Blood Biomarkers of Presymptomatic Frontotemporal Dementia

Frontotemporal dementia (FTD) is characterised by neuronal loss and pathological protein inclusions in the frontal and/or temporal lobes of the brain. The presymptomatic stage, marked by molecular changes years before symptom onset, offers a critical window for early detection, intervention, targeted monitoring, and tracking of disease progression. Currently, no validated fluid biomarker exists to distinguish this early phase of FTD. FTDGeNZ, a natural history study tracking a family with a mutation in the microtubule-associated protein tau (MAPT) gene, provides insights into presymptomatic FTD. Six family members carry the FTD-causing mutation, with the remaining members serving as non-carrier controls. In this research, we conducted case-control analyses to identify plasma-derived miRNAs and proteins as potential biomarkers of presymptomatic FTD. We utilised baseline data from six carriers and 17 controls, alongside longitudinal data from three timepoints with six carriers and 12 controls. Additionally, we optimised a pipeline to investigate plasma-derived extracellular vesicles as a source of potential molecular biomarkers. High-throughput sequencing at a depth of 24 million read pairs per sample, followed by statistical testing and qPCR validation, identified three miRNAs (let-7d-3p, miR-100-5p, miR-342-3p) as potential cross-sectional biomarkers, and two miRNAs (miR-10b-5p, miR-92b-3p) as longitudinal candidates. Statistical modelling of untargeted liquid chromatography-mass spectrometry data revealed 16 potential protein biomarkers in the cross-sectional analysis and 36 candidates in the longitudinal analysis. Notably, we observed reduced expression of three candidate miRNAs (miR-92b-3p, miR-100-5p, miR-10b-5p) in carriers, while four of their target proteins (FLNA, TLN1, TPM4, RAP1B) were upregulated. Furthermore, functional analysis revealed that FLNA, TLN1, TPM4, along with another 16 identified candidate proteins (ACTB, ACTN1, FBLN1, GAPDH, ITGA2B, ITGB3, KRT2, MSN, MYH9, PDLIM1, PFN1, PPIA, THSB1, TNXB, TPM3, VCL), were associated with actin-cytoskeletal dynamics, suggesting that these processes may become dysregulated early in FTD disease progression. This work represents the first longitudinal quantification of plasma-derived miRNA and protein expression changes in presymptomatic genetic FTD. With further follow up these findings may enable early identification of at-risk individuals and provide insights into the underlying aetiology of the disease

Balancing operational efficiency and service quality: how strategy shapes performance in the US airline industry

Purpose: We examine how operational efficiency (OE) and service quality (SQ) interact to influence profitability, contingent on a firm’s strategic orientation (SO), whether focused or non-focused. Our study introduces a new perspective linking OE, SQ and profitability through competitive priorities and the moderating role of SO. Design/methodology/approach: Using US airline panel data, we employ econometric analyses and robustness checks, including alternative model specifications, to validate our hypotheses and ensure result reliability. Findings: We find that different dimensions of OE interact with SQ in varying ways to influence profitability. For both OE measures, their interaction with SQ negatively affects profitability, aligning with theoretical expectations, although the effects are not statistically significant. These results suggest potential contingency factors shaping this relationship. Furthermore, a firm’s SO moderates the OE–SQ–profitability link. The effects are positive as hypothesized, with SO particularly moderating the interaction between labor productivity and SQ, indicating that aligning SQ and productivity with SO enhances performance. Originality/value: Our research addresses conflicting findings in the literature regarding the relationship between OE, SQ and firm performance by demonstrating the moderating effect of a firm’s SO on this relationship. Our approach, examining the interaction between various measures of OE and SQ with profitability, offers a more value-driven and managerially focused perspective. The findings suggest that the effectiveness of balancing OE and SQ to drive profitability is contingent on the firm’s SO

National report on doctors five years after graduating from New Zealand medical schools in 2011-2019

