hospital and home settings. RESULTS: Thirty eight participants volunteered views on happiness, which were related to four main themes: empty lives, a theme associated with lives devoid of contentment; happiness and the physical form principally, associated with the absence of distressing symptoms; 'love and affection' associated with family and friends; and 'realising personal meaning in life', most common among the Black Caribbean participants and related to God, prayer and the sacred world. The presence of cancer pain even when refractory did not preclude manifestations of happiness in this domain. CONCLUSIONS: We identified that happiness was central to many patients' quality of life during advanced cancer. Moreover, happiness was multidimensional and at times culturally patterned. We recommend that health and social care professionals increase their awareness and skills-set in relation to exploring happiness. Further, we recommend greater efforts are invested in cultural relativism to service the physical, psychological, social and spiritual issues that contribute towards moments of happiness among diverse communities.