Bayesian estimation in veterinary pharmacology: A conceptual and practical introduction.

Sophisticated mathematical and computational tools have become widespread and important in veterinary pharmacology. Although the theoretical basis and practical applications of these have been widely explored in the literature, statistical inference in the context of these models has received less attention. Optimization methods, often with frequentist statistical inference, have been predominant. In contrast, Bayesian statistics have not been widely applied, but offer both practical utility and arguably greater interpretability. Veterinary pharmacology applications are generally well supported by relevant prior information, from either existing substantive knowledge, or an understanding of study and model design. This facilitates practical implementation of Bayesian analyses that can take advantage of this knowledge. This essay will explore the specification of Bayesian models relevant to veterinary pharmacology, including demonstration of prior selection, and illustrate the capability of these models to generate practically useful statistics, including uncertainty statements, that are difficult or impossible to obtain otherwise. Case studies using simulated data will describe applications in clinical trials, pharmacodynamics, and pharmacokinetics, all including multilevel modeling. This content may serve as a suitable starting point for researchers in veterinary pharmacology and related disciplines considering Bayesian estimation for their applied work.

Insights into phytonutrient profile and postharvest quality management of jackfruit: A review.

Jackfruit (Artocarpus heterophyllus Lam.), also known as 'vegetarian's meat', is an excellent source of carbohydrates, protein, fiber, vitamins, minerals, and several phytochemicals. It is a climacteric fruit that exhibits an increase in ethylene biosynthesis and respiration rate during fruit ripening. The market value of jackfruit is reduced due to the deterioration of fruit quality during storage and transportation. There is a lack of standardized harvest maturity index in jackfruit, where consequently, fruit harvested at immature or overmature stages result in poor quality ripe fruit with short storage life. Other factors responsible for its short postharvest life relate to its highly perishable nature, chilling sensitivity and susceptibility to fruit rot which result in significant qualitative and quantitative losses. Various postharvest management techniques have been adopted to extend the storage life, including cold storage, controlled atmosphere storage, modified atmosphere packaging, edible coatings, chemical treatment, and non-chemical alternatives. Diversified products have been prepared from jackfruit to mitigate such losses. This comprehensive review highlights the nutritional profile, fruit ripening physiology, pre and postharvest quality management, and value addition of jackfruit as well as the way forward to reduce postharvest losses in the supply chain.

Trends in maintaining postharvest freshness and quality of Rubus berries.

Blackberries and raspberries, commonly known as Rubus berries, are commercially grown worldwide across different climates. Rubus berries contain wide array of phytochemicals, vitamins, dietary fibers, minerals, and unsaturated fatty acids. Nevertheless, these berries have short storage life which is the major constraint in their supply chains leading to higher postharvest losses. Inappropriate harvest handling, physical bruising, insect pests, and postharvest diseases lower the acceptability of fruit among consumers and other supply chain stakeholders. Additionally, the susceptibility to microbial decay, fruit softening, higher ethylene production, respiratory activity, and increased oxidation of anthocyanins, phenolics, and flavonoids considerably affects the marketability of Rubus berries at domestic and international markets. To date, several postharvest strategies such as cold storage, precooling, modified and controlled atmospheres, anti-ripening chemicals, edible coatings, biological agents, and nonchemical alternatives (heat treatment, ultrasound, irradiations, ozone) have been reported to prolong storage life, ensure food safety, and maintain the nutritional quality of Rubus berries. This review briefly encompasses multiple aspects including harvest maturity indices, regulation of fruit ripening, pre and postharvest factors affecting fruit quality, and an update on postharvest quality preservation by employing postharvest technologies to extend the storage life and maintaining the bioactive compounds in Rubus berries which are lacking in the literature. Accordingly, this review provides valuable information to the industry stakeholders and scientists offering relevant solutions, limitations in the application of certain technologies at commercial scale, highlighting research gaps, and paving the way forward for future investigations.

Behaviour change techniques in cardiovascular disease smartphone apps to improve physical activity and sedentary behaviour: Systematic review and meta-regression.

