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STUDY QUESTION Does mitochondrial deficiency affect human embryonic preimplantation development? SUMMARY ANSWER The presence of a pathogenic mitochondrial variant triggers changes in the gene expression of preimplantation human embryos, compromising their development, cell differentiation, and survival. WHAT IS KNOWN ALREADY Quantitative and qualitative anomalies of mitochondrial DNA (mtDNA) are reportedly associated with impaired human embryonic development, but the underlying mechanisms remain unexplained. STUDY DESIGN, SIZE, DURATION Taking advantage of the preimplantation genetic testing for mitochondrial disorders in at-risk couples, we have compared gene expression of 9 human embryos carrying pathogenic variants in either mtDNA genes or nuclear genes encoding mitochondrial protein to 33 age-matched control embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS Single-embryo transcriptomic analysis was performed on whole human blastocyst embryos donated to research. MAIN RESULTS AND THE ROLE OF CHANCE Specific pathogenic mitochondrial variants downregulate gene expression in preimplantation human embryos [566 genes in oxidative phosphorylation (OXPHOS)-deficient embryos], impacting transcriptional regulators, differentiation factors, and nuclear genes encoding mitochondrial proteins. These changes in gene expression primarily alter OXPHOS and cell survival pathways. LIMITATIONS, REASONS FOR CAUTION The number of OXPHOS-deficient embryos available for the study was limited owing to the rarity of this material. However, the molecular signature shared by all these embryos supports the relevance of the findings. WIDER IMPLICATIONS OF THE FINDINGS While identification of reliable markers of normal embryonic development is urgently needed in ART, our study prompts us to consider under-expression of the targeted genes reported here, as predictive biomarkers of mitochondrial dysfunction during preimplantation development. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the ‘Association Française contre les Myopathies (AFM-Téléthon)’ and the ‘La Fondation Maladies Rares’. No competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

Thoracic endovascular aortic repair (TEVAR) explantation remains a challenge due to endovascular graft ingrowth into the aortic wall with time. Surgical access into the aortic arch can be difficult either via sternotomy or thoracotomy, and proximal barbs become engaged firmly into the aortic wall. Explantation often requires extensive thoracic aortic resection, sometimes from the distal aortic arch to the abdominal aorta, followed by reconstruction, risking injury to surrounding neurovascular structures and even death. In cases of blunt thoracic aortic injury, the original injury is often healed, and failed TEVAR could theoretically be removed when thrombotic complications occur. We present a novel technique to facilitate TEVAR recapture with limited distal thoracic aorta replacement.

Platelet count is widely used for the diagnosis and follow-up of patients with dengue. Despite its close viral structural and symptomatic homology, ZIKV infection does not typically induce significant thrombocytopenia. To determine the effect of DENV-2 and ZIKV infection on human platelet precursors we utilized MEG-01 cell line to evaluate the viral infection, viability, innate gene expression and release of platelet-like particles (PLPs). DENV-2 induced a higher proportion of cell death at 48-72 h post-infection than ZIKV. The median range of intracellular NS1+/E+ cells was 11.2% (3.3%-25%) and 5% (3%-8.1%) for DENV-2 and ZIKV, respectively (p = 0.03). MEG-01 cells infected with DENV-2 quickly expressed higher levels of IFN-β, indolamine 2,3-dioxygenase and CXCL10 mRNA compared to ZIKV infected cells and DENV-2 but not ZIKV infection reduced the number PLPs from stimulated MEG-01 cells. The results shed light into mechanisms including thrombocytopenia present in patients with DENV but absent in ZIKV infections.

The benefits of performing locally low-rank (LLR) reconstructions on subsampled diffusion weighted and diffusion kurtosis imaging data employing spatiotemporal encoding (SPEN) methods, is investigated. SPEN allows for self-referenced correction of motion-induced phase errors in case of interleaved diffusion-oriented acquisitions, and allows one to overcome distortions otherwise observed along EPI's phase-encoded dimension. In combination with LLR-based reconstructions of the pooled imaging data and with a joint subsampling of b-weighted and interleaved images, additional improvements in terms of sensitivity as well as shortened acquisition times are demonstrated, without noticeable penalties. Details on how the LLR-regularized, subspace-constrained image reconstructions were adapted to SPEN are given; the improvements introduced by adopting these reconstruction frameworks for the accelerated acquisition of diffusivity and of kurtosis imaging data in both relatively homogeneous regions like the human brain and in more challenging regions like the human prostate, are presented and discussed within the context of similar efforts in the field.

