How do referees visually explore? An in-situ examination of the referential head and eye movements of football referees.

The majority of a football referee's time is spent assessing open-play situations, yet little is known about how referees search for information during this uninterrupted play. The aim of the current study was to examine the exploratory gaze behaviour of elite and sub-elite football referees in open-play game situations. Four elite (i.e. national) and eight sub-elite (i.e. regional) referees officiated an in-situ football match while wearing a mobile eye-tracker to assess their gaze behaviour. Both referential head and eye movements (i.e. moving gaze away from and then back to the ball) were measured. Results showed gaze behaviour was characterised overall by more referential head than eye movements (~75 vs 25%), which were of longer duration (~950 vs 460 ms). Moreover, elite referees employed faster referential movements (~640 vs 730 ms), spending less time with their gaze away from the ball (carrier) than the sub-elite referees. Crucially, both the referential head and eye movements were coordinated relative to key events in the match, in this case passes, showing that referees anticipate the passes to ensure that the referential movements did not occur during passes, rather before or after. The results further our understanding of the coordinative gaze behaviours that underpin expertise in officiating.

Implication of chromosomal microarray analysis prior to in-utero repair of fetal open neural tube defect.

OBJECTIVE: In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair. METHODS: This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy-assisted fetoscopic repair or open-hysterotomy fetal surgery at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. In a subset of the pregnancies (n = 77), CMA testing was also conducted. We reviewed the CMA results and divided the cohort into two groups according to whether clinically reportable copy-number variants (CNV) were detected (reportable-CNV group) or not (normal-CMA group). Surgical characteristics, complications, and maternal and early neonatal outcomes were compared between the two groups. The primary outcomes were fetal or neonatal death, hydrocephalus, motor function at 12 months of age and walking status at 30 months of age. Standard parametric and non-parametric statistical tests were employed as appropriate. RESULTS: During the study period, 146 fetuses with ONTD were eligible for and underwent in-utero repair. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA and 12 (16%) had a reportable CNV, two of which were classified as pathogenic. The first case with a pathogenic CNV was diagnosed with a 749-kb central 22q11.21 deletion spanning low-copy-repeat regions B-D of chromosome 22; the second case was diagnosed with a 1.3-Mb interstitial deletion at 1q21.1q21.2. Maternal demographics, clinical characteristics, operative data and postoperative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetric and early neonatal outcome between the study groups. Motor function at birth and at 12 months of age, and walking status at 30 months of age, were similar between the two groups. CONCLUSIONS: Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling regarding prognosis and recurrence risk. Our results indicate that the presence of a clinically reportable CNV should not a priori affect eligibility for in-utero repair, as overall pregnancy outcome is similar in these cases to that of cases with normal CMA. Nevertheless, significant CMA results will require a case-by-case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single-center series, a larger, multicenter long-term study should be considered. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Activity behaviors and relative changes in activity patterns recorded by precision technology were associated with diarrhea status in individually housed calves.

The objective of this case-control study was to quantify any association of daily activity behaviors and relative changes in activity patterns (lying time, lying bouts, step count, activity index) with diarrhea status in preweaning dairy calves. Individually housed calves sourced from auction were health-scored daily for signs of diarrhea (fecal consistency loose or watery for 2 consecutive days) for the 28 d after arrival. Calves with diarrhea were pair-matched with healthy controls (n = 13, matched by arrival date, arrival weight, and diagnosis days to diarrheic calves). Mixed linear regression models were used to evaluate the association of diarrhea status, and the diarrhea status by day interaction with activity behaviors (d -3 to d 4) and relative changes in activity patterns (d -3 to d 4) relative to diagnosis of a diarrhea bout. The serum Brix percentage at arrival and daily temperature-humidity index from the calf barn were explored as quantitative covariates, with day as a repeated measure. The baseline for relative changes in activity patterns was set at 100% on d 0. Diarrheic calves were less active; they averaged fewer steps (119.1 ± 18.81 steps/d) than healthy calves (227.4 ± 18.81 steps/d, LSM ± SEM). Diarrheic calves also averaged lower activity indices (827.34 ± 93.092 daily index) than healthy calves (1,396.32 ± 93.092 daily index). We also found also a diarrhea status by day interaction for lying time on d -3, with diarrheic calves spending more time lying (20.80 ± 0.300 h/d) than healthy calves (19.25 ± 0.300 h/d). For relative changes in activity patterns, a diarrhea status by day interaction was detectable on d -2, where diarrheic calves had greater relative changes in step counts (diarrhea 634.85 ± 87.581% vs. healthy 216.51 ± 87.581%) and activity index (diarrhea 316.83 ± 35.692% vs. healthy 150.68 ± 35.692%). Lying bouts were not associated with diarrhea status. These results show that diarrheic calves were more lethargic, and they had relative changes in activity patterns 2 d before clinical signs of diarrhea. Future research should explore the potential of an activity alert that positively indicates an individually housed calf at risk for a diarrhea bout using deviations from relative changes in individual calf activity patterns.