BACKGROUND: Smartphone apps are increasingly used to deliver physical activity and sedentary behaviour interventions for people with cardiovascular disease. However, the active components of these interventions which aim to change behaviours are unclear. AIMS: To identify behaviour change techniques used in smartphone app interventions for improving physical activity and sedentary behaviour in people with cardiovascular disease. Secondly, to investigate the association of the identified techniques on improving these behaviours. METHODS: Six databases (Medline, CINAHL Plus, Cochrane Library, SCOPUS, Sports Discus, EMBASE) were searched from 2007 to October 2020. Eligible studies used a smartphone app intervention for people with cardiovascular disease and reported a physical activity and/or sedentary behaviour outcome. The behaviour change techniques used within the apps for physical activity and/or sedentary behaviour were coded using the Behaviour Change Technique Taxonomy (v1). The association of behaviour change techniques on physical activity outcomes were explored through meta-regression. RESULTS: Forty behaviour change techniques were identified across the 19 included app-based interventions. Only two studies reported the behaviour change techniques used to target sedentary behaviour change. The most frequently used techniques for sedentary behaviour and physical activity were habit reversal and self-monitoring of behaviour respectively. In univariable analyses, action planning (ß =0.42, 90%CrI 0.07-0.78) and graded tasks (ß =0.33, 90%CrI -0.04-0.67) each had medium positive associations with increasing physical activity. Participants in interventions that used either self-monitoring outcome(s) of behaviour (i.e. outcomes other than physical activity) (ß = - 0.47, 90%CrI -0.79--0.16), biofeedback (ß = - 0.47, 90%CrI -0.81--0.15) and information about health consequences (ß = - 0.42, 90%CrI -0.74--0.07) as behaviour change techniques, appeared to do less physical activity. In the multivariable model, these predictors were not clearly removed from zero. CONCLUSION: The behaviour change techniques action planning and graded tasks are good candidates for causal testing in future experimental smartphone app designs.

A Survey of Injuries That Occurred in Veterinary Teaching Hospitals during 2017.

Knowing the frequency, extent or severity of injuries that occur to students and staff within veterinary teaching hospitals (VTHs) is necessary for proactive management of their safety. This study surveyed contemporaneously-captured incident reports likely to cause or causing injury to students and staff of veterinary teaching hospitals in Europe, the United States of America (USA), Canada, Australia, and New Zealand, recorded in 2017. Four different severities of incident were evaluated within four different cohorts of people, precipitated by five categories for cause. Within each cause-category, further subdivision was based on the nature of the incident. All colleges of veterinary medicine accredited by the American Veterinary Medical Association (AVMA) Council on Education (COE) or the Australasian Veterinary Boards Council were surveyed. Responses were received from (7/7, 100%) schools in Australia and New Zealand, 12/30 (40%) the United States of America, 1/4 (25%) Canada, 1/1 (100%) Mexico, and 1/3 (33%) United Kingdom, and no responses were received from the AVMA-COE accredited schools in the European Union. The mean incidence of incidents caused by horses was (0.4/1,000 cases), followed by food animals (0.1/1,000 cases), other animals (0.1/1,000 cases), and small animals (0.074/1,000 cases). Within veterinary teaching hospitals at many institutions, veterinary students and veterinarians are particularly at risk of injuries caused by hand-held instruments, such as scalpels and needles. Non-veterinary staff are more at risk than students or veterinarians from injuries caused by small animals. Recording and reporting of incidents is not uniform and may be lacking in detail. Some institutions' systems for record management preclude easy evaluation, and therefore may be insufficient for proactive management of health and safety as required by accreditation bodies.

Physiologically based modelling of the pharmacokinetics of three beta-lactam antibiotics after intra-mammary administration in dairy cows.

Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.

Pharmacokinetics and bioavailability after intramuscular injection of the 5-HT1A serotonin agonist R-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in domestic goats (Capra aegagrus hircus).