The practice of ovarian stimulation for IVF is undergoing a fundamental re-evaluation as recent data begin to successfully challenge the traditional paradigm that ovarian stimulation should be aimed at the retrieval of as many oocytes as possible, in the belief that this will increase pregnancy rates. An opposing view is that live birth rate should not be the only end-point in evaluating the success of IVF treatment and that equal emphasis should be placed on safety and affordability. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) committee has carried out an up-to-date literature search, with the evidence being graded according to the University of Oxford's Centre for Evidence-Based Medicine. The recommendations were formulated taking into account the quality of evidence on the efficacy, risk and cost of each intervention. ISMAAR recommends adopting a mild approach to ovarian stimulation in all clinical settings as an increasing body of evidence suggests that mild stimulation is as effective as conventional stimulation, while being safer and less expensive. Mild ovarian stimulation could replace conventional stimulation, thus making IVF safer and more accessible worldwide.

Subject head motion is a major challenge in DWI, leading to image blurring, signal losses, and biases in the estimated diffusion parameters. Here, we investigate a combined application of prospective motion correction and spatial-angular locally low-rank constrained reconstruction to obtain robust, multi-shot, high-resolution diffusion-weighted MRI under substantial motion.Single-shot EPI with retrospective motion correction can mitigate motion artifacts and resolve any mismatching of gradient encoding orientations; however, it is limited by low spatial resolution and image distortions. Multi-shot acquisition strategies could achieve higher resolution and image fidelity but increase the vulnerability to motion artifacts and phase variations related to cardiac pulsations from shot to shot. We use prospective motion correction with optical markerless motion tracking to remove artifacts and reduce image blurring due to bulk motion, combined with locally low-rank regularization to correct for remaining artifacts due to shot-to-shot phase variations.The approach was evaluated on healthy adult volunteers at 3 Tesla under different motion patterns. In multi-shot DWI, image blurring due to motion with 20 mm translations and 30° rotations was successfully removed by prospective motion correction, and aliasing artifacts caused by shot-to-shot phase variations were addressed by locally low-rank regularization. The ability of prospective motion correction to preserve the orientational information in DTI without requiring a reorientation of the b-matrix is highlighted.The described technique is proved to hold valuable potential for mapping brain diffusivity and connectivity at high resolution for studies in subjects/cohorts where motion is common, including neonates, pediatrics, and patients with neurological disorders.

Introducción: La bibliografía ha reportado una estrecha vinculación entre el virus SARS-CoV-2 y las complicaciones neurológicas que afectan al sistema nervioso. El objetivo de este trabajo es describir la evolución y tratamiento de un niño con Síndrome de Guillain-Barré, asociada a infección por SARS-CoV-2, con requerimiento de traqueostomía, en su aspecto motor, deglutorio y respiratorio. Presentación del caso: Niño de 2 años con diagnóstico presuntivo de Síndrome de Guillain-Barré. Como antecedentes, presentó disminución progresiva de la fuerza muscular asociada a dificultad respiratoria, requerimiento de intubación orotraqueal, asistencia ventilatoria mecánica y traqueostomía. Luego de 56 días de implementación del plan de destete, logró la desvinculación de la asistencia ventilatoria mecánica y 7 días más tarde la decanulación. Requirió 68 días de soporte ventilatorio. Se realizó intervención kinésica desde el inicio. Al momento del alta, el paciente lograba sedestación independiente y bipedestación con apoyo, con debilidad distal de miembros superiores e inferiores. Conclusión: Se describió la evolución de un paciente con Síndrome de Guillain-Barré y asociación con infección por SARS-CoV-2, con afectación motora, requerimiento de asistencia ventilatoria mecánica y traqueostomía. Fue dado de alta alcanzando la desvinculación del soporte ventilatorio, decanulación, alimentación oral y persistencia de déficit motor distal.

