Implementation of active injury management (AIM) in youth with acute concussion: A randomized controlled trial.

BACKGROUND: Nearly 2 million youth seek acute medical care following concussion in the U.S. each year. Current standard of care recommends rest for the first 48 h after a concussion. However, research suggests that prolonged rest may lengthen recovery time especially for patients with certain risk profiles. Research indicates that physical activity and behavioral management interventions (sleep, stress management) may enhance recovery. To date, there is limited empirical evidence to inform acute (<72 h) concussion recommendations for physical activity and behavioral management in adolescents. OBJECTIVE: To determine the effectiveness of physical activity and behavioral management for acute concussion in adolescents and young adults, and to evaluate the role of patient characteristics on treatment response. METHODS: This multicenter prospective randomized controlled trial will determine which combination of physical activity and behavioral management is most effective for patients 11-24 years old who present to the emergency department or concussion clinic within 72 h of injury. Participants are randomized into: 1) rest, 2) physical activity, 3) mobile health application (mHealth) behavioral management, or 4) physical activity and mHealth app conditions. Assessments at enrollment, 3-5 days, 14 days, 1 month, and 2 months include: concussion symptoms, balance, vestibular-ocular and cognitive assessments, quality of life, and recovery time. Somatic symptoms and other risk factors are evaluated at enrollment. Compliance with treatment and symptoms are assessed daily using actigraph and daily self-report. The primary study outcome is symptoms at 14 days. CONCLUSION: Prescribed physical activity and behavioral management may improve outcomes in youth following acute concussion.

The effects of raw-meat diets on the gastrointestinal microbiota of the cat and dog: a review.

The aim of this review is to summarise the available literature on the effects of consuming raw, red meat diets on the gastrointestinal microbiome of the cat and dog. In recent years, feeding raw meat diets to cats and dogs has increased, in part associated with trends in human nutrition for "natural" and "species-appropriate" diets. These diets range from home-prepared unprocessed, nutritionally incomplete diets to complete and balanced diets with sterilisation steps in their manufacturing process. Feeding some formats of raw meat diets has been associated with nutritional inadequacies and zoonotic transfer of pathogens. The feeding of raw meat diets has been shown to alter the gastrointestinal microbiome of the cat and dog, increasing the relative abundances of bacteria associated with protein and fat utilisation, including members of the genera Fusobacterium and Clostridium. While in humans, these genera are more commonly known for members that are associated with disease, they are a diverse group that also contains harmless commensals that are a normal component of the gastrointestinal microbiota. Moreover, members of these genera are known to produce butyrate from protein and amino acid fermentation and contribute to intestinal homeostasis in raw meat-fed dogs and cats. Currently, only a limited number of studies have examined the impacts of raw meat diets on the cat and dog microbiota, with many of these being descriptive. Additional controlled and systems-based studies are required to functionally characterise the roles of key microbial groups in the metabolism of raw meat diets, and determine their impacts on the health and nutrition of the host.

Establishing an SEIR-based framework for local modelling of COVID-19 infections, hospitalisations and deaths.

Without timely assessments of the number of COVID-19 cases requiring hospitalisation, healthcare providers will struggle to ensure an appropriate number of beds are made available. Too few could cause excess deaths while too many could result in additional waits for elective treatment. As well as supporting capacity considerations, reliably projecting future "waves" is important to inform the nature, timing and magnitude of any localised restrictions to reduce transmission. In making the case for locally owned and locally configurable models, this paper details the approach taken by one major healthcare system in founding a multi-disciplinary "Scenario Review Working Group", comprising commissioners, public health officials and academic epidemiologists. The role of this group, which met weekly during the pandemic, was to define and maintain an evolving library of plausible scenarios to underpin projections obtained through an SEIR-based compartmental model. Outputs have informed decision-making at the system's major incident Bronze, Silver and Gold Commands. This paper presents illustrated examples of use and offers practical considerations for other healthcare systems that may benefit from such a framework.

Micro-scale interactions between Arabidopsis root hairs and soil particles influence soil erosion.

Soil is essential for sustaining life on land. Plant roots play a crucial role in stabilising soil and minimising erosion, although these mechanisms are still not completely understood. Consequently, identifying and breeding for plant traits to enhance erosion resistance is challenging. Root hair mutants in Arabidopsis thaliana were studied using three different quantitative methods to isolate their effect on root-soil cohesion. We present compelling evidence that micro-scale interactions of root hairs with surrounding soil increase soil cohesion and reduce erosion. Arabidopsis seedlings with root hairs were more difficult to detach from soil, compost and sterile gel media than those with hairless roots, and it was 10-times harder to erode soil from roots with than without hairs. We also developed a model that can consistently predict the impact root hairs make to soil erosion resistance. Our study thus provides new insight into the mechanisms by which roots maintain soil stability.