This report provides the findings from Medical Schools Outcomes Database (MSOD) questionnaires administered between 2016 and 2024 to nine cohorts of doctors who had graduated from a New Zealand medical school five years previously (PGY5), between 2011 and 2019. A total of 1,926 from the 3,966 eligible doctors (48.7%) completed questionnaires. Over this time there has been a slight over-representation of women responding (women made up 58% of respondents but are approximately 55% of the 2011 to 2019 graduates). The median age of the respondents is steady, at about 29.5 years. This also matches the median age of the 2011 to 2019 graduate group at PGY5. The self-identified ethnicity of respondents indicates a trend toward an increasing prevalence of doctors identifying as Māori and/or Pacific people, however the proportions still underrepresent the proportion of Māori and Pacific people in the New Zealand population. Five years after graduating, 90% of respondents agree or strongly agree their medical work and training since graduation has helped prepare them for work as a doctor, 87% of respondents are working as a registrar and/or are in training under supervision, and 76% are enrolled in a College training programme. Of those, about 28% are enrolled in the General Practice training programme. The majority of respondents intend to be enrolled in a College training programme within the next three years (79% of all respondents at PGY6 and PGY7, 73% at PGY8). By their PGY8 year, 13% intend to be vocationally registered. Only 3% of respondents intend to work in a clinical role outside New Zealand within the next three years. In the longer term, 96% of respondents intend to work in New Zealand: 63% in a major city, 28% in a regional centre or large town, and the remainder in smaller towns. The percentage of respondents in PGY5 decided on a future medical specialty is about 93%. Consistently, the top preference is General Practice (26%), followed by Internal Medicine (13%) and Surgery (12%). Nearly half the respondents selected one of these three specialties as their first-choice preference. About 71% of respondents indicated an interest in medical teaching, and 40% an interest in research. Five years after graduation, respondents indicate both external and internal factors influence their specialty preference, with the highest ranked factors being atmosphere/work culture typical of the discipline, self-appraisal of own skills/aptitudes, influence of consultants/mentors, and work experience since graduation, in addition to interest in helping people. By comparison, the least influential factors influencing specialty preference include financial costs of vocational training, risk of litigation and associated insurance costs, financial costs of medical school education and/or debt, and influence of parents/relatives.https://www.otago.ac.nz/faculty-medicine/education/mbchb/about/accountability/external/msod-projec

Tikanga and Ethical Considerations for Visual Research with Rangatahi Māori

Visual research is a powerful tool to communicate lived experiences of marginalised communities (Hodgetts et al. 2022). However, there is still much ethical consideration to navigate in the space for researchers working with Māori engaging in visual research, particularly as it relates to Māori data sovereignty (MDS). Institutional ethics are not set up in ways that take account of tikanga in relation to visual research with Māori. Using Te Rōpū Hiko , Harnessing the Spark of Life , as a case study, we unpack how we navigated MDS in ethics when engaging with photo data. A values‐based framework grounded in kaupapa Māori principles (mātāpono) was developed to guide visual research through the first author's master's thesis, fostering critical dialogue and aligning with Māori aspirations. This framework encourages ethical integrity, participant autonomy, and cultural responsiveness in research with rangatahi Māori and their communities. This manuscript emphasises the importance of all researchers engaging respectfully with Māori communities through embedding cultural practices like Māori tikanga into research

Probing the Mechanism of Action of Battacin Analogues Against Phytophthora Using Photoaffinity Labelling Peptide Probes

Phytophthora—derived from the Greek phyton (plant) and phthora (destroyer)—is a genus of highly destructive, fungus-like microorganisms belonging to the oomycetes, commonly referred to as “water moulds.” Species within this genus pose a significant threat to biodiversity and agriculture worldwide, as exemplified by the Irish Potato Famine, which was caused by the pathogen Phytophthora infestans. In New Zealand, Phytophthora agathicida has caused extensive mortality of native kauri (Agathis australis), while Phytophthora cinnamomi significantly impacts avocado production. Current control strategies rely largely on systemic fungicides, which have limitations because of resistance development and their inability to eradicate the pathogen once it is established in the soil, underscoring the need to identify molecular targets essential to Phytophthora pathogenicity. In this study, novel photoreactive peptide probes derived from linear battacin analogues that arrested the motility of Phytophthora zoospores were developed to potentially identify molecular targets of these peptides in Phytophthora zoospores. Initial proof-of-concept probes containing only photoreactive moieties were synthesised to assess photochemical behaviour relative to literature precedents. Building on these results, proteomics-compatible probes incorporating alkyne handles were prepared to enable bioorthogonal labelling via CuAAC chemistry. These probes were applied in photoaffinity labelling experiments, allowing probe–target complexes to be visualised by fluorescence imaging following SDS-PAGE and enabling downstream proteomics-based target discovery. All probes were synthesised using solid-phase peptide synthesis and characterised by LC–MS and RP-HPLC prior to biological evaluation. Preliminary zoospore motility, germination, and anti-mycelial assays revealed concentration-dependent biological activity, supporting the suitability of these probes for target identification studies. Collectively, this work establishes a chemical biology platform for elucidating the molecular targets of battacin analogues in Phytophthora zoospores and provides a foundation for future molecular target identification relevant to disease control