To determine the bioavailability and pharmacokinetic properties of the serotonin 5-HT1A receptor agonist R-8-OH-DPAT in goats, and 0.1 mg kg-1 R-8-OH-DPAT hydrobromide was administered intramuscularly (i.m.) and intravenously (i.v.) to six goats in a two-phase cross-over design experiment. Venous blood samples were collected from the jugular vein 2, 5, 10, 15, 20, 30, 40 and 60 min following treatment and analysed by liquid chromatography tandem mass spectrometry. Bioavailability and pharmacokinetic parameters were determined by a one-compartment analysis. Mean bioavailability of R-8-OH-DPAT when injected i.m. was 66%. The mean volume of distribution in the central compartment was 1.47 L kg-1 . The mean plasma body clearance was 0.056 L kg-1  min-1 . All goats injected i.v. and two of six goats injected i.m. showed signs of serotonin toxicity. In conclusion, R-8-OH-DPAT is well absorbed following i.m. injection and the observed pharmacokinetics suggest that administration via dart is feasible. Administration of R-8-OH-DPAT hydrobromide, at a dosage of 0.1 mg kg-1 , resulted in the observation of clinical signs of serotonin toxicity in the goats. It is suggested that dosages for the clinical use of the compound should be lower in order to achieve the desired clinical effect without causing serotonin toxicity.

Biomechanical evaluation of 6 transarticular tibiotarsal immobilization methods in canine cadaveric limbs.

OBJECTIVE: To determine the effects of 6 types of transarticular immobilization techniques on tibiotarsal joint angles during stimulated weight bearing. STUDY DESIGN: Canine ex vivo biomechanical study. SAMPLE POPULATION: Canine cadaveric pelvic limbs (n = 15). METHODS: A validation study was conducted to determine tibiotarsal flexion before and after transection of the superficial digital flexor tendon in 5 canine cadaveric limbs without tibiotarsal joint immobilization. Six transarticular tibiotarsal immobilization techniques were tested sequentially in 10 canine cadaveric pelvic limbs. The tibiotarsal joint angles were measured from lateral projection radiographs before and during axial loading of 200 N. Mixed linear models were applied to determine the effects of the immobilization techniques on change in tibiotarsal joint angle under loading. RESULTS: There was no change of tibiotarsal joint angle between extended digits and flexed digits under both unloaded and loaded conditions. Change in tibiotarsal joint angles did not differ among any of the immobilization techniques tested here (mean change 1.36°, range 0-5). The main contributor to variance in angle explained by the final model was associated with the random effect for limb. CONCLUSION: Changes in tibiotarsal joint angles during single static loading in canine cadaveric limbs for the 6 immobilization techniques were minimal. CLINICAL SIGNIFICANCE: The 6 techniques appear equally effective at limiting tibiotarsal joint flexion during single axial loading of 200 N. Cyclic mechanical testing of these techniques is recommended to support our findings and validate their clinical application.

Nurse staffing levels and outcomes - mining the UK national data sets for insight.

Purpose Despite the generation of mass data by the nursing workforce, determining the impact of the contribution to patient safety remains challenging. Several cross-sectional studies have indicated a relationship between staffing and safety. The purpose of this paper is to uncover possible associations and explore if a deeper understanding of relationships between staffing and other factors such as safety could be revealed within routinely collected national data sets. Design/methodology/approach Two longitudinal routinely collected data sets consisting of 30 years of UK nurse staffing data and seven years of National Health Service (NHS) benchmark data such as survey results, safety and other indicators were used. A correlation matrix was built and a linear correlation operation was applied (Pearson product-moment correlation coefficient). Findings A number of associations were revealed within both the UK staffing data set and the NHS benchmarking data set. However, the challenges of using these data sets soon became apparent. Practical implications Staff time and effort are required to collect these data. The limitations of these data sets include inconsistent data collection and quality. The mode of data collection and the itemset collected should be reviewed to generate a data set with robust clinical application. Originality/value This paper revealed that relationships are likely to be complex and non-linear; however, the main contribution of the paper is the identification of the limitations of routinely collected data. Much time and effort is expended in collecting this data; however, its validity, usefulness and method of routine national data collection appear to require re-examination.

A viable Arabidopsis pex13 missense allele confers severe peroxisomal defects and decreases PEX5 association with peroxisomes.