Effect of kibble and raw meat diets on peripheral blood mononuclear cell gene expression profile in dogs.

Peripheral blood mononuclear cell (PBMC) gene expression microarray profiling is a minimally invasive tool used in human diet intervention studies. In this study, PBMC gene expression was determined in dogs fed kibble or raw red meat diets for 9 weeks to test the hypothesis that diet influences canine immune cell gene expression profiles. The two diets were associated with differences in PBMC gene expression profiles, which corresponded with changes in plasma IgA concentrations. Analysis of PBMC gene expression profiles might provide useful insights into the long term effects of diet on health outcomes in dogs.

Macronutrient intake of dogs, self-selecting diets varying in composition offered ad libitum.

The diet of the domestic dog has changed significantly from that of its wolf ancestor, with to date only two studies having examined macronutrient self-selection in dogs. Whilst the first focused solely on protein intake, determining an intake of 30% metabolisable energy (ME), the second investigated dietary protein, fat and carbohydrate (PFC), indicating an intake ratio of 30:63:7% by energy. This study's aim was to further elucidate macronutrient intake by providing greater macronutrient range, energy content, and to investigate over a longer duration than previous studies. Fifteen adult dogs were given access to three wet diets providing 500% of daily ME, twice daily over 10 days. The diets were nutritionally complete and formulated using the same four ingredients in different proportions to supply high levels of protein (58% ME), fat (86% ME) or carbohydrate (54% ME). Overall fat and carbohydrate consumption significantly declined from 6,382 to 917 kcals per day (p < 0.001) and 553 to 214 kcals day-1 (p < .01) respectively. Protein intake, however, remained constant over the study and ranged from 4,786 to 4,156 kcals day-1 . Such results impacted on percentage total energy intake, with fat decreasing from 68% to 52% (p < .001) and protein increasing from 29% to 44% (p < .01). Our findings suggest that dogs still possess a "feast or famine" mentality, wherein energy dense fat is prioritised over protein initially. With continued feeding over 10 days, a transition to a more balanced energy contribution from both macronutrients is evident. The study also shows that given the option, dogs do not select carbohydrate to be a significant portion of the diet. The health implications of such dietary selection are of interest.

The effect of changing the moisture levels of dry extruded and wet canned diets on physical activity in cats.

Obesity levels in cats are increasing and the main causative factor is higher energy intake v. energy expenditure over time. Therefore, altering energy expenditure by enhancing physical activity of the cat could be a strategy to reduce obesity. Hydrating commercial dry diets with water increased activity in cats; however, no study has compared this approach with feeding high-moisture canned diets. Eight healthy male neutered domestic shorthair cats were fed four different dietary treatments in a Latin square design. Treatments were a canned diet 'as is' (82 % moisture) and freeze-dried (4 %), a dry diet 'as is' (3 %) and with added water (70 %). Cat activity was measured continuously using Actical® accelerometers. Cats were group housed during the first 14 d of each period and then moved to individual cages for 7 d with faecal and urine production measured over the final 4 d. Intake was similar for each diet. The average activity over 24 h was not different between treatments (P > 0·05). However, the ratio between average activity during the day v. at night was higher when cats were fed the dry diet (P = 0·030). Total water intake and urine volume increased when the canned diet was fed (P < 0·001). The similarity in total activity of the cats on the treatments indicates that dietary moisture or diet type did not have a major effect on these cats. However, the stronger diurnal activity patterns observed in the cats when they were fed the dry diet are intriguing and require further study.

Subclinical Bacteriuria in Older Cats and its Association with Survival.

