Head-to-Head Comparison of Soluble vs. Qß VLP Circumsporozoite Protein Vaccines Reveals Selective Enhancement of NANP Repeat Responses.

Circumsporozoite protein (CSP) of Plasmodium falciparum is a promising malaria vaccine target. RTS,S, the most advanced malaria vaccine candidate consists of the central NANP repeat and carboxy-terminal region of CSP displayed on a hepatitis B virus-like particle (VLP). To build upon the success of RTS,S, we produced a near full-length Plasmodium falciparum CSP that also includes the conserved amino-terminal region of CSP. We recently showed that this soluble CSP, combined with a synthetic Toll-like-receptor-4 (TLR4) agonist in stable oil-in-water emulsion (GLA/SE), induces a potent and protective immune response in mice against transgenic parasite challenge. Here we have investigated whether the immunogenicity of soluble CSP could be further augmented by presentation on a VLP. Bacteriophage Qß VLPs can be readily produced in E.coli, they have a diameter of 25 nm and contain packaged E. coli RNA which serves as a built in adjuvant through the activation of TLR7/8. CSP was chemically conjugated to Qß and the CSP-Qß vaccine immunogenicity and efficacy were compared to adjuvanted soluble CSP in the C57Bl/6 mouse model. When formulated with adjuvants lacking a TLR4 agonist (Alum, SE and Montanide) the Qß-CSP induced higher anti-NANP repeat titers, higher levels of cytophilic IgG2b/c antibodies and a trend towards higher protection against transgenic parasite challenge as compared to soluble CSP formulated in the same adjuvant. The VLP and soluble CSP immunogenicity difference was most pronounced at low antigen dose, and within the CSP molecule, the titers against the NANP repeats were preferentially enhanced by Qß presentation. While a TLR4 agonist enhanced the immunogenicity of soluble CSP to levels comparable to the VLP vaccine, the TLR4 agonist did not further improve the immunogenicity of the Qß-CSP vaccine. The data presented here pave the way for further improvement in the Qß conjugation chemistry and evaluation of both the Qß-CSP and soluble CSP vaccines in the non-human primate model.

Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study.

OBJECTIVES: To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. DESIGN: Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. PARTICIPANTS: 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. SETTING: Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. RESULTS: Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a "way of life" rather than an "illness." Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers' familiarity with the patients' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a "chaos narrative" of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. CONCLUSIONS: Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation.

Living and dying with severe chronic obstructive pulmonary disease: multi-perspective longitudinal qualitative study.

OBJECTIVES: To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. DESIGN: Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. PARTICIPANTS: 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. SETTING: Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. RESULTS: Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a "way of life" rather than an "illness." Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers' familiarity with the patients' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a "chaos narrative" of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. CONCLUSIONS: Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation.

The impact of general practitioner morale on patient satisfaction with care: a cross-sectional study.

BACKGROUND: The association between stress and morale among general practitioners (GP) is well documented. However, the impact of GP stress or low morale on patient care is less clear. GPs in the UK now routinely survey patients about the quality of their care including organizational issues and consultation skills and the General Practice Assessment Questionnaire (GPAQ) is widely used for this purpose. We aimed to see if there was a relationship between doctor morale as measured by a validated instrument, the Morale Assessment in General Practice Index (MAGPI) and scores in the GPAQ. METHODS: All GPs in Lothian, Scotland who were collecting GPAQ data were approached and asked to complete the MAGPI. Using an anonymised linkage system, individual scores on the MAGPI were linked to the doctors' GPAQ scores. Levels of association between the scores were determined by calculating rank correlations at the level of the individual doctor. Hypothesised associations between individual MAGPI and GPAQ items were also assessed. RESULTS: 276 of 475 GPs who were approached agreed to complete a MAGPI questionnaire and successfully collected anonymous GPAQ data from an average of 49.6 patients. There was no significant correlation between the total MAGPI score and the GPAQ communication or enablement scale. There were weak correlations between "control of work" in the MAGPI scale and GPAQ items on waiting times to see doctors (r = 0.24 p < 0.01). Doctors who perceived that their patients viewed them negatively also scored lower on individual communication, accessibility and continuity of care GPAQ items. CONCLUSION: This study showed no relationship between overall GP morale and patient perception of performance. There was a weak relationship between patients' perceptions ofquality and doctors' beliefs about their workload and whether patients value them. Further research is required to elucidate the complex relationship between workload, morale and patients' perception of care.

The experience of caring for someone over 75 years of age: results from a Scottish General Practice population.

AIMS AND OBJECTIVES: To understand the unpaid carers' experiences of looking after someone aged over 75 at all stages of their caring career. BACKGROUND: The role of, and support for, unpaid carers have become central in the debates surrounding community care in the UK. This paper presents the findings of a study to elicit the complexities of the caring role and inform the Primary Health Care Team to help support carers more effectively. DESIGNS AND METHODS: A quantitative research design was employed. Carers of people over 75 years of age in a General Practice, who had been previously identified from a screening questionnaire, were sent the Carers Assessment of Difficulties Index, the Carers Assessment of Satisfactions Index and Carers Assessment of Managing Index questionnaires which examine the experience of caring. RESULTS: From a sample of 247 carers, a 70% response rate (n = 172) was achieved. Satisfactions lay in the quality of care provided; difficulties reflected the potential and actual family tensions generated; coping strategies included reframing difficulties, using humour and practical problem solving. The data show that caregivers' reactions, such as feeling angry about the situation, or the consequences of their involvement, such as tensions within the family, cause them more difficulties than the actual care-giving tasks they perform. CONCLUSION: This study adds to the understanding of carers' roles by including carers across a range of situations, including those at an early stage of their caring career. Service providers are better able to support carers if they understand the complex interplay of difficulties, rewards and personal coping strategies associated with the caring role. RELEVANCE TO PRACTICE: The study helps illuminate the less obvious, but important, emotional aspects of carers' difficulties and suggests strategies which service providers may find helpful in assessing carers' needs and determining the appropriate interventions.

Morale among general practitioners: qualitative study exploring relations between partnership arrangements, personal style, and workload.

OBJECTIVES: To explore general practitioners' experiences of wellbeing and distress at work, to identify their perceptions of the causes of and solutions to distress, and to draw out implications for improving morale in general practice. DESIGN: Three stage qualitative study consisting of one to one unstructured interviews, one to one guided interviews, and focus groups. SETTING: Fife, Lothian, and the Borders, South East Scotland. PARTICIPANTS: 63 general practitioner principals. RESULTS: Morale of general practitioners was explained by the complex interrelations between factors. Three key factors were identified: workload, personal style, and practice arrangements. Workload was commonly identified as a cause of low morale, but partnership arrangements were also a key mediating variable between increasing workload and external changes in general practice on the one hand and individual responses to these changes on the other. Integrated interventions at personal, partnership, and practice levels were seen to make considerable contributions to improving morale. Effective partnerships helped individuals to manage workload, but increasing workload was also seen to take away time and opportunities for practices to manage change and to build supportive and effective working environments. CONCLUSIONS: Solutions to the problem of low morale need integrated initiatives at individual, partnership, practice, and policy levels. Improving partnership arrangements is a key intervention, and rigorous action research is needed to evaluate different approaches.