Comparison of the marine soundscape before and during the COVID-19 pandemic in dolphin habitat in Sarasota Bay, FL.

During the COVID-19 pandemic, changes in vessel activity and associated noise have been reported globally. Sarasota Bay is home to a large and increasing number of recreational vessels as well as a long-term resident community of bottlenose dolphins, Tursiops truncatus. Data were analyzed from two hydrophones to compare the soundscape during the COVID-19 pandemic to previous years (March-May 2020 and 2018/2019). Hourly metrics were calculated: vessel passes, 95th percentile sound levels [125 Hz and 16 kHz third octave bands (TOBs), and two broader bands: 88-1122 Hz and 1781-17 959 Hz], and dolphin whistle detection to understand changes in vessel activity and the effect on wildlife. Vessel activity increased during COVID-19 restrictions by almost 80% at one site and remained the same at the other site. Of the four sound level measures, only the 125 Hz TOB and 88-1122 Hz band increased with vessel activity at both sites, suggesting that these may be appropriate measures of noise from rapid pass-bys of small vessels in very shallow (<10 m) habitats. Dolphin whistle detection decreased during COVID-19 restrictions at one site but remained the same at the site that experienced increased vessel activity. The results suggest that pandemic effects on wildlife should not be viewed as homogeneous globally.

Question prompts to empower cancer patients: results of a randomized controlled trial.

OBJECTIVE: In addition to question prompts for information transfer, we also used prompts to facilitate the expression of emotions. Our aim was to investigate how a question prompt list (QPL) is accepted by patients and whether it enhances interactional empowerment of the patients in the consultation with the radio-oncological treatment team before the beginning of radiotherapy. METHODOLOGY: Adult cancer patients before the beginning of radiotherapy were randomly assigned to the intervention group (IG) or control group (CG). The patients in the IG received a QPL with predefined subsets and subject areas. After the physician's consultation, both groups completed a self-developed, content validated questionnaire on interactional empowerment. The IG evaluated the QPL using a self-developed instrument. RESULT: A total of 279 adult cancer patients participated in the study (IG n = 139/CG n = 140). The participants of the IG reported a significantly higher interactional empowerment compared with those of the CG (t(277) = - 2.71, p = .007, 95% CI [- 1.61, - 0.26], d = 0.29). 60.4% of the IG agreed "rather" or "very" that they used the QPL in consultation with the medical team. CONCLUSION: The QPL used in the consultation improved the self-assessed competence for interaction with the medical team and strengthened the interactional empowerment. The QPL was well accepted by the patients and is to be introduced into a routine as a practicable and simple instrument in the future. The support of patients in addressing concerns and fears is an important innovation.

Microarray analysis of primary epithelial and fibroblast cells in chronic rhinosinusitis without nasal polyps.

BACKGROUND: Chronic rhinosinusitis is an inflammatory condition with an as yet unknown pathophysiology. We aimed to detect clusters of differentially regulated genes in the epithelial and fibroblast cells of patients with Chronic Rhinosinusitis without nasal polyposis (CRSsNP) and healthy controls. METHODOLOGY: Carefully phenotyped CRSsNP and healthy control participants were recruited. Primary cultures of isolated epithelial and fibroblast cells were established. Whole transcriptome analysis of the cells was performed using microarrays and replicated with quantitative RT-PCR and immunohistochemistry. RESULTS: Fibroblast cells from CRSsNP patients showed a significant upregulation (more than 2x) of the transcription factor NFE2L3 when compared to healthy controls by microarray with multiple hypothesis testing correction, qRT-PCR and immunohistochemistry. CONCLUSIONS: Here we have utilized microarray analysis to search for differentially expressed genes in isolated patient derived epithelial and fibroblast cells. The transcription factor NFE2L3 has been shown to be upregulated in fibroblast cells consistent with increasing evidence that fibroblasts play a key role in tissue specific inflammation within the paranasal sinuses.