BACKGROUND: Bacterial urinary tract infections are uncommon in cats in general but the prevalence increases to 29% in older cats with comorbidities (Veterinary Clinical Pathology 2008, 37, 317; Journal of Feline Medicine & Surgery 2007, 9, 124; Veterinary Microbiology 2009, 136, 130). Frequently, the infections are subclinical. The clinical relevance of subclinical bacteriuria (SB) is uncertain, and the optimal treatment requires clarification. OBJECTIVE: Prospective, observational study to: (i) identify the prevalence and incidence count of SB in older (≥7 years), nonazotemic cats, (ii) evaluate specific risk factors for SB, and (iii) investigate the potential relationship between untreated SB and survival. ANIMALS: Sixty-seven, nonazotemic cats were tested on 5 occasions over 3 years. METHODS: Urine samples were obtained by cystocentesis for quantitative urine culture and blood samples for measurement of serum creatinine concentration. Episodes of SB were not treated. Serum creatinine concentration, body weight, urine specific gravity, sex, and age were evaluated as potential risk factors for a positive urine culture. The association between urine culture results and survival was evaluated with Cox's proportional hazard model. RESULTS: A total of 256 urine samples was obtained. The prevalence of SB varied between 10 and 13%, and incident infections were uncommon. Female cats were 21 times more likely to have a positive urine culture than were male cats (odds ratio [OR], 21.2; confidence interval [CI], 4.1-110; P = .00028). Subclinical bacteriuria was not significantly associated with survival. CONCLUSION AND CLINICAL IMPORTANCE: Subclinical bacteriuria is common in nonazotemic, older cats. Although antimicrobial treatment was withheld, the presence of SB was not adversely associated with survival.

Epithelial Cell Adhesion Molecule Expression in Canine Tumours.

Epithelial cell adhesion molecule (EpCAM) is expressed in most human normal and neoplastic tissues of epithelial derivation and may have an association with tumour cell aggressiveness, a stem cell-like phenotype and clinical outcome. Antibody-based strategies for the targeting and capture of EpCAM-expressing tumour cells are showing promise, both as diagnostic tools and potential therapies. The aim of this study was to assess EpCAM expression in canine tumours. EpCAM expression was assessed in tumour cell lines via gene expression profiling and in formalin-fixed and paraffin wax-embedded tissues from canine carcinomas representing various anatomical sites by immunohistochemistry. EpCAM mRNA expression was higher in cell lines from carcinomas than those derived from sarcomas or haemopoietic tumours. EpCAM was expressed by >2/3 of tumour cells in 71% of canine carcinomas evaluated, irrespective of histotype, with the exception of carcinomas of the adrenal gland. Canine sarcomas and haemopoietic tumours were uniformly negative. Most canine carcinomas express EpCAM and so could be suitable for the study of EpCAM-directed diagnostics and therapeutics.

Cyclic nucleotide phosphodiesterase-1C (PDE1C) drives cell proliferation, migration and invasion in glioblastoma multiforme cells in vitro.

Cyclic nucleotides (cAMP & cGMP) are critical intracellular second messengers involved in the transduction of a diverse array of stimuli and their catabolism is mediated by phosphodiesterases (PDEs). We previously detected focal genomic amplification of PDE1C in >90 glioblastoma multiforme (GBM) cells suggesting a potential as a novel therapeutic target in these cells. In this report, we show that genomic gain of PDE1C was associated with increased expression in low passage GBM-derived cell cultures. We demonstrate that PDE1C is essential in driving cell proliferation, migration and invasion in GBM cultures since silencing of this gene significantly mitigates these functions. We also define the mechanistic basis of this functional effect through whole genome expression analysis by identifying down-stream gene effectors of PDE1C which are involved in cell cycle and cell adhesion regulation. In addition, we also demonstrate that Vinpocetine, a general PDE1 inhibitor, can also attenuate proliferation with no effect on invasion/migration. Up-regulation of at least one of this gene set (IL8, CXCL2, FOSB, NFE2L3, SUB1, SORBS2, WNT5A, and MMP1) in TCGA GBM cohorts is associated with worse outcome and PDE1C silencing down-regulated their expression, thus also indicating potential to influence patient survival. Therefore we conclude that proliferation, migration, and invasion of GBM cells could also be regulated downstream of PDE1C.

HRL-Local Infinite Triangular Array Languages

ABSTRACT A new subclass of infinite triangular arrays called hrl-local infinite triangular arrays is introduced. We introduce infinite triangular domino systems to recognize the infinite triangular picture language. Also we introduce strictly domino testable ωω-triangular array languages.

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.

BACKGROUND: Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination. PATIENTS AND METHODS: Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%. RESULTS: Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity. CONCLUSION: The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00720174.

SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model.

Somatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors, p53 and PTEN, are strongly associated with triple negative breast cancer. In addition, these tumor suppressors have important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis, we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory interleukin-6 (IL6)/Stat3/nuclear factor κB signaling. This resulted in generation of highly metastatic epithelial-to-mesenchymal transition-like cancer stem cells resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of suppressor of cytokine signaling 3 (SOCS3) resulting in low levels of this protein in basal/claudin-low cell lines and primary tumors. In non-transformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore, circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors, which currently lacks molecularly targeted therapies.

