What helps and hinders metformin adherence and persistence? A qualitative study exploring the views of people with type 2 diabetes.

AIM: To explore the views of people with type 2 diabetes who had initiated metformin monotherapy about what influences adherence and persistence. METHODS: We recruited participants through primary care, using purposive sampling, and undertook face-to-face, audio-recorded, semi-structured interviews with 10 Maori, 10 Pacific, and 10 non-Maori non-Pacific patients who had started metformin monotherapy for type 2 diabetes within the previous two years. A thematic analysis was undertaken using the Theory of Planned Behaviour as the overall theoretical framework. RESULTS: The perceived benefits of taking metformin included improving glycaemic control, preventing or slowing the progression of type 2 diabetes, and avoiding serious complications. Side effects (predominantly gastrointestinal) were the most commonly cited disadvantage. Participants employed a variety of strategies to help them take metformin regularly. Key reasons for initial sub-optimal adherence and persistence were side effects and not accepting the diagnosis of type 2 diabetes. Subsequently, omitting to take tablets was commonly unintentional (due to 'forgetfulness'). For many Pacific participants, changes in routine related to community and church events, or shift work, contributed to sub-optimal adherence. Some Maori participants would have preferred to use traditional medicines. CONCLUSION: We identified a number of factors within the scope of healthcare services that may assist healthcare providers to focus on, and address, some of the issues that appear to be of primary importance to people when they are prescribed metformin.

Evaluating the effectiveness of a programme for improving the participation and academic success of an underrepresented minority group in New Zealand.

Pacific peoples are a minority under-represented ethnic group in higher education in New Zealand. This article explores the effectiveness of a specific programme, which sought to improve outcomes of Pacific students in the tertiary environment. The aim of the evaluation was to determine the effectiveness of an intervention programme (2013-2015) to increase the participation and academic success of Pacific students in the first year in Health Sciences. The study found the academic results of Pacific students who participated in the intervention programme were significantly better compared to those who did not. The findings inform future research, suggesting that, when assessing the effectiveness of a programme, it is useful to explore the performance of the whole cohort separately to those who declared intention or interest to attend the programme. Strategies to support participation of each of these groups are likely to be different. Having a standardised approach when comparing groups will adjust for any confounding factors or prior differences. This will allow a more accurate assessment of the effectiveness of the programme being evaluated. This paper presents the importance of a robust approach to the delivery and evaluation of intervention programmes for improving outcomes for underrepresented students in the tertiary environment.

The vascular endothelial growth factor (VEGF)-E encoded by orf virus regulates keratinocyte proliferation and migration and promotes epidermal regeneration.

Vascular endothelial growth factor (VEGF)-A, a key regulator of cutaneous blood vessel formation, appears to have an additional role during wound healing, enhancing re-epithelialization. Orf virus, a zoonotic parapoxvirus, induces proliferative skin lesions that initiate in wounds and are characterized by extensive blood vessel formation, epidermal hyperplasia and rete ridge formation. The vascular changes beneath the lesion are largely due to viral-expressed VEGF-E. This study investigated using mouse skin models whether VEGF-E can induce epidermal changes such as that seen in the viral lesion. Injection of VEGF-E into normal skin increased the number of endothelial cells and blood vessels within the dermis and increased epidermal thickening and keratinocyte number. Injection of VEGF-E into wounded skin, which more closely mimics orf virus lesions, increased neo-epidermal thickness and area, promoted rete ridge formation, and enhanced wound re-epithelialization. Quantitative RT-PCR analysis showed that VEGF-E did not induce expression of epidermal-specific growth factors within the wound, but did increase matrix metalloproteinase (MMP)-2 and MMP-9 expression. In cell-based assays, VEGF-E induced keratinocyte migration and proliferation, responses that were inhibited by a neutralizing antibody against VEGF receptor (VEGFR)-2. These findings demonstrate that VEGF-E, both directly and indirectly, regulates keratinocyte function, thereby promoting epidermal regeneration.

The C-terminus of viral vascular endothelial growth factor-E partially blocks binding to VEGF receptor-1.

Vascular endothelial growth factor (VEGF) family members play important roles in embryonic development and angiogenesis during wound healing and in pathological conditions such as tumor formation. Parapoxviruses express a new member of the VEGF family which is a functional mitogen that specifically activates VEGF receptor (VEGFR)-2 but not VEGFR-1. In this study, we show that deletion from the viral VEGF of a unique C-terminal region increases both VEGFR-1 binding and VEGFR-1-mediated monocyte migration. Enzymatic removal of O-linked glycosylation from the C-terminus also increased VEGFR-1 binding and migration of THP-1 monocytes indicating that both the C-terminal residues and O-linked sugars contribute to blocking viral VEGF binding to VEGFR-1. The data suggest that conservation of the C-terminal residues throughout the viral VEGF subfamily may represent a means of reducing the immunostimulatory activities associated with VEGFR-1 activation while maintaining the ability to induce angiogenesis via VEGFR-2.

