Insights into the clinical presentation, diagnostics and outcome in dogs presenting with neurological signs secondary to infection with Neospora caninum: 41 cases (2014-2023).

OBJECTIVES: To describe the clinical signs and outcome of a large cohort of dogs presenting with neurological signs secondary to Neospora caninum infection. MATERIALS AND METHODS: Retrospective review of cases presenting to two UK referral centres with neurological signs secondary to N. caninum infection between 2014 and 2023. Presenting signs, diagnostic test results, treatment, short- and long-term outcome analysed. RESULTS: A total of 1690 cases were assessed for eligibility. Forty-four cases with a diagnosis of neosporosis were obtained. Three cases were then excluded due to non-neurological presentations (two hepatitis and one myocarditis). A total of 41 cases were included in the study. Cerebello-vestibular signs predominated; however, presenting clinical signs were varied and the neurolocalisation was often multifocal in nature (46.3%), making neosporosis an important differential diagnosis for meningoencephalitis of unknown origin. Complete clinical improvement was rare (5.6%), and relapses were common (27.8% cases with follow-up). CLINICAL SIGNIFICANCE: Neosporosis remains an important differential diagnosis for dogs at any age presenting with multifocal neurological signs. The outcome is considered poor and relapse rate is high.

Cross-Sectional Quantitative Evaluation of a Novel Patient-Reported Outcome Measure in Familial Chylomicronemia Syndrome.

Background: Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder that impacts physical, emotional, social, and cognitive functioning. The FCS-Symptom and Impact Scale (FCS-SIS) patient-reported outcome (PRO) measure assesses common symptoms and impacts of FCS. This study was conducted to evaluate cross-sectional psychometric properties of the FCS-SIS and its scoring method. Methods: This multisite, cross-sectional, observational study of individuals with FCS was conducted in the United States and Canada. Participants completed a survey composed of 7 PRO measures, including the FCS-SIS, and questions about clinical characteristics and demographics. The structure of the FCS-SIS was evaluated using inter-item and item-scale correlations and internal consistency reliability. Construct, known-groups, and criterion validity were evaluated by examining associations between FCS-SIS item and composite scores and other measures included within the survey. Results: Most of the 33 participants were female (63.6%) and White (78.1%). On average, participants reported first noticing FCS symptoms at ~16 years, with abdominal pain the most frequently reported initial symptom (n=20). Participants reported 2.5 acute pancreatitis attacks on average over the past year. Average FCS-SIS symptom item scores ranged from 1.8 to 3.9 (on a 0-to-10 scale [none-to-worst-possible]) within the 24-hour recall period, with an average Symptom composite score of 2.7. The average impact item scores on the FCS-SIS ranged from 1.6 to 3.0 (on a 0-to-4 scale), with an average Impact composite score of 2.1. Inter-item correlations between the FCS-SIS Symptom items ranged from 0.32 to 0.78. Corrected item-total correlations were highly satisfactory for Impact items, ranging from 0.62 to 0.85. All a priori validity hypotheses were supported by observed correlations and score differences between known groups. Conclusion: The results of this study support the structure, reliability, and validity of the FCS-SIS, laying the psychometric groundwork for longitudinal evaluation of its utility in assessing treatment benefit in FCS clinical studies.

Polychlorinated biphenyl and polybrominated diphenyl ether profiles vary with feeding ecology and marine rearing distribution among 10 Chinook salmon (Oncorhynchus tshawytscha) stocks in the North Pacific Ocean.