Funding Acknowledgements Type of funding sources: None. Introduction Patients undergoing percutaneous coronary interventions (PCI) are prone to a wide range of complications, one complication that is constantly correlated with worse prognosis is acute kidney injury (AKI). Gender as an independent risk factor for said complications raised some interest yet studies showed conflicting results so far. Purpose We aimed to investigate the possible relation of gender on the occurrence of AKI among ST elevation myocardial infarction (STEMI) patients undergoing PCI. Methods This retrospective observational study cohort included 2967 consecutive patients admitted with STEMI between the years 2008-2019. Their renal outcomes ware assessed according to KDIGO criteria (AKI- serum creatinine ≥ 0.3 mg/dl from baseline within 48 hours from admission) and in-hospital complications and mortality were reviewed. Results Study population included 544 females and 2400 males. Female patients were older and with more co-morbidities. The occurrence of AKI was significantly higher among females (12.7% vs. 7.8%, p Conclusions While females had higher rates of AKI and severe AKI, gender was non-significant as an independent risk factor after adjusting for other confounding variables. Other comorbidities that were more prevalent in females can account for the difference of AKI between the genders.

Funding Acknowledgements Type of funding sources: None. Background Among Patients with myocardial infarction hospitalized patients, deterioration of renal function resulting in acute kidney injury (AKI) is an important complication, associated with increased length of hospital stay, morbidity and mortality. Given large variation in care for AKI patients and poor outcomes of AKI, the interest in implementing care bundles for AKI is growing. Several reports suggested that compliance with AKI bundles among hospitalized patients resulted in better kidney and patient outcomes non, however, included acute cardiac patients. Purpose We investigated the effect of AKI care bundle (AKI-CB ) utilization on the incidence and renal outcomes of AKI in a large cohort of myocardial infarction patients treated percutaneous coronary intervention (PCI). Methods We Included ST elevation myocardial infarction (STEMI) patients admitted to the cardiac intensive care unit following PCI between January 2008- December 2020. From January 2016 AKI- CB was implemented in our cardiac intensive care unit. AKI-CB consisted of simple standardized investigations and interventions, reminding clinicians of the importance of early AKI detection, management, via strict monitoring of serum creatinine and urine analysis, planning investigations and treatment and guidance about seeking nephrologist advice. .Patients' records were evaluated for the occurrence of AKI, its severity, AKI recovery, length of hospital stay and long term mortality before and after the implementation of AKI-CB. Results 2646 patients were included (1945 patients in the years 2008-2015 and 705 patients in the years 2016-2020). Overall, 232 AKI episodes occurred within the study period (232/2646, 8.7%). Implementation of care bundles resulted in a decrease in the occurrence of AKI from 190/1945 ( 10%) to 42/705 (6%); P1 (20% vs. 25% ; p=0.07), higher AKI recovery ( 62% vs. 45% , p=0.001) and reduction in the length of hospital stay ( 5.2± 6 days vs. 5.9 ± 5 days ; p=0.02). Over a median follow up period of 48 month, mortality was significantly lower following implementation of AKI-CB ( 3.7% vs. 5.8%,p=0.002,figure 1). Using a multivariable regression model, the use of care bundles resulted in a 45% decrease in the relative risk for AKI (HR 0.55, 95% CI 0.37-0.82, p=0.003; figure 2). Conclusion Among STEMI patients, compliance with AKI-CB was independently associated with a decrease in AKI occurrence and better renal outcomes following an AKI event. Further interventions are required to improve utilization of the AKI-CB.

Microbial communities participate in many essential processes from biogeochemical cycles to the maintenance of human health. The structure and functions of these communities are dynamic properties that depend on poorly understood interactions among different species.

Supplementary figures 1 through 8.