Evaluation of the potential for anti-predator stocking to reduce crop losses due to fish predation in Greenshell™ mussel (Perna canaliculus) farms

Enormous losses of juvenile mussels are commonplace in mussel aquaculture worldwide. Fish predation is one important contributor to these losses in many mussel growing regions. The Greenshell™ mussel industry in New Zealand is particularly susceptible to fish predation, where farmers have reported losses of seed mussels of up to 100 %. The current practice for seeding juvenile Greenshell™ mussels onto coastal farms is to deploy the mussels alongside a continuous longline growing rope enclosed in a cotton stocking which holds the mussels against the rope. The mussels subsequently attach to the rope with byssus threads before the cotton degrades. During this vulnerable period, the stocking may also help to protect the juvenile mussels from fish predators whilst they are unattached to any substrate. This study investigated whether differences in the strength and weave of three types of stocking (i.e., a 54-loop weave commonly used in New Zealand, a smaller and more tightly woven stocking used in shellfish hatcheries, and a 42-loop stocking that combines two weaves of cotton together) might affect the amount of fish predation on juvenile mussels that were newly seeded onto growing rope. In an experiment, the three types of cotton stocking were each subjected to three levels of predation by restricting fish access to the growing ropes seeded with juvenile mussels by attaching full, partial and no plastic mesh cages around the ropes. The number of mussels lost from each of the treatment combinations were assessed after 12, 31, and 42 days. At 42 days on average only 15.1 % (± 1.7 SE) of the seeded juvenile mussels remained on those growing ropes subjected to full fish predation, with no differences in mussel losses among three types of socking. In contrast, on average 90.7 % (± 2.1 SE) of the seeded juvenile mussels remained on growing ropes protected from fish predation by the full mesh cages, and 87.5 % (± 3.7 SE) for partial cages. For both types of protective cages there was no difference in the numbers of remaining juvenile mussels among the three types of stocking. Remote underwater video camera observations confirmed Australasian snapper (Chrysophrys auratus) were feeding on the juvenile mussels from the dropper ropes without protective cages. These results show that physical protection by cages protects juvenile mussels from fish predation, while cotton stocking, regardless of the type of stocking, is not effective for preventing fish predation. The results also show that the majority of mussel losses in the uncaged treatment occurred in the first 12 days of the experiment, indicating that vulnerability to predation may be associated with the initial lack of byssus attachment to the growing rope. Overall, these results point to a need to develop more effective methods for mitigating the high losses of seed mussels after they are seeded onto growing ropes

Systemic lupus erythematosus in general practice

Systemic lupus erythematosus (SLE) is a rare multi-system autoimmune condition that presents symptomatically to general practice. Longer diagnostic intervals are generally associated with poorer health outcomes. The study aims to investigate the prevalence, presentation and time intervals from symptom onset to diagnosis in patients with SLE enrolled in general practice. Using computerised records from 14 general practices in Hamilton between 1 January 2000 to 20 March 2024, potential SLE cases were identified. All records were manually reviewed to identify the diagnosis based on the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria. The World Health Organization (WHO) age-standardised prevalence was calculated on definite and probable cases. Records were reviewed prior to diagnosis to understand the interval time from first presentation of symptoms to referral and diagnosis. From a total practice population of 96,348, 68 (0.1%) SLE cases were identified (55 definite, 6 probable, 7 possible). The average prevalence of SLE in 2024 was 90 per 100,000 for women and 13.5 per 100,000 for men. Pacific people were 1.6 times higher than non-Pacific people to have SLE (RR 1.57, SE 0.17, 95% CI 1.12-2.20). Most patients presented with musculoskeletal symptoms (42%) and attended to a health care professional (HCP) within one month of symptom onset (44%). The HCPs were primarily general practitioners (69.1%). The total median time from symptom onset to diagnosis was 150.5 days (4.9 months). Majority of the patients’ journey to diagnosis was primarily spent with the initial HCP (median 11.5, range 0-694, average 79.9 days) and on the wait list to see the first hospital specialist (median 34.5, range 0-276, average 53.4 days). The prevalence of SLE from these 14 practices is higher than previously reported. The total median time from symptom onset to diagnosis is within target; due to a wide range of outliers with whom it takes considerably longer to reach a diagnosis, on average patients with SLE have a delayed diagnosis. This study reveals areas to reduce delays: the time with the initial HCP, primarily general practitioners, and the wait time before seeing the first hospital specialists