Chinook salmon (Oncorhynchus tshawytscha) along the west coast of North America have experienced significant declines in abundance and body size over recent decades due to several anthropogenic stressors. Understanding the reasons underlying the relatively high levels of persistent organic pollutants (POPs) in Chinook stocks is an important need, as it informs recovery planning for this foundation species, as well for the Chinook-dependent Resident killer whales (Orcinus orca, RKW) of British Columbia (Canada) and Washington State (USA). We evaluated the influence of stock-related differences in feeding ecology, using stable isotopes, and marine rearing ground on the concentrations and patterns of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Chinook salmon. A principal components analysis (PCA) revealed a clear divergence of PCB and PBDE congener patterns between Chinook with a nearshore rearing distribution ('shelf resident') versus a more offshore distribution. Shelf resident Chinook had 12-fold higher PCB concentrations and 46-fold higher PBDE concentrations relative to offshore stocks. Shelf resident Chinook had PCB and PBDE profiles that were heavier and dominated by more bioaccumulative congeners, respectively. The higher δ13C and δ15N in shelf resident Chinook compared to the offshore rearing stocks, and their different marine distributions explain the large divergence in contaminant levels and profiles, with shelf resident stocks being heavily influenced by land-based sources of industrial contamination. Results provide compelling new insight into the drivers of contaminant accumulation in Chinook salmon, raise important questions about the consequences for their health, and explain a major pathway to the heavily POP-contaminated Resident killer whales that consume them.

Metrics for estimating vapour pressure deviation from ideality in binary mixtures.

A novel method is introduced for estimating the degree of interactions occurring between two different compounds in a binary mixture resulting in deviations from ideality as predicted by Raoult's law. Metrics of chemical similarity between binary mixture components were used as descriptors and correlated with the Root-Mean Square Error (RMSE) associated with Raoult's law calculations of total vapour pressure prediction, including Abraham descriptors, sigma moments, and several chemical properties. The best correlation was for a quantitative structure-activity relationship (QSAR) equation using differences in Abraham parameters as descriptors (r2 = 0.7585), followed by a QSAR using differences in COSMO-RS sigma moment descriptors (r2 = 0.7461), and third by a QSAR using differences in the chemical properties of log KAW, melting point, and molecular weight as descriptors (r2 = 0.6878). Of these chemical properties, Δlog KAW had the strongest correlation with deviation from Raoult's law (RMSE) and this property alone resulted in an r2 of 0.6630. These correlations are useful for assessing the expected deviation in Raoult's law estimations of vapour pressures, a key property for estimating inhalation exposure.

Regulation of mouse exploratory behaviour by irradiance and cone-opponent signals.

BACKGROUND: Animal survival depends on the ability to adjust behaviour according to environmental conditions. The circadian system plays a key role in this capability, with diel changes in the quantity (irradiance) and spectral content ('colour') of ambient illumination providing signals of time-of-day that regulate the timing of rest and activity. Light also exerts much more immediate effects on behaviour, however, that are equally important in shaping daily activity patterns. Hence, nocturnal mammals will actively avoid light and dramatically reduce their activity when light cannot be avoided. The sensory mechanisms underlying these acute effects of light are incompletely understood, particularly the importance of colour. RESULTS: To define sensory mechanisms controlling mouse behaviour, we used photoreceptor-isolating stimuli and mice with altered cone spectral sensitivity (Opn1mwR), lacking melanopsin (Opn1mwR; Opn4-/-) or cone phototransduction (Cnga3-/-) in assays of light-avoidance and activity suppression. In addition to roles for melanopsin-dependent irradiance signals, we find a major influence of spectral content in both cases. Hence, remarkably, selective increases in S-cone irradiance (producing a blue-shift in spectrum replicating twilight) drive light-seeking behaviour and promote activity. These effects are opposed by signals from longer-wavelength sensitive cones, indicating a true spectrally-opponent mechanism. Using c-Fos-mapping and multielectrode electrophysiology, we further show these effects are associated with a selective cone-opponent modulation of neural activity in the key brain site implicated in acute effects of light on behaviour, the subparaventricular zone. CONCLUSIONS: Collectively, these data reveal a mechanism whereby blue-shifts in the spectrum of environmental illumination, such as during twilight, promote mouse exploratory behaviour.

Colour opponency is widespread across the mouse subcortical visual system and differentially targets GABAergic and non-GABAergic neurons.