The effect of dietary hydroxyproline and dietary oxalate on urinary oxalate excretion in cats.

In humans and rodents, dietary hydroxyproline (hyp) and oxalate intake affect urinary oxalate (Uox) excretion. Whether Uox excretion occurs in cats was tested by feeding diets containing low oxalate (13 mg/100 g DM) with high (Hhyp-Lox), moderate (Mhyp-Lox), and low hyp (Lhyp-Lox) concentrations (3.8, 2.0, and 0.2 g/100 g DM, respectively) and low hyp with high oxalate (93 mg/100 g DM; Lhyp-Hox) to 8 adult female cats in a 48-d study using a Latin square design. Cats were randomly allocated to one of the four 12-d treatment periods and fed according to individual energy needs. Feces and urine were collected quantitatively using modified litter boxes during the final 5 d of each period. Feces were analyzed for oxalate and Ca, and urine was analyzed for specific density, pH, oxalate, Ca, P, Mg, Na, K, ammonia, citrate, urate, sulfate, and creatinine. Increasing hyp intake (0.2, 2.0, and 3.8 g/100 g DM) resulted in increased Uox excretion (Lhyp-Lox vs. Mhyp-Lox vs. Hhyp-Lox; P < 0.05), and the linear dose-response equation was Uox (mg/d) = 5.62 + 2.10 × g hyp intake/d (r(2) = 0.56; P < 0.001). Increasing oxalate intake from 13 to 93 mg/100 g DM did not affect Uox excretion but resulted in an increase in fecal oxalate output (P < 0.001) and positive oxalate balance (32.20 ± 2.06 mg/d). The results indicate that the intestinal absorption of the supplemental oxalate, and thereby its contribution to Uox, was low (5.90% ± 5.24%). Relevant increases in endogenous Uox excretion were achieved by increasing dietary hyp intake. The hyp-containing protein sources should be minimized in Ca oxalate urolith preventative diets until their effect on Uox excretion is tested. The oxalate content (up to 93 mg/100 g DM) in a diet with moderate Ca content does not contribute to Uox content.

Should assisted dying be legalised?

When an individual facing intractable pain is given an estimate of a few months to live, does hastening death become a viable and legitimate alternative for willing patients? Has the time come for physicians to do away with the traditional notion of healthcare as maintaining or improving physical and mental health, and instead accept their own limitations by facilitating death when requested? The Universities of Oxford and Cambridge held the 2013 Varsity Medical Debate on the motion "This House Would Legalise Assisted Dying". This article summarises the key arguments developed over the course of the debate. We will explore how assisted dying can affect both the patient and doctor; the nature of consent and limits of autonomy; the effects on society; the viability of a proposed model; and, perhaps most importantly, the potential need for the practice within our current medico-legal framework.

Comparison of ileal and total tract nutrient digestibility of dry dog foods.

The apparent total tract and ileal digestibility assays to measure AA absorption in commercial canine diets were compared in the present study. Five ileal cannulated dogs were fed 5 commercial dry canine foods selected to contain 19 to 30% CP in a 5 × 5 Latin square design. Ileal and total tract digestibility (apparent and standardized) of DM, OM, CP, crude fat (CF), carbohydrate, and AA (including reactive Lys) were calculated using Cr2O3 as an indigestible marker. Greater apparent total tract digestibility values were found for DM, OM, and CP (P ≤ 0.034) compared with ileal digestibility values; however, CF (P = 0.058) had a greater ileal apparent digestibility. Apparent and standardized CP digestibility values were, respectively, 5.7 and 7.4 percentage units greater when measured over the total digestive tract compared with measurement at the ileum (P = 0.034 and 0.011, respectively). Ileal apparent digestibility for N of AA (P = 0.009) and most AA (P < 0.05), except for Met, Ile, Lys, Phe, and Ala, was decreased if measured at the ileum. However, correction for endogenous losses showed only Met digestibility did not differ between measurement sites. Differences between sites in excess of 15 percentage units were recorded for AA. Apparent and standardized ileal reactive Lys digestibility was 3.1 to 15.3 percentage units greater than corresponding total tract digestibility values. For several indispensable AA, the bioavailability estimates currently used by the 2006 NRC and the 2011 Association of American Feed Control Officials to derive allowance estimates for canine adult maintenance were greater than the digestibility values of these AA in the commercial dog foods evaluated. Although the canine large intestine is relatively short, the total tract digestibility assay in dogs can overestimate the digestibility of dietary AA and CP and may not be an accurate method for the measurement of absorption. In this study, bioavailability estimates of AA appeared to be less than those used to derive allowance estimates for commercial dog foods. Further work is required if current recommendations warrant adjustment.