The role of lysosomes and autophagosomes in frontotemporal lobar degeneration.

INTRODUCTION: Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD). METHODS: We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal-associated membrane proteins 1 (LAMP-1) and 2 (LAMP-2), cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx). RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in the DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD-TDP and FTLD-tau. CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.

CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction.

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study.

AIMS: The association between the pathological features of AD and dementia is stronger in younger old persons than in older old persons suggesting that additional factors are involved in the clinical expression of dementia in the oldest old. Cumulative data suggests that neuroinflammation plays a prominent role in Alzheimer's disease (AD) and different studies reported an age-associated dysregulation of the neuroimmune system. Consequently, we sought to characterize the pattern of microglial cell activation and astrogliosis in brain post mortem tissue of pathologically confirmed cases of early and late onset AD (EOAD and LOAD) and determine their relation to age. METHODS: Immunohistochemistry (CD68 and glial fibrillary acidic protein) with morphometric analysis of astroglial profiles in 36 cases of AD and 28 similarly aged controls. RESULTS: Both EOAD and LOAD groups had higher microglial scores in CA1, entorhinal and temporal cortices, and higher astroglial response in CA1, dentate gyrus, entorhinal and temporal cortices, compared to aged matched controls. Additionally, EOAD had higher microglial scores in subiculum, entorhinal and temporal subcortical white matter, and LOAD higher astrogliosis in CA2 region. CONCLUSIONS: Overall, we found that the neuroinflammatory pathological markers in late stage AD human tissue to have a similar pattern in both EOAD and LOAD, though the severity of the pathological markers in the younger group was higher. Understanding the age effect in AD will be important when testing modifying agents that act on the neuroinflammation.

A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

Early changes in extracellular matrix in Alzheimer's disease.

AIMS: Although changes in extracellular matrix (ECM) scaffold have been reported previously in Alzheimer's disease (AD) compared to normal ageing, it is not known how alterations in the numerous components of the perivascular ECM might occur at different stages of AD. This study therefore investigates potential changes in basement membrane-associated ECM molecules in relation to increasing Braak stages. METHODS: Thirty patients were divided into three groups (control subject, subclinical AD and AD patients). ECM levels of collagen IV, perlecan and fibronectin as well as human platelet endothelial cell adhesion molecule (hPECAM) were quantified by immunohistochemistry. Von Willebrand factor staining was measured to assess vessel density. Expression levels were correlated with the presence of amyloid plaques. RESULTS: Collagen IV, perlecan and fibronectin expression was increased in subclinical AD and AD patients when compared to controls, in frontal and temporal cortex, whilst no further increase was detected between subclinical AD and AD. These changes were not associated with an increase in vessel density, which was instead decreased in the temporal cortex of AD patients. In contrast, hPECAM levels remained unchanged. Finally, we found similar pattern in levels of amyloid deposition between the different Braak stages and showed that changes in ECM components correlated with amyloid deposition. CONCLUSION: Present data support the hypothesis that significant ECM changes occur during the early stages of AD. ECM changes affecting brain microvascular functions could therefore drive disease progression and provide potential new early investigational biomarkers in AD.

Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.

Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin-1 alpha (IL-1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4-21.8] vs. 2.8 [0.9-9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4-25.1] vs. 3.6 [0.6-17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL-1α positively correlated with elevated bronchoalveolar lavage IL-8 levels (r(2)  = 0.6095, p < 0.0001) and neutrophil percentage (r(2)  = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro-inflammatory phenotype in fibroblasts via an IL-1α/IL-1R-dependent signaling pathway. In conclusion, we propose that IL-1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation.

Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins.

AIMS: A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. METHODS: Using antibodies to poly-GA, poly-GP, poly-GR, poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). RESULTS: Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly-GA antibody generally detected more DPR than poly-GP, which in turn was greater than poly-GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP-43 positive inclusions in remaining anterior horn cells. CONCLUSION: Degeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP-43 are more likely to be the cause of this.

Expert consensus statement to guide the evidence-based classification of Paralympic athletes with vision impairment: a Delphi study.