Colour vision plays many important roles in animal behaviour but the brain pathways processing colour remain surprisingly poorly understood, including in the most commonly used laboratory mammal, mice. Indeed, particular features of mouse retinal organisation present challenges in defining the mechanisms underlying colour vision in mice and have led to suggestions that this may substantially rely on 'non-classical' rod-cone opponency. By contrast, studies using mice with altered cone spectral sensitivity, to facilitate application of photoreceptor-selective stimuli, have revealed widespread cone-opponency across the subcortical visual system. To determine the extent to which such findings are truly reflective of wildtype mouse colour vision, and facilitate neural circuit mapping of colour-processing pathways using intersectional genetic approaches, we here establish and validate stimuli for selectively manipulating excitation of the native mouse S- and M-cone opsin classes. We then use these to confirm the widespread appearance of cone-opponency (> 25% of neurons) across the mouse visual thalamus and pretectum. We further extend these approaches to map the occurrence of colour-opponency across optogenetically identified GABAergic (GAD2-expressing) cells in key non-image forming visual centres (pretectum and intergeniculate leaflet/ventral lateral geniculate; IGL/vLGN). Strikingly, throughout, we find S-ON/M-OFF opponency is specifically enriched in non-GABAergic cells, with identified GABAergic cells in the IGL/VLGN entirely lacking this property. Collectively, therefore, we establish an important new approach for studying cone function in mice, confirming a surprisingly extensive appearance of cone-opponent processing in the mouse visual system and providing new insight into functional specialisation of the pathways processing such signals.

Design and development of microformulations for rapid release of small molecules and oligonucleotides.

A systemic delivery of therapeutics frequently results in sub-optimal exposure of the targeted locus and undesired side effects. To address these challenges, a platform for local delivery of diverse therapeutics by remotely controlled magnetic micro-robots was introduced. The approach involves micro-formulation of active molecules using hydrogels that exhibit wide range of loading capabilities and predictable release kinetics. This work introduces two specific hydrogels based on thiol-maleimide and PEG-PLA-diacrylate chemistries that afford high, reliable and reproducible loading and release of several model molecules including doxorubicin, 25-mer poly-dT oligonucleotide and a 5.4 kBp GFP DNA plasmid. The described formulations are suitable for micro-dosing using both conventional or remote delivery devices.

Ictal face perception disturbance, tattoos, and reclaiming the self.

We present a case of a young man with frightening ictal disturbance of face perception, or prosopometamorphopsia, arising from the left temporo-occipital region, leading to significant psychosocial impairment. A vivid forearm tattoo of the ictal experience conveyed its nature to the treating team and facilitated a psychotherapeutic process leading to significant psychosocial recovery. This case highlights the marked psychosocial and developmental impacts of epilepsy and the benefit of incorporating these into assessment and treatment.

Extensive regional variation in the phenology of insects and their response to temperature across North America.

Climate change models often assume similar responses to temperatures across the range of a species, but local adaptation or phenotypic plasticity can lead plants and animals to respond differently to temperature in different parts of their range. To date, there have been few tests of this assumption at the scale of continents, so it is unclear if this is a large-scale problem. Here, we examined the assumption that insect taxa show similar responses to temperature at 96 sites in grassy habitats across North America. We sampled insects with Malaise traps during 2019-2021 (N = 1041 samples) and examined the biomass of insects in relation to temperature and time of season. Our samples mostly contained Diptera (33%), Lepidoptera (19%), Hymenoptera (18%), and Coleoptera (10%). We found strong regional differences in the phenology of insects and their response to temperature, even within the same taxonomic group, habitat type, and time of season. For example, the biomass of nematoceran flies increased across the season in the central part of the continent, but it only showed a small increase in the Northeast and a seasonal decline in the Southeast and West. At a smaller scale, insect biomass at different traps operating on the same days was correlated up to ~75 km apart. Large-scale geographic and phenological variation in insect biomass and abundance has not been studied well, and it is a major source of controversy in previous analyses of insect declines that have aggregated studies from different locations and time periods. Our study illustrates that large-scale predictions about changes in insect populations, and their causes, will need to incorporate regional and taxonomic differences in the response to temperature.

Development of an Assessment Tool for Completion by Patients with Overweight or Obesity.