Peroxisomes are organelles that catabolize fatty acids and compartmentalize other oxidative metabolic processes in eukaryotes. Using a forward-genetic screen designed to recover severe peroxisome-defective mutants, we isolated a viable allele of the peroxisome biogenesis gene PEX13 with striking peroxisomal defects. The pex13-4 mutant requires an exogenous source of fixed carbon for pre-photosynthetic development and is resistant to the protoauxin indole-3-butyric acid. Delivery of peroxisome-targeted matrix proteins depends on the PEX5 receptor docking with PEX13 at the peroxisomal membrane, and we found severely reduced import of matrix proteins and less organelle-associated PEX5 in pex13-4 seedlings. Moreover, pex13-4 physiological and molecular defects were partially ameliorated when PEX5 was overexpressed, suggesting that PEX5 docking is partially compromised in this mutant and can be improved by increasing PEX5 levels. Because previously described Arabidopsis pex13 alleles either are lethal or confer only subtle defects, the pex13-4 mutant provides valuable insight into plant peroxisome receptor docking and matrix protein import.

The long and the short of it: Salivary telomere length as a candidate biomarker for hypertension and age-related changes in blood pressure.

Hypertension becomes more prevalent with increasing age. Telomere length (TL) has been proposed as a candidate biomarker and can be accessibly extracted from saliva. However, clarity is needed to evaluate the suitability of using TL as a predictor in such instances. This study investigated salivary TL in a cohort of older adults from the 2008 Health and Retirement Study (n = 3329; F: 58%, mean age: 69.4, SD: 10.3 years) to examine any associations with blood pressure (BP). A Bayesian robust regression model was fit using weakly informative priors to predict the effects of TL with age, sex, systolic BP (SBP), diastolic BP (DBP), and treatment status. There were small effects of treatment (ß: -0.07, 95% CrI [-0.33, 0.19], pd: 71.91%) and sex (ß: -0.10, 95% CrI [-0.27, 0.07], pd: >86.78%). Population effects showed a reduction of 0.01 log2 units in TL with each year of advancing age (95% CrI [-0.01, -0.00]). Conditional posterior predictions suggest that females, and treated individuals, experience greater change in TL with increasing age. Bayes R2 was ~2%. TL declines with increasing age, differs between sexes, and appears to be influenced by antihypertensive drugs. Overall, all effects were weak. The data do not currently support the suitability of salivary TL as a biomarker to predict or understand any age-related changes in BP.

Methyl jasmonate advances fruit ripening, colour development, and improves antioxidant quality of 'Yoho' and 'Jiro' persimmon.

Methyl jasmonate (MJ) has potential to regulate fruit ripening and quality. 'Yoho' and 'Jiro' persimmons were sprayed with MJ (0, 2, 4, and 6 mM), four weeks before anticipated harvest to evaluate its effects on fruit colour and bioactive compounds. Preharvest MJ application significantly improved fruit colour with increased a*, b*, chroma, and colour index. The MJ 6 mM application had significantly enhanced soluble solids content (SSC), reduced total chlorophyll content in peel and pulp, and soluble and total tannins in persimmons. MJ treatments exhibited higher contents of total phenolics, flavonoids, carotenoids, and antioxidant activities. Additionally, MJ treatments enhanced the activities of shikimate dehydrogenase (SKDH), phenylalanine ammonia-lyase (PAL), catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and lipoxygenase (LOX) enzymes. Overall, pre-harvest MJ application at 6 mM four weeks before anticipated harvest could be useful for advancing colour and improving bioactive compounds in 'Yoho' and 'Jiro' persimmons.

Uncontrolled pain: a call for better study design.

Studies assessing animal pain in veterinary research are often performed primarily for the benefit of animals. Frequently, the goal of these studies is to determine whether the analgesic effect of a novel treatment is clinically meaningful, and therefore has the capacity to improve the welfare of treated animals. To determine the treatment effect of a potential analgesic, control groups are necessary to allow comparison. There are negative control groups (where pain is unattenuated) and positive control groups (where pain is attenuated). Arising out of animal welfare concerns, there is growing reluctance to use negative control groups in pain studies. But for studies where pain is experimentally induced, the absence of a negative control group removes the opportunity to demonstrate that the study methods could differentiate a positive control intervention from doing nothing at all. For studies that are controlled by a single comparison group, the capacity to distinguish treatment effects from experimental noise is more difficult; especially considering that pain studies often involve small sample sizes, small and variable treatment effects, systematic error and use pain assessment measures that are unreliable. Due to these limitations, and with a focus on farm animals, we argue that many pain studies would be enhanced by the simultaneous inclusion of positive and negative control groups. This would help provide study-specific definitions of pain and pain attenuation, thereby permitting more reliable estimates of treatment effects. Adoption of our suggested refinements could improve animal welfare outcomes for millions of animals globally.