The potential for enhancement of immunity in cats by dietary supplementation.

This study was conducted to examine the potential benefits of dietary supplementation on the feline immune system. Forty three cats (8 or 9 per group) were fed a low protein control diet (22.7% DM basis), the same diet supplemented with yeast-derived nucleotides, salmon oil or l-arginine or a commercial moist high protein diet (53.0% DM basis) for a period of five weeks. The low protein diets were formulated using a commercial moist diet base with added fat and starch and fed ad libitum, along with water. Specific immune assays showed that supplementation with arginine caused a significant enhancement of lymphocyte proliferative responses to the T-cell mitogen PHA after 35 days (P=0.018), while supplementation with either nucleotides or salmon oil resulted in significant enhancement after both 14 (P=0.0048, P<0.0001 respectively) and 35 days (both P<0.0001). Dietary supplementation with arginine, nucleotides or salmon oil each led to significant increases in blood leucocyte phagocytic activity after both 14 (P=0.0003, P=0.0077, P<0.0001 respectively) and 35 days (P<0.0001). This indicates that a number of dietary ingredients have the ability to modulate the immune system of healthy cats possibly resulting in a greater ability to fight infection and disease.

Isoflavone metabolism in domestic cats (Felis catus): comparison of plasma metabolites detected after ingestion of two different dietary forms of genistein and daidzein.

Some felid diets contain isoflavones but the metabolic capacity of cats toward isoflavones is relatively unknown, despite the understanding that isoflavones have divergent biological potential according to their metabolite end products. The objective of this study was to determine the plasma metabolites detectable in domestic cats after exposure to 2 different dietary forms of isoflavones, either as a soy extract tablet (n = 6) or as part of a dietary matrix (n = 4). Serial blood samples were collected after isoflavone exposure to identify the plasma metabolites of each cat. Genistein was detected in its unconjugated form or as a monosulfate. Daidzein was detected as both a mono- and disulfate as well as in its unconjugated form. Other daidzein metabolites detected included equol mono- and disulfate, dihydrodaidzein, and O-desmethylangolensin. No ß-glucuronide metabolites of either isoflavone were detected. Equol was produced in markedly fewer cats after ingestion of a soy extract tablet as a single oral bolus compared with cats consuming an isoflavone-containing diet. The detectable metabolites of the isoflavones, genistein and daidzein, in domestic cat plasma after dietary ingestion has been described in the present study for the first time. The metabolic capacity for isoflavones by domestic cats appears to be efficient, with only minimal proportions of the ingested amount detected in their unconjugated forms. This has implications for the potential of isoflavones to exert physiological activity in the domestic cat when consumed at concentrations representative of typical dietary intake.

Seasonal and age effects on energy requirements in domestic short-hair cats (Felis catus) in a temperate environment.

There is little information known about the energy requirements of cats in temperature climates. Energy requirement of domestic short-haired cats was determined using three groups of mixed gender - old kept outside (approximately 9.9 years of age; 4.8 kg; n = 9), young kept outside (approximately 3.1 years of age; 3.9 kg; n = 8) or young kept inside (approximately 3.1 years of age; 3.9 kg; n = 8). Cats were housed individually for 5 weeks during summer (18.5 ± 0.5 °C) and winter (8.5 ± 0.4 °C) and were fed a commercially available maintenance diet ad libitum. In both periods, energy expenditure was determined from the rates of (2) H and (18) O elimination for blood H2 O over a 12 day period, from a doubly labelled water bolus (2) H2 O (0.7 g/kg BW) and H2 (18) O (0.13 g/kg BW) administered intravenously. During the summer period, macronutrient digestibility was determined. Older cats had a reduction (p < 0.05) in apparent digestibility of dry matter (approximately 9%), energy (approximately 8%) and protein (6%). There was a significant effect of age and season on energy intake and energy expenditure. While lean mass was affected by age and season, there was no effect of age or season on energy expenditure when expressed as a proportion of lean mass. Possible seasonal differences in nutrient digestibility may explain these results.