INTRODUCTION: Discussions of weight-management strategies between patients and healthcare providers can yield positive outcomes for people with overweight or obesity. Nonetheless, people with overweight or obesity encounter communication challenges and other barriers to pursuing effective weight-management strategies with their healthcare providers. The aim of this study was to develop a new self-completed assessment tool to initiate and facilitate conversations related to weight management between patients and healthcare providers. METHODS: Developing the assessment tool involved a series of steps and draft versions of the tool, based on feedback from key opinion leaders in the field of obesity (N = 4) and input from people with overweight or obesity (N = 18). Three iterative rounds of qualitative interviews were conducted in the USA. A targeted review of prior qualitative research was conducted to identify common and important impacts of obesity on patients' functioning. Standard qualitative analytical methods were used to identify concepts of importance in a concept elicitation exercise during the interviews and were evaluated for potential inclusion in the tool. Potential problems with the tool were flagged during cognitive debriefing of the draft tool. RESULTS: During 18 individual interviews, participants referenced the impact of their weight on their lives, including health and comorbidities, physical function, emotional/mental functioning, social life, and physical appearance. Over the course of the tool's development, 24 common and important impacts of obesity on patients' functioning were reduced to a final set of eight concepts in the final tool that were deemed important and relevant to both patients and key opinion leaders. CONCLUSIONS: The assessment tool is a five-item, self-completed measure expected to foster patient self-advocacy for individuals with overweight or obesity by giving them an opportunity to define their weight-management goals and discuss these, along with various medical interventions, with a healthcare provider.

Temperature-controlled Laminar Airflow (TLA) in symptomatic severe asthma - a post hoc analysis of severe exacerbations, quality of life and health economics.

PURPOSE: Uncontrolled severe asthma constitutes a major economic burden to society. Add-ons to standard inhaled treatments include inexpensive oral corticosteroids and expensive biologics. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett®) could be an effective, safe and cheaper alternative. The potential of TLA in reducing severe asthma exacerbations was addressed in a recent randomised placebo-controlled trial (RCT) in patients with severe asthma (Global Initiative for Asthma (GINA) step 4/5), but the results were inconclusive. We re-analysed the RCT with severe exacerbations stratified by the level of baseline asthma symptoms and Quality of Life. METHODS: More uncontrolled patients, defined by Asthma Control Questionnaire 7 (ACQ7) > 3, EuroQoL 5-Dimension Questionnaire Visual Analogue Scale (EQ5D-VAS) ≤ 65 and Asthma Quality of Life Questionnaire (AQLQ) ≤ 4 were selected for re-analysis. The rates of severe asthma exacerbations, changes in QoL and health-economics were analysed and compared between TLA and placebo. RESULTS: The study population included 226 patients (113 TLA / 113 placebo.) The rates of severe asthma exacerbations were reduced by 33, 31 and 25% (p = 0.083, 0.073, 0.180) for TLA compared to placebo, dependent on selected control measures (ACQ7, EQ5D-VAS, AQLQ, respectively). For patients with less control defined by AQLQ≤4, the difference in mean AQLQ0-12M between TLA and placebo was 0.31, 0.33, 0.26 (p = 0.085, 0.034, 0.150), dependent on selected covariate (AQLQ, EQ5D-VAS, ACQ7, respectively). For patients with poor control defined by ACQ7 > 3, the difference in EQ5D-5 L utility scores between TLA and placebo was significant at 9 and 12 months with a cost-effective ICER. The results from the original study did not demonstrate these differences. CONCLUSION: This post hoc analysis demonstrated an effect of TLA over placebo on severe exacerbations, asthma control and health economics in a subgroup of patients with more symptomatic severe allergic asthma. The results are consistent with the present recommendations for TLA. However, these differences were not demonstrated in the full study. Several explanations for the different outcomes have been outlined, which should be addressed in future studies. FUNDING: NIHR Health Technology Assessment Programme and Portsmouth Hospitals NHS Trust.

Exploring life engagement from the perspective of patients with major depressive disorder: a study using patient interviews.