Supplementary Table 1

Proper cellular proteostasis, essential for viability, requires a network of chaperones and cochaperones. ATP-dependent chaperonin TRiC/CCT partners with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate the folding of essential eukaryotic proteins. Using cryoEM and biochemical analyses, we determine the ATP-driven cycle of TRiC-PFD-PhLP2A interaction. In the open TRiC state, PhLP2A binds to the chamber’s equator while its N-terminal H3-domain binds to the apical domains of CCT3/4, thereby displacing PFD from TRiC. ATP-induced TRiC closure rearranges the contacts of PhLP2A domains within the closed chamber. In the presence of substrate, actin and PhLP2A segregate into opposing chambers, each binding to the positively charged inner surfaces formed by CCT1/3/6/8. Notably, actin induces a conformational change in PhLP2A, causing its N-terminal helices to extend across the inter-ring interface to directly contact a hydrophobic groove in actin. Our findings reveal an ATP-driven PhLP2A structural rearrangement cycle within the TRiC chamber to facilitate folding.Highlights-Structural analysis of TRiC-mediated folding cycle with cochaperones PhLP2A and PFD.-The interactions of PhLP2A and PFD with TRiC are mutually exclusive.-PhLP2A domains interact in a subunit-specific manner with the TRiC chamber.-PhLP2A domains are rearranged in ATP-closed TRiC to contact actin across the ring interface

Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known to participate in immune responses and play significant functions during infections, the role of MKs within the immune system remains largely unexplored. Histological studies of sepsis patients identified increased nucleated CD61+ cells (MKs) in the lungs, and CD61+ staining (likely platelets within microthrombi) in the kidneys, which correlated with the development of organ dysfunction. Detailed imaging cytometry of peripheral blood from patients with sepsis found significantly higher MK counts, which we predict would likely be misclassified by automated hematology analyzers as leukocytes. Utilizing in vitro techniques, we show that both stem cell derived MKs (SC MKs) and cells from the human megakaryoblastic leukemia cell line, Meg-01, undergo chemotaxis, interact with bacteria, and are capable of releasing chromatin webs in response to various pathogenic stimuli. Together, our observations suggest that MK cells display some basic innate immune cell behaviors and may actively respond and play functional roles in the pathophysiology of sepsis.

NMR spectroscopy is the only method to access the structural dynamics of biomolecules at high (atomistic) resolution in their native solution state. However, this method's low sensitivity has two important consequences: (i) typically experiments have to be performed at high concentrations that increase sensitivity but are not physiological, and (ii) signals have to be accumulated over long periods, complicating the determination of interaction kinetics on the order of seconds and impeding studies of unstable systems. Both limitations are of equal, fundamental relevance: non-native conditions are of limited pharmacological relevance, and the function of proteins, enzymes and nucleic acids often relies on their interaction kinetics. To overcome these limitations, we have developed applications that involve 'hyperpolarized water' to boost signal intensities in NMR of proteins and nucleic acids. The technique includes four stages: (i) preparation of the biomolecule in partially deuterated buffers, (ii) preparation of 'hyperpolarized' water featuring enhanced

Data on preimplantation genetic testing (PGT-M) in patients with genetic susceptibility to cancer are scarce in the literature, while there is, in our experience, a growing familiarity with assisted reproduction techniques (ART) among pathogenic variant heterozygotes. We performed a retrospective multicenter study of PGT-M outcomes among French patients with genetic susceptibility to cancer. Our objectives were to collect data on this complex issue, and to help cancer geneticists counsel their patients of reproductive age. We also wanted to increase awareness regarding PGT-M among cancer genetics professionals. Patients from three university hospital cancer genetics clinics who had requested PGT-M between 2000 and 2019 were included retrospectively. Data were extracted from medical records. Patients were then contacted directly to collect missing and up-to-date information. Out of 41 eligible patients, 28 agreed explicitly to participate when contacted and were therefore included. They carried PV in VHL (n = 9), APC (n = 8), CDH1 (n = 5), STK11 (n = 2), AXIN2, BRCA1, MEN1, and FH (n = 1). Seven patients were denied PGT-M based on multidisciplinary team meetings or subsequently by the ART hospital teams, two changed their minds, and two were yet to start the process. PGT-M was successful in seven patients (25%), with a mean age at PGT-M request of 27. Most had von Hippel-Lindau. PGT-M failed in the remaining ten, with a mean age at PGT-M request of 32. The main reason for failure was non-implantation of the embryo. Of these, four patients were pursuing PGT-M at the time of last contact. PGT-M outcomes in patients with cancer susceptibility syndromes were satisfactory. These patients should be informed about PGT-M more systematically, which would imply greater awareness among cancer genetics professionals regarding ART. Our series was not representative of cancer susceptibility syndromes in general; the predominance of cases with syndromes characterized by early-onset, highly penetrant disease is explained by the restrictive French guidelines.