Influence of Biological Sex and Fitness on Core Temperature Change and Sweating in Children Exercising in Warm Conditions.

PURPOSE: This study aimed to investigate the associations of biological sex and aerobic fitness (i.e., V̇O 2peak ) on the change in gastrointestinal temperature (∆ Tgi ) and whole-body sweat rate (WBSR) of children exercising in warm conditions. METHODS: Thirty-eight children (17 boys, mean ± SD = 13.7 ± 1.2 yr; 21 girls, 13.6 ± 1.8 yr) walked for 45 min at a fixed rate of metabolic heat production (8 W·kg -1 ) in 30°C and 40% relative humidity. Biological sex and relative V̇O 2peak were entered as predictors into a Bayesian hierarchical generalized additive model for Tgi . For a subsample of 13 girls with measured body composition, body fat percent was entered into a separate hierarchical generalized additive model for Tgi . Sex, V̇O 2peak , and the evaporative requirement for heat balance ( Ereq ) were entered into a Bayesian hierarchical linear regression for WBSR. RESULTS: The mean ∆ Tgi for boys was 0.71°C (90% credible interval = 0.60-0.82) and for girls 0.78°C (0.68-0.88). A predicted 20 mL·kg -1 ·min -1 higher V̇O 2peak resulted in a 0.19°C (-0.03 to 0.43) and 0.24°C (0.07-0.40) lower ∆ Tgi in boys and girls, respectively. A predicted ~13% lower body fat in the subsample of girls resulted in a 0.15°C (-0.12 to 0.45) lower ∆ Tgi . When Ereq was standardized to the grand mean, the difference in WBSR between boys and girls was -0.00 L·h -1 (-0.06 to 0.06), and a 20-mL·kg -1 ·min -1 higher predicted V̇O 2peak resulted in a mean difference in WBSR of -0.07 L·h -1 (-0.15 to 0.00). CONCLUSIONS: Biological sex did not independently influence ∆ Tgi and WBSR in children. However, a higher predicted V̇O 2peak resulted in a lower ∆ Tgi of children, which was not associated with a greater WBSR, but may be related to differences in body fat percent between high and low fitness individuals.

Biological sex does not independently influence core temperature change and sweating of children exercising in uncompensable heat stress.

The purpose of this study was to investigate the influence of biological sex, independent of differences in aerobic fitness and body fatness, on the change in gastrointestinal temperature (ΔTgi) and whole body sweat rate (WBSR) of children exercising under uncompensable heat stress. Seventeen boys (means ± SD; 13.7 ± 1.3 yr) and 18 girls (13.7 ± 1.4 yr) walked for 45 min at a fixed rate of metabolic heat production per kg body mass (8 W·kg-1) in 40°C and 30% relative humidity. Sex and peak oxygen consumption (V̇o2peak) were entered into a Bayesian hierarchical general additive model (HGAM) for Tgi. Sex, V̇o2peak, and the evaporative requirement for heat balance (Ereq) were entered into a Bayesian hierarchical linear regression for WBSR. For 26 (12 M and 14 F) of the 35 children with measured body composition, body fat percentage was entered in a separate HGAM and hierarchical linear regression for Tgi and WBSR, respectively. Conditional on sex-specific mean V̇o2peak, ΔTgi was 1.00°C [90% credible intervals (Crl): 0.84, 1.16] for boys and 1.17°C [1.01, 1.33] for girls, with a difference of 0.17°C [-0.39, 0.06]. When sex differences in V̇o2peak were accounted for, the difference in ΔTgi between boys and girls was 0.01°C [-0.25, 0.22]. The difference in WBSR between boys and girls was 0.03 L·h-1 [-0.02, 0.07], when isolated from differences in Ereq. The difference in ΔTgi between boys and girls was -0.10°C [-0.38, 0.17] when sex differences in body fat (%) were accounted for. Biological sex did not independently influence the ΔTgi and WBSR of children exercising under uncompensable heat stress.NEW & NOTEWORTHY Limited studies have investigated the thermoregulatory responses of boys and girls exercising under uncompensable heat stress. Boys and girls often differ in physiological characteristics other than biological sex, such as aerobic fitness and body fat percentage, which may confound interpretations. We investigated the influence of biological sex on exercise thermoregulation in children, independent of differences in aerobic fitness and body fatness.