Immunological Correlates of Opsonophagocytosis and Killing for Streptococcus pyogenes

Background: Streptococcus pyogenes (Strep A) causes a wide spectrum of diseases, ranging from superficial pharyngitis and invasive disease to post-immune sequelae such as acute rheumatic fever. There is currently no licensed vaccine for Strep A, and development has been hindered by a lack of known correlates of protection. Identifying immune features associated with in vitro killing of Strep A may help to define candidate correlates of protection. The overall goal of this project was to establish a correlate of killing for the emm12 Strep A strain, which is frequently associated with serious Strep A infections in Aotearoa New Zealand and globally. Methods: Immune-mediated killing of emm12 was quantified in vitro using an opsonophagocytic killing assay (OPKA) that uses HL-60 cells as a source of neutrophils. This was applied to a cohort of serum samples from children with culture-confirmed emm12 and non-emm12 Strep A pharyngitis (n=61). Sera was also analysed using a multiplex immunoassay of conserved and type-specific antigens to measure antibody responses. This incorporated detectors for all antibody isotypes (IgA, IgM, and IgG), IgG subclasses (IgG1-4), and FcγR receptors. Finally, the OPKA and immunoassay data were combined in a systems serology analysis to identify antibody features associated with killing. Results: 70% of serum samples from children that had emm12 pharyngitis were able to kill Strep A, compared with 33-55% of serum from children that had non-emm12 infections. IgG titres were the highest isotype overall, with type-specific responses to the hypervariable region of M12 (M12 HVR) and T12 the most elevated in sera from children with emm12 pharyngitis compared to healthy children. The IgG1 subclass was the most elevated across the conserved antigens, while IgG1 and IgG3 were elevated for type-specific antigens. Multivariate analysis indicated that T12 and M12 HVR-specific antibodies that bind FcγR receptors on phagocytes were enriched in the killing-positive group. Conclusion: Type-specific antibody engagement with FcγR receptors was associated with emm12 killing and appeared to align more strongly with a type-specific functional response than overall antibody magnitude alone. Future studies should determine whether killing of other Strep A strain types is similarly type-specific. These findings provide a step towards identifying a correlate of protection, which would be valuable for Strep A vaccine development

The Association between Gout and Cardiovascular Disease in Aotearoa New Zealand

Over the last two decades there has been mounting evidence of an association between gout and cardiovascular disease (CVD). In Aotearoa New Zealand (NZ), Māori and Pacific peoples have the highest prevalence of gout and have the highest rates of CVD risk factors. This thesis explores the association between gout and cardiovascular disease in three large NZ cohorts. Primary and secondary prevention CVD risk prediction equations have been developed and validated specifically for people living in Aotearoa New Zealand. This includes cardiovascular risk prediction equations for population health planning derived solely from predictors available in routinely collected national health data (VAREANZ) and individual level risk prediction equations developed from a primary prevention cohort (PREDICT-CVD). We linked national and regional health databases in Aotearoa New Zealand and used the available predictors within each cohort to investigate the association of gout with CVD outcomes. Gout was associated with an increased risk of CVD events in both women and men and the current NZ primary prevention equations underestimate CVD risk in people with gout, particularly in NZ European women and Māori men. In men with gout without prior CVD, regular allopurinol dispensing and serum urate control (<0.36mmol/L) was associated with a lower risk of CVD. In contrast, colchicine dispensing was associated with an increased risk of CVD events in men with gout without prior CVD. This research provides justification for the inclusion of gout as a CVD predictor in the NZ primary prevention equations and highlights the urgent need for culturally safe strategies to address the inequities in gout and CVD outcomes in Māori and in Pacific peoples in Aotearoa New Zealand