The standard assumption in social learning environments is that agents learn from others through choice outcomes. We argue that in many settings, agents can also infer information from others’ response times (RT), which can increase efficiency. To investigate this, we conduct a standard information cascade experiment and find that RTs do contain information that is not revealed by choice outcomes alone. When RTs are observable, subjects extract this private information and are more likely to break from incorrect cascades. Our results suggest that in environments where RTs are publicly available, the information structure may be richer than previously thought. This paper was accepted by Yan Chen, decision analysis.

AIMS Although routine echocardiographic parameters as ejection fraction are used to risk stratify for death in patients referred for echocardiography, they have limited predictive value. We speculated that non-invasive hemodynamic echocardiographic data, assessing left ventricular (LV) filling pressure and output, stratified based on the clinical Killip score, may have additive prognostic value on top of routine echocardiographic parameters. We created an echocardiographic correlate of this classification, using diastolic grade and stroke volume index (SVI) as indicators of pulmonary congestion and systemic perfusion, respectively, and evaluated the prognostic value of this correlate. METHODS A retrospective study of consecutive patients (hospitalized or not) referred for echocardiography for a range of cardiac diagnoses in a tertiary medical center. We included patients in sinus rhythm who were evaluated by 2 sonographers, and reviewed by a single cardiologist, 565 patients were included. Patients with normal filling pressures and normal SVI (>35ml/m2) were defined as eKillip class-1. Patients with pseudo-normal or restrictive diastolic patterns and normal SVI were ascribed to eKillip class-2 or 3, respectively. Those with pseudo-normal or restrictive diastolic patterns and a sub-normal SVI were defined as eKillip class-4. RESULTS EKillip class-1 was present in 382 (68%) patients, 115 (20%), 26 (5%) and 42 (7%) were in eKillip classes 2-4 respectively. Median follow-up time was 1056 days (IQR 729-1390). A total of 105 deaths occurred, in a univariate Cox regression analysis showed eKillip class was associated with all-cause mortality, hazard ratio (HR) and 95%CI were - 2.73[1.67-4.48], 3.19[1.42-7.17] and 4.79[2.58-8.89] for each eKillip class above 1, respectively (p

Context Given a shortage of specialty palliative care clinicians and geographic variation in availability, telemedicine has been proposed as one way to improve access to palliative care services for patients with cancer. However, the enduring digital divide raises questions about whether unequal access will exacerbate healthcare disparities. Objectives To examine factors associated with utilization of telemedicine as compared to in-person visits by patients with cancer in the ambulatory palliative care setting. Methods We collected data on patients seen in Supportive Oncology clinic by palliative care clinicians with an in-person or telemedicine visit from March 1 to December 30, 2020. A logistic regression with generalized estimating equation was fit to assess the association between visit type and patient characteristics. Results A total of 491 patients and 1783 visits were identified, including 1061 (60%) in-person visits and 722 (40%) telemedicine visits. Female patients were significantly more likely to utilize telemedicine than male patients (OR 1.46; 95% CI 1.11–1.90). Spanish-speaking patients (OR 0.32, 95% CI 0.17–0.61), those without insurance (OR 0.28, 95% CI 0.15–0.52), and those without an activated patient portal (Inactivated: OR 0.46, 95% CI 0.26–0.82; Pending Activation: OR 0.29, 95% CI 0.18–0.48) were less likely to utilize telemedicine. Conclusion Our study reveals disparities in telemedicine utilization in the ambulatory palliative care setting for patients with cancer who are male, Spanish-speaking, uninsured, or do not have an activated patient portal. In the wake of the COVID-19 pandemic, we can better meet the palliative care needs of patients with cancer through telemedicine only if equity is kept at the forefront of our discussions.