Minimal clinically important change of knee flexion in people with knee osteoarthritis after non-surgical interventions using a meta-analytical approach.

BACKGROUND: Minimal clinically important change (MCIC) represents the minimum patient-perceived improvement in an outcome after treatment, in an individual or within a group over time. This study aimed to determine MCIC of knee flexion in people with knee OA after non-surgical interventions using a meta-analytical approach. METHODS: Four databases (MEDLINE, Cochrane, Web of Science and CINAHL) were searched for studies of randomised clinical trials of non-surgical interventions with intervention duration of ≤ 3 months that reported change in (Δ) (mean change between baseline and immediately after the intervention) knee flexion with Δ pain or Δ function measured using tools that have established MCIC values. The risk of bias in the included studies was assessed using version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2). Bayesian meta-analytic models were used to determine relationships between Δ flexion with Δ pain and Δ function after non-surgical interventions and MCIC of knee flexion. RESULTS: Seventy-two studies (k = 72, n = 5174) were eligible. Meta-analyses included 140 intervention arms (k = 61, n = 4516) that reported Δ flexion with Δ pain using the visual analog scale (pain-VAS) and Δ function using the Western Ontario and McMaster Universities Osteoarthritis Index function subscale (function-WOMAC). Linear relationships between Δ pain at rest-VAS (0-100 mm) with Δ flexion were - 0.29 (- 0.44; - 0.15) (ß: posterior median (CrI: credible interval)). Relationships between Δ pain during activity VAS and Δ flexion were - 0.29 (- 0.41, - 0.18), and Δ pain-general VAS and Δ flexion were - 0.33 (- 0.42, - 0.23). The relationship between Δ function-WOMAC (out of 100) and Δ flexion was - 0.15 (- 0.25, - 0.07). Increased Δ flexion was associated with decreased Δ pain-VAS and increased Δ function-WOMAC. The point estimates for MCIC of knee flexion ranged from 3.8 to 6.4°. CONCLUSIONS: The estimated knee flexion MCIC values from this study are the first to be reported using a novel meta-analytical method. The novel meta-analytical method may be useful to estimate MCIC for other measures where anchor questions are problematic. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022323927.

Reducing PEX13 expression ameliorates physiological defects of late-acting peroxin mutants.

Proteins are targeted to the peroxisome matrix via processes that are mechanistically distinct from those used by other organelles. Protein entry into peroxisomes requires peroxin (PEX) proteins, including early-acting receptor (e.g. PEX5) and docking peroxins (e.g. PEX13 and PEX14) and late-acting PEX5-recycling peroxins (e.g. PEX4 and PEX6). We examined genetic interactions among Arabidopsis peroxin mutants and found that the weak pex13-1 allele had deleterious effects when combined with pex5-1 and pex14-2, which are defective in early-acting peroxins, as shown by reduced matrix protein import and enhanced physiological defects. In contrast, combining pex13-1 with pex4-1 or pex6-1, which are defective in late-acting peroxins, unexpectedly ameliorated mutant growth defects. Matrix protein import remained impaired in pex4-1 pex13-1 and pex6-1 pex13-1, suggesting that the partial suppression of pex4-1 and pex6-1 physiological defects by a weak pex13 allele may result from restoring the balance between import and export of PEX5 or other proteins that are retrotranslocated from the peroxisome with the assistance of PEX4 and PEX6. Our results suggest that symptoms caused by pex mutants defective in late-acting peroxins may result not only from defects in matrix protein import but also from inefficient removal of PEX5 from the peroxisomal membrane following cargo delivery.

