Putting conservation medicine into practice : examples from three endemic New Zealand bird species : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Conservation Biology at Massey University

Conservation medicine is increasingly being viewed as an important component of conservation biology. While programmes focussing on wildlife health are generally limited to controlling the spread of infectious diseases, there is a need to evaluate the impacts of non-infectious diseases: in particular, a critical examination of invasive management practices is overdue. Marking or tagging animals for identification is one of the most common management tools employed by conservation managers, and yet their impacts have rarely been quantified. In the kakapo, Strigops habroptilus, metallic bands applied to the tarsus were implicated in joint problems in the banded leg; in contrast to this, subcutaneously implanted passive integrated transponders appear to be safe and effective in both adults and chicks. In the North Island robin, Petroica longipes, leg bands were directly implicated in leg injuries at a rate of 2% of adults per year. The most common injury was a result of the birds trapping their hallux (back toe) between a band and their leg; this forced the leg into a flexed position and resulted in tissue damage. To accurately interpret clinical pathology data collected in wildlife health assessments, reference ranges for haematological and biochemical data should be generated for each species. In the kakapo, blood samples from 1996 and 2002 allowed these references to be produced; however, this exercise highlighted limitations that are often underappreciated in conservation medicine. Many factors can influence the results: two of these being sample storage and laboratory processing methods. Many conservation programmes cannot collect, store and process samples in an ideal environment and, thus, comparisons between ideally generated reference ranges and data from individuals collected in the field may be spurious. Similarly, opportunistic carcass collection and post-mortem examination provides valuable identification of disease agents, but the findings are difficult to interpret in terms of their importance or prevalence within populations. The description of aspergillosis in a North Island robin is a case in point. The movement of animals for conservation purposes - translocations - is becoming widespread, and has the potential to introduce diseases into disease-free areas; the stitchbird, Notiomystis cincta, is currently the focus of conservation efforts that rely on translocations. Two poorly-understood diseases were examined: facial dermatitis and sub-lingual oral fistulas. The prevalence of facial dermatitis was influenced by season and sex, with males showing a higher prevalence of the condition than females during the breeding season. Histopathology, mite isolation and a therapeutic drug trial all suggest that a burrowing mite, Knemidocoptes spp is responsible for the condition. Sub-lingual oral fistulas are more widespread than previously thought, as they are not limited to birds with obvious tongue protrusions through the tissue deficit in the lower mandible. Evidence supports the hypothesis that these fistulas are acquired after fledging, and have a limited impact on bird productivity and survival

Diametrics:A User-Friendly Web Tool for Custom Analysis of Continuous Glucose Monitoring Data

Background: Continuous Glucose Monitoring (CGM) systems have revolutionized diabetes management by providing real-time blood glucose tracking. However, there is a need for openly accessible tools that can analyze CGM data in relation to specific events like meals or exercise, which often require extensive technical skills to interpret, thus restricting its broader use among researchers and clinicians. Developing user-friendly web applications to facilitate this analysis could significantly broaden accessibility and utility.Method: Diametrics was built with a focus on ease-of-use and versatility. The application’s efficacy was validated against iglu, an established R tool with a no-code web app for CGM analysis, using data from 418 participants from three studies. The unique period-specific analysis feature was demonstrated through an illustrative case study.Results: Diametrics proved effective at replicated established CGM metrics, demonstrating high concordance with iglu. The platform supports a wide range of CGM devices, accommodates data in various formats, and offers extensive customization in the analysis settings. The case study highlighted Diametrics’ ability to integrate exercise-related data with CGM readings, enabling detailed analyses of how different exercise types, intensities, and times of day impact glucose levels.Conclusions: Diametrics is a freely available, reproducible, user-friendly, and accurate web-based tool for CGM data analysis with a unique capability to analyze data over specific time periods. With its intuitive design and open-source accessibility, Diametrics provides a valuable resource in diabetes research and management, empowering users of various technical levels to perform complex analyses with ease

Zones of Contention: A Comparative Analysis of the Impact of Two Regimes of Enrolment Regulations in New Zealand

A number of New Zealand studies have identified a relationship between enrolment regulations and school enrolments, in particular drawing attention to the negative impact that the abandonment of ‘home zones’ in 1991 have had on many lower decile and ethnically diverse schools. The progress of a group of secondary schools within a geographic area in New Zealand from before the introduction of Tomorrow’s Schools in 1989 up to 2009 is tracked using quantitative data from the Ministry of Education, New Zealand Qualifications Authority and Statistics New Zealand combined with qualitative data from interviews with those who were principals during the period. This mixed-methods approach shows that both enrolment numbers and academic achievement in three of the four schools fell and then rose almost simultaneously with the removal in 1991 and then reinstatement in 2000 of geographic home zones. The ethnic and socioeconomic polarisation that resulted from the earlier change, however, has not reversed. The quantitative and qualitative data together provide clear evidence that geographic home zones provide a level of stability and security in the provision of education at a local level that is not matched by the alternative regulatory regime that operated in the 1990s

IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses.

Mouse and human dendritic cells (DCs) are composed of functionally specialized subsets, but precise interspecies correlation is currently incomplete. Here, we showed that murine lung and gut lamina propria CD11b+ DC populations were comprised of two subsets: FLT3- and IRF4-dependent CD24(+)CD64(-) DCs and contaminating CSF-1R-dependent CD24(-)CD64(+) macrophages. Functionally, loss of CD24(+)CD11b(+) DCs abrogated CD4+ T cell-mediated interleukin-17 (IL-17) production in steady state and after Aspergillus fumigatus challenge. Human CD1c+ DCs, the equivalent of murine CD24(+)CD11b(+) DCs, also expressed IRF4, secreted IL-23, and promoted T helper 17 cell responses. Our data revealed heterogeneity in the mouse CD11b+ DC compartment and identifed mucosal tissues IRF4-expressing DCs specialized in instructing IL-17 responses in both mouse and human. The demonstration of mouse and human DC subsets specialized in driving IL-17 responses highlights the conservation of key immune functions across species and will facilitate the translation of mouse in vivo findings to advance DC-based clinical therapies

Archiving primary data: solutions for long-term studies

The recent trend for journals to require open access to primary data included in publications has been embraced by many biologists, but has caused apprehension amongst researchers engaged in long-term ecological and evolutionary studies. A worldwide survey of 73 principal investigators (Pls) with long-term studies revealed positive attitudes towards sharing data with the agreement or involvement of the PI, and 93% of PIs have historically shared data. Only 8% were in favor of uncontrolled, open access to primary data while 63% expressed serious concern. We present here their viewpoint on an issue that can have non-trivial scientific consequences. We discuss potential costs of public data archiving and provide possible solutions to meet the needs of journals and researchers

Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC

This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as $3$ ab$^{-1}$ of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as $15$ ab$^{-1}$ of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by $20-50\%$ on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Towards a Muon Collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work.Comment: 118 pages, 103 figure