Bovine papular stomatitis virus encodes a functionally distinct VEGF that binds both VEGFR-1 and VEGFR-2.

Bovine papular stomatitis virus (BPSV), a member of the genus Parapoxvirus, causes proliferative dermatitis in cattle and humans. Other species of the genus cause similar lesions, the nature of which has been attributed, at least in part, to a viral-encoded vascular endothelial growth factor (VEGF) that induces vascularization and dermal oedema through VEGF receptor-2 (VEGFR-2). The results of this study showed that BPSV strain V660 encodes a novel VEGF and that the predicted BPSV protein showed only 33-52% amino acid identity to VEGFs encoded by the other species of the genus. BPSV VEGF showed higher identity to mammalian VEGF-A (51%) than the other parapoxviral VEGFs (31-46%). Assays of the purified BPSV VEGF (BPSVV660VEGF) demonstrated that it was also functionally more similar to VEGF-A, as it showed significant binding to VEGFR-1 and induced monocyte migration. Like VEGF-A and the other viral VEGFs, BPSVV660VEGF bound VEGFR-2 with high affinity. Sequence analysis and structural modelling of BPSVV660VEGF revealed specific residues, outside the known receptor-binding face, that are predicted either to influence VEGF structure or to mediate binding directly to the VEGFRs. These results indicate that BPSVV660VEGF is a biologically active member of the VEGF family and that, via its interaction with VEGFR-2, it is likely to contribute to the proliferative and highly vascularized nature of BPSV lesions. This is also the first example of a viral VEGF acting via VEGFR-1 and influencing haematopoietic cell function. These data suggest that BPSVV660VEGF is an evolutionary and functional intermediate between VEGF-A and the other parapoxviral VEGFs.

Resolution of cervical dysplasia is associated with T-cell proliferative responses to human papillomavirus type 16 E2.

The 'high-risk' human papillomaviruses (HPVs) cause persistent infections of the anogenital region that may resolve spontaneously following activation of a protective immune response. The aim of this study was to determine whether cell-mediated immunity (CMI) to the early protein E2 was associated with disease regression and to establish whether E2 CMI and antibodies to L1 virus-like particles (VLPs) were associated markers of immunity to HPV. Lymphoproliferative responses to histidine-tagged E2 and antibody responses to VLPs were measured in patients with persistent cervical dysplasia, those whose disease had recently resolved and normal controls. Resolvers had significantly higher E2-specific lymphoproliferative responses when compared with normal controls or persisters, whereas there was no significant difference between the persisters and the normal controls. The T cells stimulated by E2 secreted high levels of gamma interferon (IFN-gamma), consistent with a type 1 helper (Th1) phenotype. VLP IgG responses were associated with current or previous HPV infection, but not with disease regression or a lymphoproliferative response to E2. Major histocompatibility complex class I-restricted T cells secreted IFN-gamma following stimulation with E1, and E2 peptides were detected more frequently in the persister group. The data showed that lymphoproliferative responses to E2 with a cytokine profile indicative of Th1 are associated with disease resolution, supporting the development of a therapeutic vaccine that activates this type of response for the treatment of individuals with pre-existing disease.

Parapoxvirus of red deer in New Zealand encodes a variant of viral vascular endothelial growth factor.

Parapoxvirus of red deer in New Zealand (PVNZ), a species of the Parapoxvirus genus, causes scabby lesions on the skin and the velvet of red deer. The three other species of the genus have each been shown to encode homologs of vascular endothelial growth factor (VEGF). We report here that PVNZ strain RD86 also encodes a VEGF and that the predicted PVNZ protein shows only 37-54% amino acid identity to VEGFs encoded by the other species of the genus. Despite this extensive sequence divergence, assays of purified PVNZ VEGF (PVNZ(RD86)VEGF) demonstrated that it shares the unique VEGF receptor (VEGFR) binding profile of the other parapoxvirus VEGFs, in that it binds VEGFR-2 and induces VEGFR-2-mediated proliferation of Ba/F3-derived cells, but does not bind VEGFR-1 or VEGFR-3. In contrast to some other viral VEGFs, it does not bind neuropilin-1. Our results indicate that PVNZ(RD86)VEGF is a biologically active member of the VEGF family and is likely to contribute to the proliferative and highly vascularized nature of PVNZ lesions. Our data also reveal that all members of the genus encode a VEGF and that an extraordinary degree of inter-species sequence variation is a general feature of the parapoxvirus VEGFs.