Biomarkers of endothelial activation and inflammation in dogs with organ dysfunction secondary to sepsis.

Introduction: Alteration in endothelial function during sepsis is thought to play a key role in the progression of organ failure. We herein compared plasma concentrations of endothelial activation biomarkers vascular endothelial growth factor (VEGF), hyaluronan (HA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF), as well as inflammatory mediator concentrations (IL-6, IL-8, IL-10, C-reactive protein and monocyte chemoattractant protein-1) in dogs with sepsis to healthy dogs. Methods: This study was a multicenter observational clinical trial conducted at two university teaching hospitals from February 2016 until July 2017. The study included 18 client-owned dogs hospitalized with sepsis and at least one distant organ dysfunction, as well as 20 healthy dogs. Plasma biomarker concentrations were measured using ELISA. Severity of illness in dogs with sepsis was calculated using the 5-variable acute physiologic and laboratory evaluation (APPLEFAST) score. Biomarker concentrations were compared between septic and healthy dogs using linear models. Results: Septic peritonitis was the most frequent source of sepsis (11/18; 61%), followed by pneumonia (4/18; 22%). Ten dogs (56%) had only 1 organ dysfunction, whereas 3 dogs (17%) had 2, 3 (17%) had 3, 1 (6%) had 4 and 1 (6%) had 5 organ dysfunctions. The median APPLEFAST score in the septic dogs was 28.5 (Q1-Q3, 24-31). Mean plasma concentrations of all endothelial and inflammatory biomarkers, except vWF, were higher in the sepsis cohort than in controls. The mean endothelial biomarker concentrations in the septic cohort ranged from ~2.7-fold higher for HA (difference in means; 118.2 ng/mL, 95% credible limit; 44.5-221.7) to ~150-fold for VEGF (difference in means; 76.6 pg./mL, 95% credible limit; 33.0-143.4), compared to the healthy cohort. Fifteen dogs with sepsis (83%) died; 7 (46%) were euthanized and 8 (53%) died during hospitalization. Conclusion: Dogs with naturally occurring sepsis and organ dysfunction had higher mean concentrations of biomarkers of endothelial activation and inflammation compared to healthy dogs, broadening our understanding of the pathophysiology of sepsis secondary to endothelial dysfunction.

Evidence for key individual characteristics associated with outcomes following combined first-line interventions for knee osteoarthritis: A systematic review.

OBJECTIVE: To identify individual characteristics associated with outcomes following combined first-line interventions for knee osteoarthritis. METHODS: MEDLINE, CINAHL, Scopus, Web of Science Core Collection and the Cochrane library were searched. Studies were included if they reported an association between baseline factors and change in pain or function following combined exercise therapy, osteoarthritis education, or weight management interventions for knee osteoarthritis. Risk of bias was assessed using Quality in Prognostic Factor Studies. Data was visualised and a narrative synthesis was conducted for key factors (age, sex, BMI, comorbidity, depression, and imaging severity). RESULTS: 32 studies were included. Being female compared to male was associated with 2-3 times the odds of a positive response. Older age was associated with reduced odds of a positive response. The effect size (less than 10% reduction) is unlikely to be clinically relevant. It was difficult to conclude whether BMI, comorbidity, depression and imaging severity were associated with pain and function outcomes following a combined first-line intervention for knee osteoarthritis. Low to very low certainty evidence was found for sex, BMI, depression, comorbidity and imaging severity and moderate certainty evidence for age. Varying study methods contributed to some difficulty in drawing clear conclusions. CONCLUSIONS: This systematic review found no clear evidence to suggest factors such as age, sex, BMI, OA severity and presence of depression or comorbidities are associated with the response to first-line interventions for knee OA. Current evidence indicates that some groups of people may respond equally to first-line interventions, such as those with or without comorbidities. First-line interventions consisting of exercise therapy, education, and weight loss for people with knee OA should be recommended irrespective of sex, age, obesity, comorbidity, depression and imaging findings.