BACKGROUND: Patient-reported outcomes can measure health aspects that are meaningful to patients, such as 'life engagement' in major depressive disorder (MDD). Expert psychiatrists recently identified ten items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR) that can be used to measure patient life engagement. This study aimed to explore the concept of patient life engagement and provide support for the IDS-SR10 Life Engagement subscale from the patient perspective. METHODS: Semi-structured video interviews were conducted with adults with MDD in the United States. Patients were asked if they ever felt engaged with life, and how this affected their feelings, activities, socializing, and thoughts. Then, patients discussed the ten expert-selected IDS-SR items, and rated the relevance of all 30 items to patient life engagement on a 4-point scale. RESULTS: Patients (N = 20) understood the 'engaged with life' concept and could provide examples from their own lives, such as increased energy/motivation (100%), being more social/spending time with others (85%), being more communicative (80%), and having better mood (75%). Nineteen patients (95%) indicated that all ten IDS-SR10 Life Engagement items were relevant to patient life engagement, and nine of the ten items had a mean score ≥ 3 (moderately relevant). Four additional items (all relating to mood) also scored ≥ 3. CONCLUSIONS: Patients found the concept of life engagement to be important and relatable, and confirmed the IDS-SR10 captures the defining non-mood-related aspects of patient life engagement. This research supports the relevance of patient life engagement as a potential clinical outcome beyond core mood symptoms, and the use of the IDS-SR10 Life Engagement subscale in patient-oriented research.

Risk factors for early death or euthanasia within 100 days of diagnosis in dogs with meningoencephalitis of unknown origin.

Meningoencephalitis of unknown origin (MUO) in the dog is an inflammatory condition of the central nervous system with variable short- and long-term prognosis. Previous studies have attempted to identify risk factors for early death; however, the findings were inconsistent and prognostication and treatment selection remain difficult for cases of MUO. The aim of this study was to compare the influence of putative prognostic factors on early survival in dogs with MUO. Logistic regression was used to analyse the effect of clinical and magnetic resonance imaging (MRI) features at diagnosis and type of immune-suppressive treatment received on survival at three-time points; 7 days, 30 days, and 100 days post-diagnosis. Ninety eight dogs were included. Dogs that were obtunded at presentation had a 6.6 times increased odds of death in the first 7 days after diagnosis, a 2.1 times increased risk of death 8-30 days after diagnosis, and a 1.9 times increased risk of death 31-100 days after diagnosis. No other clinical, MRI feature, or treatment was found to have a significant influence on survival. Obtundation at presentation was found to increase risk of early euthanasia in dogs with MUO, while the addition of an IV infusion of cytarabine to immune-suppressive corticosteroid therapy (prednisolone and/or dexamethasone) at initial treatment did not improve the odds of survival at 7, 30, or 100 days after diagnosis.

Differences in Muscle Quantity and Quality by HIV Serostatus and Sex.

OBJECTIVE: People with HIV (PWH) experience greater declines in both muscle function and muscle mass with aging. Whether changes in muscle quality and quantity with aging differ between men and women with HIV and the implications on muscle function are not established. DESIGN: In coordinated substudies of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study, participants completed physical function and falls assessments; total trunk/thigh density, inversely related to fatty infiltration, and area were quantified from computed tomography (CT) scans. METHODS: Generalized linear models were used to explore variables affecting density/area, and associations between area/density and physical function and falls. RESULTS: CT scans were available on 387 men (198 PWH) and 184 women (118 PWH). HIV serostatus was associated with greater lateralis, paraspinal, and hamstring area, but lower psoas area and density. Older age and female sex were associated with smaller trunk muscle area and lower density. Both lower muscle area and muscle density were associated with several measures of impaired physical function. The odds of falling were lower with greater hamstring density, but not associated with other measurers of muscle area or density. CONCLUSIONS: In summary, older adults with HIV appear to have smaller and less dense (fattier) psoas, a key component in truncal stability and hip flexion that could have implications on physical function. The longitudinal associations of muscle area and density with physical function require careful investigation, with a particular focus on characteristics and interventions that can preserve muscle area, density, and function over time.

Trade off-free entanglement stabilization in a superconducting qutrit-qubit system.

Quantum reservoir engineering is a powerful framework for autonomous quantum state preparation and error correction. However, traditional approaches to reservoir engineering are hindered by unavoidable coherent leakage out of the target state, which imposes an inherent trade off between achievable steady-state state fidelity and stabilization rate. In this work we demonstrate a protocol that achieves trade off-free Bell state stabilization in a qutrit-qubit system realized on a circuit-QED platform. We accomplish this by creating a purely dissipative channel for population transfer into the target state, mediated by strong parametric interactions coupling the second-excited state of a superconducting transmon and the engineered bath resonator. Our scheme achieves a state preparation fidelity of 84% with a stabilization time constant of 339 ns, leading to a 54 ns error-time product in a solid-state quantum information platform.