Routine, intermittent inotropic therapy (IIT) is still applied in advanced heart failure (HF) patients either as a bridge to definitive treatment or as a mean to improve quality of life (QOL), despite limited evidence to support its' use. Given recent reports of improved QOL and reduced HF hospitalization, with levosimendan compared with placebo in advanced HF patients, we aimed to assess the effects of switching a small group of milrinone-treated patients to levosimendan. This was performed as part of a protocol for changing our ambulatory HF clinic milrinone-based IIT to levosimendan.Single-centre study of consecutive ambulatory advanced HF patients that received ≥4 cycles of once-weekly milrinone IIT at our HF outpatient clinic, who were switched to levosimendan IIT. All patients had left ventricular ejection fraction ≤35%, elevated B-natriuretic peptide (BNP), and were in New York Heart Association Classes III-IV despite maximally tolerated guideline directed medical therapy. Patients were evaluated using BNP levels, echocardiography, cardio-pulmonary exercise test, and HF QOL questionnaire before and after 4 weeks of levosimendan IIT. The cohort included 11 patients, 10 (91%) were male and the mean age was 76 ± 12 years. After 4 weeks of levosimendan therapy, maximal OIn this small-scale study of ambulatory advanced HF patients, we observed improvements in right ventricular systolic function, maximal O

Background: Palliative care (PC) services expanded rapidly to meet the needs of coronavirus disease 2019 (COVID-19) patients, yet little is known about which patients were referred for PC consultation during the pandemic. Objective: Examine factors predictive of PC consultation for COVID-19 patients. Design: Retrospective cohort study of COVID-19 patients discharged from four hospitals (March 1–June 30, 2020). Exposures: Patient demographic, socioeconomic, and clinical factors and hospital-level characteristics. Outcome Measurement: Inpatient PC consultation. Results: Of 4319 hospitalized COVID-19 patients, 581 (14%) received PC consultation. Increasing age, serious illness (cancer, chronic obstructive pulmonary disease, and dementia), greater illness severity, and admission to the quaternary hospital were associated with receipt of PC consultation. There was no association between PC consultation and race/ethnicity, household crowding, insurance status, or hospital-factors, including inpatient, emergency department, and intensive care unit census. Conclusions: Although site variation existed, the highest acuity patients were most likely to receive PC consultation without racial/ethnic or socioeconomic disparities.

Objetivo: Describir las características clínico-demográficas de sujetos pediátricos críticos crónicos internados en un centro de desvinculación de ventilación mecánica. El objetivo secundario consiste en describir la tasa de éxito de desvinculación de la ventilación mecánica, decanulación y mortalidad. Materiales y método: Estudio descriptivo, tipo serie de casos, de sujetos pediátricos críticos crónicos internados en una unidad de rehabilitación. Resultados: La sujetos presentaron al menos dos categorías de enfermedades crónicas según la clasificación de Feudtner, y la más frecuente fue la dependencia de tecnología. Los antecedentes más frecuentes fueron las enfermedades congénitas, cardiovasculares y neurológicas. La tasa de desvinculación, decanulación, mortalidad y alta al hogar de los sujetos que ingresaron traqueostomizados fue del 50%, 18%, 9% y 27%, respectivamente. Conclusión: Los sujetos pediátricos críticos crónicos traqueostomizados internados en nuestro centro de rehabilitación presentaron al menos dos categorías de enfermedades crónicas. La mayoría eran sujetos de sexo masculino, menores de dos años y con internación prolongada. A pesar de que se desvincularon la mitad, solo el 18% lograron decanularse, con mortalidad baja. Por este motivo, los sujetos pediátricos con dependencia de tecnología y alta sobrevida requieren ser atendidos en unidades especializadas y costo-eficientes, con una mirada multidisciplinaria.