BACKGROUND: Paralympic sports are required to develop evidence-based systems that allocate athletes into 'classes' on the basis of the impact of their impairment on sport performance. However, sports for athletes with vision impairment (VI) classify athletes solely based on the WHO criteria for low vision and blindness. One key barrier to evidence-based classification is the absence of guidance on how to address classification issues unique to VI sport. The aim of this study was to reach expert consensus on how issues specific to VI sport should be addressed in evidence-based classification. METHOD: A four-round Delphi study was conducted with 25 participants who had expertise as a coach, athlete, classifier and/or administrator in Paralympic sport for VI athletes. RESULTS: The experts agreed that the current method of classification does not fulfil the requirements of Paralympic classification, and that the system should be different for each sport to account for the sports' unique visual demands. Instead of relying only on tests of visual acuity and visual field, the panel agreed that additional tests are required to better account for the impact of impairment on sport performance. There was strong agreement that all athletes should not be required to wear a blindfold as a means of equalising the impairment during competition. CONCLUSIONS: There is strong support within the Paralympic movement to change the way that VI athletes are classified. This consensus statement provides clear guidance on how the most important issues specific to VI should be addressed, removing key barriers to the development of evidence-based classification.

Patterns of cerebral amyloid angiopathy define histopathological phenotypes in Alzheimer's disease.

AIMS: Pathological heterogeneity of Aß deposition in senile plaques (SP) and cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) has been long noted. The aim of this study was to classify cases of AD according to their pattern of Aß deposition, and to seek factors which might predict, or predispose towards, this heterogeneity. METHODS: The form, distribution and severity of Aß deposition (as SP and/or CAA) was assessed semiquantitatively in immunostained sections of frontal, temporal and occipital cortex from 134 pathologically confirmed cases of AD. RESULTS: Four patterns of Aß deposition were defined. Type 1 describes cases predominantly with SP, with or without CAA within leptomeningeal vessels alone. Type 2 describes cases where, along with many SP, CAA is present in both leptomeningeal and deeper penetrating arteries. Type 3 describes cases where capillary CAA is present along with SP and arterial CAA. Type 4 describes a predominantly vascular phenotype, where Aß deposition is much more prevalent in and around blood vessels, than as SP. As would be anticipated from the group definitions, there were significant differences in the distribution and degree of CAA across the phenotype groups, although Aß deposition as SP did not vary. There were no significant differences between phenotype groups with regard to age of onset, age at death, disease duration and brain weight, or disease presentation. Women were over-represented in the type 1 phenotype and men in type 2. Genetically, type 3 (capillary subtype) cases were strongly associated with possession of the APOE ε4 allele. CONCLUSIONS: This study offers an alternative method of pathologically classifying cases of AD. Further studies may derive additional genetic, environmental or clinical factors which associate with, or may be responsible for, these varying pathological presentations of AD.

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

Oclacitinib (APOQUEL(®)) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy.

Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC50 's) ranging from 10 to 99 nm and did not inhibit a panel of 38 non-JAK kinases (IC50 's > 1000 nM). Oclacitinib was most potent at inhibiting JAK1 (IC50 = 10 nM). Oclacitinib also inhibited the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50 's ranging from 36 to 249 nM. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50 's > 1000 nM). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs.

Temporal and spatial mapping of red grouper Epinephelus morio sound production.

The goals of this project were to determine the daily, seasonal and spatial patterns of red grouper Epinephelus morio sound production on the West Florida Shelf (WFS) using passive acoustics. An 11 month time series of acoustic data from fixed recorders deployed at a known E. morio aggregation site showed that E. morio produce sounds throughout the day and during all months of the year. Increased calling (number of files containing E. morio sound) was correlated to sunrise and sunset, and peaked in late summer (July and August) and early winter (November and December). Due to the ubiquitous production of sound, large-scale spatial mapping across the WFS of E. morio sound production was feasible using recordings from shorter duration-fixed location recorders and autonomous underwater vehicles (AUVs). Epinephelus morio were primarily recorded in waters 15-93 m deep, with increased sound production detected in hard bottom areas and within the Steamboat Lumps Marine Protected Area (Steamboat Lumps). AUV tracks through Steamboat Lumps, an offshore marine reserve where E. morio hole excavations have been previously mapped, showed that hydrophone-integrated AUVs could accurately map the location of soniferous fish over spatial scales of <1 km. The results show that passive acoustics is an effective, non-invasive tool to map the distribution of this species over large spatial scales.

The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome.

BACKGROUND: Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury. METHODS: We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI. RESULTS: In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFß (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury. CONCLUSION: It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.