Surgical techniques used in the management of intra-arachnoid diverticula in dogs across four referral centres and their immediate outcome.

OBJECTIVES: To report the surgical techniques being used to treat single focal spinal intra-arachnoid diverticula in dogs, their complications and immediate postoperative outcomes. MATERIALS AND METHODS: Retrospective multi-centre case series across four referral centres. RESULTS: Fifty-seven dogs were included in the study. The most common type of surgery was durectomy (28 dogs) followed by marsupialisation (11 dogs), durotomy alone (seven dogs), shunt placement (six dogs) and stabilisation (five dogs). A higher proportion of intra-arachnoid shunt dogs became unable to walk in the immediate postoperative period (24 hours postsurgery) (4/6, 66%) compared to all dogs five of 57, 9% (2/7 durotomy alone, 3/28 durectomy alone). Of the nine dogs with immediate postoperative deterioration, seven had improved, walking without assistance, by 3 to 5 weeks postoperatively. CLINICAL SIGNIFICANCE: This study does not identify an influence of surgical technique on short-term outcome. Dogs with a thoracolumbar intra-arachnoid diverticulum that undergo a shunt placement are likely to deteriorate neurologically in the immediate 24-hour postoperative period but appear to improve by 3 to 5 weeks after surgery. Further work is required to evaluate whether one surgical technique is superior for preventing or reducing long-term relapse.

Tissue geometry drives deterministic organoid patterning.

Epithelial organoids are stem cell­derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but the structures formed are often heterogeneous and irreproducible, which limits their use in the lab and clinic. We describe methodologies for spatially and temporally controlling organoid formation, thereby rendering a stochastic process more deterministic. Bioengineered stem cell microenvironments are used to specify the initial geometry of intestinal organoids, which in turn controls their patterning and crypt formation. We leveraged the reproducibility and predictability of the culture to identify the underlying mechanisms of epithelial patterning, which may contribute to reinforcing intestinal regionalization in vivo. By controlling organoid culture, we demonstrate how these structures can be used to answer questions not readily addressable with the standard, more variable, organoid models.

Evaluation of a Preharvest Bacteriophage Therapy for Control of Salmonella within Bovine Peripheral Lymph Nodes.

ABSTRACT: A series of proof-of-concept studies were developed to determine whether a commercial bacteriophage cocktail could be utilized for the mitigation of Salmonella in bovine peripheral lymph nodes (LNs). The first objective sought to determine whether exogenous phage could be isolated from the LNs following administration. If isolation were successful, the second objective was to determine whether the phage in the LNs could effectively reduce Salmonella. Salmonella Montevideo was inoculated intradermally at multiple sites and multiple times, followed by delivery of the phage cocktail subcutaneously in two injections around each of the right and left prescapular and subiliac LNs. At the conclusion of each study, animals were euthanized, and the popliteal, prescapular, and subiliac LNs were examined. The inoculated phage was successfully isolated from the LNs; transmission electron microscopy revealed phages in the LNs of the treated cattle, and these phages were identical to those in the cocktail. Levels of phage were higher (P < 0.01) in the prescapular and subiliac LNs in the phage-treated than in the control cattle. In subsequent studies, the protocols were modified to increase Salmonella and phage levels within the LNs. Compared with the first study, overall Salmonella levels were increased in the LNs, and phage treatment decreased (P < 0.01) Salmonella in the some of the LNs. Phage levels were numerically but not significantly increased (P = 0.12) in the treated cattle. The final study was modified, hypothesizing that a 48-h postmortem period before LN removal would facilitate phage-Salmonella interaction; however, no differences (P > 0.10) in Salmonella levels were found among treatments. Salmonella-specific phages administered to live cattle can translocate to the LNs; however, these phages had limited to no effect on Salmonella in these LNs under these experimental conditions.