Huntington’s disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

Over the past few decades there has been a dramatic increase in the scale and complexity of data collected from free ranging animals. Advances in data collection have outstripped the development of sufficiently powerful analytical tools. As such, researchers require the ability to store, analyse, interpret and visualise large quantities of animal derived telemetry data. This is achieved through a combination of statistical analysis algorithms and accompanying data analysis software. During the austral summer of 2003/04, a multi-species animal tracking project was conducted at Heard Island. Over a period of 40 days, the offshore movements of Antarctic fur seals, Macaroni penguins and King penguins were tracked using animal-borne transmitters and the Argos satellite system. This project required real-time analysis capabilities to integrate data from multiple predator movements with other contemporaneous data sources. This thesis describes the development of these tools, from the initial package used to direct field efforts to the creation of sophisticated mathematical approaches to the analysis and interpretation of these data. Though developed in response to the Heard Island project, the work presented here is generally applicable to all Argos derived animal movement data. The outcomes of this work are: 1) A purpose built software system that archived, analysed and visualised satellite derived location data. This system provided researchers with near real-time estimates of areas of intensive foraging activity. It was designed to support the quantitative requirements of the predator-prey study at Heard Island. 2) A concise set of equations for the generation of weighted kernel smoothed utilisation distributions (UD). These equations can directly take geographic coordinates (latitude and longitude) without the need for preliminary conversion to a Cartesian based system such as universal transverse Mercator. UDs of animal location tracks were created using weighted and non-weighted kernels and the effect of using different methods for determining smoothing parameter were explored. This study found that the predictive ability of the UD was most effective when using a weighted kernel in conjunction with likelihood crossvalidation.3) A new type of speed filter that uses an evolutionary optimisation algorithm to incorporate an elliptical location error into the positional estimates provided by Argos. When tested against the output of the commonly used filter defined in McConnell et al. 1992, the optimising filter was found to remove half as many locations. 4) A time weighted probability density function (PDF) of speeds travelled by multiple individuals was used to create a population level estimate of movement behaviour. This PDF was incorporated into an algorithm for interpolating movement between locations. The optimisation framework was used to guide the interpolated system so that its PDF matched that of the population level PDF. This system utilised knowledge of location error in conjunction with the population distribution. The interpolated data was then used to generate a weighted kernel density estimate or UD of the animal's movements. This method is called model interpolated kernel smoothing (MIKS). A series of validation tests were conducted to assess the performance of this MIKS to simpler forms of UD such as that created with linear interpolation. MIKS was found to out perform the other types of UD. 5) A flexible software platform for the development of location filtering and location interpolation algorithms that incorporates a form of evolutionary optimisation known as extremal optimisation. This system, written in C++, provides all the functionality required to implement the algorithms described in this thesis. It includes a database for the archival and rapid retrieval of Argos satellite data. It also provides a framework for building a spatial location analysis system. Finally, it provides links to various data analysis and presentation packages including ParaView and R. This series of studies provides a set of analytical tools and supporting software for the interpretation of animal movement data. It utilises a novel approach to exploring probability distributions which will create new opportunities for the development of analytical techniques in the future.

We estimate a general mixture of Markov jump processes. The key novel feature of the proposed mixture is that the transition intensity matrices of the Markov processes comprising the mixture are entirely unconstrained. The Markov processes are mixed with distributions that depend on the initial state of the mixture process. The new mixture is estimated from its continuously observed realizations using the EM algorithm, which provides the maximum likelihood (ML) estimates of the mixture's parameters. We derive the asymptotic properties of the ML estimators. To obtain estimated standard errors of the ML estimates of the mixture's parameters, an explicit form of the observed Fisher information matrix is derived. In its new form, the information matrix simplifies the conditional expectation of outer product of the complete-data score function in the Louis (1982) general matrix formula for the observed Fisher information matrix. Simulation study verifies the estimates' accuracy and confirms the consistency and asymptotic normality of the estimators. The developed methods are applied to a medical dataset, for which the likelihood ratio test rejects the constrained mixture in favor of the proposed unconstrained one. This application exemplifies the usefulness of a new unconstrained mixture for identification and characterization of homogeneous subpopulations in a heterogeneous population., 24 pages, 1 figure